Clinical Review

Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.¹ The disease is moderate to severe for approximately 1 in 6 individuals with psoriasis.² These patients, particularly those with symptoms that are refractory to topical therapy and/or phototherapy, can benefit from the use of biologic agents, which are monoclonal antibodies and fusion proteins engineered to inhibit the action of cytokines that drive psoriatic inflammation.

In February 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of biologics in treating adult patients with psoriasis.³ The prior guidelines were released in 2008 when just 3 biologics—etanercept, infliximab, and adalimumab—were approved by the US Food and Drug Administration (FDA) for the management of psoriasis. These older recommendations were mostly based on studies of the efficacy and safety of biologics for patients with psoriatic arthritis.⁴ Over the last 11 years, 8 novel biologics have gained FDA approval, and numerous large phase 2 and phase 3 trials evaluating the risks and benefits of biologics have been conducted. The new guidelines contain considerably more detail and are based on evidence more specific to psoriasis rather than to psoriatic arthritis. Given the large repertoire of biologics available today and the increased amount of published research regarding each one, these guidelines may aid dermatologists in choosing the optimal biologic and managing therapy.

The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and adverse events of the 10 biologics that have been FDA approved for the treatment of psoriasis as of March 2019, plus risankizumab, which was pending FDA approval at the time of publication and was later approved in April 2019. They also address dosing regimens, potential to combine biologics with other therapies, and different forms of psoriasis for which each may be effective.³ The purpose of this discussion is to present these guidelines in a condensed form to prescribers of biologic therapies and review the most clinically significant considerations during each step of treatment. Of note, we highlight only treatment of adult patients and do not discuss information relevant to risankizumab, as it was not FDA approved when the AAD-NPF guidelines were released.

Choosing a Biologic

Biologic therapy may be considered for patients with psoriasis that affects more than 3% of the body’s surface and is recalcitrant to localized therapies. There is no particular first-line biologic recommended for all patients with psoriasis; rather, choice of therapy should be individualized to the patient, considering factors such as body parts affected, comorbidities, lifestyle, and drug cost.

All 10 FDA-approved biologics (Table) have been ranked by the AAD and NPF as having grade A evidence for efficacy as monotherapy in the treatment of moderate to severe plaque-type psoriasis. Involvement of difficult-to-treat areas may be considered when choosing a specific therapy. The tumor necrosis factor α (TNF-α) inhibitors etanercept and adalimumab, the IL-17 inhibitor secukinumab, and the IL-23 inhibitor guselkumab have the greatest evidence for efficacy in treatment of nail disease. For scalp involvement, etanercept and guselkumab have the highest-quality evidence, and for palmoplantar disease, adalimumab, secukinumab, and guselkumab are considered the most effective. The TNF-α inhibitors are considered the optimal treatment option for concurrent psoriatic arthritis, though the IL-12/IL-23 inhibitor ustekinumab and the IL-17 inhibitors secukinumab and ixekizumab also have shown grade A evidence of efficacy. Of note, because TNF-α inhibitors received the earliest FDA approval, there is most evidence available for this class. Therapies with lower evidence quality for certain forms of psoriasis may show real-world effectiveness in individual patients, though more trials will be necessary to generate a body of evidence to change these clinical recommendations.

Overweight and obese patients also require unique considerations when choosing a biologic. Infliximab is the only approved psoriasis biologic that utilizes proportional-to-weight dosing and hence may be particularly efficacious in patients with higher body mass. Ustekinumab dosing also takes patient weight into consideration; patients heavier than 100 kg should receive 90-mg doses at initiation and during maintenance compared to 45 mg for patients who weigh 100 kg or less. Other approved biologics also may be utilized in these patients but may require closer monitoring of treatment efficacy.

There are few serious contraindications for specific biologic therapies. Any history of allergic reaction to a particular therapy is an absolute contraindication to its use. In patients for whom IL-17 inhibitor treatment is being considered, inflammatory bowel disease (IBD) should be ruled out given the likelihood that IL-17 could reactivate or worsen IBD. Of note, TNF-α inhibitors and ustekinumab are approved therapies for patients with IBD and may be recommended in patients with comorbid psoriasis. Phase 2 and phase 3 trials have found no reactivation or worsening of IBD in patients with psoriasis who were treated with the IL-23 inhibitor tildrakizumab,⁶ and phase 2 trials of treatment of IBD with guselkumab are currently underway (ClinicalTrials.gov Identifier NCT03466411). In patients with New York Heart Association class III and class IV congestive heart failure or multiple sclerosis, initiation of TNF-α inhibitors should be avoided. Among 3 phase 3 trials encompassing nearly 3000 patients treated with the IL-17 inhibitor brodalumab, a total of 3 patients died by suicide^7,8; hence, the FDA has issued a black box warning cautioning against use of this drug in patients with history of suicidal ideation or recent suicidal behavior. Although a causal relationship between brodalumab and suicide has not been well established,⁹ a thorough psychiatric history should be obtained in those initiating treatment with brodalumab.

Initiation of Therapy

Prior to initiating biologic therapy, it is important to obtain a complete blood cell count, complete metabolic panel, tuberculosis testing, and hepatitis B virus (HBV) and hepatitis C virus serologies. Testing for human immunodeficiency virus may be pursued at the clinician’s discretion. It is important to address any positive or concerning results prior to starting biologics. In patients with active infections, therapy may be initiated alongside guidance from an infectious disease specialist. Those with a positive purified protein derivative test, T-SPOT test, or QuantiFERON-TB Gold test must be referred for chest radiographs to rule out active tuberculosis. Patients with active HBV infection should receive appropriate referral to initiate antiviral therapy as well as core antibody testing, and those with active hepatitis C virus infection may only receive biologics under the combined discretion of a dermatologist and an appropriate specialist. Patients with human immunodeficiency virus must concurrently receive highly active antiretroviral therapy, show normal CD4⁺ T-cell count and undetectable viral load, and have no recent history of opportunistic infection.

Therapy should be commenced using specific dosing regimens, which are unique for each biologic (Table). Patients also must be educated on routine follow-up to assess treatment response and tolerability.

Assessment and Optimization of Treatment Response

Patients taking biologics may experience primary treatment failure, defined as lack of response to therapy from initiation. One predisposing factor may be increased body mass; patients who are overweight and obese are less likely to respond to standard regimens of TNF-α inhibitors and 45-mg dosing of ustekinumab. In most cases, however, the cause of primary nonresponse is unpredictable. For patients in whom therapy has failed within the recommended initial time frame (Table), dose escalation or shortening of dosing intervals may be pursued. Recommended dosing adjustments are outlined in the Table. Alternatively, patients may be switched to a different biologic.

If desired effectiveness is not reached with biologic monotherapy, topical corticosteroids, topical vitamin D analogues, or narrowband UVB light therapy may be concurrently used for difficult-to-treat areas. Evidence for safety and effectiveness of systemic adjuncts to biologics is moderate to low, warranting caution with their use. Methotrexate, cyclosporine, and apremilast have synergistic effects with biologics, though they may increase the risk for immunosuppression-related complications. Acitretin, an oral retinoid, likely is the most reasonable systemic adjunct to biologics because of its lack of immunosuppressive properties.

In patients with a suboptimal response to biologics, particularly those taking therapies that require frequent dosing, poor compliance should be considered.¹⁰ These patients may be switched to a biologic with less-frequent maintenance dosing (Table). Ustekinumab and tildrakizumab may be the best options for optimizing compliance, as they require dosing only once every 12 weeks after administration of loading doses.

Secondary treatment failure is diminished efficacy of treatment following successful initial response despite no changes in regimen. The best-known factor contributing to secondary nonresponse to biologics is the development of antidrug antibodies (ADAs), a phenomenon known as immunogenicity. The development of efficacy-limiting ADAs has been observed in response to most biologics, though ADAs against etanercept and guselkumab do not limit therapeutic response. Patients taking adalimumab and infliximab have particularly well-documented efficacy-limiting immunogenicity, and those who develop ADAs to infliximab are considered more prone to developing infusion reactions. Methotrexate, which limits antibody formation, may concomitantly be prescribed in patients who experience secondary treatment failure. It should be considered in all patients taking infliximab to increase efficacy and tolerability of therapy.

Considerations During Active Therapy

In addition to monitoring adherence and response to regimens, dermatologists must be heavily involved in counseling patients regarding the risks and adverse effects associated with these therapies. During maintenance therapy with biologics, patients must follow up with the prescriber at minimum every 3 to 6 months to evaluate for continued efficacy of treatment, extent of side effects, and effects of treatment on overall health and quality of life. Given the immunosuppressive effects of biologics, annual testing for tuberculosis should be considered in high-risk individuals. In those who are considered at low risk, tuberculosis testing may be done at the discretion of the dermatologist. In those with a history of HBV infection, HBV serologies should be pursued routinely given the risk for reactivation.

Annual screening for nonmelanoma skin cancer should be performed in all patients taking biologics. Tumor necrosis factor α inhibitor therapy in particular confers an elevated risk for cutaneous squamous cell carcinoma, especially in patients who are immunosuppressed at baseline and those with history of UV phototherapy. Use of acitretin alongside TNF-α inhibitors or ustekinumab may prevent squamous cell carcinoma formation in high-risk patients.

Because infliximab treatment poses an elevated risk of liver injury,¹¹ liver function tests should be repeated 3 months following initiation of treatment and then every 6 to 12 months subsequently if results are normal. Periodic assessment of suicidal ideation is recommended in patients on brodalumab therapy, which may necessitate more frequent follow-up visits and potentially psychiatry referrals in certain patients. Patients taking IL-17 inhibitors, particularly those who are concurrently taking methotrexate, are at increased risk for developing mucocutaneous Candida infections; these patients should be monitored for such infections and treated appropriately.¹²

It is additionally important for prescribing dermatologists to ensure that patients on biologics are following up with their general providers to receive timely age-appropriate preventative screenings and vaccines. Inactivated vaccinations may be administered during therapy with any biologic; however, live vaccinations may induce systemic infection in those who are immunocompromised, which theoretically includes individuals taking biologic agents, though incidence data in this patient population are scarce.¹³ Some experts believe that administration of live vaccines warrants temporary discontinuation of biologic therapy for 2 to 3 half-lives before and after vaccination (Table). Others recommend stopping treatment at least 4 weeks before and until 2 weeks after vaccination. For patients taking biologics with half-lives greater than 20 days, which would theoretically require stopping the drug 2 months prior to vaccination, the benefit of vaccination should be weighed against the risk of prolonged discontinuation of therapy. Until recently, this recommendation was particularly important, as a live herpes zoster vaccination was recommended by the Centers for Disease Control and Prevention for adults older than 60 years. In 2017, a new inactivated herpes zoster vaccine was introduced and is now the preferred vaccine for all patients older than 50 years.¹⁴ It is especially important that patients on biologics receive this vaccine to avoid temporary drug discontinuation.

Evidence that any particular class of biologics increases risk for solid tumors or lymphoreticular malignancy is limited. One case-control analysis reported that more than 12 months of treatment with TNF-α inhibitors may increase risk for malignancy; however, the confidence interval reported hardly allows for statistical significance.¹⁵ Another retrospective cohort study found no elevated incidence of cancer in patients on TNF-α inhibitors compared to nonbiologic comparators.¹⁶ Ustekinumab was shown to confer no increased risk for malignancy in 1 large study,¹⁵ but no large studies have been conducted for other classes of drugs. Given the limited and inconclusive evidence available, the guidelines recommend that age-appropriate cancer screenings recommended for the general population should be pursued in patients taking biologics.

Surgery while taking biologics may lead to stress-induced augmentation of immunosuppression, resulting in elevated risk of infection.¹⁷ Low-risk surgeries that do not warrant discontinuation of treatment include endoscopic, ophthalmologic, dermatologic, orthopedic, and breast procedures. In patients preparing for elective surgery in which respiratory, gastrointestinal, or genitourinary tracts will be entered, biologics may be discontinued at least 3 half-lives (Table) prior to surgery if the dermatologist and surgeon collaboratively deem that risk of infection outweighs benefit of continued therapy.¹⁸ Therapy may be resumed within 1 to 2 weeks postoperatively if there are no surgical complications.

Switching Biologics

Changing therapy to another biologic should be considered if there is no response to treatment or the patient experiences adverse effects while taking a particular biologic. Because evidence is limited regarding the ideal time frame between discontinuation of a prior medication and initiation of a new biologic, this interval should be determined at the discretion of the provider based on the patient’s disease severity and response to prior treatment. For individuals who experience primary or secondary treatment failure while maintaining appropriate dosing and treatment compliance, switching to a different biologic is recommended to maximize treatment response.¹⁹ Changing therapy to a biologic within the same class is generally effective,²⁰ and switching to a biologic with another mechanism of action should be considered if a class-specific adverse effect is the major reason for altering the regimen. Nonetheless, some patients may be unresponsive to biologic changes. Further research is necessary to determine which biologics may be most effective when previously used biologics have failed and particular factors that may predispose patients to biologic unresponsiveness.

Resuming Biologic Treatment Following Cessation

In cases where therapy is discontinued for any reason, it may be necessary to repeat initiation dosing when resuming treatment. In patients with severe or flaring disease or if more than 3 to 4 half-lives have passed since the most recent dose, it may be necessary to restart therapy with the loading dose (Table). Unfortunately, restarting therapy may preclude some patients from experiencing the maximal response that they attained prior to cessation. In such cases, switching biologic therapy to a different class may prove beneficial.

Final Thoughts

These recommendations contain valuable information that will assist dermatologists when initiating biologics and managing outcomes of their psoriasis patients. It is, however, crucial to bear in mind that these guidelines serve as merely a tool. Given the paucity of comprehensive research, particularly regarding some of the more recently approved therapies, there are many questions that are unanswered within the guidelines. Their utility for each individual patient situation is therefore limited, and clinical judgement may outweigh the information presented. The recommendations nevertheless provide a pivotal and unprecedented framework that promotes discourse among patients, dermatologists, and other providers to optimize the efficacy of biologic therapy for psoriasis.

Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.¹ The disease is moderate to severe for approximately 1 in 6 individuals with psoriasis.² These patients, particularly those with symptoms that are refractory to topical therapy and/or phototherapy, can benefit from the use of biologic agents, which are monoclonal antibodies and fusion proteins engineered to inhibit the action of cytokines that drive psoriatic inflammation.

In February 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of biologics in treating adult patients with psoriasis.³ The prior guidelines were released in 2008 when just 3 biologics—etanercept, infliximab, and adalimumab—were approved by the US Food and Drug Administration (FDA) for the management of psoriasis. These older recommendations were mostly based on studies of the efficacy and safety of biologics for patients with psoriatic arthritis.⁴ Over the last 11 years, 8 novel biologics have gained FDA approval, and numerous large phase 2 and phase 3 trials evaluating the risks and benefits of biologics have been conducted. The new guidelines contain considerably more detail and are based on evidence more specific to psoriasis rather than to psoriatic arthritis. Given the large repertoire of biologics available today and the increased amount of published research regarding each one, these guidelines may aid dermatologists in choosing the optimal biologic and managing therapy.

The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and adverse events of the 10 biologics that have been FDA approved for the treatment of psoriasis as of March 2019, plus risankizumab, which was pending FDA approval at the time of publication and was later approved in April 2019. They also address dosing regimens, potential to combine biologics with other therapies, and different forms of psoriasis for which each may be effective.³ The purpose of this discussion is to present these guidelines in a condensed form to prescribers of biologic therapies and review the most clinically significant considerations during each step of treatment. Of note, we highlight only treatment of adult patients and do not discuss information relevant to risankizumab, as it was not FDA approved when the AAD-NPF guidelines were released.

Choosing a Biologic

Biologic therapy may be considered for patients with psoriasis that affects more than 3% of the body’s surface and is recalcitrant to localized therapies. There is no particular first-line biologic recommended for all patients with psoriasis; rather, choice of therapy should be individualized to the patient, considering factors such as body parts affected, comorbidities, lifestyle, and drug cost.

All 10 FDA-approved biologics (Table) have been ranked by the AAD and NPF as having grade A evidence for efficacy as monotherapy in the treatment of moderate to severe plaque-type psoriasis. Involvement of difficult-to-treat areas may be considered when choosing a specific therapy. The tumor necrosis factor α (TNF-α) inhibitors etanercept and adalimumab, the IL-17 inhibitor secukinumab, and the IL-23 inhibitor guselkumab have the greatest evidence for efficacy in treatment of nail disease. For scalp involvement, etanercept and guselkumab have the highest-quality evidence, and for palmoplantar disease, adalimumab, secukinumab, and guselkumab are considered the most effective. The TNF-α inhibitors are considered the optimal treatment option for concurrent psoriatic arthritis, though the IL-12/IL-23 inhibitor ustekinumab and the IL-17 inhibitors secukinumab and ixekizumab also have shown grade A evidence of efficacy. Of note, because TNF-α inhibitors received the earliest FDA approval, there is most evidence available for this class. Therapies with lower evidence quality for certain forms of psoriasis may show real-world effectiveness in individual patients, though more trials will be necessary to generate a body of evidence to change these clinical recommendations.

Overweight and obese patients also require unique considerations when choosing a biologic. Infliximab is the only approved psoriasis biologic that utilizes proportional-to-weight dosing and hence may be particularly efficacious in patients with higher body mass. Ustekinumab dosing also takes patient weight into consideration; patients heavier than 100 kg should receive 90-mg doses at initiation and during maintenance compared to 45 mg for patients who weigh 100 kg or less. Other approved biologics also may be utilized in these patients but may require closer monitoring of treatment efficacy.

There are few serious contraindications for specific biologic therapies. Any history of allergic reaction to a particular therapy is an absolute contraindication to its use. In patients for whom IL-17 inhibitor treatment is being considered, inflammatory bowel disease (IBD) should be ruled out given the likelihood that IL-17 could reactivate or worsen IBD. Of note, TNF-α inhibitors and ustekinumab are approved therapies for patients with IBD and may be recommended in patients with comorbid psoriasis. Phase 2 and phase 3 trials have found no reactivation or worsening of IBD in patients with psoriasis who were treated with the IL-23 inhibitor tildrakizumab,⁶ and phase 2 trials of treatment of IBD with guselkumab are currently underway (ClinicalTrials.gov Identifier NCT03466411). In patients with New York Heart Association class III and class IV congestive heart failure or multiple sclerosis, initiation of TNF-α inhibitors should be avoided. Among 3 phase 3 trials encompassing nearly 3000 patients treated with the IL-17 inhibitor brodalumab, a total of 3 patients died by suicide^7,8; hence, the FDA has issued a black box warning cautioning against use of this drug in patients with history of suicidal ideation or recent suicidal behavior. Although a causal relationship between brodalumab and suicide has not been well established,⁹ a thorough psychiatric history should be obtained in those initiating treatment with brodalumab.

Initiation of Therapy

Prior to initiating biologic therapy, it is important to obtain a complete blood cell count, complete metabolic panel, tuberculosis testing, and hepatitis B virus (HBV) and hepatitis C virus serologies. Testing for human immunodeficiency virus may be pursued at the clinician’s discretion. It is important to address any positive or concerning results prior to starting biologics. In patients with active infections, therapy may be initiated alongside guidance from an infectious disease specialist. Those with a positive purified protein derivative test, T-SPOT test, or QuantiFERON-TB Gold test must be referred for chest radiographs to rule out active tuberculosis. Patients with active HBV infection should receive appropriate referral to initiate antiviral therapy as well as core antibody testing, and those with active hepatitis C virus infection may only receive biologics under the combined discretion of a dermatologist and an appropriate specialist. Patients with human immunodeficiency virus must concurrently receive highly active antiretroviral therapy, show normal CD4⁺ T-cell count and undetectable viral load, and have no recent history of opportunistic infection.

Therapy should be commenced using specific dosing regimens, which are unique for each biologic (Table). Patients also must be educated on routine follow-up to assess treatment response and tolerability.

Assessment and Optimization of Treatment Response

Patients taking biologics may experience primary treatment failure, defined as lack of response to therapy from initiation. One predisposing factor may be increased body mass; patients who are overweight and obese are less likely to respond to standard regimens of TNF-α inhibitors and 45-mg dosing of ustekinumab. In most cases, however, the cause of primary nonresponse is unpredictable. For patients in whom therapy has failed within the recommended initial time frame (Table), dose escalation or shortening of dosing intervals may be pursued. Recommended dosing adjustments are outlined in the Table. Alternatively, patients may be switched to a different biologic.

If desired effectiveness is not reached with biologic monotherapy, topical corticosteroids, topical vitamin D analogues, or narrowband UVB light therapy may be concurrently used for difficult-to-treat areas. Evidence for safety and effectiveness of systemic adjuncts to biologics is moderate to low, warranting caution with their use. Methotrexate, cyclosporine, and apremilast have synergistic effects with biologics, though they may increase the risk for immunosuppression-related complications. Acitretin, an oral retinoid, likely is the most reasonable systemic adjunct to biologics because of its lack of immunosuppressive properties.

In patients with a suboptimal response to biologics, particularly those taking therapies that require frequent dosing, poor compliance should be considered.¹⁰ These patients may be switched to a biologic with less-frequent maintenance dosing (Table). Ustekinumab and tildrakizumab may be the best options for optimizing compliance, as they require dosing only once every 12 weeks after administration of loading doses.

Secondary treatment failure is diminished efficacy of treatment following successful initial response despite no changes in regimen. The best-known factor contributing to secondary nonresponse to biologics is the development of antidrug antibodies (ADAs), a phenomenon known as immunogenicity. The development of efficacy-limiting ADAs has been observed in response to most biologics, though ADAs against etanercept and guselkumab do not limit therapeutic response. Patients taking adalimumab and infliximab have particularly well-documented efficacy-limiting immunogenicity, and those who develop ADAs to infliximab are considered more prone to developing infusion reactions. Methotrexate, which limits antibody formation, may concomitantly be prescribed in patients who experience secondary treatment failure. It should be considered in all patients taking infliximab to increase efficacy and tolerability of therapy.

Considerations During Active Therapy

In addition to monitoring adherence and response to regimens, dermatologists must be heavily involved in counseling patients regarding the risks and adverse effects associated with these therapies. During maintenance therapy with biologics, patients must follow up with the prescriber at minimum every 3 to 6 months to evaluate for continued efficacy of treatment, extent of side effects, and effects of treatment on overall health and quality of life. Given the immunosuppressive effects of biologics, annual testing for tuberculosis should be considered in high-risk individuals. In those who are considered at low risk, tuberculosis testing may be done at the discretion of the dermatologist. In those with a history of HBV infection, HBV serologies should be pursued routinely given the risk for reactivation.

Annual screening for nonmelanoma skin cancer should be performed in all patients taking biologics. Tumor necrosis factor α inhibitor therapy in particular confers an elevated risk for cutaneous squamous cell carcinoma, especially in patients who are immunosuppressed at baseline and those with history of UV phototherapy. Use of acitretin alongside TNF-α inhibitors or ustekinumab may prevent squamous cell carcinoma formation in high-risk patients.

Because infliximab treatment poses an elevated risk of liver injury,¹¹ liver function tests should be repeated 3 months following initiation of treatment and then every 6 to 12 months subsequently if results are normal. Periodic assessment of suicidal ideation is recommended in patients on brodalumab therapy, which may necessitate more frequent follow-up visits and potentially psychiatry referrals in certain patients. Patients taking IL-17 inhibitors, particularly those who are concurrently taking methotrexate, are at increased risk for developing mucocutaneous Candida infections; these patients should be monitored for such infections and treated appropriately.¹²

It is additionally important for prescribing dermatologists to ensure that patients on biologics are following up with their general providers to receive timely age-appropriate preventative screenings and vaccines. Inactivated vaccinations may be administered during therapy with any biologic; however, live vaccinations may induce systemic infection in those who are immunocompromised, which theoretically includes individuals taking biologic agents, though incidence data in this patient population are scarce.¹³ Some experts believe that administration of live vaccines warrants temporary discontinuation of biologic therapy for 2 to 3 half-lives before and after vaccination (Table). Others recommend stopping treatment at least 4 weeks before and until 2 weeks after vaccination. For patients taking biologics with half-lives greater than 20 days, which would theoretically require stopping the drug 2 months prior to vaccination, the benefit of vaccination should be weighed against the risk of prolonged discontinuation of therapy. Until recently, this recommendation was particularly important, as a live herpes zoster vaccination was recommended by the Centers for Disease Control and Prevention for adults older than 60 years. In 2017, a new inactivated herpes zoster vaccine was introduced and is now the preferred vaccine for all patients older than 50 years.¹⁴ It is especially important that patients on biologics receive this vaccine to avoid temporary drug discontinuation.

Evidence that any particular class of biologics increases risk for solid tumors or lymphoreticular malignancy is limited. One case-control analysis reported that more than 12 months of treatment with TNF-α inhibitors may increase risk for malignancy; however, the confidence interval reported hardly allows for statistical significance.¹⁵ Another retrospective cohort study found no elevated incidence of cancer in patients on TNF-α inhibitors compared to nonbiologic comparators.¹⁶ Ustekinumab was shown to confer no increased risk for malignancy in 1 large study,¹⁵ but no large studies have been conducted for other classes of drugs. Given the limited and inconclusive evidence available, the guidelines recommend that age-appropriate cancer screenings recommended for the general population should be pursued in patients taking biologics.

Surgery while taking biologics may lead to stress-induced augmentation of immunosuppression, resulting in elevated risk of infection.¹⁷ Low-risk surgeries that do not warrant discontinuation of treatment include endoscopic, ophthalmologic, dermatologic, orthopedic, and breast procedures. In patients preparing for elective surgery in which respiratory, gastrointestinal, or genitourinary tracts will be entered, biologics may be discontinued at least 3 half-lives (Table) prior to surgery if the dermatologist and surgeon collaboratively deem that risk of infection outweighs benefit of continued therapy.¹⁸ Therapy may be resumed within 1 to 2 weeks postoperatively if there are no surgical complications.

Switching Biologics

Changing therapy to another biologic should be considered if there is no response to treatment or the patient experiences adverse effects while taking a particular biologic. Because evidence is limited regarding the ideal time frame between discontinuation of a prior medication and initiation of a new biologic, this interval should be determined at the discretion of the provider based on the patient’s disease severity and response to prior treatment. For individuals who experience primary or secondary treatment failure while maintaining appropriate dosing and treatment compliance, switching to a different biologic is recommended to maximize treatment response.¹⁹ Changing therapy to a biologic within the same class is generally effective,²⁰ and switching to a biologic with another mechanism of action should be considered if a class-specific adverse effect is the major reason for altering the regimen. Nonetheless, some patients may be unresponsive to biologic changes. Further research is necessary to determine which biologics may be most effective when previously used biologics have failed and particular factors that may predispose patients to biologic unresponsiveness.

Resuming Biologic Treatment Following Cessation

In cases where therapy is discontinued for any reason, it may be necessary to repeat initiation dosing when resuming treatment. In patients with severe or flaring disease or if more than 3 to 4 half-lives have passed since the most recent dose, it may be necessary to restart therapy with the loading dose (Table). Unfortunately, restarting therapy may preclude some patients from experiencing the maximal response that they attained prior to cessation. In such cases, switching biologic therapy to a different class may prove beneficial.

Final Thoughts

These recommendations contain valuable information that will assist dermatologists when initiating biologics and managing outcomes of their psoriasis patients. It is, however, crucial to bear in mind that these guidelines serve as merely a tool. Given the paucity of comprehensive research, particularly regarding some of the more recently approved therapies, there are many questions that are unanswered within the guidelines. Their utility for each individual patient situation is therefore limited, and clinical judgement may outweigh the information presented. The recommendations nevertheless provide a pivotal and unprecedented framework that promotes discourse among patients, dermatologists, and other providers to optimize the efficacy of biologic therapy for psoriasis.

Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.¹ The disease is moderate to severe for approximately 1 in 6 individuals with psoriasis.² These patients, particularly those with symptoms that are refractory to topical therapy and/or phototherapy, can benefit from the use of biologic agents, which are monoclonal antibodies and fusion proteins engineered to inhibit the action of cytokines that drive psoriatic inflammation.

In February 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of biologics in treating adult patients with psoriasis.³ The prior guidelines were released in 2008 when just 3 biologics—etanercept, infliximab, and adalimumab—were approved by the US Food and Drug Administration (FDA) for the management of psoriasis. These older recommendations were mostly based on studies of the efficacy and safety of biologics for patients with psoriatic arthritis.⁴ Over the last 11 years, 8 novel biologics have gained FDA approval, and numerous large phase 2 and phase 3 trials evaluating the risks and benefits of biologics have been conducted. The new guidelines contain considerably more detail and are based on evidence more specific to psoriasis rather than to psoriatic arthritis. Given the large repertoire of biologics available today and the increased amount of published research regarding each one, these guidelines may aid dermatologists in choosing the optimal biologic and managing therapy.

The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and adverse events of the 10 biologics that have been FDA approved for the treatment of psoriasis as of March 2019, plus risankizumab, which was pending FDA approval at the time of publication and was later approved in April 2019. They also address dosing regimens, potential to combine biologics with other therapies, and different forms of psoriasis for which each may be effective.³ The purpose of this discussion is to present these guidelines in a condensed form to prescribers of biologic therapies and review the most clinically significant considerations during each step of treatment. Of note, we highlight only treatment of adult patients and do not discuss information relevant to risankizumab, as it was not FDA approved when the AAD-NPF guidelines were released.

Choosing a Biologic

Biologic therapy may be considered for patients with psoriasis that affects more than 3% of the body’s surface and is recalcitrant to localized therapies. There is no particular first-line biologic recommended for all patients with psoriasis; rather, choice of therapy should be individualized to the patient, considering factors such as body parts affected, comorbidities, lifestyle, and drug cost.

All 10 FDA-approved biologics (Table) have been ranked by the AAD and NPF as having grade A evidence for efficacy as monotherapy in the treatment of moderate to severe plaque-type psoriasis. Involvement of difficult-to-treat areas may be considered when choosing a specific therapy. The tumor necrosis factor α (TNF-α) inhibitors etanercept and adalimumab, the IL-17 inhibitor secukinumab, and the IL-23 inhibitor guselkumab have the greatest evidence for efficacy in treatment of nail disease. For scalp involvement, etanercept and guselkumab have the highest-quality evidence, and for palmoplantar disease, adalimumab, secukinumab, and guselkumab are considered the most effective. The TNF-α inhibitors are considered the optimal treatment option for concurrent psoriatic arthritis, though the IL-12/IL-23 inhibitor ustekinumab and the IL-17 inhibitors secukinumab and ixekizumab also have shown grade A evidence of efficacy. Of note, because TNF-α inhibitors received the earliest FDA approval, there is most evidence available for this class. Therapies with lower evidence quality for certain forms of psoriasis may show real-world effectiveness in individual patients, though more trials will be necessary to generate a body of evidence to change these clinical recommendations.

Overweight and obese patients also require unique considerations when choosing a biologic. Infliximab is the only approved psoriasis biologic that utilizes proportional-to-weight dosing and hence may be particularly efficacious in patients with higher body mass. Ustekinumab dosing also takes patient weight into consideration; patients heavier than 100 kg should receive 90-mg doses at initiation and during maintenance compared to 45 mg for patients who weigh 100 kg or less. Other approved biologics also may be utilized in these patients but may require closer monitoring of treatment efficacy.

There are few serious contraindications for specific biologic therapies. Any history of allergic reaction to a particular therapy is an absolute contraindication to its use. In patients for whom IL-17 inhibitor treatment is being considered, inflammatory bowel disease (IBD) should be ruled out given the likelihood that IL-17 could reactivate or worsen IBD. Of note, TNF-α inhibitors and ustekinumab are approved therapies for patients with IBD and may be recommended in patients with comorbid psoriasis. Phase 2 and phase 3 trials have found no reactivation or worsening of IBD in patients with psoriasis who were treated with the IL-23 inhibitor tildrakizumab,⁶ and phase 2 trials of treatment of IBD with guselkumab are currently underway (ClinicalTrials.gov Identifier NCT03466411). In patients with New York Heart Association class III and class IV congestive heart failure or multiple sclerosis, initiation of TNF-α inhibitors should be avoided. Among 3 phase 3 trials encompassing nearly 3000 patients treated with the IL-17 inhibitor brodalumab, a total of 3 patients died by suicide^7,8; hence, the FDA has issued a black box warning cautioning against use of this drug in patients with history of suicidal ideation or recent suicidal behavior. Although a causal relationship between brodalumab and suicide has not been well established,⁹ a thorough psychiatric history should be obtained in those initiating treatment with brodalumab.

Initiation of Therapy

Prior to initiating biologic therapy, it is important to obtain a complete blood cell count, complete metabolic panel, tuberculosis testing, and hepatitis B virus (HBV) and hepatitis C virus serologies. Testing for human immunodeficiency virus may be pursued at the clinician’s discretion. It is important to address any positive or concerning results prior to starting biologics. In patients with active infections, therapy may be initiated alongside guidance from an infectious disease specialist. Those with a positive purified protein derivative test, T-SPOT test, or QuantiFERON-TB Gold test must be referred for chest radiographs to rule out active tuberculosis. Patients with active HBV infection should receive appropriate referral to initiate antiviral therapy as well as core antibody testing, and those with active hepatitis C virus infection may only receive biologics under the combined discretion of a dermatologist and an appropriate specialist. Patients with human immunodeficiency virus must concurrently receive highly active antiretroviral therapy, show normal CD4⁺ T-cell count and undetectable viral load, and have no recent history of opportunistic infection.

Therapy should be commenced using specific dosing regimens, which are unique for each biologic (Table). Patients also must be educated on routine follow-up to assess treatment response and tolerability.

Assessment and Optimization of Treatment Response

Patients taking biologics may experience primary treatment failure, defined as lack of response to therapy from initiation. One predisposing factor may be increased body mass; patients who are overweight and obese are less likely to respond to standard regimens of TNF-α inhibitors and 45-mg dosing of ustekinumab. In most cases, however, the cause of primary nonresponse is unpredictable. For patients in whom therapy has failed within the recommended initial time frame (Table), dose escalation or shortening of dosing intervals may be pursued. Recommended dosing adjustments are outlined in the Table. Alternatively, patients may be switched to a different biologic.

If desired effectiveness is not reached with biologic monotherapy, topical corticosteroids, topical vitamin D analogues, or narrowband UVB light therapy may be concurrently used for difficult-to-treat areas. Evidence for safety and effectiveness of systemic adjuncts to biologics is moderate to low, warranting caution with their use. Methotrexate, cyclosporine, and apremilast have synergistic effects with biologics, though they may increase the risk for immunosuppression-related complications. Acitretin, an oral retinoid, likely is the most reasonable systemic adjunct to biologics because of its lack of immunosuppressive properties.

In patients with a suboptimal response to biologics, particularly those taking therapies that require frequent dosing, poor compliance should be considered.¹⁰ These patients may be switched to a biologic with less-frequent maintenance dosing (Table). Ustekinumab and tildrakizumab may be the best options for optimizing compliance, as they require dosing only once every 12 weeks after administration of loading doses.

Secondary treatment failure is diminished efficacy of treatment following successful initial response despite no changes in regimen. The best-known factor contributing to secondary nonresponse to biologics is the development of antidrug antibodies (ADAs), a phenomenon known as immunogenicity. The development of efficacy-limiting ADAs has been observed in response to most biologics, though ADAs against etanercept and guselkumab do not limit therapeutic response. Patients taking adalimumab and infliximab have particularly well-documented efficacy-limiting immunogenicity, and those who develop ADAs to infliximab are considered more prone to developing infusion reactions. Methotrexate, which limits antibody formation, may concomitantly be prescribed in patients who experience secondary treatment failure. It should be considered in all patients taking infliximab to increase efficacy and tolerability of therapy.

Considerations During Active Therapy

In addition to monitoring adherence and response to regimens, dermatologists must be heavily involved in counseling patients regarding the risks and adverse effects associated with these therapies. During maintenance therapy with biologics, patients must follow up with the prescriber at minimum every 3 to 6 months to evaluate for continued efficacy of treatment, extent of side effects, and effects of treatment on overall health and quality of life. Given the immunosuppressive effects of biologics, annual testing for tuberculosis should be considered in high-risk individuals. In those who are considered at low risk, tuberculosis testing may be done at the discretion of the dermatologist. In those with a history of HBV infection, HBV serologies should be pursued routinely given the risk for reactivation.

Annual screening for nonmelanoma skin cancer should be performed in all patients taking biologics. Tumor necrosis factor α inhibitor therapy in particular confers an elevated risk for cutaneous squamous cell carcinoma, especially in patients who are immunosuppressed at baseline and those with history of UV phototherapy. Use of acitretin alongside TNF-α inhibitors or ustekinumab may prevent squamous cell carcinoma formation in high-risk patients.

Because infliximab treatment poses an elevated risk of liver injury,¹¹ liver function tests should be repeated 3 months following initiation of treatment and then every 6 to 12 months subsequently if results are normal. Periodic assessment of suicidal ideation is recommended in patients on brodalumab therapy, which may necessitate more frequent follow-up visits and potentially psychiatry referrals in certain patients. Patients taking IL-17 inhibitors, particularly those who are concurrently taking methotrexate, are at increased risk for developing mucocutaneous Candida infections; these patients should be monitored for such infections and treated appropriately.¹²

It is additionally important for prescribing dermatologists to ensure that patients on biologics are following up with their general providers to receive timely age-appropriate preventative screenings and vaccines. Inactivated vaccinations may be administered during therapy with any biologic; however, live vaccinations may induce systemic infection in those who are immunocompromised, which theoretically includes individuals taking biologic agents, though incidence data in this patient population are scarce.¹³ Some experts believe that administration of live vaccines warrants temporary discontinuation of biologic therapy for 2 to 3 half-lives before and after vaccination (Table). Others recommend stopping treatment at least 4 weeks before and until 2 weeks after vaccination. For patients taking biologics with half-lives greater than 20 days, which would theoretically require stopping the drug 2 months prior to vaccination, the benefit of vaccination should be weighed against the risk of prolonged discontinuation of therapy. Until recently, this recommendation was particularly important, as a live herpes zoster vaccination was recommended by the Centers for Disease Control and Prevention for adults older than 60 years. In 2017, a new inactivated herpes zoster vaccine was introduced and is now the preferred vaccine for all patients older than 50 years.¹⁴ It is especially important that patients on biologics receive this vaccine to avoid temporary drug discontinuation.

Evidence that any particular class of biologics increases risk for solid tumors or lymphoreticular malignancy is limited. One case-control analysis reported that more than 12 months of treatment with TNF-α inhibitors may increase risk for malignancy; however, the confidence interval reported hardly allows for statistical significance.¹⁵ Another retrospective cohort study found no elevated incidence of cancer in patients on TNF-α inhibitors compared to nonbiologic comparators.¹⁶ Ustekinumab was shown to confer no increased risk for malignancy in 1 large study,¹⁵ but no large studies have been conducted for other classes of drugs. Given the limited and inconclusive evidence available, the guidelines recommend that age-appropriate cancer screenings recommended for the general population should be pursued in patients taking biologics.

Surgery while taking biologics may lead to stress-induced augmentation of immunosuppression, resulting in elevated risk of infection.¹⁷ Low-risk surgeries that do not warrant discontinuation of treatment include endoscopic, ophthalmologic, dermatologic, orthopedic, and breast procedures. In patients preparing for elective surgery in which respiratory, gastrointestinal, or genitourinary tracts will be entered, biologics may be discontinued at least 3 half-lives (Table) prior to surgery if the dermatologist and surgeon collaboratively deem that risk of infection outweighs benefit of continued therapy.¹⁸ Therapy may be resumed within 1 to 2 weeks postoperatively if there are no surgical complications.

Switching Biologics

Changing therapy to another biologic should be considered if there is no response to treatment or the patient experiences adverse effects while taking a particular biologic. Because evidence is limited regarding the ideal time frame between discontinuation of a prior medication and initiation of a new biologic, this interval should be determined at the discretion of the provider based on the patient’s disease severity and response to prior treatment. For individuals who experience primary or secondary treatment failure while maintaining appropriate dosing and treatment compliance, switching to a different biologic is recommended to maximize treatment response.¹⁹ Changing therapy to a biologic within the same class is generally effective,²⁰ and switching to a biologic with another mechanism of action should be considered if a class-specific adverse effect is the major reason for altering the regimen. Nonetheless, some patients may be unresponsive to biologic changes. Further research is necessary to determine which biologics may be most effective when previously used biologics have failed and particular factors that may predispose patients to biologic unresponsiveness.

Resuming Biologic Treatment Following Cessation

In cases where therapy is discontinued for any reason, it may be necessary to repeat initiation dosing when resuming treatment. In patients with severe or flaring disease or if more than 3 to 4 half-lives have passed since the most recent dose, it may be necessary to restart therapy with the loading dose (Table). Unfortunately, restarting therapy may preclude some patients from experiencing the maximal response that they attained prior to cessation. In such cases, switching biologic therapy to a different class may prove beneficial.

Final Thoughts

These recommendations contain valuable information that will assist dermatologists when initiating biologics and managing outcomes of their psoriasis patients. It is, however, crucial to bear in mind that these guidelines serve as merely a tool. Given the paucity of comprehensive research, particularly regarding some of the more recently approved therapies, there are many questions that are unanswered within the guidelines. Their utility for each individual patient situation is therefore limited, and clinical judgement may outweigh the information presented. The recommendations nevertheless provide a pivotal and unprecedented framework that promotes discourse among patients, dermatologists, and other providers to optimize the efficacy of biologic therapy for psoriasis.

Recent advances in our understanding of psoriatic immune pathways have led to new generations of targeted therapies developed over the last 5 years. Although the pathogenesis of psoriasis remains to be fully elucidated, the success of these targeted therapies has confirmed a critical role of the IL-23/helper T cell (T_H17) axis in maintaining the psoriatic immune cascade, a positive feedback loop in which IL-17, IL-12, and IL-23 released from myeloid dendritic cells lead to activation of helperT cells. Activated helper T cells—namely T_H1, T_H17, and T_H22—release IL-17, IL-22, and other proinflammatory cytokines, amplifying the immune response and leading to keratinocyte proliferation and immune cell migration to psoriatic lesions. Inhibition of IL-17 and IL-23 by several biologics disrupts this aberrant inflammatory cascade and has led to dramatic improvements in outcomes, particularly among patients with moderate to severe disease.

Numerous biologics targeting these pathways and several oral treatments have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis; in addition, a number of promising therapies are on the horizon, and knowledge of these medications might help guide our treatment approach to the patient with psoriasis. This article provides an update on the most recent (as of 2019) approved therapies and medications in the pipeline for moderate to severe plaque psoriasis, with a focus on systemic agents in phase 3 clinical trials. (Medications targeting psoriatic arthritis, biosimilars, and existing medications approved by the FDA prior to 2019 will not be discussed.)

Risankizumab

Risankizumab-rzaa (formerly BI 655066) is a humanized IgG1 monoclonal antibody that targets the p19 subunit of IL-23, selectively inhibiting the role of this critical cytokine in psoriatic inflammation.

Phase 1 Trial
In a phase 1 proof-of-concept study, 39 patients with moderate to severe plaque psoriasis received varying dosages of intravenous or subcutaneous risankizumab or placebo.¹ At week 12, the percentage of risankizumab-treated patients achieving reduction in the psoriasis area and severity index (PASI) score by 75% (PASI 75), 90% (PASI 90), and 100% (PASI 100) was 87% (27/31; P<.001 vs placebo), 58% (18/31; P=.007 vs placebo), and 16% (5/31; P=.590 vs placebo), respectively. Improvements in PASI scores were observed as early as week 2. Adverse events (AEs) were reported by 65% of the risankizumab group and 88% of the placebo group. Serious AEs were reported in 4 patients receiving risankizumab, none of which were considered related to the study medication.¹

Phase 2 Trial
A phase 2 comparator trial demonstrated noninferiority at higher dosages of risankizumab in comparison to the IL-12/IL-23 inhibitor ustekinumab.² Among 166 participants with moderate to severe plaque psoriasis, PASI 90 at week 12 was met by 77% of participants receiving 90 or 180 mg of risankizumab compared to 40% receiving ustekinumab (P<.001). Onset of activity with risankizumab was faster and the duration of effect longer vs ustekinumab; by week 8, at least PASI 75 was achieved by approximately 80% of participants in the 90-mg and 180-mg risankizumab groups compared to 60% in the ustekinumab group; PASI score reductions generally were maintained for as long as 20 weeks after the final dose of risankizumab was administered.²

Phase 3 Trials
The 52-week UltIMMa-1 and UltIMMa-2 phase 3 trials compared subcutaneous risankizumab (150 mg) to ustekinumab (45 or 90 mg [weight-based dosing]) or placebo administered at weeks 0, 4, 16, 28, and 40 in approximately 1000 patients with moderate to severe plaque psoriasis.³ Patients initially assigned to placebo switched to risankizumab 150 mg at week 16. At week 16, PASI 90 was achieved by 75.3% of risankizumab-treated patients, 42.0% of ustekinumab-treated patients, and 4.9% of placebo-treated patients in UltIMMa-1, and by 74.8% of risankizumab-treated patients, 47.5% of ustekinumab-treated patients, and 2.0% of placebo-treated patients in UltIMMa-2 (P<.0001 vs placebo and ustekinumab for both studies). Achievement of a static physician’s global assessment (sPGA) score of 0 or 1 at week 16 similarly favored risankizumab, with 87.8%, 63.0%, and 7.8% of patients in UltIMMa-1 meeting an sPGA score of 0 or 1 in the risankizumab, ustekinumab, and placebo groups, respectively, and 83.7%, 61.6%, and 5.1% in UltIMMa-2 meeting an sPGA score of 0 or 1 in the risankizumab, ustekinumab, and placebo groups, respectively (P<.0001 vs placebo and ustekinumab for both studies). Among patients initially assigned to risankizumab, improvements in PASI and sPGA continued to increase until week 52, with 81.9% achieving PASI 90 at week 52 compared to 44.0% on ustekinumab in UltIMMa-1, and 80.6% achieving PASI 90 at week 52 compared to 50.5% on ustekinumab in UltIMMa-2 (P<.0001 vs ustekinumab for both studies). Treatment-emergent AE profiles were similar for risankizumab and ustekinumab in both studies, and there were no unexpected safety findings.³

Risankizumab received FDA approval for the treatment of moderate to severe plaque psoriasis in April 2019.

Bimekizumab

Bimekizumab (UCB4940), a humanized IgG1 monoclonal antibody, selectively neutralizes the biologic functions of IL-17A and IL-17F, the latter of which has only recently been implicated in contributing to the psoriatic immune cascade.⁴

First-in-Human Study
Thirty-nine participants with mild psoriasis demonstrated efficacy after single-dose intravenous bimekizumab, with maximal improvements in all measures of disease activity observed between weeks 8 and 12 in participants receiving 160 to 640 mg.⁵

Proof-of-Concept Phase 1b Study
A subsequent trial of 53 participants with psoriatic arthritis demonstrated sustained efficacy to week 20 with varying dosages of intravenous bimekizumab.⁶ At week 8, PASI 100 was met by 86.7% of participants receiving the top 3 dosages of bimekizumab compared to none of the placebo-treated participants. Treatment-emergent AEs, including neutropenia and elevation of liver transaminases, were mostly mild to moderate and resolved spontaneously. There were 3 severe AEs and 3 serious AEs, none of which were related to treatment.⁶

Importantly, bimekizumab was shown in this small study to have the potential to be highly effective at treating psoriatic arthritis. American College of Rheumatology ACR20, ACR50, and ACR70 response criteria were very high, with an ACR20 of 80% and an ACR50 of 40%.⁶ Further trials are necessary to gather more data and confirm these findings; however, these levels of response are higher than those of any other biologic on the market.

Phase 2b Dose-Ranging Study
In this trial, 250 participants with moderate to severe plaque psoriasis received either 64 mg, 160 mg with a 320-mg loading dose, 320 mg, or 480 mg of subcutaneous bimekizumab or placebo at weeks 0, 4, and 8.⁷ At week 12, PASI 90 was achieved by significantly more patients in all bimekizumab-treated groups compared to the placebo group (46.2%–79.1% vs 0%; P<.0001 for all dosages); PASI 100 also was achieved by significantly more bimekizumab-treated patients (27.9%–60.0% vs 0%; P<.0002). Improvement began as early as week 4, with clinically meaningful responses observed in all bimekizumab groups across all measures of disease activity. Treatment-emergent AEs occurred more frequently in bimekizumab-treated participants (61%) than in placebo-treated participants (36%); the most common AEs were nasopharyngitis and upper respiratory tract infection. Of note, fungal infections were reported by 4.3% of participants receiving bimekizumab; all cases were localized superficial infection, and none led to discontinuation. Three serious AEs were reported, none of which were considered related to the study treatment.⁷

Mirikizumab

Mirikizumab (LY3074828) is a humanized IgG4 monoclonal antibody that selectively binds and inhibits the p19 subunit of IL-23, with no action on IL-12.

Phase 1 Trial
Mirikizumab was shown to improve PASI scores in patients with plaque psoriasis.⁸

Phase 2 Trial
Subsequently, a trial of 205 participants with moderate to severe plaque psoriasis compared 3 dosing regimens of subcutaneous mirikizumab—30, 100, or 300 mg—at weeks 0 and 8 compared to placebo.⁹ Primary end point results at week 16 demonstrated PASI 90 response rates of 0%, 29% (P=.009), 59% (P<.001), and 67% (P<.001) in the placebo, 30-mg, 100-mg, and 300-mg mirikizumab groups, respectively. Complete clearance of psoriasis, measured by PASI 100 and sPGA 0, was achieved by 0%, 16%, 31%, and 31%, respectively (P=.039 for 30 mg vs placebo; P=.007 for the higher dosage groups vs placebo). Response rates for all efficacy outcomes were statistically significantly higher for all mirikizumab treatment groups compared to placebo and were highest in the 100-mg and 300-mg treatment groups. Frequencies of participants reporting AEs were similar across treatment and placebo groups.⁹

Oral Medications

Only a few small-molecule, orally bioavailable therapies are on the market for the treatment of psoriasis, some of which are associated with unfavorable side-effect profiles that preclude long-term therapy.

BMS-986165
The intracellular signaling enzyme tyrosine kinase 2 is involved in functional responses of IL-12 and IL-23. BMS-986165, a potent oral inhibitor of tyrosine kinase 2 with greater selectivity than other tyrosine kinase inhibitors, demonstrated efficacy in a phase 2 trial of 267 participants with moderate to severe plaque psoriasis receiving any of 5 dosing regimens—3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, and 12 mg daily—compared to placebo.¹⁰ At week 12, the percentage of patients with a 75% or greater reduction in PASI was 7% with placebo, 9% with 3 mg every other day (P=.49 vs placebo), 39% with 3 mg daily (P<.001 vs placebo), 69% with 3 mg twice daily (P<.001 vs placebo), 67% with 6 mg twice daily (P<.001 vs placebo), and 75% with 12 mg once daily (P<.001 vs placebo). Adverse events occurred in 51% of patients in the placebo group and in 55% to 80% of BMS-986165–treated patients; the most common AEs were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection.¹⁰

A phase 3 trial comparing BMS-986165 with placebo and apremilast is underway (ClinicalTrials.gov Identifier NCT03611751).

Piclidenoson (CF101)
A novel small molecule that binds the Gi protein–associated A₃ adenosine receptor piclidenoson induces an anti-inflammatory response via deregulation of the Wnt and nuclear factor κB signal transduction pathways, leading to downregulation of proinflammatory cytokines, including IL-17 and IL-23.¹¹

In a phase 2 dose-ranging study, 75 patients with moderate to severe plaque psoriasis received varying dosages—1, 2, or 4 mg—of oral piclidenoson or placebo twice daily for 12 weeks.¹² Progressive improvement in the mean change from baseline PASI score was observed in the 2-mg group, with statistically significant differences at weeks 8 and 12 compared to placebo (P=.047 and P=.031, respectively). At week 12, 35.3% of the 2-mg group achieved at least PASI 50. Improvements in PASI were less pronounced in the 4-mg group, and no therapeutic benefit was observed in the 1-mg group. Of the 20 AEs reported, 15 possibly were related to the study drug; 1 AE was severe.¹²

In a subsequent phase 2/3 trial, patients with moderate to severe plaque psoriasis received piclidenoson—1 or 2 mg—or placebo twice daily.¹³ At week 12, PASI 75 was achieved by 8.5% of patients in the 2-mg group and by 6.9% of patients receiving placebo (P=.621), thereby not meeting the primary study end point. Results at week 32 were more encouraging. In the 2-mg group, PASI mean percentage improvement was 57% (P<.002) compared to baseline, with linear improvements observed in PASI 50 (63.5%), PASI 75 (35.5%), PASI 90 (24.7%), and PASI 100 (10.6%).¹³

A phase 3 trial comparing piclidenoson 2 and 3 mg to apremilast and placebo is in progress (ClinicalTrials.gov Identifier NCT03168256).

Future Directions

Despite abundant options for treating moderate to severe plaque psoriasis and psoriatic arthritis, the pipeline remains rich. Novel treatments might have improved efficacy, favorable safety profiles, and different modes of administration compared to current medications. In addition to the novel therapeutics covered here, several treatments are in development further down the pipeline, with only phase 1 or 2 data available. Remtolumab (ABT-122), a tumor necrosis factor α– and IL-17A–targeted immunoglobulin, is unique among biologics, given its dual inhibition of tumor necrosis factor α and IL-17A.¹⁴ M1095 (ALX-0761), a novel trivalent bispecific nanobody, is another intriguing candidate. This dual inhibitor of IL-17A/F might exhibit a number of advantages over conventional antibodies, including better tissue penetration, reduced immunogenicity, and a longer half-life (ClinicalTrials.gov Identifier NCT03384745).^15,16

As always with drug development, numerous medications that were under development failed to meet primary end points in phase 2 trials and have therefore been discontinued, including namilumab and prurisol. It is reassuring that the pace of drug discovery and development in psoriasis does not seem to be slowing; to our patients’ benefit, we will have an array of treatments available to tailor therapy to the individual.

Recent advances in our understanding of psoriatic immune pathways have led to new generations of targeted therapies developed over the last 5 years. Although the pathogenesis of psoriasis remains to be fully elucidated, the success of these targeted therapies has confirmed a critical role of the IL-23/helper T cell (T_H17) axis in maintaining the psoriatic immune cascade, a positive feedback loop in which IL-17, IL-12, and IL-23 released from myeloid dendritic cells lead to activation of helperT cells. Activated helper T cells—namely T_H1, T_H17, and T_H22—release IL-17, IL-22, and other proinflammatory cytokines, amplifying the immune response and leading to keratinocyte proliferation and immune cell migration to psoriatic lesions. Inhibition of IL-17 and IL-23 by several biologics disrupts this aberrant inflammatory cascade and has led to dramatic improvements in outcomes, particularly among patients with moderate to severe disease.

Numerous biologics targeting these pathways and several oral treatments have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis; in addition, a number of promising therapies are on the horizon, and knowledge of these medications might help guide our treatment approach to the patient with psoriasis. This article provides an update on the most recent (as of 2019) approved therapies and medications in the pipeline for moderate to severe plaque psoriasis, with a focus on systemic agents in phase 3 clinical trials. (Medications targeting psoriatic arthritis, biosimilars, and existing medications approved by the FDA prior to 2019 will not be discussed.)

Risankizumab

Risankizumab-rzaa (formerly BI 655066) is a humanized IgG1 monoclonal antibody that targets the p19 subunit of IL-23, selectively inhibiting the role of this critical cytokine in psoriatic inflammation.

Phase 1 Trial
In a phase 1 proof-of-concept study, 39 patients with moderate to severe plaque psoriasis received varying dosages of intravenous or subcutaneous risankizumab or placebo.¹ At week 12, the percentage of risankizumab-treated patients achieving reduction in the psoriasis area and severity index (PASI) score by 75% (PASI 75), 90% (PASI 90), and 100% (PASI 100) was 87% (27/31; P<.001 vs placebo), 58% (18/31; P=.007 vs placebo), and 16% (5/31; P=.590 vs placebo), respectively. Improvements in PASI scores were observed as early as week 2. Adverse events (AEs) were reported by 65% of the risankizumab group and 88% of the placebo group. Serious AEs were reported in 4 patients receiving risankizumab, none of which were considered related to the study medication.¹

Phase 2 Trial
A phase 2 comparator trial demonstrated noninferiority at higher dosages of risankizumab in comparison to the IL-12/IL-23 inhibitor ustekinumab.² Among 166 participants with moderate to severe plaque psoriasis, PASI 90 at week 12 was met by 77% of participants receiving 90 or 180 mg of risankizumab compared to 40% receiving ustekinumab (P<.001). Onset of activity with risankizumab was faster and the duration of effect longer vs ustekinumab; by week 8, at least PASI 75 was achieved by approximately 80% of participants in the 90-mg and 180-mg risankizumab groups compared to 60% in the ustekinumab group; PASI score reductions generally were maintained for as long as 20 weeks after the final dose of risankizumab was administered.²

Phase 3 Trials
The 52-week UltIMMa-1 and UltIMMa-2 phase 3 trials compared subcutaneous risankizumab (150 mg) to ustekinumab (45 or 90 mg [weight-based dosing]) or placebo administered at weeks 0, 4, 16, 28, and 40 in approximately 1000 patients with moderate to severe plaque psoriasis.³ Patients initially assigned to placebo switched to risankizumab 150 mg at week 16. At week 16, PASI 90 was achieved by 75.3% of risankizumab-treated patients, 42.0% of ustekinumab-treated patients, and 4.9% of placebo-treated patients in UltIMMa-1, and by 74.8% of risankizumab-treated patients, 47.5% of ustekinumab-treated patients, and 2.0% of placebo-treated patients in UltIMMa-2 (P<.0001 vs placebo and ustekinumab for both studies). Achievement of a static physician’s global assessment (sPGA) score of 0 or 1 at week 16 similarly favored risankizumab, with 87.8%, 63.0%, and 7.8% of patients in UltIMMa-1 meeting an sPGA score of 0 or 1 in the risankizumab, ustekinumab, and placebo groups, respectively, and 83.7%, 61.6%, and 5.1% in UltIMMa-2 meeting an sPGA score of 0 or 1 in the risankizumab, ustekinumab, and placebo groups, respectively (P<.0001 vs placebo and ustekinumab for both studies). Among patients initially assigned to risankizumab, improvements in PASI and sPGA continued to increase until week 52, with 81.9% achieving PASI 90 at week 52 compared to 44.0% on ustekinumab in UltIMMa-1, and 80.6% achieving PASI 90 at week 52 compared to 50.5% on ustekinumab in UltIMMa-2 (P<.0001 vs ustekinumab for both studies). Treatment-emergent AE profiles were similar for risankizumab and ustekinumab in both studies, and there were no unexpected safety findings.³

Risankizumab received FDA approval for the treatment of moderate to severe plaque psoriasis in April 2019.

Bimekizumab

Bimekizumab (UCB4940), a humanized IgG1 monoclonal antibody, selectively neutralizes the biologic functions of IL-17A and IL-17F, the latter of which has only recently been implicated in contributing to the psoriatic immune cascade.⁴

First-in-Human Study
Thirty-nine participants with mild psoriasis demonstrated efficacy after single-dose intravenous bimekizumab, with maximal improvements in all measures of disease activity observed between weeks 8 and 12 in participants receiving 160 to 640 mg.⁵

Proof-of-Concept Phase 1b Study
A subsequent trial of 53 participants with psoriatic arthritis demonstrated sustained efficacy to week 20 with varying dosages of intravenous bimekizumab.⁶ At week 8, PASI 100 was met by 86.7% of participants receiving the top 3 dosages of bimekizumab compared to none of the placebo-treated participants. Treatment-emergent AEs, including neutropenia and elevation of liver transaminases, were mostly mild to moderate and resolved spontaneously. There were 3 severe AEs and 3 serious AEs, none of which were related to treatment.⁶

Importantly, bimekizumab was shown in this small study to have the potential to be highly effective at treating psoriatic arthritis. American College of Rheumatology ACR20, ACR50, and ACR70 response criteria were very high, with an ACR20 of 80% and an ACR50 of 40%.⁶ Further trials are necessary to gather more data and confirm these findings; however, these levels of response are higher than those of any other biologic on the market.

Phase 2b Dose-Ranging Study
In this trial, 250 participants with moderate to severe plaque psoriasis received either 64 mg, 160 mg with a 320-mg loading dose, 320 mg, or 480 mg of subcutaneous bimekizumab or placebo at weeks 0, 4, and 8.⁷ At week 12, PASI 90 was achieved by significantly more patients in all bimekizumab-treated groups compared to the placebo group (46.2%–79.1% vs 0%; P<.0001 for all dosages); PASI 100 also was achieved by significantly more bimekizumab-treated patients (27.9%–60.0% vs 0%; P<.0002). Improvement began as early as week 4, with clinically meaningful responses observed in all bimekizumab groups across all measures of disease activity. Treatment-emergent AEs occurred more frequently in bimekizumab-treated participants (61%) than in placebo-treated participants (36%); the most common AEs were nasopharyngitis and upper respiratory tract infection. Of note, fungal infections were reported by 4.3% of participants receiving bimekizumab; all cases were localized superficial infection, and none led to discontinuation. Three serious AEs were reported, none of which were considered related to the study treatment.⁷

Mirikizumab

Mirikizumab (LY3074828) is a humanized IgG4 monoclonal antibody that selectively binds and inhibits the p19 subunit of IL-23, with no action on IL-12.

Phase 1 Trial
Mirikizumab was shown to improve PASI scores in patients with plaque psoriasis.⁸

Phase 2 Trial
Subsequently, a trial of 205 participants with moderate to severe plaque psoriasis compared 3 dosing regimens of subcutaneous mirikizumab—30, 100, or 300 mg—at weeks 0 and 8 compared to placebo.⁹ Primary end point results at week 16 demonstrated PASI 90 response rates of 0%, 29% (P=.009), 59% (P<.001), and 67% (P<.001) in the placebo, 30-mg, 100-mg, and 300-mg mirikizumab groups, respectively. Complete clearance of psoriasis, measured by PASI 100 and sPGA 0, was achieved by 0%, 16%, 31%, and 31%, respectively (P=.039 for 30 mg vs placebo; P=.007 for the higher dosage groups vs placebo). Response rates for all efficacy outcomes were statistically significantly higher for all mirikizumab treatment groups compared to placebo and were highest in the 100-mg and 300-mg treatment groups. Frequencies of participants reporting AEs were similar across treatment and placebo groups.⁹

Oral Medications

Only a few small-molecule, orally bioavailable therapies are on the market for the treatment of psoriasis, some of which are associated with unfavorable side-effect profiles that preclude long-term therapy.

BMS-986165
The intracellular signaling enzyme tyrosine kinase 2 is involved in functional responses of IL-12 and IL-23. BMS-986165, a potent oral inhibitor of tyrosine kinase 2 with greater selectivity than other tyrosine kinase inhibitors, demonstrated efficacy in a phase 2 trial of 267 participants with moderate to severe plaque psoriasis receiving any of 5 dosing regimens—3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, and 12 mg daily—compared to placebo.¹⁰ At week 12, the percentage of patients with a 75% or greater reduction in PASI was 7% with placebo, 9% with 3 mg every other day (P=.49 vs placebo), 39% with 3 mg daily (P<.001 vs placebo), 69% with 3 mg twice daily (P<.001 vs placebo), 67% with 6 mg twice daily (P<.001 vs placebo), and 75% with 12 mg once daily (P<.001 vs placebo). Adverse events occurred in 51% of patients in the placebo group and in 55% to 80% of BMS-986165–treated patients; the most common AEs were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection.¹⁰

A phase 3 trial comparing BMS-986165 with placebo and apremilast is underway (ClinicalTrials.gov Identifier NCT03611751).

Piclidenoson (CF101)
A novel small molecule that binds the Gi protein–associated A₃ adenosine receptor piclidenoson induces an anti-inflammatory response via deregulation of the Wnt and nuclear factor κB signal transduction pathways, leading to downregulation of proinflammatory cytokines, including IL-17 and IL-23.¹¹

In a phase 2 dose-ranging study, 75 patients with moderate to severe plaque psoriasis received varying dosages—1, 2, or 4 mg—of oral piclidenoson or placebo twice daily for 12 weeks.¹² Progressive improvement in the mean change from baseline PASI score was observed in the 2-mg group, with statistically significant differences at weeks 8 and 12 compared to placebo (P=.047 and P=.031, respectively). At week 12, 35.3% of the 2-mg group achieved at least PASI 50. Improvements in PASI were less pronounced in the 4-mg group, and no therapeutic benefit was observed in the 1-mg group. Of the 20 AEs reported, 15 possibly were related to the study drug; 1 AE was severe.¹²

In a subsequent phase 2/3 trial, patients with moderate to severe plaque psoriasis received piclidenoson—1 or 2 mg—or placebo twice daily.¹³ At week 12, PASI 75 was achieved by 8.5% of patients in the 2-mg group and by 6.9% of patients receiving placebo (P=.621), thereby not meeting the primary study end point. Results at week 32 were more encouraging. In the 2-mg group, PASI mean percentage improvement was 57% (P<.002) compared to baseline, with linear improvements observed in PASI 50 (63.5%), PASI 75 (35.5%), PASI 90 (24.7%), and PASI 100 (10.6%).¹³

A phase 3 trial comparing piclidenoson 2 and 3 mg to apremilast and placebo is in progress (ClinicalTrials.gov Identifier NCT03168256).

Future Directions

Despite abundant options for treating moderate to severe plaque psoriasis and psoriatic arthritis, the pipeline remains rich. Novel treatments might have improved efficacy, favorable safety profiles, and different modes of administration compared to current medications. In addition to the novel therapeutics covered here, several treatments are in development further down the pipeline, with only phase 1 or 2 data available. Remtolumab (ABT-122), a tumor necrosis factor α– and IL-17A–targeted immunoglobulin, is unique among biologics, given its dual inhibition of tumor necrosis factor α and IL-17A.¹⁴ M1095 (ALX-0761), a novel trivalent bispecific nanobody, is another intriguing candidate. This dual inhibitor of IL-17A/F might exhibit a number of advantages over conventional antibodies, including better tissue penetration, reduced immunogenicity, and a longer half-life (ClinicalTrials.gov Identifier NCT03384745).^15,16

As always with drug development, numerous medications that were under development failed to meet primary end points in phase 2 trials and have therefore been discontinued, including namilumab and prurisol. It is reassuring that the pace of drug discovery and development in psoriasis does not seem to be slowing; to our patients’ benefit, we will have an array of treatments available to tailor therapy to the individual.

Recent advances in our understanding of psoriatic immune pathways have led to new generations of targeted therapies developed over the last 5 years. Although the pathogenesis of psoriasis remains to be fully elucidated, the success of these targeted therapies has confirmed a critical role of the IL-23/helper T cell (T_H17) axis in maintaining the psoriatic immune cascade, a positive feedback loop in which IL-17, IL-12, and IL-23 released from myeloid dendritic cells lead to activation of helperT cells. Activated helper T cells—namely T_H1, T_H17, and T_H22—release IL-17, IL-22, and other proinflammatory cytokines, amplifying the immune response and leading to keratinocyte proliferation and immune cell migration to psoriatic lesions. Inhibition of IL-17 and IL-23 by several biologics disrupts this aberrant inflammatory cascade and has led to dramatic improvements in outcomes, particularly among patients with moderate to severe disease.

Numerous biologics targeting these pathways and several oral treatments have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis; in addition, a number of promising therapies are on the horizon, and knowledge of these medications might help guide our treatment approach to the patient with psoriasis. This article provides an update on the most recent (as of 2019) approved therapies and medications in the pipeline for moderate to severe plaque psoriasis, with a focus on systemic agents in phase 3 clinical trials. (Medications targeting psoriatic arthritis, biosimilars, and existing medications approved by the FDA prior to 2019 will not be discussed.)

Risankizumab

Risankizumab-rzaa (formerly BI 655066) is a humanized IgG1 monoclonal antibody that targets the p19 subunit of IL-23, selectively inhibiting the role of this critical cytokine in psoriatic inflammation.

Phase 1 Trial
In a phase 1 proof-of-concept study, 39 patients with moderate to severe plaque psoriasis received varying dosages of intravenous or subcutaneous risankizumab or placebo.¹ At week 12, the percentage of risankizumab-treated patients achieving reduction in the psoriasis area and severity index (PASI) score by 75% (PASI 75), 90% (PASI 90), and 100% (PASI 100) was 87% (27/31; P<.001 vs placebo), 58% (18/31; P=.007 vs placebo), and 16% (5/31; P=.590 vs placebo), respectively. Improvements in PASI scores were observed as early as week 2. Adverse events (AEs) were reported by 65% of the risankizumab group and 88% of the placebo group. Serious AEs were reported in 4 patients receiving risankizumab, none of which were considered related to the study medication.¹

Phase 2 Trial
A phase 2 comparator trial demonstrated noninferiority at higher dosages of risankizumab in comparison to the IL-12/IL-23 inhibitor ustekinumab.² Among 166 participants with moderate to severe plaque psoriasis, PASI 90 at week 12 was met by 77% of participants receiving 90 or 180 mg of risankizumab compared to 40% receiving ustekinumab (P<.001). Onset of activity with risankizumab was faster and the duration of effect longer vs ustekinumab; by week 8, at least PASI 75 was achieved by approximately 80% of participants in the 90-mg and 180-mg risankizumab groups compared to 60% in the ustekinumab group; PASI score reductions generally were maintained for as long as 20 weeks after the final dose of risankizumab was administered.²

Phase 3 Trials
The 52-week UltIMMa-1 and UltIMMa-2 phase 3 trials compared subcutaneous risankizumab (150 mg) to ustekinumab (45 or 90 mg [weight-based dosing]) or placebo administered at weeks 0, 4, 16, 28, and 40 in approximately 1000 patients with moderate to severe plaque psoriasis.³ Patients initially assigned to placebo switched to risankizumab 150 mg at week 16. At week 16, PASI 90 was achieved by 75.3% of risankizumab-treated patients, 42.0% of ustekinumab-treated patients, and 4.9% of placebo-treated patients in UltIMMa-1, and by 74.8% of risankizumab-treated patients, 47.5% of ustekinumab-treated patients, and 2.0% of placebo-treated patients in UltIMMa-2 (P<.0001 vs placebo and ustekinumab for both studies). Achievement of a static physician’s global assessment (sPGA) score of 0 or 1 at week 16 similarly favored risankizumab, with 87.8%, 63.0%, and 7.8% of patients in UltIMMa-1 meeting an sPGA score of 0 or 1 in the risankizumab, ustekinumab, and placebo groups, respectively, and 83.7%, 61.6%, and 5.1% in UltIMMa-2 meeting an sPGA score of 0 or 1 in the risankizumab, ustekinumab, and placebo groups, respectively (P<.0001 vs placebo and ustekinumab for both studies). Among patients initially assigned to risankizumab, improvements in PASI and sPGA continued to increase until week 52, with 81.9% achieving PASI 90 at week 52 compared to 44.0% on ustekinumab in UltIMMa-1, and 80.6% achieving PASI 90 at week 52 compared to 50.5% on ustekinumab in UltIMMa-2 (P<.0001 vs ustekinumab for both studies). Treatment-emergent AE profiles were similar for risankizumab and ustekinumab in both studies, and there were no unexpected safety findings.³

Risankizumab received FDA approval for the treatment of moderate to severe plaque psoriasis in April 2019.

Bimekizumab

Bimekizumab (UCB4940), a humanized IgG1 monoclonal antibody, selectively neutralizes the biologic functions of IL-17A and IL-17F, the latter of which has only recently been implicated in contributing to the psoriatic immune cascade.⁴

First-in-Human Study
Thirty-nine participants with mild psoriasis demonstrated efficacy after single-dose intravenous bimekizumab, with maximal improvements in all measures of disease activity observed between weeks 8 and 12 in participants receiving 160 to 640 mg.⁵

Proof-of-Concept Phase 1b Study
A subsequent trial of 53 participants with psoriatic arthritis demonstrated sustained efficacy to week 20 with varying dosages of intravenous bimekizumab.⁶ At week 8, PASI 100 was met by 86.7% of participants receiving the top 3 dosages of bimekizumab compared to none of the placebo-treated participants. Treatment-emergent AEs, including neutropenia and elevation of liver transaminases, were mostly mild to moderate and resolved spontaneously. There were 3 severe AEs and 3 serious AEs, none of which were related to treatment.⁶

Importantly, bimekizumab was shown in this small study to have the potential to be highly effective at treating psoriatic arthritis. American College of Rheumatology ACR20, ACR50, and ACR70 response criteria were very high, with an ACR20 of 80% and an ACR50 of 40%.⁶ Further trials are necessary to gather more data and confirm these findings; however, these levels of response are higher than those of any other biologic on the market.

Phase 2b Dose-Ranging Study
In this trial, 250 participants with moderate to severe plaque psoriasis received either 64 mg, 160 mg with a 320-mg loading dose, 320 mg, or 480 mg of subcutaneous bimekizumab or placebo at weeks 0, 4, and 8.⁷ At week 12, PASI 90 was achieved by significantly more patients in all bimekizumab-treated groups compared to the placebo group (46.2%–79.1% vs 0%; P<.0001 for all dosages); PASI 100 also was achieved by significantly more bimekizumab-treated patients (27.9%–60.0% vs 0%; P<.0002). Improvement began as early as week 4, with clinically meaningful responses observed in all bimekizumab groups across all measures of disease activity. Treatment-emergent AEs occurred more frequently in bimekizumab-treated participants (61%) than in placebo-treated participants (36%); the most common AEs were nasopharyngitis and upper respiratory tract infection. Of note, fungal infections were reported by 4.3% of participants receiving bimekizumab; all cases were localized superficial infection, and none led to discontinuation. Three serious AEs were reported, none of which were considered related to the study treatment.⁷

Mirikizumab

Mirikizumab (LY3074828) is a humanized IgG4 monoclonal antibody that selectively binds and inhibits the p19 subunit of IL-23, with no action on IL-12.

Phase 1 Trial
Mirikizumab was shown to improve PASI scores in patients with plaque psoriasis.⁸

Phase 2 Trial
Subsequently, a trial of 205 participants with moderate to severe plaque psoriasis compared 3 dosing regimens of subcutaneous mirikizumab—30, 100, or 300 mg—at weeks 0 and 8 compared to placebo.⁹ Primary end point results at week 16 demonstrated PASI 90 response rates of 0%, 29% (P=.009), 59% (P<.001), and 67% (P<.001) in the placebo, 30-mg, 100-mg, and 300-mg mirikizumab groups, respectively. Complete clearance of psoriasis, measured by PASI 100 and sPGA 0, was achieved by 0%, 16%, 31%, and 31%, respectively (P=.039 for 30 mg vs placebo; P=.007 for the higher dosage groups vs placebo). Response rates for all efficacy outcomes were statistically significantly higher for all mirikizumab treatment groups compared to placebo and were highest in the 100-mg and 300-mg treatment groups. Frequencies of participants reporting AEs were similar across treatment and placebo groups.⁹

Oral Medications

Only a few small-molecule, orally bioavailable therapies are on the market for the treatment of psoriasis, some of which are associated with unfavorable side-effect profiles that preclude long-term therapy.

BMS-986165
The intracellular signaling enzyme tyrosine kinase 2 is involved in functional responses of IL-12 and IL-23. BMS-986165, a potent oral inhibitor of tyrosine kinase 2 with greater selectivity than other tyrosine kinase inhibitors, demonstrated efficacy in a phase 2 trial of 267 participants with moderate to severe plaque psoriasis receiving any of 5 dosing regimens—3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, and 12 mg daily—compared to placebo.¹⁰ At week 12, the percentage of patients with a 75% or greater reduction in PASI was 7% with placebo, 9% with 3 mg every other day (P=.49 vs placebo), 39% with 3 mg daily (P<.001 vs placebo), 69% with 3 mg twice daily (P<.001 vs placebo), 67% with 6 mg twice daily (P<.001 vs placebo), and 75% with 12 mg once daily (P<.001 vs placebo). Adverse events occurred in 51% of patients in the placebo group and in 55% to 80% of BMS-986165–treated patients; the most common AEs were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection.¹⁰

A phase 3 trial comparing BMS-986165 with placebo and apremilast is underway (ClinicalTrials.gov Identifier NCT03611751).

Piclidenoson (CF101)
A novel small molecule that binds the Gi protein–associated A₃ adenosine receptor piclidenoson induces an anti-inflammatory response via deregulation of the Wnt and nuclear factor κB signal transduction pathways, leading to downregulation of proinflammatory cytokines, including IL-17 and IL-23.¹¹

In a phase 2 dose-ranging study, 75 patients with moderate to severe plaque psoriasis received varying dosages—1, 2, or 4 mg—of oral piclidenoson or placebo twice daily for 12 weeks.¹² Progressive improvement in the mean change from baseline PASI score was observed in the 2-mg group, with statistically significant differences at weeks 8 and 12 compared to placebo (P=.047 and P=.031, respectively). At week 12, 35.3% of the 2-mg group achieved at least PASI 50. Improvements in PASI were less pronounced in the 4-mg group, and no therapeutic benefit was observed in the 1-mg group. Of the 20 AEs reported, 15 possibly were related to the study drug; 1 AE was severe.¹²

In a subsequent phase 2/3 trial, patients with moderate to severe plaque psoriasis received piclidenoson—1 or 2 mg—or placebo twice daily.¹³ At week 12, PASI 75 was achieved by 8.5% of patients in the 2-mg group and by 6.9% of patients receiving placebo (P=.621), thereby not meeting the primary study end point. Results at week 32 were more encouraging. In the 2-mg group, PASI mean percentage improvement was 57% (P<.002) compared to baseline, with linear improvements observed in PASI 50 (63.5%), PASI 75 (35.5%), PASI 90 (24.7%), and PASI 100 (10.6%).¹³

A phase 3 trial comparing piclidenoson 2 and 3 mg to apremilast and placebo is in progress (ClinicalTrials.gov Identifier NCT03168256).

Future Directions

Despite abundant options for treating moderate to severe plaque psoriasis and psoriatic arthritis, the pipeline remains rich. Novel treatments might have improved efficacy, favorable safety profiles, and different modes of administration compared to current medications. In addition to the novel therapeutics covered here, several treatments are in development further down the pipeline, with only phase 1 or 2 data available. Remtolumab (ABT-122), a tumor necrosis factor α– and IL-17A–targeted immunoglobulin, is unique among biologics, given its dual inhibition of tumor necrosis factor α and IL-17A.¹⁴ M1095 (ALX-0761), a novel trivalent bispecific nanobody, is another intriguing candidate. This dual inhibitor of IL-17A/F might exhibit a number of advantages over conventional antibodies, including better tissue penetration, reduced immunogenicity, and a longer half-life (ClinicalTrials.gov Identifier NCT03384745).^15,16

As always with drug development, numerous medications that were under development failed to meet primary end points in phase 2 trials and have therefore been discontinued, including namilumab and prurisol. It is reassuring that the pace of drug discovery and development in psoriasis does not seem to be slowing; to our patients’ benefit, we will have an array of treatments available to tailor therapy to the individual.

Patients experiencing sacroiliac joint (SIJ) dysfunction might show symptoms that overlap with those seen in lumbar spine pathology. This article reviews diagnostic tools that assist practitioners to discern the true pain generator in patients with low back pain (LBP) and therapeutic approaches when the cause is SIJ dysfunction.

Prevalence

Most of the US population will experience LBP at some point in their lives. A 2002 National Health Interview survey found that more than one-quarter (26.4%) of 31 044 respondents had complained of LBP in the previous 3 months.¹ About 74 million individuals in the US experienced LBP in the past 3 months.¹ A full 10% of the US population is expected to suffer from chronic LBP, and it is estimated that 2.3% of all visits to physicians are related to LBP.¹

The etiology of LBP often is unclear even after thorough clinical and radiographic evaluation because of the myriad possible mechanisms. Degenerative disc disease, facet arthropathy, ligamentous hypertrophy, muscle spasm, hip arthropathy, and SIJ dysfunction are potential pain generators and exact clinical and radiographic correlation is not always possible. Compounding this difficulty is the lack of specificity with current diagnostic techniques. For example, many patients will have disc desiccation or herniation without any LBP or radicular symptoms on radiographic studies, such as X-rays, computed tomography (CT), and magnetic resonance imaging (MRI). As such, providers of patients with diffuse radiographic abnormalities often have to identify a specific pain generator, which might not have any role in the patient’s pain.

Other tests, such as electromyographic studies, positron emission tomography (PET) scans, discography, and epidural steroid injections, can help pinpoint a specific pain generator. These tests might help determine whether the patient has a surgically treatable condition and could help predict whether a patient’s symptoms will respond to surgery.

However, the standard spine surgery workup often fails to identify an obvious pain generator in many individuals. The significant number of patients that fall into this category has prompted spine surgeons to consider other potential etiologies for LBP, and SIJ dysfunction has become a rapidly developing field of research.

Sacroiliac Joint Dysfunction

The SIJ is a bilateral, C-shaped synovial joint surrounded by a fibrous capsule and affixes the sacrum to the ilia. Several sacral ligaments and pelvic muscles support the SIJ. The L5 nerve ventral ramus and lumbosacral trunk pass anteriorly and the S1 nerve ventral ramus passes inferiorly to the joint capsule. The SIJ is innervated by the dorsal rami of L4-S3 nerve roots, transmitting nociception and temperature. Mechanisms of injury to the SIJ could arise from intra- and extra-articular etiologies, including capsular disruption, ligamentous tension, muscular inflammation, shearing, fractures, arthritis, and infection.² Patients could develop SIJ pain spontaneously or after a traumatic event or repetitive shear.³ Risk factors for developing SIJ dysfunction include a history of lumbar fusion, scoliosis, leg length discrepancies, sustained athletic activity, pregnancy, seronegative HLA-B27 spondyloarthropathies, or gait abnormalities. Inflammation of the SIJ and surrounding structures secondary to an environmental insult in susceptible individuals is a common theme among these etiologies.²

Pain from the SIJ is localized to an area of approximately 3 cm × 10 cm that is inferior to the ipsilateral posterior superior iliac spine.⁴ Referred pain maps from SIJ dysfunction extend in the L5-S1 nerve distributions, commonly seen in the buttocks, groin, posterior thigh, and lower leg with radicular symptoms. However, this pain distribution demonstrates extensive variability among patients and bears strong similarities to discogenic or facet joint sources of LBP.^5-7 Direct communication has been shown between the SIJ and adjacent neural structures, namely the L5 nerve, sacral foramina, and the lumbosacral plexus. These direct pathways could explain an inflammatory mechanism for lower extremity symptoms seen in SIJ dysfunction.⁸

The prevalence of SIJ dysfunction among patients with LBP is estimated to be 15% to 30%, an extraordinary number given the total number of patients presenting with LBP every year.⁹ These patients might represent a significant segment of patients with an unrevealing standard spine evaluation. Despite the large number of patients who experience SIJ dysfunction, there is disagreement about optimal methods for diagnosis and treatment.

Diagnosis

The International Association for the Study of Pain has proposed criteria for evaluating patients who have suspected SIJ dysfunction: Pain must be in the SIJ area, should be reproducible by performing specific provocative maneuvers, and must be relieved by injection of local anesthetic into the SIJ.¹⁰ These criteria provide a sound foundation, but in clinical practice, patients often defy categorization.

The presence of pain in the area inferior to the posterior superior iliac spine and lateral to the gluteal fold with pain referral patterns in the L5-S1 nerve distributions is highly sensitive for identifying patients with SIJ dysfunction. Furthermore, pain arising from the SIJ will not be above the level of the L5 nerve sensory distribution. However, this diagnostic finding alone is not specific and might represent other etiologies known to produce similar pain, such as intervertebral discs and facet joints. Patients with SIJ dysfunction often describe their pain as sciatica-like, recurrent, and triggered with bending or twisting motions. It is worsened with any activity loading the SIJ, such as walking, climbing stairs, standing, or sitting upright. SIJ pain might be accompanied by dyspareunia and changes in bladder function because of the nerves involved.¹¹

The use of provocative maneuvers for testing SIJ dysfunction is controversial because of the high rate of false positives and the inability to distinguish whether the SIJ or an adjacent structure is affected. However, the diagnostic utility of specific stress tests has been studied, and clusters of tests are recommended if a health care provider (HCP) suspects SIJ dysfunction. A diagnostic algorithm should first focus on using the distraction test and the thigh thrust test. Distraction is done by applying vertically oriented pressure to the anterior superior iliac spine while aiming posteriorly, therefore distracting the SIJ. During the thigh thrust test the examiner fixates the patient’s sacrum against the table with the left hand and applies a vertical force through the line of the femur aiming posteriorly, producing a posterior shearing force at the SIJ. Studies show that the thigh thrust test is the most sensitive, and the distraction test is the most specific. If both tests are positive, there is reasonable evidence to suggest SIJ dysfunction as the source of LBP.

If there are not 2 positive results, the addition of the compression test, followed by the sacral thrust test also can point to the diagnosis. The compression test is performed with vertical downward force applied to the iliac crest with the patient lying on each side, compressing the SIJ by transverse pressure across the pelvis. The sacral thrust test is performed with vertical force applied to the midline posterior sacrum at its apex directed anteriorly with the patient lying prone, producing a shearing force at the SIJs. The Gaenslen test uses a torsion force by applying a superior and posterior force to the right knee and posteriorly directed force to the left knee. Omitting the Gaenslen test has not been shown to compromise diagnostic efficacy of the other tests and can be safely excluded.¹²

A HCP can rule out SIJ dysfunction if these provocation tests are negative. However, the diagnostic predictive value of these tests is subject to variability among HCPs, and their reliability is increased when used in clusters.^9,13

Imaging for the SIJ should begin with anterior/posterior, oblique, and lateral view plain X-rays of the pelvis (Figures 1 and 2), which will rule out other pathologies by identifying other sources of LBP, such as spondylolisthesis or hip osteoarthritis. HCPs should obtain lumbar and pelvis CT images to identify inflammatory or degenerative changes within the SIJ. CT images provide the high resolution that is needed to identify pathologies, such as fractures and tumors within the pelvic ring that could cause similar pain. MRI does not reliably depict a dysfunctional ligamentous apparatus within the SIJ; however, it can help identify inflammatory sacroiliitis, such as is seen in the spondyloarthropathies.^11,14 Recent studies show combined single photon emission tomography and CT (SPECT-CT) might be the most promising imaging modality to reveal mechanical failure of load transfer with increased scintigraphic uptake in the posterior and superior SIJ ligamentous attachments. The joint loses its characteristic “dumbbell” shape in affected patients with about 50% higher uptake than unaffected joints. These findings were evident in patients who experienced pelvic trauma or during the peripartum period.^15,16

Fluoroscopy-guided intra-articular injection of a local anesthetic (lidocaine) and/or a corticosteroid (triamcinolone) has the dual functionality of diagnosis and treatment (Figure 3). It often is considered the most reliable method to diagnose SIJ dysfunction and has the benefit of pain relief for up to 1 year. However, intra-articular injections lack diagnostic validity because the solution often extravasates to extracapsular structures. This confounds the source of the pain and makes it difficult to interpret these diagnostic injections. In addition, the injection might not reach the entire SIJ capsule and could result in a false-negative diagnosis.^17,18 Periarticular injections have been shown to result in better pain relief in patients diagnosed with SIJ dysfunction than intra-articular injections. Periarticular injections also are easier to perform and could be a first-step option for these patients.¹⁹

Treatment

Nonoperative management of SIJ dysfunction includes exercise programs, physical therapy, manual manipulation therapy, sacroiliac belts, and periodic articular injections. Efficacy of these methods is variable, and analgesics often do not significantly benefit this type of pain. Another nonoperative approach is radiofrequency ablation (RFA) of the lumbar dorsal rami and lateral sacral branches, which can vary based on the number of rami treated as well as the technique used. About two-thirds of patients report pain relief after RFA.2 When successful, pain is relieved for 6 to 12 months, which is a temporary yet effective option for patients experiencing SIJ dysfunction.^14,20

Fusion Surgery

Cadaver studies show that biomechanical stabilization of the SIJ leads to decreased range of motion in flexion/extension, lateral bending, and axial rotation. This results in a decreased need for periarticular muscular and ligamentous support, therefore facilitating load transfer across the SIJ.^21,22 Patients undergoing minimally invasive surgery report better pain relief compared with those receiving open surgery at 12 months postoperatively.²³ The 2 main SIJ fusion approaches used are the lateral transarticular and the dorsal approaches. In the dorsal approach, the SIJ is distracted and allograft dowels or titanium cages with graft are inserted into the joint space posteriorly through the back. When approaching laterally, hollow screw implants filled with graft or triangular titanium implants are placed across the joint, accessing the SIJ through the iliac bones using imaging guidance. This lateral transiliac approach using porous titanium triangular rods currently is the most studied technique.²⁴

A recent prospective, multicenter trial included 423 patients with SIJ dysfunction who were randomized to receive SIJ fusion with triangular titanium implants vs a control group who received nonoperative management. Patients in the SIJ fusion group showed substantially greater improvement in pain (81.4%) compared with that of the nonoperative group (26.1%) 6 months after surgery. Pain relief in the SIJ fusion group was maintained at > 80% at 1 and 2 year follow-up, while the nonoperative group’s pain relief decreased to < 10% at the follow-ups. Measures of quality of life and disability also improved for the SIJ fusion group compared with that of the nonoperative group. Patients who were crossed over from conservative management to SIJ fusion after 6 months demonstrated improvements that were similar to those in the SIJ fusion group by the end of the study. Only 3% of patients required surgical revision. The strongest predictor of pain relief after surgery was a diagnostic SIJ anesthetic block of 30 to 60 minutes, which resulted in > 75% pain reduction.^21,25 Additional predictors of successful SIJ fusion include nonsmokers, nonopioid users, and older patients who have a longer time course of SIJ pain.²⁶

Another study investigating the outcomes of SIJ fusion, RFA, and conservative management with a 6-year follow-up demonstrated similar results.²⁷ This further confirms the durability of the surgical group’s outcome, which sustained significant improvement compared with RFA and conservative management group in pain relief, daily function, and opioid use.

HCPs should consider SIJ fusion for patients who have at least 6 months of unsuccessful nonoperative management, significant SIJ pain (> 5 in a 10-point scale), ≥ 3 positive provocation tests, and at least 50% pain relief (> 75% preferred) with diagnostic intra-articular anesthetic injection.¹⁴ It is reasonable for primary care providers to refer these patients to a neurosurgeon or orthopedic spine surgeon for possible fusion. Patients with earlier lumbar/lumbosacral spinal fusions and persistent LBP should be evaluated for potential SIJ dysfunction. SIJ dysfunction after lumbosacral fusion could be considered a form of distal pseudarthrosis resulting from increased motion at the joint. One study found its incidence correlated with the number of segments fused in the lumbar spine.²⁸ Another study found that about one-third of patients with persistent LBP after lumbosacral fusion could be attributed to SIJ dysfunction.²⁹

Case Presentation

A 27-year-old female army veteran presented with bilateral buttock pain, which she described as a dull, aching pain across her sacral region, 8 out of 10 in severity. The pain was in a L5-S1 pattern. The pain was bilateral, with the right side worse than the left, and worsened with lateral bending and load transferring. She reported no numbness, tingling, or weakness.

On physical examination, she had full strength in her lower extremities and intact sensation. She reported tenderness to palpation of the sacrum and SIJ. Her gait was normal. The patient had positive thigh thrust and distraction tests. Lumbar spine X-ray, CT, MRI, and electromyographic studies did not show any pathology. She described little or no relief with analgesics or physical therapy. Previous L4-L5 and L5-S1 facet anesthetic injections and transforaminal epidural steroid injections provided minimal pain relief immediately after the procedures. Bilateral SIJ anesthetic injections under fluoroscopic guidance decreased her pain severity from a 7 to 3 out of 10 for 2 to 3 months before returning to her baseline. Radiofrequency ablation of the right SIJ under fluoroscopy provided moderate relief for about 4 months.

After exhausting nonoperative management for SIJ dysfunction without adequate pain control, the patient was referred to neurosurgery for surgical fusion. The patient was deemed an appropriate surgical candidate and underwent a right-sided SIJ fusion (Figures 4 and 5). At her 6-month and 1-year follow-up appointments, she had lasting pain relief, 2 out of 10.

Conclusion

SIJ dysfunction is widely overlooked because of the difficulty in distinguishing it from other similarly presenting syndromes. However, with a detailed history, appropriate physical maneuvers, imaging, and adequate response to intra-articular anesthetic, providers can reach an accurate diagnosis that will inform subsequent treatments. After failure of nonsurgical methods, patients with SIJ dysfunction should be considered for minimally invasive fusion techniques, which have proven to be a safe, effective, and viable treatment option.

Patients experiencing sacroiliac joint (SIJ) dysfunction might show symptoms that overlap with those seen in lumbar spine pathology. This article reviews diagnostic tools that assist practitioners to discern the true pain generator in patients with low back pain (LBP) and therapeutic approaches when the cause is SIJ dysfunction.

Prevalence

Most of the US population will experience LBP at some point in their lives. A 2002 National Health Interview survey found that more than one-quarter (26.4%) of 31 044 respondents had complained of LBP in the previous 3 months.¹ About 74 million individuals in the US experienced LBP in the past 3 months.¹ A full 10% of the US population is expected to suffer from chronic LBP, and it is estimated that 2.3% of all visits to physicians are related to LBP.¹

The etiology of LBP often is unclear even after thorough clinical and radiographic evaluation because of the myriad possible mechanisms. Degenerative disc disease, facet arthropathy, ligamentous hypertrophy, muscle spasm, hip arthropathy, and SIJ dysfunction are potential pain generators and exact clinical and radiographic correlation is not always possible. Compounding this difficulty is the lack of specificity with current diagnostic techniques. For example, many patients will have disc desiccation or herniation without any LBP or radicular symptoms on radiographic studies, such as X-rays, computed tomography (CT), and magnetic resonance imaging (MRI). As such, providers of patients with diffuse radiographic abnormalities often have to identify a specific pain generator, which might not have any role in the patient’s pain.

Other tests, such as electromyographic studies, positron emission tomography (PET) scans, discography, and epidural steroid injections, can help pinpoint a specific pain generator. These tests might help determine whether the patient has a surgically treatable condition and could help predict whether a patient’s symptoms will respond to surgery.

However, the standard spine surgery workup often fails to identify an obvious pain generator in many individuals. The significant number of patients that fall into this category has prompted spine surgeons to consider other potential etiologies for LBP, and SIJ dysfunction has become a rapidly developing field of research.

Sacroiliac Joint Dysfunction

The SIJ is a bilateral, C-shaped synovial joint surrounded by a fibrous capsule and affixes the sacrum to the ilia. Several sacral ligaments and pelvic muscles support the SIJ. The L5 nerve ventral ramus and lumbosacral trunk pass anteriorly and the S1 nerve ventral ramus passes inferiorly to the joint capsule. The SIJ is innervated by the dorsal rami of L4-S3 nerve roots, transmitting nociception and temperature. Mechanisms of injury to the SIJ could arise from intra- and extra-articular etiologies, including capsular disruption, ligamentous tension, muscular inflammation, shearing, fractures, arthritis, and infection.² Patients could develop SIJ pain spontaneously or after a traumatic event or repetitive shear.³ Risk factors for developing SIJ dysfunction include a history of lumbar fusion, scoliosis, leg length discrepancies, sustained athletic activity, pregnancy, seronegative HLA-B27 spondyloarthropathies, or gait abnormalities. Inflammation of the SIJ and surrounding structures secondary to an environmental insult in susceptible individuals is a common theme among these etiologies.²

Pain from the SIJ is localized to an area of approximately 3 cm × 10 cm that is inferior to the ipsilateral posterior superior iliac spine.⁴ Referred pain maps from SIJ dysfunction extend in the L5-S1 nerve distributions, commonly seen in the buttocks, groin, posterior thigh, and lower leg with radicular symptoms. However, this pain distribution demonstrates extensive variability among patients and bears strong similarities to discogenic or facet joint sources of LBP.^5-7 Direct communication has been shown between the SIJ and adjacent neural structures, namely the L5 nerve, sacral foramina, and the lumbosacral plexus. These direct pathways could explain an inflammatory mechanism for lower extremity symptoms seen in SIJ dysfunction.⁸

The prevalence of SIJ dysfunction among patients with LBP is estimated to be 15% to 30%, an extraordinary number given the total number of patients presenting with LBP every year.⁹ These patients might represent a significant segment of patients with an unrevealing standard spine evaluation. Despite the large number of patients who experience SIJ dysfunction, there is disagreement about optimal methods for diagnosis and treatment.

Diagnosis

The International Association for the Study of Pain has proposed criteria for evaluating patients who have suspected SIJ dysfunction: Pain must be in the SIJ area, should be reproducible by performing specific provocative maneuvers, and must be relieved by injection of local anesthetic into the SIJ.¹⁰ These criteria provide a sound foundation, but in clinical practice, patients often defy categorization.

The presence of pain in the area inferior to the posterior superior iliac spine and lateral to the gluteal fold with pain referral patterns in the L5-S1 nerve distributions is highly sensitive for identifying patients with SIJ dysfunction. Furthermore, pain arising from the SIJ will not be above the level of the L5 nerve sensory distribution. However, this diagnostic finding alone is not specific and might represent other etiologies known to produce similar pain, such as intervertebral discs and facet joints. Patients with SIJ dysfunction often describe their pain as sciatica-like, recurrent, and triggered with bending or twisting motions. It is worsened with any activity loading the SIJ, such as walking, climbing stairs, standing, or sitting upright. SIJ pain might be accompanied by dyspareunia and changes in bladder function because of the nerves involved.¹¹

The use of provocative maneuvers for testing SIJ dysfunction is controversial because of the high rate of false positives and the inability to distinguish whether the SIJ or an adjacent structure is affected. However, the diagnostic utility of specific stress tests has been studied, and clusters of tests are recommended if a health care provider (HCP) suspects SIJ dysfunction. A diagnostic algorithm should first focus on using the distraction test and the thigh thrust test. Distraction is done by applying vertically oriented pressure to the anterior superior iliac spine while aiming posteriorly, therefore distracting the SIJ. During the thigh thrust test the examiner fixates the patient’s sacrum against the table with the left hand and applies a vertical force through the line of the femur aiming posteriorly, producing a posterior shearing force at the SIJ. Studies show that the thigh thrust test is the most sensitive, and the distraction test is the most specific. If both tests are positive, there is reasonable evidence to suggest SIJ dysfunction as the source of LBP.

If there are not 2 positive results, the addition of the compression test, followed by the sacral thrust test also can point to the diagnosis. The compression test is performed with vertical downward force applied to the iliac crest with the patient lying on each side, compressing the SIJ by transverse pressure across the pelvis. The sacral thrust test is performed with vertical force applied to the midline posterior sacrum at its apex directed anteriorly with the patient lying prone, producing a shearing force at the SIJs. The Gaenslen test uses a torsion force by applying a superior and posterior force to the right knee and posteriorly directed force to the left knee. Omitting the Gaenslen test has not been shown to compromise diagnostic efficacy of the other tests and can be safely excluded.¹²

A HCP can rule out SIJ dysfunction if these provocation tests are negative. However, the diagnostic predictive value of these tests is subject to variability among HCPs, and their reliability is increased when used in clusters.^9,13

Imaging for the SIJ should begin with anterior/posterior, oblique, and lateral view plain X-rays of the pelvis (Figures 1 and 2), which will rule out other pathologies by identifying other sources of LBP, such as spondylolisthesis or hip osteoarthritis. HCPs should obtain lumbar and pelvis CT images to identify inflammatory or degenerative changes within the SIJ. CT images provide the high resolution that is needed to identify pathologies, such as fractures and tumors within the pelvic ring that could cause similar pain. MRI does not reliably depict a dysfunctional ligamentous apparatus within the SIJ; however, it can help identify inflammatory sacroiliitis, such as is seen in the spondyloarthropathies.^11,14 Recent studies show combined single photon emission tomography and CT (SPECT-CT) might be the most promising imaging modality to reveal mechanical failure of load transfer with increased scintigraphic uptake in the posterior and superior SIJ ligamentous attachments. The joint loses its characteristic “dumbbell” shape in affected patients with about 50% higher uptake than unaffected joints. These findings were evident in patients who experienced pelvic trauma or during the peripartum period.^15,16

Fluoroscopy-guided intra-articular injection of a local anesthetic (lidocaine) and/or a corticosteroid (triamcinolone) has the dual functionality of diagnosis and treatment (Figure 3). It often is considered the most reliable method to diagnose SIJ dysfunction and has the benefit of pain relief for up to 1 year. However, intra-articular injections lack diagnostic validity because the solution often extravasates to extracapsular structures. This confounds the source of the pain and makes it difficult to interpret these diagnostic injections. In addition, the injection might not reach the entire SIJ capsule and could result in a false-negative diagnosis.^17,18 Periarticular injections have been shown to result in better pain relief in patients diagnosed with SIJ dysfunction than intra-articular injections. Periarticular injections also are easier to perform and could be a first-step option for these patients.¹⁹

Treatment

Nonoperative management of SIJ dysfunction includes exercise programs, physical therapy, manual manipulation therapy, sacroiliac belts, and periodic articular injections. Efficacy of these methods is variable, and analgesics often do not significantly benefit this type of pain. Another nonoperative approach is radiofrequency ablation (RFA) of the lumbar dorsal rami and lateral sacral branches, which can vary based on the number of rami treated as well as the technique used. About two-thirds of patients report pain relief after RFA.2 When successful, pain is relieved for 6 to 12 months, which is a temporary yet effective option for patients experiencing SIJ dysfunction.^14,20

Fusion Surgery

Cadaver studies show that biomechanical stabilization of the SIJ leads to decreased range of motion in flexion/extension, lateral bending, and axial rotation. This results in a decreased need for periarticular muscular and ligamentous support, therefore facilitating load transfer across the SIJ.^21,22 Patients undergoing minimally invasive surgery report better pain relief compared with those receiving open surgery at 12 months postoperatively.²³ The 2 main SIJ fusion approaches used are the lateral transarticular and the dorsal approaches. In the dorsal approach, the SIJ is distracted and allograft dowels or titanium cages with graft are inserted into the joint space posteriorly through the back. When approaching laterally, hollow screw implants filled with graft or triangular titanium implants are placed across the joint, accessing the SIJ through the iliac bones using imaging guidance. This lateral transiliac approach using porous titanium triangular rods currently is the most studied technique.²⁴

A recent prospective, multicenter trial included 423 patients with SIJ dysfunction who were randomized to receive SIJ fusion with triangular titanium implants vs a control group who received nonoperative management. Patients in the SIJ fusion group showed substantially greater improvement in pain (81.4%) compared with that of the nonoperative group (26.1%) 6 months after surgery. Pain relief in the SIJ fusion group was maintained at > 80% at 1 and 2 year follow-up, while the nonoperative group’s pain relief decreased to < 10% at the follow-ups. Measures of quality of life and disability also improved for the SIJ fusion group compared with that of the nonoperative group. Patients who were crossed over from conservative management to SIJ fusion after 6 months demonstrated improvements that were similar to those in the SIJ fusion group by the end of the study. Only 3% of patients required surgical revision. The strongest predictor of pain relief after surgery was a diagnostic SIJ anesthetic block of 30 to 60 minutes, which resulted in > 75% pain reduction.^21,25 Additional predictors of successful SIJ fusion include nonsmokers, nonopioid users, and older patients who have a longer time course of SIJ pain.²⁶

Another study investigating the outcomes of SIJ fusion, RFA, and conservative management with a 6-year follow-up demonstrated similar results.²⁷ This further confirms the durability of the surgical group’s outcome, which sustained significant improvement compared with RFA and conservative management group in pain relief, daily function, and opioid use.

HCPs should consider SIJ fusion for patients who have at least 6 months of unsuccessful nonoperative management, significant SIJ pain (> 5 in a 10-point scale), ≥ 3 positive provocation tests, and at least 50% pain relief (> 75% preferred) with diagnostic intra-articular anesthetic injection.¹⁴ It is reasonable for primary care providers to refer these patients to a neurosurgeon or orthopedic spine surgeon for possible fusion. Patients with earlier lumbar/lumbosacral spinal fusions and persistent LBP should be evaluated for potential SIJ dysfunction. SIJ dysfunction after lumbosacral fusion could be considered a form of distal pseudarthrosis resulting from increased motion at the joint. One study found its incidence correlated with the number of segments fused in the lumbar spine.²⁸ Another study found that about one-third of patients with persistent LBP after lumbosacral fusion could be attributed to SIJ dysfunction.²⁹

Case Presentation

A 27-year-old female army veteran presented with bilateral buttock pain, which she described as a dull, aching pain across her sacral region, 8 out of 10 in severity. The pain was in a L5-S1 pattern. The pain was bilateral, with the right side worse than the left, and worsened with lateral bending and load transferring. She reported no numbness, tingling, or weakness.

On physical examination, she had full strength in her lower extremities and intact sensation. She reported tenderness to palpation of the sacrum and SIJ. Her gait was normal. The patient had positive thigh thrust and distraction tests. Lumbar spine X-ray, CT, MRI, and electromyographic studies did not show any pathology. She described little or no relief with analgesics or physical therapy. Previous L4-L5 and L5-S1 facet anesthetic injections and transforaminal epidural steroid injections provided minimal pain relief immediately after the procedures. Bilateral SIJ anesthetic injections under fluoroscopic guidance decreased her pain severity from a 7 to 3 out of 10 for 2 to 3 months before returning to her baseline. Radiofrequency ablation of the right SIJ under fluoroscopy provided moderate relief for about 4 months.

After exhausting nonoperative management for SIJ dysfunction without adequate pain control, the patient was referred to neurosurgery for surgical fusion. The patient was deemed an appropriate surgical candidate and underwent a right-sided SIJ fusion (Figures 4 and 5). At her 6-month and 1-year follow-up appointments, she had lasting pain relief, 2 out of 10.

Conclusion

SIJ dysfunction is widely overlooked because of the difficulty in distinguishing it from other similarly presenting syndromes. However, with a detailed history, appropriate physical maneuvers, imaging, and adequate response to intra-articular anesthetic, providers can reach an accurate diagnosis that will inform subsequent treatments. After failure of nonsurgical methods, patients with SIJ dysfunction should be considered for minimally invasive fusion techniques, which have proven to be a safe, effective, and viable treatment option.

Patients experiencing sacroiliac joint (SIJ) dysfunction might show symptoms that overlap with those seen in lumbar spine pathology. This article reviews diagnostic tools that assist practitioners to discern the true pain generator in patients with low back pain (LBP) and therapeutic approaches when the cause is SIJ dysfunction.

Prevalence

Most of the US population will experience LBP at some point in their lives. A 2002 National Health Interview survey found that more than one-quarter (26.4%) of 31 044 respondents had complained of LBP in the previous 3 months.¹ About 74 million individuals in the US experienced LBP in the past 3 months.¹ A full 10% of the US population is expected to suffer from chronic LBP, and it is estimated that 2.3% of all visits to physicians are related to LBP.¹

The etiology of LBP often is unclear even after thorough clinical and radiographic evaluation because of the myriad possible mechanisms. Degenerative disc disease, facet arthropathy, ligamentous hypertrophy, muscle spasm, hip arthropathy, and SIJ dysfunction are potential pain generators and exact clinical and radiographic correlation is not always possible. Compounding this difficulty is the lack of specificity with current diagnostic techniques. For example, many patients will have disc desiccation or herniation without any LBP or radicular symptoms on radiographic studies, such as X-rays, computed tomography (CT), and magnetic resonance imaging (MRI). As such, providers of patients with diffuse radiographic abnormalities often have to identify a specific pain generator, which might not have any role in the patient’s pain.

Other tests, such as electromyographic studies, positron emission tomography (PET) scans, discography, and epidural steroid injections, can help pinpoint a specific pain generator. These tests might help determine whether the patient has a surgically treatable condition and could help predict whether a patient’s symptoms will respond to surgery.

However, the standard spine surgery workup often fails to identify an obvious pain generator in many individuals. The significant number of patients that fall into this category has prompted spine surgeons to consider other potential etiologies for LBP, and SIJ dysfunction has become a rapidly developing field of research.

Sacroiliac Joint Dysfunction

The SIJ is a bilateral, C-shaped synovial joint surrounded by a fibrous capsule and affixes the sacrum to the ilia. Several sacral ligaments and pelvic muscles support the SIJ. The L5 nerve ventral ramus and lumbosacral trunk pass anteriorly and the S1 nerve ventral ramus passes inferiorly to the joint capsule. The SIJ is innervated by the dorsal rami of L4-S3 nerve roots, transmitting nociception and temperature. Mechanisms of injury to the SIJ could arise from intra- and extra-articular etiologies, including capsular disruption, ligamentous tension, muscular inflammation, shearing, fractures, arthritis, and infection.² Patients could develop SIJ pain spontaneously or after a traumatic event or repetitive shear.³ Risk factors for developing SIJ dysfunction include a history of lumbar fusion, scoliosis, leg length discrepancies, sustained athletic activity, pregnancy, seronegative HLA-B27 spondyloarthropathies, or gait abnormalities. Inflammation of the SIJ and surrounding structures secondary to an environmental insult in susceptible individuals is a common theme among these etiologies.²

Pain from the SIJ is localized to an area of approximately 3 cm × 10 cm that is inferior to the ipsilateral posterior superior iliac spine.⁴ Referred pain maps from SIJ dysfunction extend in the L5-S1 nerve distributions, commonly seen in the buttocks, groin, posterior thigh, and lower leg with radicular symptoms. However, this pain distribution demonstrates extensive variability among patients and bears strong similarities to discogenic or facet joint sources of LBP.^5-7 Direct communication has been shown between the SIJ and adjacent neural structures, namely the L5 nerve, sacral foramina, and the lumbosacral plexus. These direct pathways could explain an inflammatory mechanism for lower extremity symptoms seen in SIJ dysfunction.⁸

The prevalence of SIJ dysfunction among patients with LBP is estimated to be 15% to 30%, an extraordinary number given the total number of patients presenting with LBP every year.⁹ These patients might represent a significant segment of patients with an unrevealing standard spine evaluation. Despite the large number of patients who experience SIJ dysfunction, there is disagreement about optimal methods for diagnosis and treatment.

Diagnosis

The International Association for the Study of Pain has proposed criteria for evaluating patients who have suspected SIJ dysfunction: Pain must be in the SIJ area, should be reproducible by performing specific provocative maneuvers, and must be relieved by injection of local anesthetic into the SIJ.¹⁰ These criteria provide a sound foundation, but in clinical practice, patients often defy categorization.

The presence of pain in the area inferior to the posterior superior iliac spine and lateral to the gluteal fold with pain referral patterns in the L5-S1 nerve distributions is highly sensitive for identifying patients with SIJ dysfunction. Furthermore, pain arising from the SIJ will not be above the level of the L5 nerve sensory distribution. However, this diagnostic finding alone is not specific and might represent other etiologies known to produce similar pain, such as intervertebral discs and facet joints. Patients with SIJ dysfunction often describe their pain as sciatica-like, recurrent, and triggered with bending or twisting motions. It is worsened with any activity loading the SIJ, such as walking, climbing stairs, standing, or sitting upright. SIJ pain might be accompanied by dyspareunia and changes in bladder function because of the nerves involved.¹¹

The use of provocative maneuvers for testing SIJ dysfunction is controversial because of the high rate of false positives and the inability to distinguish whether the SIJ or an adjacent structure is affected. However, the diagnostic utility of specific stress tests has been studied, and clusters of tests are recommended if a health care provider (HCP) suspects SIJ dysfunction. A diagnostic algorithm should first focus on using the distraction test and the thigh thrust test. Distraction is done by applying vertically oriented pressure to the anterior superior iliac spine while aiming posteriorly, therefore distracting the SIJ. During the thigh thrust test the examiner fixates the patient’s sacrum against the table with the left hand and applies a vertical force through the line of the femur aiming posteriorly, producing a posterior shearing force at the SIJ. Studies show that the thigh thrust test is the most sensitive, and the distraction test is the most specific. If both tests are positive, there is reasonable evidence to suggest SIJ dysfunction as the source of LBP.

If there are not 2 positive results, the addition of the compression test, followed by the sacral thrust test also can point to the diagnosis. The compression test is performed with vertical downward force applied to the iliac crest with the patient lying on each side, compressing the SIJ by transverse pressure across the pelvis. The sacral thrust test is performed with vertical force applied to the midline posterior sacrum at its apex directed anteriorly with the patient lying prone, producing a shearing force at the SIJs. The Gaenslen test uses a torsion force by applying a superior and posterior force to the right knee and posteriorly directed force to the left knee. Omitting the Gaenslen test has not been shown to compromise diagnostic efficacy of the other tests and can be safely excluded.¹²

A HCP can rule out SIJ dysfunction if these provocation tests are negative. However, the diagnostic predictive value of these tests is subject to variability among HCPs, and their reliability is increased when used in clusters.^9,13

Imaging for the SIJ should begin with anterior/posterior, oblique, and lateral view plain X-rays of the pelvis (Figures 1 and 2), which will rule out other pathologies by identifying other sources of LBP, such as spondylolisthesis or hip osteoarthritis. HCPs should obtain lumbar and pelvis CT images to identify inflammatory or degenerative changes within the SIJ. CT images provide the high resolution that is needed to identify pathologies, such as fractures and tumors within the pelvic ring that could cause similar pain. MRI does not reliably depict a dysfunctional ligamentous apparatus within the SIJ; however, it can help identify inflammatory sacroiliitis, such as is seen in the spondyloarthropathies.^11,14 Recent studies show combined single photon emission tomography and CT (SPECT-CT) might be the most promising imaging modality to reveal mechanical failure of load transfer with increased scintigraphic uptake in the posterior and superior SIJ ligamentous attachments. The joint loses its characteristic “dumbbell” shape in affected patients with about 50% higher uptake than unaffected joints. These findings were evident in patients who experienced pelvic trauma or during the peripartum period.^15,16

Fluoroscopy-guided intra-articular injection of a local anesthetic (lidocaine) and/or a corticosteroid (triamcinolone) has the dual functionality of diagnosis and treatment (Figure 3). It often is considered the most reliable method to diagnose SIJ dysfunction and has the benefit of pain relief for up to 1 year. However, intra-articular injections lack diagnostic validity because the solution often extravasates to extracapsular structures. This confounds the source of the pain and makes it difficult to interpret these diagnostic injections. In addition, the injection might not reach the entire SIJ capsule and could result in a false-negative diagnosis.^17,18 Periarticular injections have been shown to result in better pain relief in patients diagnosed with SIJ dysfunction than intra-articular injections. Periarticular injections also are easier to perform and could be a first-step option for these patients.¹⁹

Treatment

Nonoperative management of SIJ dysfunction includes exercise programs, physical therapy, manual manipulation therapy, sacroiliac belts, and periodic articular injections. Efficacy of these methods is variable, and analgesics often do not significantly benefit this type of pain. Another nonoperative approach is radiofrequency ablation (RFA) of the lumbar dorsal rami and lateral sacral branches, which can vary based on the number of rami treated as well as the technique used. About two-thirds of patients report pain relief after RFA.2 When successful, pain is relieved for 6 to 12 months, which is a temporary yet effective option for patients experiencing SIJ dysfunction.^14,20

Fusion Surgery

Cadaver studies show that biomechanical stabilization of the SIJ leads to decreased range of motion in flexion/extension, lateral bending, and axial rotation. This results in a decreased need for periarticular muscular and ligamentous support, therefore facilitating load transfer across the SIJ.^21,22 Patients undergoing minimally invasive surgery report better pain relief compared with those receiving open surgery at 12 months postoperatively.²³ The 2 main SIJ fusion approaches used are the lateral transarticular and the dorsal approaches. In the dorsal approach, the SIJ is distracted and allograft dowels or titanium cages with graft are inserted into the joint space posteriorly through the back. When approaching laterally, hollow screw implants filled with graft or triangular titanium implants are placed across the joint, accessing the SIJ through the iliac bones using imaging guidance. This lateral transiliac approach using porous titanium triangular rods currently is the most studied technique.²⁴

A recent prospective, multicenter trial included 423 patients with SIJ dysfunction who were randomized to receive SIJ fusion with triangular titanium implants vs a control group who received nonoperative management. Patients in the SIJ fusion group showed substantially greater improvement in pain (81.4%) compared with that of the nonoperative group (26.1%) 6 months after surgery. Pain relief in the SIJ fusion group was maintained at > 80% at 1 and 2 year follow-up, while the nonoperative group’s pain relief decreased to < 10% at the follow-ups. Measures of quality of life and disability also improved for the SIJ fusion group compared with that of the nonoperative group. Patients who were crossed over from conservative management to SIJ fusion after 6 months demonstrated improvements that were similar to those in the SIJ fusion group by the end of the study. Only 3% of patients required surgical revision. The strongest predictor of pain relief after surgery was a diagnostic SIJ anesthetic block of 30 to 60 minutes, which resulted in > 75% pain reduction.^21,25 Additional predictors of successful SIJ fusion include nonsmokers, nonopioid users, and older patients who have a longer time course of SIJ pain.²⁶

Another study investigating the outcomes of SIJ fusion, RFA, and conservative management with a 6-year follow-up demonstrated similar results.²⁷ This further confirms the durability of the surgical group’s outcome, which sustained significant improvement compared with RFA and conservative management group in pain relief, daily function, and opioid use.

HCPs should consider SIJ fusion for patients who have at least 6 months of unsuccessful nonoperative management, significant SIJ pain (> 5 in a 10-point scale), ≥ 3 positive provocation tests, and at least 50% pain relief (> 75% preferred) with diagnostic intra-articular anesthetic injection.¹⁴ It is reasonable for primary care providers to refer these patients to a neurosurgeon or orthopedic spine surgeon for possible fusion. Patients with earlier lumbar/lumbosacral spinal fusions and persistent LBP should be evaluated for potential SIJ dysfunction. SIJ dysfunction after lumbosacral fusion could be considered a form of distal pseudarthrosis resulting from increased motion at the joint. One study found its incidence correlated with the number of segments fused in the lumbar spine.²⁸ Another study found that about one-third of patients with persistent LBP after lumbosacral fusion could be attributed to SIJ dysfunction.²⁹

Case Presentation

A 27-year-old female army veteran presented with bilateral buttock pain, which she described as a dull, aching pain across her sacral region, 8 out of 10 in severity. The pain was in a L5-S1 pattern. The pain was bilateral, with the right side worse than the left, and worsened with lateral bending and load transferring. She reported no numbness, tingling, or weakness.

On physical examination, she had full strength in her lower extremities and intact sensation. She reported tenderness to palpation of the sacrum and SIJ. Her gait was normal. The patient had positive thigh thrust and distraction tests. Lumbar spine X-ray, CT, MRI, and electromyographic studies did not show any pathology. She described little or no relief with analgesics or physical therapy. Previous L4-L5 and L5-S1 facet anesthetic injections and transforaminal epidural steroid injections provided minimal pain relief immediately after the procedures. Bilateral SIJ anesthetic injections under fluoroscopic guidance decreased her pain severity from a 7 to 3 out of 10 for 2 to 3 months before returning to her baseline. Radiofrequency ablation of the right SIJ under fluoroscopy provided moderate relief for about 4 months.

After exhausting nonoperative management for SIJ dysfunction without adequate pain control, the patient was referred to neurosurgery for surgical fusion. The patient was deemed an appropriate surgical candidate and underwent a right-sided SIJ fusion (Figures 4 and 5). At her 6-month and 1-year follow-up appointments, she had lasting pain relief, 2 out of 10.

Conclusion

SIJ dysfunction is widely overlooked because of the difficulty in distinguishing it from other similarly presenting syndromes. However, with a detailed history, appropriate physical maneuvers, imaging, and adequate response to intra-articular anesthetic, providers can reach an accurate diagnosis that will inform subsequent treatments. After failure of nonsurgical methods, patients with SIJ dysfunction should be considered for minimally invasive fusion techniques, which have proven to be a safe, effective, and viable treatment option.

The term cataract is derived from the Latin word “catarractes,” which means “waterfall,” as the foamy white opacity of an advanced cataract can be likened to a tempestuous cascade. Cataract is the leading cause of preventable blindness worldwide.^1,2 It is no surprise, therefore, that cataract surgery is the most frequently performed ophthalmic surgical procedure worldwide. Cataract surgeries may reach 30 million annual cases by 2020.³ Given the large number of surgeries being performed, postsurgical complications are not uncommon.

Early postoperative complications from lens exchange (cataract) surgery include increased intraocular pressure (IOP), corneal edema, and corneal wound leakage.⁴ Corneal wound leakage is not uncommon; one study showed that, in 100 cases, almost one-third of incisions leaked.⁵ A 2014 prospective study of 500 postcataract surgery eyes revealed that 48.8% had fluid egress.⁶ Early detection is important so that efforts to restore corneal integrity can immediately be implemented. If not caught early, patients are at risk for developing a cascade of sequelae, including endophthalmitis.

The majority of corneal wound leaks postphacoemulsification are self-limiting and self-sealing. Moderate wound leaks require treatment, as in the following case. Strategies to detect, image, and treat wound leaks are covered in this discussion.

Case Presentation

A 69-year-old male veteran presented with no complaints for a 1-day postoperative visit following right eye phacoemulsification cataract extraction. His best corrected visual acuity in the right eye was 20/40, and his pinhole visual acuity was 20/25+2. On slit-lamp examination, the temporally located main incision appeared well-adhered and was found to be Seidel negative; however, the inferior paracentesis wound was found to be Seidel positive, demonstrating a slow leak. Intraocular pressure (IOP) measured with tonopen was 9 mm Hg.

A bandage soft contact lens was placed on the eye. The patient was instructed not to rub or place any pressure on the eye and to avoid bending and heavy lifting. He was also instructed to continue his postoperative medications (prednisolone 1% every 2 hours and polymyxin B sulfate 4 times daily) in his right eye. A follow-up appointment was scheduled for the next day.

The patient presented for his postoperative day-2 visit with a best corrected visual acuity in the right eye of 20/20. He reported no visual problems, no eye pain, and mentioned that he had had a comfortable night sleep. A slit-lamp examination revealed trace diffuse injection in the operative eye, predominantly central Descemet membrane folds, 1+ stromal edema, and a Seidel negative main incision wound. However, the inferior paracentesis wound showed a moderate leak (Seidel positive), and the anterior chamber showed a 1+ cell and flare. Goldmann tonometry revealed an IOP of 5 mm Hg, indicating hypotony.

Anterior segment cube 512 x 128 optical coherence tomography (OCT) was obtained with the bandage contact lens (Figures 1 and 2), and then repeated with the bandage contact lens removed (Figures 3 and 4). OCT imaging confirmed epithelial and endothelial gaping, loss of coaptation, and a localized detachment of the Descemet membrane. The veteran was referred to his surgeon that same day, and 2 limbal vicryl sutures were placed. The patient was instructed to continue prednisolone 1% 4 times daily and polymyxin B sulfate every 2 hours; erythromycin ointment 3 times daily was added to his regimen.

He was scheduled for a follow-up examination 1 week later. At that visit, the wound was no longer leaking and IOP had risen to a preoperative value of 17 mm Hg. The corneal sutures were removed at the 1-month postoperative examination and a follow-up was scheduled for 4 months later. An anterior segment OCT was obtained (Figure 5).

Discussion

In July 1967, Charles Kelman, MD, suggested using a dental ultrasonic tool, normally employed to clean teeth, to fragment the nucleus of the crystalline lens. Dr. Kelman’s first operation using phacoemulsification on a human eye took 3 hours.⁷ As the procedure for cataract removal has been refined, complication rates and surgical times have vastly improved.

Phacoemulsification is the most commonly performed outpatient surgery in the US; about 3 million cases are performed annually. Due to the high volume of cases, adverse events (AEs) are not uncommon. The incidence of complications following phacoemulsification is < 5%; the frequency of severe complications has been estimated at < 0.7%.⁸ Severe complications include endophthalmitis, suprachoroidal hemorrhage, and/or retinal detachment.⁹ Studies have shown a decline in rates of sight-threatening AEs from 1994 to 2006.⁹ A retrospective study of 45,082 veterans from 2005 to 2007 identified that a preoperative disease burden such as diabetes mellitus, chronic pulmonary disease, age-related macular degeneration, and diabetes with ophthalmic manifestations, was positively associated with a greater risk of cataract surgical complications.¹⁰

Complications

The level of a surgeon’s proficiency with phacoemulsification is directly correlated to the number of operations performed; there is a lower complication rate among more experienced surgeons, including those who work in high-volume settings.^11,12 One study identified that the AE rate within 14 days of surgery was 0.8% for surgeons performing 50 to 250 cataract surgeries per year, but only 0.1% for those performing > 1000 cataract surgeries annually.¹²

Potential postoperative lens exchange complications include increased IOP, corneal wound leakage, corneal edema, bullous keratopathy, cystoid macular edema, retinal detachment, and endophthalmitis (Table 1). A corneal wound leak can provide a potential ingress for bacteria, putting the patient at risk for endophthalmitis, perhaps the most devastating complication following cataract surgery.

Endophthalmitis

Endophthalmitis has been reported to occur in .001% to .327% of patients during postoperative care.^5,13-17 Early detection is important to maintain corneal integrity and prevent a cascade of detrimental ocular sequalae including the potential for endophthalmitis. According to Zaida and colleagues, endophthalmitis occurred in fewer than 1 of 1000 consecutive cases.¹⁴ A leaking clear corneal incision wound on the first day postoperatively has been associated with a 44-fold increased risk of endophthalmitis.¹³

Causes of endophthalmitis

In a retrospective case-controlled series of 57 patients with postcataract endophthalmitis, implantation of an intraocular lens with a resultant wound abnormality was thought to be the causative factor in 5%.¹⁷ Another source of endophthalmitis can be the intraocular lens (IOL), which may act as a vector for bacteria. By placing the IOL against the conjunctiva or exposing it to the theater air during surgery, bacteria can be introduced prior to implantation.¹⁷ Immunosuppressive treatment is the only patient antecedent factor that can be considered a predictor for endopthalmitis.¹⁷

The internal corneal seal is IOP dependent, and postoperative ocular hypotony may cause a seemingly watertight wound to leak. Taban and colleagues used anterior segment OCT to image numerous self-sealing incisions. They found that the corneal incision wound more tightly seals at higher IOPs. Additionally, more perpendicular (larger angle) incisions seal better at a lower IOP while less perpendicular (smaller angle) incisions seal better at a higher IOP (Figure 6).¹⁸

Incision Placement

Studies have shown that the main incision site is more clinically competent than is the side port incision site, as in our case study.¹⁹ Side-port incisions have a 1- or 2-plane architectural profile in contrast to the 3-plane profile typical of a main incision.¹⁹ Recent advances including the conversion to clear-corneal incisions of diminishing size, techniques used for wound construction, phacoemulsification machine design, and small-incision IOLs, should further reduce the prevalence and complications of wound compromise.²⁰

Seidel Testing

Seidel testing is the most common method to evaluate corneal wound integrity and identify leaks. A drop of topical anesthetic is instilled in the eye and then a fluorescein strip (not fluorescein sodium and benoxinate hydrochloride ophthalmic solution, which may become less sterile since it has a multiuse container) is applied to the superior conjunctiva. The clinician then looks for evidence of fluid egress using the cobalt blue filter. The patient is instructed to blink once. Fluid egress appears as a black stream as the fluorescein dye becomes diluted by aqueous humor escaping the nonintact wound and the appearance of bright green dye surrounds the leak site. The term Seidel positive indicates a leak. An estimate should be made of the rate and volume of fluid exiting the wound.

Gonioscopy

Gonioscopy can be used to evaluate the postsurgical incision, more specifically for identification and management of internal incision wound gape. On gonioscopy, internal wound gape appears as an elongated oval opening resembling a fish mouth. If internal incision wound gape is identified gonioscopically before surgery is complete, the leak can be managed intraoperatively. The surgeon can irrigate along the length of the incision to remove cortical fragments or viscoelastic that may cause internal wound gaping. If unsuccessful, rapidly deepening the anterior chamber with balanced salt solution through the paracentesis incision may be employed. These methods may improve wound stability, reduce risk of postoperative hyphema, lower the incidence of endophthalmitis, and lessen the likelihood of late against-the-rule drift.²¹

Anterior Segment Optical Coherence Tomography

Instances when Seidel testing was negative despite actual wound gaping have been described.^22,23 Anterior segment OCT is useful to evaluate incision architecture. A 2007 United Kingdom study investigated the corneal architecture in the immediate postoperative period following phacoemulsification using anterior segment OCT. This study showed the benefits of identifying architectural features such as epithelial gaping, endothelial gaping, stripping of Descemet membrane, and loss of coaptation. These features were found to be more common at low IOP and could represent a significant risk factor for endophthalmitis.²⁴ Another study published by Behrens and colleagues indicated that a localized detachment of Descemet membrane may be more common than observed with slit-lamp (Figure 7). Corneal gaping, especially if along the entire length of the surgical wound, may lead to inadvertent bacterial access into the anterior chamber.²⁵ 

Anterior segment OCT imaging was first described by Izatt and colleagues in 1994.²⁶ Unlike posterior segment OCT, anterior segment OCT requires a greater depth of field and higher energy levels as images are commonly distorted by refraction at boundaries where the refractive index changes. Longer infrared wavelengths improve the penetration through tissues that scatter light, such as the sclera and limbus, which allows visualization, for example, of the iridocorneal angle.^27,28

Two main scan patterns are used for anterior segment OCT: 512 x 128 cube scan (4-mm width x 4-mm length) and 5-line raster (3-mm length) with adjustable rotation and spacing. A recent software update allows measurement of corneal thickness, visualization of anterior chamber angle structures along with topographic analysis, anterior and posterior elevation maps of the cornea, and reliable pachymetric maps.^29,30 The anterior segment cube acquires a series of 128 horizontal scan lines each composed of 512 A-scans. These high-definition scans acquire vertical and horizontal directions composed of 1024 A-scans each. This cube may be used to measure corneal thickness and visualize corneal architecture, creating a 3-D image of the data (Figure 8). The anterior segment 5-line raster scans through 5 parallel lines of equal length to view high-resolution images of the anterior chamber angle and cornea. Each line, fixed at 3-mm in length, is composed of 4096 A-scans.³¹ Anterior segment cube OCT allows identification of subtle variations in incision architecture at different locations across the width of the OCT image.

Bandage Soft Contact Lens

Upon reviewing the anterior segment OCT images of our patient with the bandage contact lens in place, it was evident that the adherent ocular bandage was protecting the incision. A tighter fitting bandage contact lens is ideal and adheres firmly to any area of epithelial damage and epithelial gaping to help seal the incision, protecting the wound and improving structural integrity. The bandage contact lens is gradually replaced by new cells via re-epithelialization; thus, it behaves as an adjunct to natural wound healing. A bandage contact lens also improves patient comfort.

It is hypothesized that a bandage contact lens improves the structural integrity of the incision site and helps prevent leaking, hypotony, and minor wound leaks. One study revealed a statistically significant lower IOP in nonbandage contact lens patients by an average of 6 mm Hg (mean [SD] 13.4 mm Hg [5.3]; range, 5 - 23 mm Hg) vs patients with a bandage contact lens (mean [SD] 19.4 mm Hg [5.9]; range, 11 - 29 mm Hg) in the immediate postoperative period.³² The authors suggested that the bandage contact lens may prevent microleaks, resulting in a higher IOP.

Aqueous Suppressants

Aqueous suppressants are a great option when IOP is abnormally elevated by decreasing the IOP and allowing the cornea to heal and self-seal.Effective aqueous suppressants are β blockers and carbonic anhydrase inhibitors.

After phacoemulsification ocular hypotony (< 6 mm Hg) occurs most commonly due to wound leakage or excessive intraocular inflammation. However, with the presence of corneal wound leakage and ocular hypotony, aqueous suppressants are not the best option.

Further Management of Wound Leaks

Management of a postoperative wound leak will vary based on severity. The majority of mild leaks are self-sealing. Anterior segment OCT helps the clinician to identify microleaks in an otherwise Seidel negative eye. If wound leakage is moderate with a formed anterior chamber, the use of a bandage contact lens is a good option, as can be the prescription of aqueous suppressants, depending on IOP.³³

If the anterior chamber is flat, iris prolapse is apparent, or extremely low IOP exists, the patient needs to be referred to the surgeon. Current standard of care directs the surgeon to use sutures to further manage corneal wound leak. However, several studies have recognized the increased risk of suture-related complications, such as induced astigmatism, corneal opacities, incomplete wound closure, and corneal neovascularization.^6,34-38 Other wound closure options include polyethylene glycol-based products, corneal welding, cyanoacrylate, or fibrin (Table 2).³⁹ Traditionally nylon sutures have been used for clear corneal incision wound closure. However, tissue adhesives are gaining popularity as a substitute for sutures in wound closure.⁴⁰

Cyanoacrylate

Numerous studies have been published on the efficacy of cyanoacrylate as a substitute for sutures, specifically in clear corneal incisions. AEs of cyanoacrylate include a transient foreign-body sensation and diffuse or focal bulbar conjunctival hyperemia.^41,42 Shigemitsu and Majima found that fibrin and cyanoacrylate glue had tensile strength similar to sutures when used in cataract surgery.39 
Polyethylene glycol-based products, also used in artificial tears and contact lens materials, may also help seal wound leaks. Another agent is ReSure (Ocular Therapeutix, Bedford, MA), an FDA-approved synthetic, polyethylene glycol hydrogel sealant that is 90% water after polymerization. ReSure has been shown to be safe and effective in sealing cataract surgical clear corneal incisions.^6,43 ReSure takes about 20 seconds to prepare, and placement is aided by the use of a blue dye that dissipates within hours. This hydrogel will gradually slough off in the tears once the tissue has fully regenerated; there is no need to remove the sealant.⁴⁴

Rossi and colleagues evaluated the efficacy of corneal welding to close wounds after cataract surgery. The technique involves laser-assisted closure of the corneal wound(s) by a diode laser that welds the stroma.⁴⁵ Corneal welding takes seconds to achieve good closure without significant astigmatism or inflammation; however very careful application of the light absorbing dyes is required as they are toxic if allowed to enter the anterior chamber.^45-47

Conclusion

Optometrists may be called to manage patients during both the preoperative and postoperative phases of cataract surgical care. Those who participate in postoperative care should carefully evaluate for the presence of wound leak or wound gape as a potential complication. The OCT may be employed to evaluate patients suspected of having these leaks or gapes. Proficiency in the interpretation of OCT results and more traditional evaluation methods allows for successful detection of wound leaks or gapes. The timely diagnosis and treatment of postoperative wound leaks allow for the best possible outcomes for cataract surgery patients.

The term cataract is derived from the Latin word “catarractes,” which means “waterfall,” as the foamy white opacity of an advanced cataract can be likened to a tempestuous cascade. Cataract is the leading cause of preventable blindness worldwide.^1,2 It is no surprise, therefore, that cataract surgery is the most frequently performed ophthalmic surgical procedure worldwide. Cataract surgeries may reach 30 million annual cases by 2020.³ Given the large number of surgeries being performed, postsurgical complications are not uncommon.

Early postoperative complications from lens exchange (cataract) surgery include increased intraocular pressure (IOP), corneal edema, and corneal wound leakage.⁴ Corneal wound leakage is not uncommon; one study showed that, in 100 cases, almost one-third of incisions leaked.⁵ A 2014 prospective study of 500 postcataract surgery eyes revealed that 48.8% had fluid egress.⁶ Early detection is important so that efforts to restore corneal integrity can immediately be implemented. If not caught early, patients are at risk for developing a cascade of sequelae, including endophthalmitis.

The majority of corneal wound leaks postphacoemulsification are self-limiting and self-sealing. Moderate wound leaks require treatment, as in the following case. Strategies to detect, image, and treat wound leaks are covered in this discussion.

Case Presentation

A 69-year-old male veteran presented with no complaints for a 1-day postoperative visit following right eye phacoemulsification cataract extraction. His best corrected visual acuity in the right eye was 20/40, and his pinhole visual acuity was 20/25+2. On slit-lamp examination, the temporally located main incision appeared well-adhered and was found to be Seidel negative; however, the inferior paracentesis wound was found to be Seidel positive, demonstrating a slow leak. Intraocular pressure (IOP) measured with tonopen was 9 mm Hg.

A bandage soft contact lens was placed on the eye. The patient was instructed not to rub or place any pressure on the eye and to avoid bending and heavy lifting. He was also instructed to continue his postoperative medications (prednisolone 1% every 2 hours and polymyxin B sulfate 4 times daily) in his right eye. A follow-up appointment was scheduled for the next day.

The patient presented for his postoperative day-2 visit with a best corrected visual acuity in the right eye of 20/20. He reported no visual problems, no eye pain, and mentioned that he had had a comfortable night sleep. A slit-lamp examination revealed trace diffuse injection in the operative eye, predominantly central Descemet membrane folds, 1+ stromal edema, and a Seidel negative main incision wound. However, the inferior paracentesis wound showed a moderate leak (Seidel positive), and the anterior chamber showed a 1+ cell and flare. Goldmann tonometry revealed an IOP of 5 mm Hg, indicating hypotony.

Anterior segment cube 512 x 128 optical coherence tomography (OCT) was obtained with the bandage contact lens (Figures 1 and 2), and then repeated with the bandage contact lens removed (Figures 3 and 4). OCT imaging confirmed epithelial and endothelial gaping, loss of coaptation, and a localized detachment of the Descemet membrane. The veteran was referred to his surgeon that same day, and 2 limbal vicryl sutures were placed. The patient was instructed to continue prednisolone 1% 4 times daily and polymyxin B sulfate every 2 hours; erythromycin ointment 3 times daily was added to his regimen.

He was scheduled for a follow-up examination 1 week later. At that visit, the wound was no longer leaking and IOP had risen to a preoperative value of 17 mm Hg. The corneal sutures were removed at the 1-month postoperative examination and a follow-up was scheduled for 4 months later. An anterior segment OCT was obtained (Figure 5).

Discussion

In July 1967, Charles Kelman, MD, suggested using a dental ultrasonic tool, normally employed to clean teeth, to fragment the nucleus of the crystalline lens. Dr. Kelman’s first operation using phacoemulsification on a human eye took 3 hours.⁷ As the procedure for cataract removal has been refined, complication rates and surgical times have vastly improved.

Phacoemulsification is the most commonly performed outpatient surgery in the US; about 3 million cases are performed annually. Due to the high volume of cases, adverse events (AEs) are not uncommon. The incidence of complications following phacoemulsification is < 5%; the frequency of severe complications has been estimated at < 0.7%.⁸ Severe complications include endophthalmitis, suprachoroidal hemorrhage, and/or retinal detachment.⁹ Studies have shown a decline in rates of sight-threatening AEs from 1994 to 2006.⁹ A retrospective study of 45,082 veterans from 2005 to 2007 identified that a preoperative disease burden such as diabetes mellitus, chronic pulmonary disease, age-related macular degeneration, and diabetes with ophthalmic manifestations, was positively associated with a greater risk of cataract surgical complications.¹⁰

Complications

The level of a surgeon’s proficiency with phacoemulsification is directly correlated to the number of operations performed; there is a lower complication rate among more experienced surgeons, including those who work in high-volume settings.^11,12 One study identified that the AE rate within 14 days of surgery was 0.8% for surgeons performing 50 to 250 cataract surgeries per year, but only 0.1% for those performing > 1000 cataract surgeries annually.¹²

Potential postoperative lens exchange complications include increased IOP, corneal wound leakage, corneal edema, bullous keratopathy, cystoid macular edema, retinal detachment, and endophthalmitis (Table 1). A corneal wound leak can provide a potential ingress for bacteria, putting the patient at risk for endophthalmitis, perhaps the most devastating complication following cataract surgery.

Endophthalmitis

Endophthalmitis has been reported to occur in .001% to .327% of patients during postoperative care.^5,13-17 Early detection is important to maintain corneal integrity and prevent a cascade of detrimental ocular sequalae including the potential for endophthalmitis. According to Zaida and colleagues, endophthalmitis occurred in fewer than 1 of 1000 consecutive cases.¹⁴ A leaking clear corneal incision wound on the first day postoperatively has been associated with a 44-fold increased risk of endophthalmitis.¹³

Causes of endophthalmitis

In a retrospective case-controlled series of 57 patients with postcataract endophthalmitis, implantation of an intraocular lens with a resultant wound abnormality was thought to be the causative factor in 5%.¹⁷ Another source of endophthalmitis can be the intraocular lens (IOL), which may act as a vector for bacteria. By placing the IOL against the conjunctiva or exposing it to the theater air during surgery, bacteria can be introduced prior to implantation.¹⁷ Immunosuppressive treatment is the only patient antecedent factor that can be considered a predictor for endopthalmitis.¹⁷

The internal corneal seal is IOP dependent, and postoperative ocular hypotony may cause a seemingly watertight wound to leak. Taban and colleagues used anterior segment OCT to image numerous self-sealing incisions. They found that the corneal incision wound more tightly seals at higher IOPs. Additionally, more perpendicular (larger angle) incisions seal better at a lower IOP while less perpendicular (smaller angle) incisions seal better at a higher IOP (Figure 6).¹⁸

Incision Placement

Studies have shown that the main incision site is more clinically competent than is the side port incision site, as in our case study.¹⁹ Side-port incisions have a 1- or 2-plane architectural profile in contrast to the 3-plane profile typical of a main incision.¹⁹ Recent advances including the conversion to clear-corneal incisions of diminishing size, techniques used for wound construction, phacoemulsification machine design, and small-incision IOLs, should further reduce the prevalence and complications of wound compromise.²⁰

Seidel Testing

Seidel testing is the most common method to evaluate corneal wound integrity and identify leaks. A drop of topical anesthetic is instilled in the eye and then a fluorescein strip (not fluorescein sodium and benoxinate hydrochloride ophthalmic solution, which may become less sterile since it has a multiuse container) is applied to the superior conjunctiva. The clinician then looks for evidence of fluid egress using the cobalt blue filter. The patient is instructed to blink once. Fluid egress appears as a black stream as the fluorescein dye becomes diluted by aqueous humor escaping the nonintact wound and the appearance of bright green dye surrounds the leak site. The term Seidel positive indicates a leak. An estimate should be made of the rate and volume of fluid exiting the wound.

Gonioscopy

Gonioscopy can be used to evaluate the postsurgical incision, more specifically for identification and management of internal incision wound gape. On gonioscopy, internal wound gape appears as an elongated oval opening resembling a fish mouth. If internal incision wound gape is identified gonioscopically before surgery is complete, the leak can be managed intraoperatively. The surgeon can irrigate along the length of the incision to remove cortical fragments or viscoelastic that may cause internal wound gaping. If unsuccessful, rapidly deepening the anterior chamber with balanced salt solution through the paracentesis incision may be employed. These methods may improve wound stability, reduce risk of postoperative hyphema, lower the incidence of endophthalmitis, and lessen the likelihood of late against-the-rule drift.²¹

Anterior Segment Optical Coherence Tomography

Instances when Seidel testing was negative despite actual wound gaping have been described.^22,23 Anterior segment OCT is useful to evaluate incision architecture. A 2007 United Kingdom study investigated the corneal architecture in the immediate postoperative period following phacoemulsification using anterior segment OCT. This study showed the benefits of identifying architectural features such as epithelial gaping, endothelial gaping, stripping of Descemet membrane, and loss of coaptation. These features were found to be more common at low IOP and could represent a significant risk factor for endophthalmitis.²⁴ Another study published by Behrens and colleagues indicated that a localized detachment of Descemet membrane may be more common than observed with slit-lamp (Figure 7). Corneal gaping, especially if along the entire length of the surgical wound, may lead to inadvertent bacterial access into the anterior chamber.²⁵ 

Anterior segment OCT imaging was first described by Izatt and colleagues in 1994.²⁶ Unlike posterior segment OCT, anterior segment OCT requires a greater depth of field and higher energy levels as images are commonly distorted by refraction at boundaries where the refractive index changes. Longer infrared wavelengths improve the penetration through tissues that scatter light, such as the sclera and limbus, which allows visualization, for example, of the iridocorneal angle.^27,28

Two main scan patterns are used for anterior segment OCT: 512 x 128 cube scan (4-mm width x 4-mm length) and 5-line raster (3-mm length) with adjustable rotation and spacing. A recent software update allows measurement of corneal thickness, visualization of anterior chamber angle structures along with topographic analysis, anterior and posterior elevation maps of the cornea, and reliable pachymetric maps.^29,30 The anterior segment cube acquires a series of 128 horizontal scan lines each composed of 512 A-scans. These high-definition scans acquire vertical and horizontal directions composed of 1024 A-scans each. This cube may be used to measure corneal thickness and visualize corneal architecture, creating a 3-D image of the data (Figure 8). The anterior segment 5-line raster scans through 5 parallel lines of equal length to view high-resolution images of the anterior chamber angle and cornea. Each line, fixed at 3-mm in length, is composed of 4096 A-scans.³¹ Anterior segment cube OCT allows identification of subtle variations in incision architecture at different locations across the width of the OCT image.

Bandage Soft Contact Lens

Upon reviewing the anterior segment OCT images of our patient with the bandage contact lens in place, it was evident that the adherent ocular bandage was protecting the incision. A tighter fitting bandage contact lens is ideal and adheres firmly to any area of epithelial damage and epithelial gaping to help seal the incision, protecting the wound and improving structural integrity. The bandage contact lens is gradually replaced by new cells via re-epithelialization; thus, it behaves as an adjunct to natural wound healing. A bandage contact lens also improves patient comfort.

It is hypothesized that a bandage contact lens improves the structural integrity of the incision site and helps prevent leaking, hypotony, and minor wound leaks. One study revealed a statistically significant lower IOP in nonbandage contact lens patients by an average of 6 mm Hg (mean [SD] 13.4 mm Hg [5.3]; range, 5 - 23 mm Hg) vs patients with a bandage contact lens (mean [SD] 19.4 mm Hg [5.9]; range, 11 - 29 mm Hg) in the immediate postoperative period.³² The authors suggested that the bandage contact lens may prevent microleaks, resulting in a higher IOP.

Aqueous Suppressants

Aqueous suppressants are a great option when IOP is abnormally elevated by decreasing the IOP and allowing the cornea to heal and self-seal.Effective aqueous suppressants are β blockers and carbonic anhydrase inhibitors.

After phacoemulsification ocular hypotony (< 6 mm Hg) occurs most commonly due to wound leakage or excessive intraocular inflammation. However, with the presence of corneal wound leakage and ocular hypotony, aqueous suppressants are not the best option.

Further Management of Wound Leaks

Management of a postoperative wound leak will vary based on severity. The majority of mild leaks are self-sealing. Anterior segment OCT helps the clinician to identify microleaks in an otherwise Seidel negative eye. If wound leakage is moderate with a formed anterior chamber, the use of a bandage contact lens is a good option, as can be the prescription of aqueous suppressants, depending on IOP.³³

If the anterior chamber is flat, iris prolapse is apparent, or extremely low IOP exists, the patient needs to be referred to the surgeon. Current standard of care directs the surgeon to use sutures to further manage corneal wound leak. However, several studies have recognized the increased risk of suture-related complications, such as induced astigmatism, corneal opacities, incomplete wound closure, and corneal neovascularization.^6,34-38 Other wound closure options include polyethylene glycol-based products, corneal welding, cyanoacrylate, or fibrin (Table 2).³⁹ Traditionally nylon sutures have been used for clear corneal incision wound closure. However, tissue adhesives are gaining popularity as a substitute for sutures in wound closure.⁴⁰

Cyanoacrylate

Numerous studies have been published on the efficacy of cyanoacrylate as a substitute for sutures, specifically in clear corneal incisions. AEs of cyanoacrylate include a transient foreign-body sensation and diffuse or focal bulbar conjunctival hyperemia.^41,42 Shigemitsu and Majima found that fibrin and cyanoacrylate glue had tensile strength similar to sutures when used in cataract surgery.39 
Polyethylene glycol-based products, also used in artificial tears and contact lens materials, may also help seal wound leaks. Another agent is ReSure (Ocular Therapeutix, Bedford, MA), an FDA-approved synthetic, polyethylene glycol hydrogel sealant that is 90% water after polymerization. ReSure has been shown to be safe and effective in sealing cataract surgical clear corneal incisions.^6,43 ReSure takes about 20 seconds to prepare, and placement is aided by the use of a blue dye that dissipates within hours. This hydrogel will gradually slough off in the tears once the tissue has fully regenerated; there is no need to remove the sealant.⁴⁴

Rossi and colleagues evaluated the efficacy of corneal welding to close wounds after cataract surgery. The technique involves laser-assisted closure of the corneal wound(s) by a diode laser that welds the stroma.⁴⁵ Corneal welding takes seconds to achieve good closure without significant astigmatism or inflammation; however very careful application of the light absorbing dyes is required as they are toxic if allowed to enter the anterior chamber.^45-47

Conclusion

Optometrists may be called to manage patients during both the preoperative and postoperative phases of cataract surgical care. Those who participate in postoperative care should carefully evaluate for the presence of wound leak or wound gape as a potential complication. The OCT may be employed to evaluate patients suspected of having these leaks or gapes. Proficiency in the interpretation of OCT results and more traditional evaluation methods allows for successful detection of wound leaks or gapes. The timely diagnosis and treatment of postoperative wound leaks allow for the best possible outcomes for cataract surgery patients.

The term cataract is derived from the Latin word “catarractes,” which means “waterfall,” as the foamy white opacity of an advanced cataract can be likened to a tempestuous cascade. Cataract is the leading cause of preventable blindness worldwide.^1,2 It is no surprise, therefore, that cataract surgery is the most frequently performed ophthalmic surgical procedure worldwide. Cataract surgeries may reach 30 million annual cases by 2020.³ Given the large number of surgeries being performed, postsurgical complications are not uncommon.

Early postoperative complications from lens exchange (cataract) surgery include increased intraocular pressure (IOP), corneal edema, and corneal wound leakage.⁴ Corneal wound leakage is not uncommon; one study showed that, in 100 cases, almost one-third of incisions leaked.⁵ A 2014 prospective study of 500 postcataract surgery eyes revealed that 48.8% had fluid egress.⁶ Early detection is important so that efforts to restore corneal integrity can immediately be implemented. If not caught early, patients are at risk for developing a cascade of sequelae, including endophthalmitis.

The majority of corneal wound leaks postphacoemulsification are self-limiting and self-sealing. Moderate wound leaks require treatment, as in the following case. Strategies to detect, image, and treat wound leaks are covered in this discussion.

Case Presentation

A 69-year-old male veteran presented with no complaints for a 1-day postoperative visit following right eye phacoemulsification cataract extraction. His best corrected visual acuity in the right eye was 20/40, and his pinhole visual acuity was 20/25+2. On slit-lamp examination, the temporally located main incision appeared well-adhered and was found to be Seidel negative; however, the inferior paracentesis wound was found to be Seidel positive, demonstrating a slow leak. Intraocular pressure (IOP) measured with tonopen was 9 mm Hg.

A bandage soft contact lens was placed on the eye. The patient was instructed not to rub or place any pressure on the eye and to avoid bending and heavy lifting. He was also instructed to continue his postoperative medications (prednisolone 1% every 2 hours and polymyxin B sulfate 4 times daily) in his right eye. A follow-up appointment was scheduled for the next day.

The patient presented for his postoperative day-2 visit with a best corrected visual acuity in the right eye of 20/20. He reported no visual problems, no eye pain, and mentioned that he had had a comfortable night sleep. A slit-lamp examination revealed trace diffuse injection in the operative eye, predominantly central Descemet membrane folds, 1+ stromal edema, and a Seidel negative main incision wound. However, the inferior paracentesis wound showed a moderate leak (Seidel positive), and the anterior chamber showed a 1+ cell and flare. Goldmann tonometry revealed an IOP of 5 mm Hg, indicating hypotony.

Anterior segment cube 512 x 128 optical coherence tomography (OCT) was obtained with the bandage contact lens (Figures 1 and 2), and then repeated with the bandage contact lens removed (Figures 3 and 4). OCT imaging confirmed epithelial and endothelial gaping, loss of coaptation, and a localized detachment of the Descemet membrane. The veteran was referred to his surgeon that same day, and 2 limbal vicryl sutures were placed. The patient was instructed to continue prednisolone 1% 4 times daily and polymyxin B sulfate every 2 hours; erythromycin ointment 3 times daily was added to his regimen.

He was scheduled for a follow-up examination 1 week later. At that visit, the wound was no longer leaking and IOP had risen to a preoperative value of 17 mm Hg. The corneal sutures were removed at the 1-month postoperative examination and a follow-up was scheduled for 4 months later. An anterior segment OCT was obtained (Figure 5).

Discussion

In July 1967, Charles Kelman, MD, suggested using a dental ultrasonic tool, normally employed to clean teeth, to fragment the nucleus of the crystalline lens. Dr. Kelman’s first operation using phacoemulsification on a human eye took 3 hours.⁷ As the procedure for cataract removal has been refined, complication rates and surgical times have vastly improved.

Phacoemulsification is the most commonly performed outpatient surgery in the US; about 3 million cases are performed annually. Due to the high volume of cases, adverse events (AEs) are not uncommon. The incidence of complications following phacoemulsification is < 5%; the frequency of severe complications has been estimated at < 0.7%.⁸ Severe complications include endophthalmitis, suprachoroidal hemorrhage, and/or retinal detachment.⁹ Studies have shown a decline in rates of sight-threatening AEs from 1994 to 2006.⁹ A retrospective study of 45,082 veterans from 2005 to 2007 identified that a preoperative disease burden such as diabetes mellitus, chronic pulmonary disease, age-related macular degeneration, and diabetes with ophthalmic manifestations, was positively associated with a greater risk of cataract surgical complications.¹⁰

Complications

The level of a surgeon’s proficiency with phacoemulsification is directly correlated to the number of operations performed; there is a lower complication rate among more experienced surgeons, including those who work in high-volume settings.^11,12 One study identified that the AE rate within 14 days of surgery was 0.8% for surgeons performing 50 to 250 cataract surgeries per year, but only 0.1% for those performing > 1000 cataract surgeries annually.¹²

Potential postoperative lens exchange complications include increased IOP, corneal wound leakage, corneal edema, bullous keratopathy, cystoid macular edema, retinal detachment, and endophthalmitis (Table 1). A corneal wound leak can provide a potential ingress for bacteria, putting the patient at risk for endophthalmitis, perhaps the most devastating complication following cataract surgery.

Endophthalmitis

Endophthalmitis has been reported to occur in .001% to .327% of patients during postoperative care.^5,13-17 Early detection is important to maintain corneal integrity and prevent a cascade of detrimental ocular sequalae including the potential for endophthalmitis. According to Zaida and colleagues, endophthalmitis occurred in fewer than 1 of 1000 consecutive cases.¹⁴ A leaking clear corneal incision wound on the first day postoperatively has been associated with a 44-fold increased risk of endophthalmitis.¹³

Causes of endophthalmitis

In a retrospective case-controlled series of 57 patients with postcataract endophthalmitis, implantation of an intraocular lens with a resultant wound abnormality was thought to be the causative factor in 5%.¹⁷ Another source of endophthalmitis can be the intraocular lens (IOL), which may act as a vector for bacteria. By placing the IOL against the conjunctiva or exposing it to the theater air during surgery, bacteria can be introduced prior to implantation.¹⁷ Immunosuppressive treatment is the only patient antecedent factor that can be considered a predictor for endopthalmitis.¹⁷

The internal corneal seal is IOP dependent, and postoperative ocular hypotony may cause a seemingly watertight wound to leak. Taban and colleagues used anterior segment OCT to image numerous self-sealing incisions. They found that the corneal incision wound more tightly seals at higher IOPs. Additionally, more perpendicular (larger angle) incisions seal better at a lower IOP while less perpendicular (smaller angle) incisions seal better at a higher IOP (Figure 6).¹⁸

Incision Placement

Studies have shown that the main incision site is more clinically competent than is the side port incision site, as in our case study.¹⁹ Side-port incisions have a 1- or 2-plane architectural profile in contrast to the 3-plane profile typical of a main incision.¹⁹ Recent advances including the conversion to clear-corneal incisions of diminishing size, techniques used for wound construction, phacoemulsification machine design, and small-incision IOLs, should further reduce the prevalence and complications of wound compromise.²⁰

Seidel Testing

Seidel testing is the most common method to evaluate corneal wound integrity and identify leaks. A drop of topical anesthetic is instilled in the eye and then a fluorescein strip (not fluorescein sodium and benoxinate hydrochloride ophthalmic solution, which may become less sterile since it has a multiuse container) is applied to the superior conjunctiva. The clinician then looks for evidence of fluid egress using the cobalt blue filter. The patient is instructed to blink once. Fluid egress appears as a black stream as the fluorescein dye becomes diluted by aqueous humor escaping the nonintact wound and the appearance of bright green dye surrounds the leak site. The term Seidel positive indicates a leak. An estimate should be made of the rate and volume of fluid exiting the wound.

Gonioscopy

Gonioscopy can be used to evaluate the postsurgical incision, more specifically for identification and management of internal incision wound gape. On gonioscopy, internal wound gape appears as an elongated oval opening resembling a fish mouth. If internal incision wound gape is identified gonioscopically before surgery is complete, the leak can be managed intraoperatively. The surgeon can irrigate along the length of the incision to remove cortical fragments or viscoelastic that may cause internal wound gaping. If unsuccessful, rapidly deepening the anterior chamber with balanced salt solution through the paracentesis incision may be employed. These methods may improve wound stability, reduce risk of postoperative hyphema, lower the incidence of endophthalmitis, and lessen the likelihood of late against-the-rule drift.²¹

Anterior Segment Optical Coherence Tomography

Instances when Seidel testing was negative despite actual wound gaping have been described.^22,23 Anterior segment OCT is useful to evaluate incision architecture. A 2007 United Kingdom study investigated the corneal architecture in the immediate postoperative period following phacoemulsification using anterior segment OCT. This study showed the benefits of identifying architectural features such as epithelial gaping, endothelial gaping, stripping of Descemet membrane, and loss of coaptation. These features were found to be more common at low IOP and could represent a significant risk factor for endophthalmitis.²⁴ Another study published by Behrens and colleagues indicated that a localized detachment of Descemet membrane may be more common than observed with slit-lamp (Figure 7). Corneal gaping, especially if along the entire length of the surgical wound, may lead to inadvertent bacterial access into the anterior chamber.²⁵ 

Anterior segment OCT imaging was first described by Izatt and colleagues in 1994.²⁶ Unlike posterior segment OCT, anterior segment OCT requires a greater depth of field and higher energy levels as images are commonly distorted by refraction at boundaries where the refractive index changes. Longer infrared wavelengths improve the penetration through tissues that scatter light, such as the sclera and limbus, which allows visualization, for example, of the iridocorneal angle.^27,28

Two main scan patterns are used for anterior segment OCT: 512 x 128 cube scan (4-mm width x 4-mm length) and 5-line raster (3-mm length) with adjustable rotation and spacing. A recent software update allows measurement of corneal thickness, visualization of anterior chamber angle structures along with topographic analysis, anterior and posterior elevation maps of the cornea, and reliable pachymetric maps.^29,30 The anterior segment cube acquires a series of 128 horizontal scan lines each composed of 512 A-scans. These high-definition scans acquire vertical and horizontal directions composed of 1024 A-scans each. This cube may be used to measure corneal thickness and visualize corneal architecture, creating a 3-D image of the data (Figure 8). The anterior segment 5-line raster scans through 5 parallel lines of equal length to view high-resolution images of the anterior chamber angle and cornea. Each line, fixed at 3-mm in length, is composed of 4096 A-scans.³¹ Anterior segment cube OCT allows identification of subtle variations in incision architecture at different locations across the width of the OCT image.

Bandage Soft Contact Lens

Upon reviewing the anterior segment OCT images of our patient with the bandage contact lens in place, it was evident that the adherent ocular bandage was protecting the incision. A tighter fitting bandage contact lens is ideal and adheres firmly to any area of epithelial damage and epithelial gaping to help seal the incision, protecting the wound and improving structural integrity. The bandage contact lens is gradually replaced by new cells via re-epithelialization; thus, it behaves as an adjunct to natural wound healing. A bandage contact lens also improves patient comfort.

It is hypothesized that a bandage contact lens improves the structural integrity of the incision site and helps prevent leaking, hypotony, and minor wound leaks. One study revealed a statistically significant lower IOP in nonbandage contact lens patients by an average of 6 mm Hg (mean [SD] 13.4 mm Hg [5.3]; range, 5 - 23 mm Hg) vs patients with a bandage contact lens (mean [SD] 19.4 mm Hg [5.9]; range, 11 - 29 mm Hg) in the immediate postoperative period.³² The authors suggested that the bandage contact lens may prevent microleaks, resulting in a higher IOP.

Aqueous Suppressants

Aqueous suppressants are a great option when IOP is abnormally elevated by decreasing the IOP and allowing the cornea to heal and self-seal.Effective aqueous suppressants are β blockers and carbonic anhydrase inhibitors.

After phacoemulsification ocular hypotony (< 6 mm Hg) occurs most commonly due to wound leakage or excessive intraocular inflammation. However, with the presence of corneal wound leakage and ocular hypotony, aqueous suppressants are not the best option.

Further Management of Wound Leaks

Management of a postoperative wound leak will vary based on severity. The majority of mild leaks are self-sealing. Anterior segment OCT helps the clinician to identify microleaks in an otherwise Seidel negative eye. If wound leakage is moderate with a formed anterior chamber, the use of a bandage contact lens is a good option, as can be the prescription of aqueous suppressants, depending on IOP.³³

If the anterior chamber is flat, iris prolapse is apparent, or extremely low IOP exists, the patient needs to be referred to the surgeon. Current standard of care directs the surgeon to use sutures to further manage corneal wound leak. However, several studies have recognized the increased risk of suture-related complications, such as induced astigmatism, corneal opacities, incomplete wound closure, and corneal neovascularization.^6,34-38 Other wound closure options include polyethylene glycol-based products, corneal welding, cyanoacrylate, or fibrin (Table 2).³⁹ Traditionally nylon sutures have been used for clear corneal incision wound closure. However, tissue adhesives are gaining popularity as a substitute for sutures in wound closure.⁴⁰

Cyanoacrylate

Numerous studies have been published on the efficacy of cyanoacrylate as a substitute for sutures, specifically in clear corneal incisions. AEs of cyanoacrylate include a transient foreign-body sensation and diffuse or focal bulbar conjunctival hyperemia.^41,42 Shigemitsu and Majima found that fibrin and cyanoacrylate glue had tensile strength similar to sutures when used in cataract surgery.39 
Polyethylene glycol-based products, also used in artificial tears and contact lens materials, may also help seal wound leaks. Another agent is ReSure (Ocular Therapeutix, Bedford, MA), an FDA-approved synthetic, polyethylene glycol hydrogel sealant that is 90% water after polymerization. ReSure has been shown to be safe and effective in sealing cataract surgical clear corneal incisions.^6,43 ReSure takes about 20 seconds to prepare, and placement is aided by the use of a blue dye that dissipates within hours. This hydrogel will gradually slough off in the tears once the tissue has fully regenerated; there is no need to remove the sealant.⁴⁴

Rossi and colleagues evaluated the efficacy of corneal welding to close wounds after cataract surgery. The technique involves laser-assisted closure of the corneal wound(s) by a diode laser that welds the stroma.⁴⁵ Corneal welding takes seconds to achieve good closure without significant astigmatism or inflammation; however very careful application of the light absorbing dyes is required as they are toxic if allowed to enter the anterior chamber.^45-47

Conclusion

Optometrists may be called to manage patients during both the preoperative and postoperative phases of cataract surgical care. Those who participate in postoperative care should carefully evaluate for the presence of wound leak or wound gape as a potential complication. The OCT may be employed to evaluate patients suspected of having these leaks or gapes. Proficiency in the interpretation of OCT results and more traditional evaluation methods allows for successful detection of wound leaks or gapes. The timely diagnosis and treatment of postoperative wound leaks allow for the best possible outcomes for cataract surgery patients.

Hypoactive sexual desire disorder (HSDD) is the most prevalent sexual health problem in women of all ages, with population-based studies showing that about 36% to 39% of women report low sexual desire, and 8% to 10% meet the diagnostic criteria of low sexual desire and associated distress.^1,2 An expanded definition of HSDD may include³:

• lack of motivation for sexual activity (reduced or absent spontaneous desire or responsive desire to erotic cues and stimulation; inability to maintain desire or interest through sexual activity)

• loss of desire to initiate or participate in sexual activity (including avoiding situations that could lead to sexual activity) combined with significant personal distress (frustration, loss, sadness, worry) (FIGURE).⁴

Despite the high prevalence of HSDD, patients often are uncomfortable and reluctant to voice concerns about low sexual desire to their ObGyn. Further, clinicians may feel ill equipped to diagnose and treat patients with HSDD. ObGyns, however, are well positioned to initiate a general discussion about sexual concerns with patients and use screening tools, such as the Decreased Sexual Desire Screener (DSDS), to facilitate a discussion and clarify a diagnosis of generalized acquired HSDD (TABLES 1 and 2).⁵ Helpful guidance on HSDD is available from the American College of Obstetricians and Gynecologists and the International Society for the Study of Women’s Sexual Health.^6-8

Importantly, clinicians have a new treatment option they can offer to patients with HSDD. Bremelanotide was approved by the US Food and Drug Administration (FDA) on June 21, 2019, to treat acquired, generalized HSDD in premenopausal women. Up until this approval, flibanserin (approved in 2015) was the only drug FDA approved for the treatment of HSDD.

Assessing and treating HSDD today can be likened to managing depression 30 years ago, before selective serotonin receptor inhibitors were available. ObGyns would refer patients with depression to other health care providers, or not even ask patients about depressive symptoms because we had so little to offer. Once safe and effective antidepressants became available, knowing we could provide pharmacologic options made inquiring about depressive symptoms and the use of screening tools more readily incorporated into standard clinical practice. Depression is now recognized as a medical condition with biologic underpinnings, just like HSDD, and treatment options are available for both disorders.

For this Update, I had the opportunity to discuss the clinical trial experience with bremelanotide for HSDD with Dr. Sheryl Kingsberg, including efficacy and safety, dosage and administration, contraindications, and adverse events. She also details an ideal patient for treatment with bremelanotide, and we review pertinent aspects of flibanserin for comparative purposes.

Bremelanotide: A new therapeutic option

According to the product labeling for bremelanotide, the drug is indicated for the treatment of premenopausal women with acquired, generalized HSDD (low sexual desire that causes marked distress or interpersonal difficulty).⁹ This means that the HSDD developed in a woman who previously did not have problems with sexual desire, and that it occurred regardless of the type of stimulation, situation, or partner. In addition, the HSDD should not result from a coexisting medical or psychiatric condition, problems with the relationship, or the effects of a medication or drug substance.

Flibanserin also is indicated for the treatment of premenopausal women with HSDD. While both bremelanotide and flibanserin have indications only for premenopausal women, 2 studies of flibanserin in postmenopausal women have been published.^10,11 Results from these studies in naturally menopausal women suggest that flibanserin may be efficacious in this population, with improvement in sexual desire, reduced distress associated with low desire, and improvement in the number of satisfying sexual events (SSEs).

No trials of bremelanotide in postmenopausal women have been published, but since this drug acts on central nervous system receptors, as does flibanserin, it may have similar effectiveness in postmenopausal women as well.

Continue to: Clinical trials show bremelanotide improves desire, reduces distress...

Clinical trials show bremelanotide improves desire, reduces distress 

Two phase 3 clinical trials, dubbed the Reconnect studies, demonstrated that, compared with placebo, bremelanotide was associated with statistically significant improvements in sexual desire and levels of distress regarding sexual desire. 

The 2 identical, randomized, placebo-controlled multicenter trials included 1,247 premenopausal women with HSDD of at least 6 months' duration.^9,12 Bremelanotide 1.75 mg (or placebo) was self-administered subcutaneously with an autoinjector on an as-desired basis. The 24-week double-blind treatment period was followed by a 52-week open-label extension study. 

The co-primary efficacy end points were the change from baseline to end-of-study (week 24 of the double-blind treatment period) in the 1) Female Sexual Function Index (FSFI) desire domain score and 2) feeling bothered by low sexual desire as measured by Question 13 on the Female Sexual Distress Scale (FSDS). An increase in the FSFI desire domain score over time denotes improvement in sexual desire, while a decrease in the FSDS Question 13 score over time indicates improvement in the level of distress associated with low sexual desire. 

In the 2 clinical studies, the mean change from baseline (SD) in the FSFI desire domain score, which ranged from 1.2 to 6.0 at study outset (higher scores indicate greater desire), was: 

• study 1: 0.5 (1.1) in the bremelanotide-treated women and 0.2 (1.0) in the placebo-treated women (P = .0002) 
• study 2: 0.6 (1.0) in the bremelanotide group versus 0.2 (0.9) in the placebo group (P<.0001). 

For FSDS Question 13, for which the score range was 0 to 4 (higher scores indicate greater bother), the mean change from baseline score was: 

• study 1: -0.7 (1.2) in the bremelanotide-treated group compared with -0.4 (1.1) in the placebo-treated group (P<.0001) 
• study 2: -0.7 (1.1) in the bremelanotide group and -0.4 (1.1) in the placebo group (P = .0053). 

It should be noted that, in the past, SSEs were used as a primary end point in clinical studies. However, we have shifted from SSEs to desire and distress as an end point because SSEs have little to do with desire. Women worry about and are distressed by the fact that they no longer have sexual appetite. They no longer "want to want" even though their body will be responsive and they can have an orgasm. That is exemplified by the woman in our case scenario (see box, page 18), who very much wants the experience of being able to anticipate with pleasure the idea of having an enjoyable connection with her partner. 

Continue to: Physiologic target: The melanocortin receptor...

Physiologic target: The melanocortin receptor 

Bremelanotide's theorized mechanism of action is that it works to rebalance neurotransmitters that are implicated in causing HSDD, acting as an agonist on the melanocortin receptor to promote dopamine release and allow women to perceive sexual cues as rewarding. They can then respond to those cues the way they used to and therefore experience desire. Flibanserin has affinity for serotonin (5-hydroxytryptamine [5-HT]) receptors, with agonist and antagonist activity, as well as moderate antagonist activity on some dopamine receptors. 

The bottom line is that we now have treatments to address the underlying biologic aspect of HSDD, which is a biopsychosocial disorder. Again, this has parallels to depression and its biologic mechanism, for which we have effective treatments. 

Dosing is an as-needed injection 

Unlike the daily nighttime oral dose required with flibanserin, bremelanotide is a 1.75-mg dose administered as a subcutaneous injection (in either the thigh or the abdomen) with a pen-like autoinjector, on an as-needed basis. It should be administered at least 45 minutes before anticipated sexual activity. That is a benefit for many women who do not want to take a daily pill when they know that their "desire to desire" may be once per week or once every other week. 

Regarding the drug delivery mode, nobody dropped out of the bremelanotide clinical trials because of having to take an injection with an autoinjector, which employs a very thin needle and is virtually painless. A small number of bremelanotide-treated women, about 13%, had injection site reactions (compared with 8% in the placebo group), which is common with subcutaneous injection. Even in the phase 2 clinical trial, in which a syringe was used to administer the drug, no participants discontinued the study because of the injection mode. 

There are no clear pharmacokinetic data on how long bremelanotide's effects last, but it may be anywhere from 8 to 16 hours. Patients should not take more than 1 dose within 24 hours--but since the effect may last up to 16 hours that should not be a problem--and use of more than 8 doses per month is not recommended. 

While bremelanotide improves desire, certainly better than placebo, there is also some peripheral improvement in arousal, although women in the trials had only HSDD. We do not know whether bremelanotide would treat arousal disorder, but it will help women with or without arousal difficulties associated with their HSDD, as shown in a subgroup analysis in the trials.¹³ 

Counsel patients on treatment potentialities 

Clinicians should be aware of several precautions with bremelanotide use. 
Blood pressure increases. After each dose of bremelanotide, transient increases in blood pressure (6 mm Hg in systolic and 3 mm Hg in diastolic blood pressure) and reductions in heart rate (up to 5 beats per minute) occur; these measurements return to baseline usually within 12 hours postdose.⁹ When you think about whether having sexual desire will increase blood pressure, this may be physiologic. It is similar to walking up a flight of stairs. 

The drug is not recommended, however, for use in patients at high risk for cardiovascular disease, and it is contraindicated in women with uncontrolled hypertension or known cardiovascular disease. Blood pressure should be well controlled before bremelanotide is initiated--use of antihypertensive agents is not contraindicated with bremelanotide as the drugs do not interact. 

Clinicians are not required to participate in a Risk Evaluation and Mitigation Strategy (REMS) program to prescribe bremelanotide as they are with flibanserin (because of the increased risk of severe hypotension and syncope due to flibanserin's interaction with alcohol). 

Drug interactions. Bremelanotide is a melanocortin receptor agonist--a unique compound. Antidepressants, other psychoactive medications, and oral contraceptives are not contraindicated with bremelanotide as there are no known interactions. Alcohol use also is not a contraindication or caution, in contrast to flibanserin. (In April, the FDA issued a labeling change order for flibanserin, specifying that alcohol does not have to be avoided completely when taking flibanserin, but that women should discontinue drinking alcohol at least 2 hours before taking the drug at bedtime, or skip the flibanserin dose that evening.¹⁴) Bremelanotide may slow gastric emptying, though, so when a patient is taking oral drugs that require threshold concentrations for efficacy, such as antibiotics, they should avoid bremelanotide. In addition, some drugs, such as indomethacin, may have a delayed onset of action with concomitant bremelanotide use.⁹ 

Importantly, patients should avoid using bremelanotide if they are taking an oral naltrexone product for treatment of alcohol or opioid addiction, because bremelanotide may decrease systemic exposure of oral naltrexone. That would potentially lead to naltrexone treatment failure and its consequences.⁹ 

Skin pigmentation changes. Hyperpigmentation occurred with bremelanotide use on the face, gingiva, and breasts, as reported in the clinical trials, in 1% of treated patients who received up to 8 doses per month, compared with no such occurrences in placebo-treated patients. In addition, 38% of patients who received bremelanotide daily for 8 days developed focal hyperpigmentation. It was not confirmed in all patients whether the hyperpigmentation resolved. Women with dark skin were more likely to develop hyperpigmentation.⁹ 

Common adverse reactions. The most common adverse reactions with bremelanotide treatment are nausea, flushing, injection site reactions, and headache, with most events being mild to moderate in intensity. In the clinical trials, 40% of the bremelanotide-treated women experienced nausea (compared with 1% of placebo-treated women), with most occurrences being mild; for most participants nausea improved with the second dose. Women had nausea that either went away or was intermittent, or it was mild enough that the drug benefits outweighed the tolerability costs--of women who experienced nausea, 92% continued in the trial, and 8% dropped out because of nausea.⁹ 

Final considerations 

Asking patients about sexual function and using sexual function screening tools can help clinicians identify patients with the decreased sexual desire and associated distress characteristic of HSDD. ObGyns are the appropriate clinicians to treat these women and soon will have 2 pharmacologic options--bremelanotide (anticipated to be available in Fall 2019) and flibanserin--to offer patients with this biopsychosocial disorder that can adversely impact well-being and quality of life. Clinicians should individualize treatment, which may include psychotherapeutic counseling, and counsel patients on appropriate drug use and potential adverse effects. 

AMAG Pharmaceuticals, Inc. has announced that they will have a copay assistance program for bremelanotide, where the first prescription of four autoinjectors will be a $0 copay, followed by a $99 copay or less for refills.¹⁵  

Hypoactive sexual desire disorder (HSDD) is the most prevalent sexual health problem in women of all ages, with population-based studies showing that about 36% to 39% of women report low sexual desire, and 8% to 10% meet the diagnostic criteria of low sexual desire and associated distress.^1,2 An expanded definition of HSDD may include³:

• lack of motivation for sexual activity (reduced or absent spontaneous desire or responsive desire to erotic cues and stimulation; inability to maintain desire or interest through sexual activity)

• loss of desire to initiate or participate in sexual activity (including avoiding situations that could lead to sexual activity) combined with significant personal distress (frustration, loss, sadness, worry) (FIGURE).⁴

Despite the high prevalence of HSDD, patients often are uncomfortable and reluctant to voice concerns about low sexual desire to their ObGyn. Further, clinicians may feel ill equipped to diagnose and treat patients with HSDD. ObGyns, however, are well positioned to initiate a general discussion about sexual concerns with patients and use screening tools, such as the Decreased Sexual Desire Screener (DSDS), to facilitate a discussion and clarify a diagnosis of generalized acquired HSDD (TABLES 1 and 2).⁵ Helpful guidance on HSDD is available from the American College of Obstetricians and Gynecologists and the International Society for the Study of Women’s Sexual Health.^6-8

Importantly, clinicians have a new treatment option they can offer to patients with HSDD. Bremelanotide was approved by the US Food and Drug Administration (FDA) on June 21, 2019, to treat acquired, generalized HSDD in premenopausal women. Up until this approval, flibanserin (approved in 2015) was the only drug FDA approved for the treatment of HSDD.

Assessing and treating HSDD today can be likened to managing depression 30 years ago, before selective serotonin receptor inhibitors were available. ObGyns would refer patients with depression to other health care providers, or not even ask patients about depressive symptoms because we had so little to offer. Once safe and effective antidepressants became available, knowing we could provide pharmacologic options made inquiring about depressive symptoms and the use of screening tools more readily incorporated into standard clinical practice. Depression is now recognized as a medical condition with biologic underpinnings, just like HSDD, and treatment options are available for both disorders.

For this Update, I had the opportunity to discuss the clinical trial experience with bremelanotide for HSDD with Dr. Sheryl Kingsberg, including efficacy and safety, dosage and administration, contraindications, and adverse events. She also details an ideal patient for treatment with bremelanotide, and we review pertinent aspects of flibanserin for comparative purposes.

Bremelanotide: A new therapeutic option

According to the product labeling for bremelanotide, the drug is indicated for the treatment of premenopausal women with acquired, generalized HSDD (low sexual desire that causes marked distress or interpersonal difficulty).⁹ This means that the HSDD developed in a woman who previously did not have problems with sexual desire, and that it occurred regardless of the type of stimulation, situation, or partner. In addition, the HSDD should not result from a coexisting medical or psychiatric condition, problems with the relationship, or the effects of a medication or drug substance.

Flibanserin also is indicated for the treatment of premenopausal women with HSDD. While both bremelanotide and flibanserin have indications only for premenopausal women, 2 studies of flibanserin in postmenopausal women have been published.^10,11 Results from these studies in naturally menopausal women suggest that flibanserin may be efficacious in this population, with improvement in sexual desire, reduced distress associated with low desire, and improvement in the number of satisfying sexual events (SSEs).

No trials of bremelanotide in postmenopausal women have been published, but since this drug acts on central nervous system receptors, as does flibanserin, it may have similar effectiveness in postmenopausal women as well.

Continue to: Clinical trials show bremelanotide improves desire, reduces distress...

Clinical trials show bremelanotide improves desire, reduces distress 

Two phase 3 clinical trials, dubbed the Reconnect studies, demonstrated that, compared with placebo, bremelanotide was associated with statistically significant improvements in sexual desire and levels of distress regarding sexual desire. 

The 2 identical, randomized, placebo-controlled multicenter trials included 1,247 premenopausal women with HSDD of at least 6 months' duration.^9,12 Bremelanotide 1.75 mg (or placebo) was self-administered subcutaneously with an autoinjector on an as-desired basis. The 24-week double-blind treatment period was followed by a 52-week open-label extension study. 

The co-primary efficacy end points were the change from baseline to end-of-study (week 24 of the double-blind treatment period) in the 1) Female Sexual Function Index (FSFI) desire domain score and 2) feeling bothered by low sexual desire as measured by Question 13 on the Female Sexual Distress Scale (FSDS). An increase in the FSFI desire domain score over time denotes improvement in sexual desire, while a decrease in the FSDS Question 13 score over time indicates improvement in the level of distress associated with low sexual desire. 

In the 2 clinical studies, the mean change from baseline (SD) in the FSFI desire domain score, which ranged from 1.2 to 6.0 at study outset (higher scores indicate greater desire), was: 

• study 1: 0.5 (1.1) in the bremelanotide-treated women and 0.2 (1.0) in the placebo-treated women (P = .0002) 
• study 2: 0.6 (1.0) in the bremelanotide group versus 0.2 (0.9) in the placebo group (P<.0001). 

For FSDS Question 13, for which the score range was 0 to 4 (higher scores indicate greater bother), the mean change from baseline score was: 

• study 1: -0.7 (1.2) in the bremelanotide-treated group compared with -0.4 (1.1) in the placebo-treated group (P<.0001) 
• study 2: -0.7 (1.1) in the bremelanotide group and -0.4 (1.1) in the placebo group (P = .0053). 

It should be noted that, in the past, SSEs were used as a primary end point in clinical studies. However, we have shifted from SSEs to desire and distress as an end point because SSEs have little to do with desire. Women worry about and are distressed by the fact that they no longer have sexual appetite. They no longer "want to want" even though their body will be responsive and they can have an orgasm. That is exemplified by the woman in our case scenario (see box, page 18), who very much wants the experience of being able to anticipate with pleasure the idea of having an enjoyable connection with her partner. 

Continue to: Physiologic target: The melanocortin receptor...

Physiologic target: The melanocortin receptor 

Bremelanotide's theorized mechanism of action is that it works to rebalance neurotransmitters that are implicated in causing HSDD, acting as an agonist on the melanocortin receptor to promote dopamine release and allow women to perceive sexual cues as rewarding. They can then respond to those cues the way they used to and therefore experience desire. Flibanserin has affinity for serotonin (5-hydroxytryptamine [5-HT]) receptors, with agonist and antagonist activity, as well as moderate antagonist activity on some dopamine receptors. 

The bottom line is that we now have treatments to address the underlying biologic aspect of HSDD, which is a biopsychosocial disorder. Again, this has parallels to depression and its biologic mechanism, for which we have effective treatments. 

Dosing is an as-needed injection 

Unlike the daily nighttime oral dose required with flibanserin, bremelanotide is a 1.75-mg dose administered as a subcutaneous injection (in either the thigh or the abdomen) with a pen-like autoinjector, on an as-needed basis. It should be administered at least 45 minutes before anticipated sexual activity. That is a benefit for many women who do not want to take a daily pill when they know that their "desire to desire" may be once per week or once every other week. 

Regarding the drug delivery mode, nobody dropped out of the bremelanotide clinical trials because of having to take an injection with an autoinjector, which employs a very thin needle and is virtually painless. A small number of bremelanotide-treated women, about 13%, had injection site reactions (compared with 8% in the placebo group), which is common with subcutaneous injection. Even in the phase 2 clinical trial, in which a syringe was used to administer the drug, no participants discontinued the study because of the injection mode. 

There are no clear pharmacokinetic data on how long bremelanotide's effects last, but it may be anywhere from 8 to 16 hours. Patients should not take more than 1 dose within 24 hours--but since the effect may last up to 16 hours that should not be a problem--and use of more than 8 doses per month is not recommended. 

While bremelanotide improves desire, certainly better than placebo, there is also some peripheral improvement in arousal, although women in the trials had only HSDD. We do not know whether bremelanotide would treat arousal disorder, but it will help women with or without arousal difficulties associated with their HSDD, as shown in a subgroup analysis in the trials.¹³ 

Counsel patients on treatment potentialities 

Clinicians should be aware of several precautions with bremelanotide use. 
Blood pressure increases. After each dose of bremelanotide, transient increases in blood pressure (6 mm Hg in systolic and 3 mm Hg in diastolic blood pressure) and reductions in heart rate (up to 5 beats per minute) occur; these measurements return to baseline usually within 12 hours postdose.⁹ When you think about whether having sexual desire will increase blood pressure, this may be physiologic. It is similar to walking up a flight of stairs. 

The drug is not recommended, however, for use in patients at high risk for cardiovascular disease, and it is contraindicated in women with uncontrolled hypertension or known cardiovascular disease. Blood pressure should be well controlled before bremelanotide is initiated--use of antihypertensive agents is not contraindicated with bremelanotide as the drugs do not interact. 

Clinicians are not required to participate in a Risk Evaluation and Mitigation Strategy (REMS) program to prescribe bremelanotide as they are with flibanserin (because of the increased risk of severe hypotension and syncope due to flibanserin's interaction with alcohol). 

Drug interactions. Bremelanotide is a melanocortin receptor agonist--a unique compound. Antidepressants, other psychoactive medications, and oral contraceptives are not contraindicated with bremelanotide as there are no known interactions. Alcohol use also is not a contraindication or caution, in contrast to flibanserin. (In April, the FDA issued a labeling change order for flibanserin, specifying that alcohol does not have to be avoided completely when taking flibanserin, but that women should discontinue drinking alcohol at least 2 hours before taking the drug at bedtime, or skip the flibanserin dose that evening.¹⁴) Bremelanotide may slow gastric emptying, though, so when a patient is taking oral drugs that require threshold concentrations for efficacy, such as antibiotics, they should avoid bremelanotide. In addition, some drugs, such as indomethacin, may have a delayed onset of action with concomitant bremelanotide use.⁹ 

Importantly, patients should avoid using bremelanotide if they are taking an oral naltrexone product for treatment of alcohol or opioid addiction, because bremelanotide may decrease systemic exposure of oral naltrexone. That would potentially lead to naltrexone treatment failure and its consequences.⁹ 

Skin pigmentation changes. Hyperpigmentation occurred with bremelanotide use on the face, gingiva, and breasts, as reported in the clinical trials, in 1% of treated patients who received up to 8 doses per month, compared with no such occurrences in placebo-treated patients. In addition, 38% of patients who received bremelanotide daily for 8 days developed focal hyperpigmentation. It was not confirmed in all patients whether the hyperpigmentation resolved. Women with dark skin were more likely to develop hyperpigmentation.⁹ 

Common adverse reactions. The most common adverse reactions with bremelanotide treatment are nausea, flushing, injection site reactions, and headache, with most events being mild to moderate in intensity. In the clinical trials, 40% of the bremelanotide-treated women experienced nausea (compared with 1% of placebo-treated women), with most occurrences being mild; for most participants nausea improved with the second dose. Women had nausea that either went away or was intermittent, or it was mild enough that the drug benefits outweighed the tolerability costs--of women who experienced nausea, 92% continued in the trial, and 8% dropped out because of nausea.⁹ 

Final considerations 

Asking patients about sexual function and using sexual function screening tools can help clinicians identify patients with the decreased sexual desire and associated distress characteristic of HSDD. ObGyns are the appropriate clinicians to treat these women and soon will have 2 pharmacologic options--bremelanotide (anticipated to be available in Fall 2019) and flibanserin--to offer patients with this biopsychosocial disorder that can adversely impact well-being and quality of life. Clinicians should individualize treatment, which may include psychotherapeutic counseling, and counsel patients on appropriate drug use and potential adverse effects. 

AMAG Pharmaceuticals, Inc. has announced that they will have a copay assistance program for bremelanotide, where the first prescription of four autoinjectors will be a $0 copay, followed by a $99 copay or less for refills.¹⁵  

Hypoactive sexual desire disorder (HSDD) is the most prevalent sexual health problem in women of all ages, with population-based studies showing that about 36% to 39% of women report low sexual desire, and 8% to 10% meet the diagnostic criteria of low sexual desire and associated distress.^1,2 An expanded definition of HSDD may include³:

• lack of motivation for sexual activity (reduced or absent spontaneous desire or responsive desire to erotic cues and stimulation; inability to maintain desire or interest through sexual activity)

• loss of desire to initiate or participate in sexual activity (including avoiding situations that could lead to sexual activity) combined with significant personal distress (frustration, loss, sadness, worry) (FIGURE).⁴

Despite the high prevalence of HSDD, patients often are uncomfortable and reluctant to voice concerns about low sexual desire to their ObGyn. Further, clinicians may feel ill equipped to diagnose and treat patients with HSDD. ObGyns, however, are well positioned to initiate a general discussion about sexual concerns with patients and use screening tools, such as the Decreased Sexual Desire Screener (DSDS), to facilitate a discussion and clarify a diagnosis of generalized acquired HSDD (TABLES 1 and 2).⁵ Helpful guidance on HSDD is available from the American College of Obstetricians and Gynecologists and the International Society for the Study of Women’s Sexual Health.^6-8

Importantly, clinicians have a new treatment option they can offer to patients with HSDD. Bremelanotide was approved by the US Food and Drug Administration (FDA) on June 21, 2019, to treat acquired, generalized HSDD in premenopausal women. Up until this approval, flibanserin (approved in 2015) was the only drug FDA approved for the treatment of HSDD.

Assessing and treating HSDD today can be likened to managing depression 30 years ago, before selective serotonin receptor inhibitors were available. ObGyns would refer patients with depression to other health care providers, or not even ask patients about depressive symptoms because we had so little to offer. Once safe and effective antidepressants became available, knowing we could provide pharmacologic options made inquiring about depressive symptoms and the use of screening tools more readily incorporated into standard clinical practice. Depression is now recognized as a medical condition with biologic underpinnings, just like HSDD, and treatment options are available for both disorders.

For this Update, I had the opportunity to discuss the clinical trial experience with bremelanotide for HSDD with Dr. Sheryl Kingsberg, including efficacy and safety, dosage and administration, contraindications, and adverse events. She also details an ideal patient for treatment with bremelanotide, and we review pertinent aspects of flibanserin for comparative purposes.

Bremelanotide: A new therapeutic option

According to the product labeling for bremelanotide, the drug is indicated for the treatment of premenopausal women with acquired, generalized HSDD (low sexual desire that causes marked distress or interpersonal difficulty).⁹ This means that the HSDD developed in a woman who previously did not have problems with sexual desire, and that it occurred regardless of the type of stimulation, situation, or partner. In addition, the HSDD should not result from a coexisting medical or psychiatric condition, problems with the relationship, or the effects of a medication or drug substance.

Flibanserin also is indicated for the treatment of premenopausal women with HSDD. While both bremelanotide and flibanserin have indications only for premenopausal women, 2 studies of flibanserin in postmenopausal women have been published.^10,11 Results from these studies in naturally menopausal women suggest that flibanserin may be efficacious in this population, with improvement in sexual desire, reduced distress associated with low desire, and improvement in the number of satisfying sexual events (SSEs).

No trials of bremelanotide in postmenopausal women have been published, but since this drug acts on central nervous system receptors, as does flibanserin, it may have similar effectiveness in postmenopausal women as well.

Continue to: Clinical trials show bremelanotide improves desire, reduces distress...

Clinical trials show bremelanotide improves desire, reduces distress 

Two phase 3 clinical trials, dubbed the Reconnect studies, demonstrated that, compared with placebo, bremelanotide was associated with statistically significant improvements in sexual desire and levels of distress regarding sexual desire. 

The 2 identical, randomized, placebo-controlled multicenter trials included 1,247 premenopausal women with HSDD of at least 6 months' duration.^9,12 Bremelanotide 1.75 mg (or placebo) was self-administered subcutaneously with an autoinjector on an as-desired basis. The 24-week double-blind treatment period was followed by a 52-week open-label extension study. 

The co-primary efficacy end points were the change from baseline to end-of-study (week 24 of the double-blind treatment period) in the 1) Female Sexual Function Index (FSFI) desire domain score and 2) feeling bothered by low sexual desire as measured by Question 13 on the Female Sexual Distress Scale (FSDS). An increase in the FSFI desire domain score over time denotes improvement in sexual desire, while a decrease in the FSDS Question 13 score over time indicates improvement in the level of distress associated with low sexual desire. 

In the 2 clinical studies, the mean change from baseline (SD) in the FSFI desire domain score, which ranged from 1.2 to 6.0 at study outset (higher scores indicate greater desire), was: 

• study 1: 0.5 (1.1) in the bremelanotide-treated women and 0.2 (1.0) in the placebo-treated women (P = .0002) 
• study 2: 0.6 (1.0) in the bremelanotide group versus 0.2 (0.9) in the placebo group (P<.0001). 

For FSDS Question 13, for which the score range was 0 to 4 (higher scores indicate greater bother), the mean change from baseline score was: 

• study 1: -0.7 (1.2) in the bremelanotide-treated group compared with -0.4 (1.1) in the placebo-treated group (P<.0001) 
• study 2: -0.7 (1.1) in the bremelanotide group and -0.4 (1.1) in the placebo group (P = .0053). 

It should be noted that, in the past, SSEs were used as a primary end point in clinical studies. However, we have shifted from SSEs to desire and distress as an end point because SSEs have little to do with desire. Women worry about and are distressed by the fact that they no longer have sexual appetite. They no longer "want to want" even though their body will be responsive and they can have an orgasm. That is exemplified by the woman in our case scenario (see box, page 18), who very much wants the experience of being able to anticipate with pleasure the idea of having an enjoyable connection with her partner. 

Continue to: Physiologic target: The melanocortin receptor...

Physiologic target: The melanocortin receptor 

Bremelanotide's theorized mechanism of action is that it works to rebalance neurotransmitters that are implicated in causing HSDD, acting as an agonist on the melanocortin receptor to promote dopamine release and allow women to perceive sexual cues as rewarding. They can then respond to those cues the way they used to and therefore experience desire. Flibanserin has affinity for serotonin (5-hydroxytryptamine [5-HT]) receptors, with agonist and antagonist activity, as well as moderate antagonist activity on some dopamine receptors. 

The bottom line is that we now have treatments to address the underlying biologic aspect of HSDD, which is a biopsychosocial disorder. Again, this has parallels to depression and its biologic mechanism, for which we have effective treatments. 

Dosing is an as-needed injection 

Unlike the daily nighttime oral dose required with flibanserin, bremelanotide is a 1.75-mg dose administered as a subcutaneous injection (in either the thigh or the abdomen) with a pen-like autoinjector, on an as-needed basis. It should be administered at least 45 minutes before anticipated sexual activity. That is a benefit for many women who do not want to take a daily pill when they know that their "desire to desire" may be once per week or once every other week. 

Regarding the drug delivery mode, nobody dropped out of the bremelanotide clinical trials because of having to take an injection with an autoinjector, which employs a very thin needle and is virtually painless. A small number of bremelanotide-treated women, about 13%, had injection site reactions (compared with 8% in the placebo group), which is common with subcutaneous injection. Even in the phase 2 clinical trial, in which a syringe was used to administer the drug, no participants discontinued the study because of the injection mode. 

There are no clear pharmacokinetic data on how long bremelanotide's effects last, but it may be anywhere from 8 to 16 hours. Patients should not take more than 1 dose within 24 hours--but since the effect may last up to 16 hours that should not be a problem--and use of more than 8 doses per month is not recommended. 

While bremelanotide improves desire, certainly better than placebo, there is also some peripheral improvement in arousal, although women in the trials had only HSDD. We do not know whether bremelanotide would treat arousal disorder, but it will help women with or without arousal difficulties associated with their HSDD, as shown in a subgroup analysis in the trials.¹³ 

Counsel patients on treatment potentialities 

Clinicians should be aware of several precautions with bremelanotide use. 
Blood pressure increases. After each dose of bremelanotide, transient increases in blood pressure (6 mm Hg in systolic and 3 mm Hg in diastolic blood pressure) and reductions in heart rate (up to 5 beats per minute) occur; these measurements return to baseline usually within 12 hours postdose.⁹ When you think about whether having sexual desire will increase blood pressure, this may be physiologic. It is similar to walking up a flight of stairs. 

The drug is not recommended, however, for use in patients at high risk for cardiovascular disease, and it is contraindicated in women with uncontrolled hypertension or known cardiovascular disease. Blood pressure should be well controlled before bremelanotide is initiated--use of antihypertensive agents is not contraindicated with bremelanotide as the drugs do not interact. 

Clinicians are not required to participate in a Risk Evaluation and Mitigation Strategy (REMS) program to prescribe bremelanotide as they are with flibanserin (because of the increased risk of severe hypotension and syncope due to flibanserin's interaction with alcohol). 

Drug interactions. Bremelanotide is a melanocortin receptor agonist--a unique compound. Antidepressants, other psychoactive medications, and oral contraceptives are not contraindicated with bremelanotide as there are no known interactions. Alcohol use also is not a contraindication or caution, in contrast to flibanserin. (In April, the FDA issued a labeling change order for flibanserin, specifying that alcohol does not have to be avoided completely when taking flibanserin, but that women should discontinue drinking alcohol at least 2 hours before taking the drug at bedtime, or skip the flibanserin dose that evening.¹⁴) Bremelanotide may slow gastric emptying, though, so when a patient is taking oral drugs that require threshold concentrations for efficacy, such as antibiotics, they should avoid bremelanotide. In addition, some drugs, such as indomethacin, may have a delayed onset of action with concomitant bremelanotide use.⁹ 

Importantly, patients should avoid using bremelanotide if they are taking an oral naltrexone product for treatment of alcohol or opioid addiction, because bremelanotide may decrease systemic exposure of oral naltrexone. That would potentially lead to naltrexone treatment failure and its consequences.⁹ 

Skin pigmentation changes. Hyperpigmentation occurred with bremelanotide use on the face, gingiva, and breasts, as reported in the clinical trials, in 1% of treated patients who received up to 8 doses per month, compared with no such occurrences in placebo-treated patients. In addition, 38% of patients who received bremelanotide daily for 8 days developed focal hyperpigmentation. It was not confirmed in all patients whether the hyperpigmentation resolved. Women with dark skin were more likely to develop hyperpigmentation.⁹ 

Common adverse reactions. The most common adverse reactions with bremelanotide treatment are nausea, flushing, injection site reactions, and headache, with most events being mild to moderate in intensity. In the clinical trials, 40% of the bremelanotide-treated women experienced nausea (compared with 1% of placebo-treated women), with most occurrences being mild; for most participants nausea improved with the second dose. Women had nausea that either went away or was intermittent, or it was mild enough that the drug benefits outweighed the tolerability costs--of women who experienced nausea, 92% continued in the trial, and 8% dropped out because of nausea.⁹ 

Final considerations 

Asking patients about sexual function and using sexual function screening tools can help clinicians identify patients with the decreased sexual desire and associated distress characteristic of HSDD. ObGyns are the appropriate clinicians to treat these women and soon will have 2 pharmacologic options--bremelanotide (anticipated to be available in Fall 2019) and flibanserin--to offer patients with this biopsychosocial disorder that can adversely impact well-being and quality of life. Clinicians should individualize treatment, which may include psychotherapeutic counseling, and counsel patients on appropriate drug use and potential adverse effects. 

AMAG Pharmaceuticals, Inc. has announced that they will have a copay assistance program for bremelanotide, where the first prescription of four autoinjectors will be a $0 copay, followed by a $99 copay or less for refills.¹⁵  

Morcellation of gynecologic surgical specimens became controversial after concerns arose about the potential for inadvertent spread of malignant cells throughout the abdomen and pelvis during tissue morcellation of suspected benign disease. In 2014, the US Food and Drug Administration (FDA) issued a warningagainst the use of laparoscopic power morcellation specifically for myomectomy or hysterectomy in the treatment of leiomyomas (fibroids) because of the risk of spreading undiagnosed malignancy throughout the abdomen and pelvis.¹ This warning was issued after a high-profile case occurred in Boston in which an occult uterine sarcoma was morcellated during a supracervical robot-assisted hysterectomy for suspected benign fibroids.

Recently, the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion with updated recommendations for practice detailing the risks associated with morcellation and suggestions for patient counseling regarding morcellation.²

In this review, we summarize the techniques and risks of morcellation, the epidemiology of undiagnosed uterine malignancies, practice changes noted at our institution, and clinical recommendations moving forward. A case scenario illustrates keys steps in preoperative evaluation and counseling.

Morcellation uses—and risks

Morcellation is the surgical process of dividing a large tissue specimen into smaller pieces to facilitate their removal through the small incisions made in minimally invasive surgery. Morcellation may be performed with a power instrument or manually.

In power morcellation, an electromechanical instrument is used to cut or shave the specimen; in manual morcellation, the surgeon uses a knife to carve the specimen. Power morcellation is performed through a laparoscopic incision, while the manual technique is performed through a minilaparotomy or vaginally after hysterectomy (TABLE). Unlike uncontained morcellation, contained morcellation involves the use of a laparoscopic bag to hold the specimen and therefore prevent tissue dissemination in the abdomen and pelvis.

Morcellation has greatly expanded our ability to perform minimally invasive surgery—for example, in patients with specimens that cannot be extracted en bloc through the vagina after hysterectomy or, in the case of myomectomy or supracervical hysterectomy without a colpotomy, through small laparoscopic ports. Minimally invasive surgery improves patient care, as it is associated with lower rates of infection, blood loss, venous thromboembolism, wound and bowel complications, postoperative pain, and shorter overall recovery time and hospital stay versus traditional open surgery.^3,4 Furthermore, laparoscopic hysterectomy has a 3-fold lower risk of mortality compared with open hysterectomy.⁴ For these reasons, ACOG recommends choosing a minimally invasive approach for all benign hysterectomies whenever feasible.³

With abundant data supporting the use of a minimally invasive approach, laparoscopic morcellation allowed procedures involving larger tissue specimens to be accomplished without the addition of a minilaparotomy for tissue extraction. However, disseminating potentially malignant tissue throughout the abdomen and pelvis during the morcellation process remains a risk. While tissue spread can occur with either power or manual morcellation, the case that drew media attention to the controversy used power morcellation, and thus intense scrutiny focused on this technique. Morcellation has additional risks, including direct injury to surrounding organs, disruption of the pathologic specimen, and distribution of benign tissue throughout the abdomen and pelvis, such as fibroid, endometriosis, and adenomyosis implants.^5-7

Continue to: The challenge of leiomyosarcoma...

The challenge of leiomyosarcoma

The primary controversy surrounding morcellation of fibroid tissue specimens is the potential for undiagnosed malignancy, namely uterine leiomyosarcoma or endometrial stromal sarcoma. While other gynecologic malignancies, including cervical and endometrial cancers, are more common and potentially could be disseminated by morcellation, these cancers are more reliably diagnosed preoperatively with cervical and endometrial biopsies, and they do not tend to mimic benign diseases.

Epidemiology and risk factors. Uterine leiomyosarcoma is rare, with an estimated incidence of 0.36 per 100,000 woman-years.⁸ However, leiomyosarcoma can mimic the appearance and clinical course of benign fibroids, making preoperative diagnosis difficult. Risk factors for leiomyosarcoma include postmenopausal status, with a median age of 54 years at diagnosis, tamoxifen use longer than 5 years, black race, history of pelvic radiation, and certain hereditary cancer syndromes, such as Lynch syndrome.^9-11 Because of these risk factors, preoperative evaluation is crucial to determine the most appropriate surgical method for removal of a large, fibroid uterus (see “Employ shared decision making”).

Estimated incidence at benign hysterectomy. The incidence of leiomyosarcoma diagnosed at the time of benign hysterectomy or myomectomy has been studied extensively since the FDA’s 2014 warning was released, with varying rates identified.^11,12 The FDA’s analysis cited a risk of 1 in 498 for unsuspected leiomyosarcoma and 1 in 352 for uterine sarcoma.¹ Notably, this analysis excluded studies of women undergoing surgery for presumed fibroids in which no leiomyosarcoma was found on pathology, likely inflating the quoted prevalence. The FDA and other entities subsequently performed further analyses, but a systematic literature review and meta-analysis by the Agency for Healthcare Research and Quality (AHRQ) in 2017 is probably the most accurate. That review included 160 studies and reported a prevalence of less than 1 in 10,000 to 1 in 770, lower than the FDA-cited rate.¹³

Prognosis. The overall prognosis for women with leiomyosarcoma is poor. Studies indicate a 5-year survival rate of only 55.4%, even in stage 1 disease that is apparently confined to the uterus.⁹ Although evidence is limited linking morcellation to increased recurrence of leiomyosarcoma, data from small, single-center, retrospective studies cite a worse prognosis, higher risk of recurrence, and shorter progression-free survival after sarcoma morcellation compared with patients who underwent en bloc resection.^12,14 Of note, these studies evaluated patients who underwent uncontained morcellation of specimens with unsuspected leiomyosarcoma.

CASE Woman with enlarged, irregular uterus and heavy bleeding

A 40-year-old woman (G2P2) with a history of 2 uncomplicated vaginal deliveries presents for evaluation of heavy uterine bleeding. She has regular periods, every 28 days, and she bleeds for 7 days, saturating 6 pads per day. She is currently taking only oral iron therapy as recommended by her primary care physician. Over the last 1 to 2 years she has felt that her abdomen has been getting larger and that her pants do not fit as well. She is otherwise in excellent health, exercises regularly, and has a full-time job. She has not been sexually active in several months.

The patient’s vitals are within normal limits and her body mass index (BMI) is 35 kg/m2.Pelvic examination reveals that she has an enlarged, irregular uterus with the fundus at the level of the umbilicus. The exam is otherwise unremarkable. On further questioning, the patient does not desire future fertility.

What next steps would you include in this patient’s workup, including imaging studies or lab tests? What surgical options would you give her? How would your management differ if this patient were 70 years old (postmenopausal)?

Continue to: Perform a thorough preoperative evaluation to optimize outcomes...

Perform a thorough preoperative evaluation to optimize outcomes

Women like this case patient who present with symptoms that may lead to treatment with myomectomy or hysterectomy should undergo appropriate preoperative testing to evaluate for malignancy.

According to ACOG guidance, patients should undergo a preoperative endometrial biopsy if they¹⁵:

• are older than 45 years with abnormal uterine bleeding
• are younger than 45 years with unopposed estrogen exposure (including obesity or polycystic ovary syndrome)
• have persistent bleeding, or
• failed medical management.

Our case patient is younger than 45 but is obese (BMI, 35) and therefore is a candidate for endometrial biopsy. Additionally, all patients should have up-to-date cervical cancer screening. ACOG also recommends appropriate use of imaging with ultrasonography or magnetic resonance imaging (MRI), although imaging is not recommended solely to evaluate for malignancy, as it cannot rule out the diagnosis of many gynecologic malignancies, including leiomyosarcoma.²

Currently, no tests are available to completely exclude a preoperative diagnosis of leiomyosarcoma. While studies have evaluated the use of MRI combined with lactate dehydrogenase isoenzyme testing, the evidence is weak, and this method is not recommended. Sarcoma is detected by endometrial sampling only 30% to 60% of the time, but it should be performed if the patient meets criteria for sampling or if she has other risk factors for malignancy.¹⁶ There are no data to support biopsy of presumed benign fibroids prior to surgical intervention. Patients should be evaluated with a careful history and physical examination for other uterine sarcoma risk factors.

Employ shared decision making

Clinicians should use shared decision making with patients to facilitate decisions on morcellation use in gynecologic surgeries for suspected benign fibroids. Informed consent must be obtained after thorough discussion and counseling regarding the literature on morcellation.¹⁷ For all patients, including the case patient described, this discussion should include alternative treatment options, surgical approach with associated risks, the use of morcellation, the incidence of leiomyosarcoma with presumed benign fibroids, leiomyosarcoma prognosis, and the risk of disseminating benign or undiagnosed cancerous tissue throughout the abdomen and pelvis.

Some would argue that the risks of laparotomy outweigh the possible risks associated with morcellation during a minimally invasive myomectomy or hysterectomy. However, this risk analysis is not uniform across all patients, and it is likely that in older women, because they have an a priori increased risk of malignancy in general, including leiomyosarcoma, the risks of power morcellation may outweigh the risks of open surgery.¹⁸ Younger women have a much lower risk of leiomyosarcoma, and thus discussion and consideration of the patient’s age should be a part of counseling. If the case patient described was 70 years of age, power morcellation might not be recommended, but these decisions require an in-depth discussion with the patient to make an informed decision and ensure patient autonomy.

The contained morcellation approach

Many surgeons who perform minimally invasive procedures use contained morcellation. In this approach, specimens are placed in a containment bag and morcellated with either power instruments or manually to ensure no dissemination of tissue. Manual contained morcellation can be done through a minilaparotomy or the vagina, depending on the procedure performed, while power contained morcellation is performed through a 15-mm laparoscopic incision.

Continue to: Currently, one containment bag has been...

Currently, one containment bag has been FDA approved for use in laparoscopic contained power morcellation.¹⁹ Use of a containment bag increases operative time by approximately 20 minutes, due to the additional steps required to accomplish the procedure.²⁰ Its use, however, suggests a decrease in the risk of possible disease spread and it is feasible with appropriate surgeon training.

One study demonstrated the safety and feasibility of power morcellation within an insufflated containment bag, and subsequent follow-up revealed negative intraperitoneal washings.^21,22 In another study evaluating tissue dissemination with contained morcellation of tissue stained with dye, the authors noted actual spillage of tissue fragments in only one case.²³ Although more information is needed to confirm prevention of tissue dissemination and the safety of contained tissue morcellation, these studies provide promising data supporting the use of tissue morcellation in appropriate cases in order to perform minimally invasive surgery with larger specimens.

CASE Next steps and treatment outcome

The patient has up-to-date and negative cervical cancer screening. The complete blood count is notable for a hemoglobin level of 11.0 g/dL (normal range, 12.1 to 15.1 g/dL). You perform an endometrial biopsy; results are negative for malignancy. You order pelvic ultrasonography to better characterize the location and size of the fibroids. It shows multiple leiomyomas throughout the myometrium, with the 2 largest fibroids (measuring 5 and 7 cm) located in the left anterior and right posterolateral aspects of the uterus, respectively. Several 3- to 4-cm fibroids appear to be disrupting the endometrial canal, and there is no evidence of an endometrial polyp. There do not appear to be any cervical or lower uterine segment fibroids, which may have further complicated the proposed surgery.

You discuss treatment options for abnormal uterine bleeding with the patient, including initiation of combined oral contraceptive pills, placement of a levonorgestrel-containing intrauterine device, endometrial ablation, uterine artery embolization, and hysterectomy. You discuss the risks and benefits of each approach, keeping in mind the fibroids that are disrupting the contour of the endometrial canal and causing her bulk symptoms.

The patient ultimately decides to undergo a hysterectomy and would like it to be performed with a minimally invasive procedure, if possible. Because of the size of her uterus, you discuss the use of contained power morcellation, including the risks and benefits. You have a thorough discussion about the risk of occult malignancy, although she is at lower risk because of her age, and she consents.

The patient undergoes an uncomplicated total laparoscopic hysterectomy with bilateral salpingectomy. The specimen is removed using contained power morcellation through the umbilical port site. She has an unremarkable immediate postoperative course and is discharged on postoperative Day 1.

You see the patient in the clinic 2 weeks later. She reports minimal pain or discomfort and has no other complaints. Her abdominal incisions are healing well. You review the final pathology report with her, which showed no evidence of malignancy.

Society guidance on clinical applications

In current clinical practice, many surgeons have converted to exclusively performing contained morcellation in appropriate patients with a low risk of uterine leiomyosarcoma. At our institution, uncontained morcellation has not been performed since the FDA’s 2014 warning.

ACOG and AAGL (formerly the American Association of Gynecologic Laparoscopists) recommend use of containment bags as a solution to continue minimally invasive surgery for large specimens without the risk of possible tissue dissemination, although more in-depth surgeon training is likely required for accurate technique.^2,24 The Society of Gynecologic Oncology (SGO) states that power morcellation or any other techniques that divide the uterus in the abdomen are contraindicated in patients with documented or highly suspected malignancy.²⁵

With the presented data of risks associated with uncontained morcellation and agreement of the ACOG, AAGL, and SGO professional societies, we recommend that all morcellation be performed in a contained fashion to prevent the dissemination of benign or undiagnosed malignant tissue throughout the abdomen and pelvis. Shared decision making and counseling on the risks, benefits, and alternatives are paramount for patients to make informed decisions about their medical care. Continued exploration of techniques and methods for safe tissue extraction is still needed to improve minimally invasive surgical options for all women.

Morcellation of gynecologic surgical specimens became controversial after concerns arose about the potential for inadvertent spread of malignant cells throughout the abdomen and pelvis during tissue morcellation of suspected benign disease. In 2014, the US Food and Drug Administration (FDA) issued a warningagainst the use of laparoscopic power morcellation specifically for myomectomy or hysterectomy in the treatment of leiomyomas (fibroids) because of the risk of spreading undiagnosed malignancy throughout the abdomen and pelvis.¹ This warning was issued after a high-profile case occurred in Boston in which an occult uterine sarcoma was morcellated during a supracervical robot-assisted hysterectomy for suspected benign fibroids.

Recently, the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion with updated recommendations for practice detailing the risks associated with morcellation and suggestions for patient counseling regarding morcellation.²

In this review, we summarize the techniques and risks of morcellation, the epidemiology of undiagnosed uterine malignancies, practice changes noted at our institution, and clinical recommendations moving forward. A case scenario illustrates keys steps in preoperative evaluation and counseling.

Morcellation uses—and risks

Morcellation is the surgical process of dividing a large tissue specimen into smaller pieces to facilitate their removal through the small incisions made in minimally invasive surgery. Morcellation may be performed with a power instrument or manually.

In power morcellation, an electromechanical instrument is used to cut or shave the specimen; in manual morcellation, the surgeon uses a knife to carve the specimen. Power morcellation is performed through a laparoscopic incision, while the manual technique is performed through a minilaparotomy or vaginally after hysterectomy (TABLE). Unlike uncontained morcellation, contained morcellation involves the use of a laparoscopic bag to hold the specimen and therefore prevent tissue dissemination in the abdomen and pelvis.

Morcellation has greatly expanded our ability to perform minimally invasive surgery—for example, in patients with specimens that cannot be extracted en bloc through the vagina after hysterectomy or, in the case of myomectomy or supracervical hysterectomy without a colpotomy, through small laparoscopic ports. Minimally invasive surgery improves patient care, as it is associated with lower rates of infection, blood loss, venous thromboembolism, wound and bowel complications, postoperative pain, and shorter overall recovery time and hospital stay versus traditional open surgery.^3,4 Furthermore, laparoscopic hysterectomy has a 3-fold lower risk of mortality compared with open hysterectomy.⁴ For these reasons, ACOG recommends choosing a minimally invasive approach for all benign hysterectomies whenever feasible.³

With abundant data supporting the use of a minimally invasive approach, laparoscopic morcellation allowed procedures involving larger tissue specimens to be accomplished without the addition of a minilaparotomy for tissue extraction. However, disseminating potentially malignant tissue throughout the abdomen and pelvis during the morcellation process remains a risk. While tissue spread can occur with either power or manual morcellation, the case that drew media attention to the controversy used power morcellation, and thus intense scrutiny focused on this technique. Morcellation has additional risks, including direct injury to surrounding organs, disruption of the pathologic specimen, and distribution of benign tissue throughout the abdomen and pelvis, such as fibroid, endometriosis, and adenomyosis implants.^5-7

Continue to: The challenge of leiomyosarcoma...

The challenge of leiomyosarcoma

The primary controversy surrounding morcellation of fibroid tissue specimens is the potential for undiagnosed malignancy, namely uterine leiomyosarcoma or endometrial stromal sarcoma. While other gynecologic malignancies, including cervical and endometrial cancers, are more common and potentially could be disseminated by morcellation, these cancers are more reliably diagnosed preoperatively with cervical and endometrial biopsies, and they do not tend to mimic benign diseases.

Epidemiology and risk factors. Uterine leiomyosarcoma is rare, with an estimated incidence of 0.36 per 100,000 woman-years.⁸ However, leiomyosarcoma can mimic the appearance and clinical course of benign fibroids, making preoperative diagnosis difficult. Risk factors for leiomyosarcoma include postmenopausal status, with a median age of 54 years at diagnosis, tamoxifen use longer than 5 years, black race, history of pelvic radiation, and certain hereditary cancer syndromes, such as Lynch syndrome.^9-11 Because of these risk factors, preoperative evaluation is crucial to determine the most appropriate surgical method for removal of a large, fibroid uterus (see “Employ shared decision making”).

Estimated incidence at benign hysterectomy. The incidence of leiomyosarcoma diagnosed at the time of benign hysterectomy or myomectomy has been studied extensively since the FDA’s 2014 warning was released, with varying rates identified.^11,12 The FDA’s analysis cited a risk of 1 in 498 for unsuspected leiomyosarcoma and 1 in 352 for uterine sarcoma.¹ Notably, this analysis excluded studies of women undergoing surgery for presumed fibroids in which no leiomyosarcoma was found on pathology, likely inflating the quoted prevalence. The FDA and other entities subsequently performed further analyses, but a systematic literature review and meta-analysis by the Agency for Healthcare Research and Quality (AHRQ) in 2017 is probably the most accurate. That review included 160 studies and reported a prevalence of less than 1 in 10,000 to 1 in 770, lower than the FDA-cited rate.¹³

Prognosis. The overall prognosis for women with leiomyosarcoma is poor. Studies indicate a 5-year survival rate of only 55.4%, even in stage 1 disease that is apparently confined to the uterus.⁹ Although evidence is limited linking morcellation to increased recurrence of leiomyosarcoma, data from small, single-center, retrospective studies cite a worse prognosis, higher risk of recurrence, and shorter progression-free survival after sarcoma morcellation compared with patients who underwent en bloc resection.^12,14 Of note, these studies evaluated patients who underwent uncontained morcellation of specimens with unsuspected leiomyosarcoma.

CASE Woman with enlarged, irregular uterus and heavy bleeding

A 40-year-old woman (G2P2) with a history of 2 uncomplicated vaginal deliveries presents for evaluation of heavy uterine bleeding. She has regular periods, every 28 days, and she bleeds for 7 days, saturating 6 pads per day. She is currently taking only oral iron therapy as recommended by her primary care physician. Over the last 1 to 2 years she has felt that her abdomen has been getting larger and that her pants do not fit as well. She is otherwise in excellent health, exercises regularly, and has a full-time job. She has not been sexually active in several months.

The patient’s vitals are within normal limits and her body mass index (BMI) is 35 kg/m2.Pelvic examination reveals that she has an enlarged, irregular uterus with the fundus at the level of the umbilicus. The exam is otherwise unremarkable. On further questioning, the patient does not desire future fertility.

What next steps would you include in this patient’s workup, including imaging studies or lab tests? What surgical options would you give her? How would your management differ if this patient were 70 years old (postmenopausal)?

Continue to: Perform a thorough preoperative evaluation to optimize outcomes...

Perform a thorough preoperative evaluation to optimize outcomes

Women like this case patient who present with symptoms that may lead to treatment with myomectomy or hysterectomy should undergo appropriate preoperative testing to evaluate for malignancy.

According to ACOG guidance, patients should undergo a preoperative endometrial biopsy if they¹⁵:

• are older than 45 years with abnormal uterine bleeding
• are younger than 45 years with unopposed estrogen exposure (including obesity or polycystic ovary syndrome)
• have persistent bleeding, or
• failed medical management.

Our case patient is younger than 45 but is obese (BMI, 35) and therefore is a candidate for endometrial biopsy. Additionally, all patients should have up-to-date cervical cancer screening. ACOG also recommends appropriate use of imaging with ultrasonography or magnetic resonance imaging (MRI), although imaging is not recommended solely to evaluate for malignancy, as it cannot rule out the diagnosis of many gynecologic malignancies, including leiomyosarcoma.²

Currently, no tests are available to completely exclude a preoperative diagnosis of leiomyosarcoma. While studies have evaluated the use of MRI combined with lactate dehydrogenase isoenzyme testing, the evidence is weak, and this method is not recommended. Sarcoma is detected by endometrial sampling only 30% to 60% of the time, but it should be performed if the patient meets criteria for sampling or if she has other risk factors for malignancy.¹⁶ There are no data to support biopsy of presumed benign fibroids prior to surgical intervention. Patients should be evaluated with a careful history and physical examination for other uterine sarcoma risk factors.

Employ shared decision making

Clinicians should use shared decision making with patients to facilitate decisions on morcellation use in gynecologic surgeries for suspected benign fibroids. Informed consent must be obtained after thorough discussion and counseling regarding the literature on morcellation.¹⁷ For all patients, including the case patient described, this discussion should include alternative treatment options, surgical approach with associated risks, the use of morcellation, the incidence of leiomyosarcoma with presumed benign fibroids, leiomyosarcoma prognosis, and the risk of disseminating benign or undiagnosed cancerous tissue throughout the abdomen and pelvis.

Some would argue that the risks of laparotomy outweigh the possible risks associated with morcellation during a minimally invasive myomectomy or hysterectomy. However, this risk analysis is not uniform across all patients, and it is likely that in older women, because they have an a priori increased risk of malignancy in general, including leiomyosarcoma, the risks of power morcellation may outweigh the risks of open surgery.¹⁸ Younger women have a much lower risk of leiomyosarcoma, and thus discussion and consideration of the patient’s age should be a part of counseling. If the case patient described was 70 years of age, power morcellation might not be recommended, but these decisions require an in-depth discussion with the patient to make an informed decision and ensure patient autonomy.

The contained morcellation approach

Many surgeons who perform minimally invasive procedures use contained morcellation. In this approach, specimens are placed in a containment bag and morcellated with either power instruments or manually to ensure no dissemination of tissue. Manual contained morcellation can be done through a minilaparotomy or the vagina, depending on the procedure performed, while power contained morcellation is performed through a 15-mm laparoscopic incision.

Continue to: Currently, one containment bag has been...

Currently, one containment bag has been FDA approved for use in laparoscopic contained power morcellation.¹⁹ Use of a containment bag increases operative time by approximately 20 minutes, due to the additional steps required to accomplish the procedure.²⁰ Its use, however, suggests a decrease in the risk of possible disease spread and it is feasible with appropriate surgeon training.

One study demonstrated the safety and feasibility of power morcellation within an insufflated containment bag, and subsequent follow-up revealed negative intraperitoneal washings.^21,22 In another study evaluating tissue dissemination with contained morcellation of tissue stained with dye, the authors noted actual spillage of tissue fragments in only one case.²³ Although more information is needed to confirm prevention of tissue dissemination and the safety of contained tissue morcellation, these studies provide promising data supporting the use of tissue morcellation in appropriate cases in order to perform minimally invasive surgery with larger specimens.

CASE Next steps and treatment outcome

The patient has up-to-date and negative cervical cancer screening. The complete blood count is notable for a hemoglobin level of 11.0 g/dL (normal range, 12.1 to 15.1 g/dL). You perform an endometrial biopsy; results are negative for malignancy. You order pelvic ultrasonography to better characterize the location and size of the fibroids. It shows multiple leiomyomas throughout the myometrium, with the 2 largest fibroids (measuring 5 and 7 cm) located in the left anterior and right posterolateral aspects of the uterus, respectively. Several 3- to 4-cm fibroids appear to be disrupting the endometrial canal, and there is no evidence of an endometrial polyp. There do not appear to be any cervical or lower uterine segment fibroids, which may have further complicated the proposed surgery.

You discuss treatment options for abnormal uterine bleeding with the patient, including initiation of combined oral contraceptive pills, placement of a levonorgestrel-containing intrauterine device, endometrial ablation, uterine artery embolization, and hysterectomy. You discuss the risks and benefits of each approach, keeping in mind the fibroids that are disrupting the contour of the endometrial canal and causing her bulk symptoms.

The patient ultimately decides to undergo a hysterectomy and would like it to be performed with a minimally invasive procedure, if possible. Because of the size of her uterus, you discuss the use of contained power morcellation, including the risks and benefits. You have a thorough discussion about the risk of occult malignancy, although she is at lower risk because of her age, and she consents.

The patient undergoes an uncomplicated total laparoscopic hysterectomy with bilateral salpingectomy. The specimen is removed using contained power morcellation through the umbilical port site. She has an unremarkable immediate postoperative course and is discharged on postoperative Day 1.

You see the patient in the clinic 2 weeks later. She reports minimal pain or discomfort and has no other complaints. Her abdominal incisions are healing well. You review the final pathology report with her, which showed no evidence of malignancy.

Society guidance on clinical applications

In current clinical practice, many surgeons have converted to exclusively performing contained morcellation in appropriate patients with a low risk of uterine leiomyosarcoma. At our institution, uncontained morcellation has not been performed since the FDA’s 2014 warning.

ACOG and AAGL (formerly the American Association of Gynecologic Laparoscopists) recommend use of containment bags as a solution to continue minimally invasive surgery for large specimens without the risk of possible tissue dissemination, although more in-depth surgeon training is likely required for accurate technique.^2,24 The Society of Gynecologic Oncology (SGO) states that power morcellation or any other techniques that divide the uterus in the abdomen are contraindicated in patients with documented or highly suspected malignancy.²⁵

With the presented data of risks associated with uncontained morcellation and agreement of the ACOG, AAGL, and SGO professional societies, we recommend that all morcellation be performed in a contained fashion to prevent the dissemination of benign or undiagnosed malignant tissue throughout the abdomen and pelvis. Shared decision making and counseling on the risks, benefits, and alternatives are paramount for patients to make informed decisions about their medical care. Continued exploration of techniques and methods for safe tissue extraction is still needed to improve minimally invasive surgical options for all women.

Morcellation of gynecologic surgical specimens became controversial after concerns arose about the potential for inadvertent spread of malignant cells throughout the abdomen and pelvis during tissue morcellation of suspected benign disease. In 2014, the US Food and Drug Administration (FDA) issued a warningagainst the use of laparoscopic power morcellation specifically for myomectomy or hysterectomy in the treatment of leiomyomas (fibroids) because of the risk of spreading undiagnosed malignancy throughout the abdomen and pelvis.¹ This warning was issued after a high-profile case occurred in Boston in which an occult uterine sarcoma was morcellated during a supracervical robot-assisted hysterectomy for suspected benign fibroids.

Recently, the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion with updated recommendations for practice detailing the risks associated with morcellation and suggestions for patient counseling regarding morcellation.²

In this review, we summarize the techniques and risks of morcellation, the epidemiology of undiagnosed uterine malignancies, practice changes noted at our institution, and clinical recommendations moving forward. A case scenario illustrates keys steps in preoperative evaluation and counseling.

Morcellation uses—and risks

Morcellation is the surgical process of dividing a large tissue specimen into smaller pieces to facilitate their removal through the small incisions made in minimally invasive surgery. Morcellation may be performed with a power instrument or manually.

In power morcellation, an electromechanical instrument is used to cut or shave the specimen; in manual morcellation, the surgeon uses a knife to carve the specimen. Power morcellation is performed through a laparoscopic incision, while the manual technique is performed through a minilaparotomy or vaginally after hysterectomy (TABLE). Unlike uncontained morcellation, contained morcellation involves the use of a laparoscopic bag to hold the specimen and therefore prevent tissue dissemination in the abdomen and pelvis.

Morcellation has greatly expanded our ability to perform minimally invasive surgery—for example, in patients with specimens that cannot be extracted en bloc through the vagina after hysterectomy or, in the case of myomectomy or supracervical hysterectomy without a colpotomy, through small laparoscopic ports. Minimally invasive surgery improves patient care, as it is associated with lower rates of infection, blood loss, venous thromboembolism, wound and bowel complications, postoperative pain, and shorter overall recovery time and hospital stay versus traditional open surgery.^3,4 Furthermore, laparoscopic hysterectomy has a 3-fold lower risk of mortality compared with open hysterectomy.⁴ For these reasons, ACOG recommends choosing a minimally invasive approach for all benign hysterectomies whenever feasible.³

With abundant data supporting the use of a minimally invasive approach, laparoscopic morcellation allowed procedures involving larger tissue specimens to be accomplished without the addition of a minilaparotomy for tissue extraction. However, disseminating potentially malignant tissue throughout the abdomen and pelvis during the morcellation process remains a risk. While tissue spread can occur with either power or manual morcellation, the case that drew media attention to the controversy used power morcellation, and thus intense scrutiny focused on this technique. Morcellation has additional risks, including direct injury to surrounding organs, disruption of the pathologic specimen, and distribution of benign tissue throughout the abdomen and pelvis, such as fibroid, endometriosis, and adenomyosis implants.^5-7

Continue to: The challenge of leiomyosarcoma...

The challenge of leiomyosarcoma

The primary controversy surrounding morcellation of fibroid tissue specimens is the potential for undiagnosed malignancy, namely uterine leiomyosarcoma or endometrial stromal sarcoma. While other gynecologic malignancies, including cervical and endometrial cancers, are more common and potentially could be disseminated by morcellation, these cancers are more reliably diagnosed preoperatively with cervical and endometrial biopsies, and they do not tend to mimic benign diseases.

Epidemiology and risk factors. Uterine leiomyosarcoma is rare, with an estimated incidence of 0.36 per 100,000 woman-years.⁸ However, leiomyosarcoma can mimic the appearance and clinical course of benign fibroids, making preoperative diagnosis difficult. Risk factors for leiomyosarcoma include postmenopausal status, with a median age of 54 years at diagnosis, tamoxifen use longer than 5 years, black race, history of pelvic radiation, and certain hereditary cancer syndromes, such as Lynch syndrome.^9-11 Because of these risk factors, preoperative evaluation is crucial to determine the most appropriate surgical method for removal of a large, fibroid uterus (see “Employ shared decision making”).

Estimated incidence at benign hysterectomy. The incidence of leiomyosarcoma diagnosed at the time of benign hysterectomy or myomectomy has been studied extensively since the FDA’s 2014 warning was released, with varying rates identified.^11,12 The FDA’s analysis cited a risk of 1 in 498 for unsuspected leiomyosarcoma and 1 in 352 for uterine sarcoma.¹ Notably, this analysis excluded studies of women undergoing surgery for presumed fibroids in which no leiomyosarcoma was found on pathology, likely inflating the quoted prevalence. The FDA and other entities subsequently performed further analyses, but a systematic literature review and meta-analysis by the Agency for Healthcare Research and Quality (AHRQ) in 2017 is probably the most accurate. That review included 160 studies and reported a prevalence of less than 1 in 10,000 to 1 in 770, lower than the FDA-cited rate.¹³

Prognosis. The overall prognosis for women with leiomyosarcoma is poor. Studies indicate a 5-year survival rate of only 55.4%, even in stage 1 disease that is apparently confined to the uterus.⁹ Although evidence is limited linking morcellation to increased recurrence of leiomyosarcoma, data from small, single-center, retrospective studies cite a worse prognosis, higher risk of recurrence, and shorter progression-free survival after sarcoma morcellation compared with patients who underwent en bloc resection.^12,14 Of note, these studies evaluated patients who underwent uncontained morcellation of specimens with unsuspected leiomyosarcoma.

CASE Woman with enlarged, irregular uterus and heavy bleeding

A 40-year-old woman (G2P2) with a history of 2 uncomplicated vaginal deliveries presents for evaluation of heavy uterine bleeding. She has regular periods, every 28 days, and she bleeds for 7 days, saturating 6 pads per day. She is currently taking only oral iron therapy as recommended by her primary care physician. Over the last 1 to 2 years she has felt that her abdomen has been getting larger and that her pants do not fit as well. She is otherwise in excellent health, exercises regularly, and has a full-time job. She has not been sexually active in several months.

The patient’s vitals are within normal limits and her body mass index (BMI) is 35 kg/m2.Pelvic examination reveals that she has an enlarged, irregular uterus with the fundus at the level of the umbilicus. The exam is otherwise unremarkable. On further questioning, the patient does not desire future fertility.

What next steps would you include in this patient’s workup, including imaging studies or lab tests? What surgical options would you give her? How would your management differ if this patient were 70 years old (postmenopausal)?

Continue to: Perform a thorough preoperative evaluation to optimize outcomes...

Perform a thorough preoperative evaluation to optimize outcomes

Women like this case patient who present with symptoms that may lead to treatment with myomectomy or hysterectomy should undergo appropriate preoperative testing to evaluate for malignancy.

According to ACOG guidance, patients should undergo a preoperative endometrial biopsy if they¹⁵:

• are older than 45 years with abnormal uterine bleeding
• are younger than 45 years with unopposed estrogen exposure (including obesity or polycystic ovary syndrome)
• have persistent bleeding, or
• failed medical management.

Our case patient is younger than 45 but is obese (BMI, 35) and therefore is a candidate for endometrial biopsy. Additionally, all patients should have up-to-date cervical cancer screening. ACOG also recommends appropriate use of imaging with ultrasonography or magnetic resonance imaging (MRI), although imaging is not recommended solely to evaluate for malignancy, as it cannot rule out the diagnosis of many gynecologic malignancies, including leiomyosarcoma.²

Currently, no tests are available to completely exclude a preoperative diagnosis of leiomyosarcoma. While studies have evaluated the use of MRI combined with lactate dehydrogenase isoenzyme testing, the evidence is weak, and this method is not recommended. Sarcoma is detected by endometrial sampling only 30% to 60% of the time, but it should be performed if the patient meets criteria for sampling or if she has other risk factors for malignancy.¹⁶ There are no data to support biopsy of presumed benign fibroids prior to surgical intervention. Patients should be evaluated with a careful history and physical examination for other uterine sarcoma risk factors.

Employ shared decision making

Clinicians should use shared decision making with patients to facilitate decisions on morcellation use in gynecologic surgeries for suspected benign fibroids. Informed consent must be obtained after thorough discussion and counseling regarding the literature on morcellation.¹⁷ For all patients, including the case patient described, this discussion should include alternative treatment options, surgical approach with associated risks, the use of morcellation, the incidence of leiomyosarcoma with presumed benign fibroids, leiomyosarcoma prognosis, and the risk of disseminating benign or undiagnosed cancerous tissue throughout the abdomen and pelvis.

Some would argue that the risks of laparotomy outweigh the possible risks associated with morcellation during a minimally invasive myomectomy or hysterectomy. However, this risk analysis is not uniform across all patients, and it is likely that in older women, because they have an a priori increased risk of malignancy in general, including leiomyosarcoma, the risks of power morcellation may outweigh the risks of open surgery.¹⁸ Younger women have a much lower risk of leiomyosarcoma, and thus discussion and consideration of the patient’s age should be a part of counseling. If the case patient described was 70 years of age, power morcellation might not be recommended, but these decisions require an in-depth discussion with the patient to make an informed decision and ensure patient autonomy.

The contained morcellation approach

Many surgeons who perform minimally invasive procedures use contained morcellation. In this approach, specimens are placed in a containment bag and morcellated with either power instruments or manually to ensure no dissemination of tissue. Manual contained morcellation can be done through a minilaparotomy or the vagina, depending on the procedure performed, while power contained morcellation is performed through a 15-mm laparoscopic incision.

Continue to: Currently, one containment bag has been...

Currently, one containment bag has been FDA approved for use in laparoscopic contained power morcellation.¹⁹ Use of a containment bag increases operative time by approximately 20 minutes, due to the additional steps required to accomplish the procedure.²⁰ Its use, however, suggests a decrease in the risk of possible disease spread and it is feasible with appropriate surgeon training.

One study demonstrated the safety and feasibility of power morcellation within an insufflated containment bag, and subsequent follow-up revealed negative intraperitoneal washings.^21,22 In another study evaluating tissue dissemination with contained morcellation of tissue stained with dye, the authors noted actual spillage of tissue fragments in only one case.²³ Although more information is needed to confirm prevention of tissue dissemination and the safety of contained tissue morcellation, these studies provide promising data supporting the use of tissue morcellation in appropriate cases in order to perform minimally invasive surgery with larger specimens.

CASE Next steps and treatment outcome

The patient has up-to-date and negative cervical cancer screening. The complete blood count is notable for a hemoglobin level of 11.0 g/dL (normal range, 12.1 to 15.1 g/dL). You perform an endometrial biopsy; results are negative for malignancy. You order pelvic ultrasonography to better characterize the location and size of the fibroids. It shows multiple leiomyomas throughout the myometrium, with the 2 largest fibroids (measuring 5 and 7 cm) located in the left anterior and right posterolateral aspects of the uterus, respectively. Several 3- to 4-cm fibroids appear to be disrupting the endometrial canal, and there is no evidence of an endometrial polyp. There do not appear to be any cervical or lower uterine segment fibroids, which may have further complicated the proposed surgery.

You discuss treatment options for abnormal uterine bleeding with the patient, including initiation of combined oral contraceptive pills, placement of a levonorgestrel-containing intrauterine device, endometrial ablation, uterine artery embolization, and hysterectomy. You discuss the risks and benefits of each approach, keeping in mind the fibroids that are disrupting the contour of the endometrial canal and causing her bulk symptoms.

The patient ultimately decides to undergo a hysterectomy and would like it to be performed with a minimally invasive procedure, if possible. Because of the size of her uterus, you discuss the use of contained power morcellation, including the risks and benefits. You have a thorough discussion about the risk of occult malignancy, although she is at lower risk because of her age, and she consents.

The patient undergoes an uncomplicated total laparoscopic hysterectomy with bilateral salpingectomy. The specimen is removed using contained power morcellation through the umbilical port site. She has an unremarkable immediate postoperative course and is discharged on postoperative Day 1.

You see the patient in the clinic 2 weeks later. She reports minimal pain or discomfort and has no other complaints. Her abdominal incisions are healing well. You review the final pathology report with her, which showed no evidence of malignancy.

Society guidance on clinical applications

In current clinical practice, many surgeons have converted to exclusively performing contained morcellation in appropriate patients with a low risk of uterine leiomyosarcoma. At our institution, uncontained morcellation has not been performed since the FDA’s 2014 warning.

ACOG and AAGL (formerly the American Association of Gynecologic Laparoscopists) recommend use of containment bags as a solution to continue minimally invasive surgery for large specimens without the risk of possible tissue dissemination, although more in-depth surgeon training is likely required for accurate technique.^2,24 The Society of Gynecologic Oncology (SGO) states that power morcellation or any other techniques that divide the uterus in the abdomen are contraindicated in patients with documented or highly suspected malignancy.²⁵

With the presented data of risks associated with uncontained morcellation and agreement of the ACOG, AAGL, and SGO professional societies, we recommend that all morcellation be performed in a contained fashion to prevent the dissemination of benign or undiagnosed malignant tissue throughout the abdomen and pelvis. Shared decision making and counseling on the risks, benefits, and alternatives are paramount for patients to make informed decisions about their medical care. Continued exploration of techniques and methods for safe tissue extraction is still needed to improve minimally invasive surgical options for all women.

CASE HT for vasomotor symptoms in perimenopausal woman with cognitive concerns

Jackie is a 49-year-old woman. Her body mass index is 33 kg/m², and she has mild hypertension that is effectively controlled with antihypertensive medications. Otherwise, she is in good health.During her annual gynecologic exam, she reports that for the past 9 months her menstrual cycles have not been as regular as they used to be and that 3 months ago she skipped a cycle. She is having bothersome vasomotor symptoms (VMS) and is concerned about her memory. She says she is forgetful at work and in social situations. During a recent presentation, she could not remember the name of one of her former clients. At a work happy hour, she forgot the name of her coworker’s husband, although she did remember it later after returning home.

Her mother has Alzheimer disease (AD), and Jackie worries about whether she, too, might be developing dementia and whether her memory will fail her in social situations.

She is concerned about using hormone therapy (HT) for her vasomotor symptoms because she has heard that it can lead to breast cancer and/or AD.

How would you advise her?

HT remains the most effective treatment for bothersome VMS, but concerns about its cognitive safety persist. Such concerns, and indeed a black-box warning about the risk of dementia with HT use, initially arose following the 2003 publication of the Women’s Health Initiative Memory Study (WHIMS), a randomized, placebo-controlled trial of HT for the primary prevention of dementia in women aged 65 years and older at baseline.¹ The study found that combination estrogen/progestin therapy was associated with a 2-fold increase in dementia when compared with placebo.

One of the critical questions arising even before WHIMS was whether the cognitive risks associated with HT that were seen in WHIMS apply to younger women. Attempting to answer the question and adding fuel to the fire are the results of a recent case-control study from Finland.² This study compared HT use in Finnish women with and without AD and found that HT use was higher among Finnish women with AD compared with those without AD, regardless of age. The authors concluded, “Our data must be implemented into information for the present and future users of HT, even though the absolute risk increase is small.”

However, given the limitations inherent to observational and registry studies, and the contrasting findings of 3 high-quality, randomized controlled trials (RCTs; more details below), providers actually can reassure younger peri- and postmenopausal women about the cognitive safety of HT.³ They also can explain to patients that cognitive symptoms like the ones described in the case example are normal and provide general guidance to midlife women on how to optimize brain health.

Continue to: Closer look at WHI and RCT research pinpoints cognitively neutral HT...

Closer look at WHI and RCT research pinpoints cognitively neutral HT

In WHIMS, the combination of conjugated equine estrogen (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) led to a doubling of the risk of all-cause dementia compared with placebo in a sample of 4,532 women aged 65 years and older at baseline.¹ CEE alone (0.625 mg) did not lead to an increased risk of all-cause dementia.⁴

Whether those formulations led to cognitive impairment in younger postmenopausal women was the focus of WHIMS-Younger (WHIMS-Y), which involved WHI participants aged 50 to 55 years at baseline.⁵ Results revealed neutral cognitive effects (ie, no differences in cognitive performance in women randomly assigned to HT or placebo) in women tested 7.2 years after the end of the WHI trial. WHIMS-Y findings indicated that there were no sustained cognitive risks of CEE or CEE/MPA therapy. Two randomized, placebo-controlled trials involving younger postmenopausal women yielded similar findings.^6,7 HT shown to produce cognitively neutral effects during active treatment included transdermal estradiol plus micronized progesterone,⁶ CEE plus progesterone,⁶ and oral estradiol plus vaginal progesterone gel.⁷ The findings of these randomized trials are critical for guiding decisions regarding the cognitive risks of HT in early postmenopausal women (TABLE 1).

What about women with VMS?

A key gap in knowledge about the cognitive effects of HT is whether HT confers cognitive advantages to women with bothersome VMS. This is a striking absence given that the key indication for HT is the treatment of VMS. While some symptomatic women were included in the trials of HT in younger postmenopausal women described above, no large trial to date has selectively enrolled women with moderate-to-severe VMS to determine if HT is cognitively neutral, beneficial, or detrimental in that group. Some studies involving midlife women have found associations between VMS (as measured with ambulatory skin conductance monitors) and multiple measures of brain health, including memory performance,⁸ small ischemic lesions on structural brain scans,⁹ and altered brain function.¹⁰ In a small trial of a nonhormonal intervention for VMS, improvement in VMS following the intervention was directly related to improvement in memory performance.¹¹ The reliability of these findings continues to be evaluated but raises the hypothesis that VMS treatments might improve memory in midlife women.

Memory complaints common among midlife women

About 60% of women report an undesirable change in memory performance at midlife as compared with earlier in their lives.^12,13 Complaints of forgetfulness are higher in perimenopausal and postmenopausal women compared with premenopausal women, even when those women are similar in age.¹⁴ Two large prospective studies found that memory performance decreases during the perimenopause and then rebounds, suggesting a transient decrease in memory.^15,16 Although cognitive complaints are common among women in their 40s and 50s, AD is rare in that age group. The risk is largely limited to those women with a parent who developed dementia before age 65, as such cases suggest a familial form of AD.

Continue to: What causes cognitive difficulties during midlife?

What causes cognitive difficulties during midlife?

First, some cognitive decline is expected at midlife based on increasing age. Second, above and beyond the role of chronologic aging (ie, getting one year older each year), ovarian aging plays a role. A role of estrogen was verified in clinical trials showing that memory decreased following oophorectomy in premenopausal women in their 40s but returned to presurgical levels following treatment with estrogen therapy (ET).¹⁷ Cohort studies indicate that women who undergo oophorectomy before the typical age of menopause are at increased risk for cognitive impairment or dementia, but those who take ET after oophorectomy until the typical age of menopause do not show that risk.¹⁸

Third, cognitive problems are linked not only to VMS but also to sleep disturbance, depressed mood, and increased anxiety—all of which are common in midlife women.^15,19 Lastly, health factors play a role. Hypertension, obesity, insulin resistance, diabetes, and smoking are associated with adverse brain changes at midlife.²⁰

Giving advice to your patients

First, normalize the cognitive complaints, noting that some cognitive changes are an expected part of aging for all people regardless of whether they are male or female. Advise that while the best studies indicate that these cognitive lapses are especially common in perimenopausal women, they appear to be temporary; women are likely to resume normal cognitive function once the hormonal changes associated with menopause subside.^15,16 Note that the one unknown is the role that VMS play in memory problems and that some studies indicate a link between VMS and cognitive problems. Women may experience some cognitive improvement if VMS are effectively treated.

Advise patients that the Endocrine Society, the North American Menopause Society (NAMS), and the International Menopause Society all have published guidelines saying that the benefits of HT outweigh the risks for most women aged 50 to 60 years.²¹ For concerns about the cognitive adverse effects of HT, discuss the best quality evidence—that which comes from randomized trials—which shows no harmful effects of HT in midlife women.^5-7 Especially reassuring is that one of these high-quality studies was conducted by the same researchers who found that HT can be risky in older women (ie, the WHI Investigators).⁵

Going one step further: Protecting brain health

As primary care providers to midlife women, ObGyns can go one step further and advise patients on how to proactively nurture their brain health. Great evidence-based resources for information on maintaining brain health include the Alzheimer’s Association (https://www.alz.org) and the Women’s Brain Health Initiative (https://womensbrainhealth.org). Primary prevention of AD begins decades before the typical age of an AD diagnosis, and many risk factors for AD are modifiable.²² Patients can keep their brains healthy through myriad approaches including treating hypertension, reducing body mass index, engaging in regular aerobic exercise (brisk walking is fine), eating a Mediterranean diet, maintaining an active social life, and engaging in novel challenging activities like learning a new language or a new skill like dancing.²⁰

Also important is the overlap between cognitive issues, mood, and alcohol use. In the opening case, Jackie mentions alcohol use and social withdrawal. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), low-risk drinking for women is defined as no more than 3 drinks on any single day and no more than 7 drinks per week.²³ Heavy alcohol use not only affects brain function but also mood, and depressed mood can lead women to drink excessively.²⁴

In addition, Jackie’s mother has AD, and that stressor can contribute to depressed feelings, especially if Jackie is involved in caregiving. A quick screen for depression with an instrument like the Patient Health Questionnaire-2 (PHQ-2; TABLE 2)²⁵ can rule out a more serious mood disorder—an approach that is particularly important for patients with a history of major depression, as 58% of those patients experience a major depressive episode during the menopausal transition.²⁶ For this reason, it is important to ask patients like Jackie if they have a history of depression; if they do and were treated medically, consider prescribing the antidepressant that worked in the past. For information on menopause and mood-related issues, providers can access new guidelines from NAMS and the National Network of Depression Centers (NNDC).²⁷ There is also a handy patient information sheet to accompany those guidelines on the NAMS website (https://www.menopause.org/).

Continue to: CASE Resolved...

CASE Resolved

When approaching Jackie, most importantly, I would normalize her experience and tell her that memory problems are common in the menopausal transition, especially for women with bothersome VMS. Research suggests that the memory problems she is experiencing are related to hormonal changes and not to AD, and that her memory will likely improve once she has transitioned through the menopause. I would tell her that AD is rare at midlife unless there is a family history of early onset of AD (before age 65), and I would verify the age at which her mother was diagnosed to confirm that it was late-onset AD.

For now, I would recommend that she be prescribed HT for her bothersome hot flashes using one of the “safe” formulations in the Table on page 24. I also would tell her that there is much she can do to lower her risk of AD and that it is best to start now as she enters her 50s because that is when AD changes typically start in the brain, and she can start to prevent those changes now.

I would tell her that experts in the field of AD agree that these lifestyle interventions are currently the best way to prevent AD and that the more of them she engages in, the more her brain will benefit. I would advise her to continue to manage her hypertension and to consider ways of lowering her BMI to enhance her brain health. Engaging in regular brisk walking or other aerobic exercise, as well as incorporating more of the Mediterranean diet into her daily food intake would also benefit her brain. As a working woman, she is exercising her brain, and she should consider other cognitively challenging activities to keep her brain in good shape.

I would follow up with her in a few months to see if her memory functioning is better. If it is not, and if her VMS continue to be bothersome, I would increase her dose of HT. Only if her VMS are treated but her memory problems are getting worse would I screen her with a Mini-Mental State Exam and refer her to a neurologist for an evaluation.
 

CASE HT for vasomotor symptoms in perimenopausal woman with cognitive concerns

Jackie is a 49-year-old woman. Her body mass index is 33 kg/m², and she has mild hypertension that is effectively controlled with antihypertensive medications. Otherwise, she is in good health.During her annual gynecologic exam, she reports that for the past 9 months her menstrual cycles have not been as regular as they used to be and that 3 months ago she skipped a cycle. She is having bothersome vasomotor symptoms (VMS) and is concerned about her memory. She says she is forgetful at work and in social situations. During a recent presentation, she could not remember the name of one of her former clients. At a work happy hour, she forgot the name of her coworker’s husband, although she did remember it later after returning home.

Her mother has Alzheimer disease (AD), and Jackie worries about whether she, too, might be developing dementia and whether her memory will fail her in social situations.

She is concerned about using hormone therapy (HT) for her vasomotor symptoms because she has heard that it can lead to breast cancer and/or AD.

How would you advise her?

HT remains the most effective treatment for bothersome VMS, but concerns about its cognitive safety persist. Such concerns, and indeed a black-box warning about the risk of dementia with HT use, initially arose following the 2003 publication of the Women’s Health Initiative Memory Study (WHIMS), a randomized, placebo-controlled trial of HT for the primary prevention of dementia in women aged 65 years and older at baseline.¹ The study found that combination estrogen/progestin therapy was associated with a 2-fold increase in dementia when compared with placebo.

One of the critical questions arising even before WHIMS was whether the cognitive risks associated with HT that were seen in WHIMS apply to younger women. Attempting to answer the question and adding fuel to the fire are the results of a recent case-control study from Finland.² This study compared HT use in Finnish women with and without AD and found that HT use was higher among Finnish women with AD compared with those without AD, regardless of age. The authors concluded, “Our data must be implemented into information for the present and future users of HT, even though the absolute risk increase is small.”

However, given the limitations inherent to observational and registry studies, and the contrasting findings of 3 high-quality, randomized controlled trials (RCTs; more details below), providers actually can reassure younger peri- and postmenopausal women about the cognitive safety of HT.³ They also can explain to patients that cognitive symptoms like the ones described in the case example are normal and provide general guidance to midlife women on how to optimize brain health.

Continue to: Closer look at WHI and RCT research pinpoints cognitively neutral HT...

Closer look at WHI and RCT research pinpoints cognitively neutral HT

In WHIMS, the combination of conjugated equine estrogen (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) led to a doubling of the risk of all-cause dementia compared with placebo in a sample of 4,532 women aged 65 years and older at baseline.¹ CEE alone (0.625 mg) did not lead to an increased risk of all-cause dementia.⁴

Whether those formulations led to cognitive impairment in younger postmenopausal women was the focus of WHIMS-Younger (WHIMS-Y), which involved WHI participants aged 50 to 55 years at baseline.⁵ Results revealed neutral cognitive effects (ie, no differences in cognitive performance in women randomly assigned to HT or placebo) in women tested 7.2 years after the end of the WHI trial. WHIMS-Y findings indicated that there were no sustained cognitive risks of CEE or CEE/MPA therapy. Two randomized, placebo-controlled trials involving younger postmenopausal women yielded similar findings.^6,7 HT shown to produce cognitively neutral effects during active treatment included transdermal estradiol plus micronized progesterone,⁶ CEE plus progesterone,⁶ and oral estradiol plus vaginal progesterone gel.⁷ The findings of these randomized trials are critical for guiding decisions regarding the cognitive risks of HT in early postmenopausal women (TABLE 1).

What about women with VMS?

A key gap in knowledge about the cognitive effects of HT is whether HT confers cognitive advantages to women with bothersome VMS. This is a striking absence given that the key indication for HT is the treatment of VMS. While some symptomatic women were included in the trials of HT in younger postmenopausal women described above, no large trial to date has selectively enrolled women with moderate-to-severe VMS to determine if HT is cognitively neutral, beneficial, or detrimental in that group. Some studies involving midlife women have found associations between VMS (as measured with ambulatory skin conductance monitors) and multiple measures of brain health, including memory performance,⁸ small ischemic lesions on structural brain scans,⁹ and altered brain function.¹⁰ In a small trial of a nonhormonal intervention for VMS, improvement in VMS following the intervention was directly related to improvement in memory performance.¹¹ The reliability of these findings continues to be evaluated but raises the hypothesis that VMS treatments might improve memory in midlife women.

Memory complaints common among midlife women

About 60% of women report an undesirable change in memory performance at midlife as compared with earlier in their lives.^12,13 Complaints of forgetfulness are higher in perimenopausal and postmenopausal women compared with premenopausal women, even when those women are similar in age.¹⁴ Two large prospective studies found that memory performance decreases during the perimenopause and then rebounds, suggesting a transient decrease in memory.^15,16 Although cognitive complaints are common among women in their 40s and 50s, AD is rare in that age group. The risk is largely limited to those women with a parent who developed dementia before age 65, as such cases suggest a familial form of AD.

Continue to: What causes cognitive difficulties during midlife?

What causes cognitive difficulties during midlife?

First, some cognitive decline is expected at midlife based on increasing age. Second, above and beyond the role of chronologic aging (ie, getting one year older each year), ovarian aging plays a role. A role of estrogen was verified in clinical trials showing that memory decreased following oophorectomy in premenopausal women in their 40s but returned to presurgical levels following treatment with estrogen therapy (ET).¹⁷ Cohort studies indicate that women who undergo oophorectomy before the typical age of menopause are at increased risk for cognitive impairment or dementia, but those who take ET after oophorectomy until the typical age of menopause do not show that risk.¹⁸

Third, cognitive problems are linked not only to VMS but also to sleep disturbance, depressed mood, and increased anxiety—all of which are common in midlife women.^15,19 Lastly, health factors play a role. Hypertension, obesity, insulin resistance, diabetes, and smoking are associated with adverse brain changes at midlife.²⁰

Giving advice to your patients

First, normalize the cognitive complaints, noting that some cognitive changes are an expected part of aging for all people regardless of whether they are male or female. Advise that while the best studies indicate that these cognitive lapses are especially common in perimenopausal women, they appear to be temporary; women are likely to resume normal cognitive function once the hormonal changes associated with menopause subside.^15,16 Note that the one unknown is the role that VMS play in memory problems and that some studies indicate a link between VMS and cognitive problems. Women may experience some cognitive improvement if VMS are effectively treated.

Advise patients that the Endocrine Society, the North American Menopause Society (NAMS), and the International Menopause Society all have published guidelines saying that the benefits of HT outweigh the risks for most women aged 50 to 60 years.²¹ For concerns about the cognitive adverse effects of HT, discuss the best quality evidence—that which comes from randomized trials—which shows no harmful effects of HT in midlife women.^5-7 Especially reassuring is that one of these high-quality studies was conducted by the same researchers who found that HT can be risky in older women (ie, the WHI Investigators).⁵

Going one step further: Protecting brain health

As primary care providers to midlife women, ObGyns can go one step further and advise patients on how to proactively nurture their brain health. Great evidence-based resources for information on maintaining brain health include the Alzheimer’s Association (https://www.alz.org) and the Women’s Brain Health Initiative (https://womensbrainhealth.org). Primary prevention of AD begins decades before the typical age of an AD diagnosis, and many risk factors for AD are modifiable.²² Patients can keep their brains healthy through myriad approaches including treating hypertension, reducing body mass index, engaging in regular aerobic exercise (brisk walking is fine), eating a Mediterranean diet, maintaining an active social life, and engaging in novel challenging activities like learning a new language or a new skill like dancing.²⁰

Also important is the overlap between cognitive issues, mood, and alcohol use. In the opening case, Jackie mentions alcohol use and social withdrawal. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), low-risk drinking for women is defined as no more than 3 drinks on any single day and no more than 7 drinks per week.²³ Heavy alcohol use not only affects brain function but also mood, and depressed mood can lead women to drink excessively.²⁴

In addition, Jackie’s mother has AD, and that stressor can contribute to depressed feelings, especially if Jackie is involved in caregiving. A quick screen for depression with an instrument like the Patient Health Questionnaire-2 (PHQ-2; TABLE 2)²⁵ can rule out a more serious mood disorder—an approach that is particularly important for patients with a history of major depression, as 58% of those patients experience a major depressive episode during the menopausal transition.²⁶ For this reason, it is important to ask patients like Jackie if they have a history of depression; if they do and were treated medically, consider prescribing the antidepressant that worked in the past. For information on menopause and mood-related issues, providers can access new guidelines from NAMS and the National Network of Depression Centers (NNDC).²⁷ There is also a handy patient information sheet to accompany those guidelines on the NAMS website (https://www.menopause.org/).

Continue to: CASE Resolved...

CASE Resolved

When approaching Jackie, most importantly, I would normalize her experience and tell her that memory problems are common in the menopausal transition, especially for women with bothersome VMS. Research suggests that the memory problems she is experiencing are related to hormonal changes and not to AD, and that her memory will likely improve once she has transitioned through the menopause. I would tell her that AD is rare at midlife unless there is a family history of early onset of AD (before age 65), and I would verify the age at which her mother was diagnosed to confirm that it was late-onset AD.

For now, I would recommend that she be prescribed HT for her bothersome hot flashes using one of the “safe” formulations in the Table on page 24. I also would tell her that there is much she can do to lower her risk of AD and that it is best to start now as she enters her 50s because that is when AD changes typically start in the brain, and she can start to prevent those changes now.

I would tell her that experts in the field of AD agree that these lifestyle interventions are currently the best way to prevent AD and that the more of them she engages in, the more her brain will benefit. I would advise her to continue to manage her hypertension and to consider ways of lowering her BMI to enhance her brain health. Engaging in regular brisk walking or other aerobic exercise, as well as incorporating more of the Mediterranean diet into her daily food intake would also benefit her brain. As a working woman, she is exercising her brain, and she should consider other cognitively challenging activities to keep her brain in good shape.

I would follow up with her in a few months to see if her memory functioning is better. If it is not, and if her VMS continue to be bothersome, I would increase her dose of HT. Only if her VMS are treated but her memory problems are getting worse would I screen her with a Mini-Mental State Exam and refer her to a neurologist for an evaluation.
 

CASE HT for vasomotor symptoms in perimenopausal woman with cognitive concerns

Jackie is a 49-year-old woman. Her body mass index is 33 kg/m², and she has mild hypertension that is effectively controlled with antihypertensive medications. Otherwise, she is in good health.During her annual gynecologic exam, she reports that for the past 9 months her menstrual cycles have not been as regular as they used to be and that 3 months ago she skipped a cycle. She is having bothersome vasomotor symptoms (VMS) and is concerned about her memory. She says she is forgetful at work and in social situations. During a recent presentation, she could not remember the name of one of her former clients. At a work happy hour, she forgot the name of her coworker’s husband, although she did remember it later after returning home.

Her mother has Alzheimer disease (AD), and Jackie worries about whether she, too, might be developing dementia and whether her memory will fail her in social situations.

She is concerned about using hormone therapy (HT) for her vasomotor symptoms because she has heard that it can lead to breast cancer and/or AD.

How would you advise her?

HT remains the most effective treatment for bothersome VMS, but concerns about its cognitive safety persist. Such concerns, and indeed a black-box warning about the risk of dementia with HT use, initially arose following the 2003 publication of the Women’s Health Initiative Memory Study (WHIMS), a randomized, placebo-controlled trial of HT for the primary prevention of dementia in women aged 65 years and older at baseline.¹ The study found that combination estrogen/progestin therapy was associated with a 2-fold increase in dementia when compared with placebo.

One of the critical questions arising even before WHIMS was whether the cognitive risks associated with HT that were seen in WHIMS apply to younger women. Attempting to answer the question and adding fuel to the fire are the results of a recent case-control study from Finland.² This study compared HT use in Finnish women with and without AD and found that HT use was higher among Finnish women with AD compared with those without AD, regardless of age. The authors concluded, “Our data must be implemented into information for the present and future users of HT, even though the absolute risk increase is small.”

However, given the limitations inherent to observational and registry studies, and the contrasting findings of 3 high-quality, randomized controlled trials (RCTs; more details below), providers actually can reassure younger peri- and postmenopausal women about the cognitive safety of HT.³ They also can explain to patients that cognitive symptoms like the ones described in the case example are normal and provide general guidance to midlife women on how to optimize brain health.

Continue to: Closer look at WHI and RCT research pinpoints cognitively neutral HT...

Closer look at WHI and RCT research pinpoints cognitively neutral HT

In WHIMS, the combination of conjugated equine estrogen (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) led to a doubling of the risk of all-cause dementia compared with placebo in a sample of 4,532 women aged 65 years and older at baseline.¹ CEE alone (0.625 mg) did not lead to an increased risk of all-cause dementia.⁴

Whether those formulations led to cognitive impairment in younger postmenopausal women was the focus of WHIMS-Younger (WHIMS-Y), which involved WHI participants aged 50 to 55 years at baseline.⁵ Results revealed neutral cognitive effects (ie, no differences in cognitive performance in women randomly assigned to HT or placebo) in women tested 7.2 years after the end of the WHI trial. WHIMS-Y findings indicated that there were no sustained cognitive risks of CEE or CEE/MPA therapy. Two randomized, placebo-controlled trials involving younger postmenopausal women yielded similar findings.^6,7 HT shown to produce cognitively neutral effects during active treatment included transdermal estradiol plus micronized progesterone,⁶ CEE plus progesterone,⁶ and oral estradiol plus vaginal progesterone gel.⁷ The findings of these randomized trials are critical for guiding decisions regarding the cognitive risks of HT in early postmenopausal women (TABLE 1).

What about women with VMS?

A key gap in knowledge about the cognitive effects of HT is whether HT confers cognitive advantages to women with bothersome VMS. This is a striking absence given that the key indication for HT is the treatment of VMS. While some symptomatic women were included in the trials of HT in younger postmenopausal women described above, no large trial to date has selectively enrolled women with moderate-to-severe VMS to determine if HT is cognitively neutral, beneficial, or detrimental in that group. Some studies involving midlife women have found associations between VMS (as measured with ambulatory skin conductance monitors) and multiple measures of brain health, including memory performance,⁸ small ischemic lesions on structural brain scans,⁹ and altered brain function.¹⁰ In a small trial of a nonhormonal intervention for VMS, improvement in VMS following the intervention was directly related to improvement in memory performance.¹¹ The reliability of these findings continues to be evaluated but raises the hypothesis that VMS treatments might improve memory in midlife women.

Memory complaints common among midlife women

About 60% of women report an undesirable change in memory performance at midlife as compared with earlier in their lives.^12,13 Complaints of forgetfulness are higher in perimenopausal and postmenopausal women compared with premenopausal women, even when those women are similar in age.¹⁴ Two large prospective studies found that memory performance decreases during the perimenopause and then rebounds, suggesting a transient decrease in memory.^15,16 Although cognitive complaints are common among women in their 40s and 50s, AD is rare in that age group. The risk is largely limited to those women with a parent who developed dementia before age 65, as such cases suggest a familial form of AD.

Continue to: What causes cognitive difficulties during midlife?

What causes cognitive difficulties during midlife?

First, some cognitive decline is expected at midlife based on increasing age. Second, above and beyond the role of chronologic aging (ie, getting one year older each year), ovarian aging plays a role. A role of estrogen was verified in clinical trials showing that memory decreased following oophorectomy in premenopausal women in their 40s but returned to presurgical levels following treatment with estrogen therapy (ET).¹⁷ Cohort studies indicate that women who undergo oophorectomy before the typical age of menopause are at increased risk for cognitive impairment or dementia, but those who take ET after oophorectomy until the typical age of menopause do not show that risk.¹⁸

Third, cognitive problems are linked not only to VMS but also to sleep disturbance, depressed mood, and increased anxiety—all of which are common in midlife women.^15,19 Lastly, health factors play a role. Hypertension, obesity, insulin resistance, diabetes, and smoking are associated with adverse brain changes at midlife.²⁰

Giving advice to your patients

First, normalize the cognitive complaints, noting that some cognitive changes are an expected part of aging for all people regardless of whether they are male or female. Advise that while the best studies indicate that these cognitive lapses are especially common in perimenopausal women, they appear to be temporary; women are likely to resume normal cognitive function once the hormonal changes associated with menopause subside.^15,16 Note that the one unknown is the role that VMS play in memory problems and that some studies indicate a link between VMS and cognitive problems. Women may experience some cognitive improvement if VMS are effectively treated.

Advise patients that the Endocrine Society, the North American Menopause Society (NAMS), and the International Menopause Society all have published guidelines saying that the benefits of HT outweigh the risks for most women aged 50 to 60 years.²¹ For concerns about the cognitive adverse effects of HT, discuss the best quality evidence—that which comes from randomized trials—which shows no harmful effects of HT in midlife women.^5-7 Especially reassuring is that one of these high-quality studies was conducted by the same researchers who found that HT can be risky in older women (ie, the WHI Investigators).⁵

Going one step further: Protecting brain health

As primary care providers to midlife women, ObGyns can go one step further and advise patients on how to proactively nurture their brain health. Great evidence-based resources for information on maintaining brain health include the Alzheimer’s Association (https://www.alz.org) and the Women’s Brain Health Initiative (https://womensbrainhealth.org). Primary prevention of AD begins decades before the typical age of an AD diagnosis, and many risk factors for AD are modifiable.²² Patients can keep their brains healthy through myriad approaches including treating hypertension, reducing body mass index, engaging in regular aerobic exercise (brisk walking is fine), eating a Mediterranean diet, maintaining an active social life, and engaging in novel challenging activities like learning a new language or a new skill like dancing.²⁰

Also important is the overlap between cognitive issues, mood, and alcohol use. In the opening case, Jackie mentions alcohol use and social withdrawal. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), low-risk drinking for women is defined as no more than 3 drinks on any single day and no more than 7 drinks per week.²³ Heavy alcohol use not only affects brain function but also mood, and depressed mood can lead women to drink excessively.²⁴

In addition, Jackie’s mother has AD, and that stressor can contribute to depressed feelings, especially if Jackie is involved in caregiving. A quick screen for depression with an instrument like the Patient Health Questionnaire-2 (PHQ-2; TABLE 2)²⁵ can rule out a more serious mood disorder—an approach that is particularly important for patients with a history of major depression, as 58% of those patients experience a major depressive episode during the menopausal transition.²⁶ For this reason, it is important to ask patients like Jackie if they have a history of depression; if they do and were treated medically, consider prescribing the antidepressant that worked in the past. For information on menopause and mood-related issues, providers can access new guidelines from NAMS and the National Network of Depression Centers (NNDC).²⁷ There is also a handy patient information sheet to accompany those guidelines on the NAMS website (https://www.menopause.org/).

Continue to: CASE Resolved...

CASE Resolved

When approaching Jackie, most importantly, I would normalize her experience and tell her that memory problems are common in the menopausal transition, especially for women with bothersome VMS. Research suggests that the memory problems she is experiencing are related to hormonal changes and not to AD, and that her memory will likely improve once she has transitioned through the menopause. I would tell her that AD is rare at midlife unless there is a family history of early onset of AD (before age 65), and I would verify the age at which her mother was diagnosed to confirm that it was late-onset AD.

For now, I would recommend that she be prescribed HT for her bothersome hot flashes using one of the “safe” formulations in the Table on page 24. I also would tell her that there is much she can do to lower her risk of AD and that it is best to start now as she enters her 50s because that is when AD changes typically start in the brain, and she can start to prevent those changes now.

I would tell her that experts in the field of AD agree that these lifestyle interventions are currently the best way to prevent AD and that the more of them she engages in, the more her brain will benefit. I would advise her to continue to manage her hypertension and to consider ways of lowering her BMI to enhance her brain health. Engaging in regular brisk walking or other aerobic exercise, as well as incorporating more of the Mediterranean diet into her daily food intake would also benefit her brain. As a working woman, she is exercising her brain, and she should consider other cognitively challenging activities to keep her brain in good shape.

I would follow up with her in a few months to see if her memory functioning is better. If it is not, and if her VMS continue to be bothersome, I would increase her dose of HT. Only if her VMS are treated but her memory problems are getting worse would I screen her with a Mini-Mental State Exam and refer her to a neurologist for an evaluation.
 

Postmenopausal bleeding (PMB) is the presenting sign in most cases of endometrial carcinoma. Prompt evaluation of PMB can exclude, or diagnose, endometrial carcinoma.¹ Although no general consensus exists for PMB evaluation, it involves endometrial assessment with transvaginal ultrasonography (TVUS) and subsequent endometrial biopsy when a thickened endometrium is found. When biopsy results reveal insufficient or scant tissue, further investigation into the etiology of PMB should include office hysteroscopy with possible directed biopsy. In this article I discuss the prevalence of PMB and steps for evaluation, providing clinical takeaways.

Postmenopausal bleeding: Its risk for cancer

Abnormal uterine bleeding (AUB) in a postmenopausal woman is of particular concern to the gynecologist and the patient because of the increased possibility of endometrial carcinoma in this age group. AUB is present in more than 90% of postmenopausal women with endometrial carcinoma, which leads to diagnosis in the early stages of the disease. Approximately 3% to 7% of postmenopausal women with PMB will have endometrial carcinoma.² Most women with PMB, however, experience bleeding secondary to atrophic changes of the vagina or endometrium and not to endometrial carcinoma. (FIGURE 1, VIDEO 1) In addition, women who take gonadal steroids for hormone replacement therapy (HRT) may experience breakthrough bleeding that leads to initial investigation with TVUS.

Video 1

Vidyard Video

The risk of malignancy in polyps in postmenopausal women over the age of 59 who present with PMB is approximately 12%, and hysteroscopic resection should routinely be performed. For asymptomatic patients, the risk of a malignant lesion is low—approximately 3%—and for these women intervention should be assessed individually for the risks of carcinoma and benefits of hysteroscopic removal.³

Clinical takeaway. The high possibility of endometrial carcinoma in postmenopausal women warrants that any patient who is symptomatic with PMB should be presumed to have endometrial cancer until the diagnostic evaluation process proves she does not.

Evaluation of postmenopausal bleeding

Transvaginal ultrasound

As mentioned, no general consensus exists for the evaluation of PMB; however, initial evaluation by TVUS is recommended. The American College of Obstetricians and Gynecologists (ACOG) concluded that when the endometrium measures ≤4 mm with TVUS, the likelihood that bleeding is secondary to endometrial carcinoma is less than 1% (negative predictive value 99%), and endometrial biopsy is not recommended.³ Endometrial sampling in this clinical scenario likely will result in insufficient tissue for evaluation, and it is reasonable to consider initial management for atrophy. A thickened endometrium on TVUS (>4 mm in a postmenopausal woman with PMB) warrants additional evaluation with endometrial sampling (FIGURE 2).

Clinical takeaway. A thickened endometrium on TVUS ≥4 mm in a postmenopausal woman with PMB warrants additional evaluation with endometrial sampling.

Endometrial biopsy

An endometrial biopsy is performed to determine whether endometrial cancer or precancer is present in women with AUB. ACOG recommends that endometrial biopsy be performed for women older than age 45. It is also appropriate in women younger than 45 years if they have risk factors for developing endometrial cancer, including unopposed estrogen exposure (obesity, ovulatory dysfunction), failed medical management of AUB, or persistence of AUB.⁴

Continue to: Endometrial biopsy has some...

 

 

Endometrial biopsy has some diagnostic shortcomings, however. In 2016 a systematic review and meta-analysis found that, in women with PMB, the specificity of endometrial biopsy was 98% to 100% (accurate diagnosis with a positive result). The sensitivity (ability to make an accurate diagnosis) of endometrial biopsy to identify endometrial pathology (carcinoma, atypical hyperplasia, and polyps) is lower than typically thought. These investigators found an endometrial biopsy failure rate of 11% (range, 1% to 53%) and rate of insufficient samples of 31% (range, 7% to 76%). In women with insufficient or failed samples, endometrial cancer or precancer was found in 7% (range, 0% to 18%).⁵ Therefore, a negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative. The results of endometrial biopsy are only an endpoint to the evaluation of PMB when atypical hyperplasia or endometrial cancer is identified.

Clinical takeaway. A negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative.

 

Hysteroscopy

Hysteroscopy is the gold standard for evaluating the uterine cavity, diagnosing intrauterine pathology, and operative intervention for some causes of AUB. It also is easily performed in the office. This makes the hysteroscope an essential instrument for the gynecologist. Dr. Linda Bradley, a preeminent leader in hysteroscopic surgical education, has coined the phrase, “My hysteroscope is my stethoscope.”⁶ As gynecologists, we should be as adept at using a hysteroscope in the office as the cardiologist is at using a stethoscope.

It has been known for some time that hysteroscopy improves our diagnostic capabilities over blinded procedures such as endometrial biopsy and dilation and curettage (D&C). As far back as 1989, Dr. Frank Loffer reported the increased sensitivity (ability to make an accurate diagnosis) of hysteroscopy with directed biopsy over blinded D&C (98% vs 65%) in the evaluation of AUB.⁷ Evaluation of the endometrium with D&C is no longer recommended; yet today, few gynecologists perform hysteroscopic-directed biopsy for AUB evaluation instead of blinded tissue sampling despite the clinical superiority and in-office capabilities (FIGURE 3).

Continue to: Hysteroscopy and endometrial carcinoma...

 

 

Hysteroscopy and endometrial carcinoma

The most common type of gynecologic cancer in the United States is endometrial adenocarcinoma (type 1 endometrial cancer). There is some concern about the effect of hysteroscopy on endometrial cancer prognosis and the spread of cells to the peritoneum at the time of hysteroscopy. A large meta-analysis found that hysteroscopy performed in the presence of type 1 endometrial cancer statistically significantly increased the likelihood of positive intraperitoneal cytology; however, it did not alter the clinical outcome. It was recommended that hysteroscopy not be avoided for this reason and is helpful in the diagnosis of endometrial cancer, especially in the early stages of disease.⁸

For endometrial cancer type 2 (serous carcinoma, clear cell carcinoma, and carcinosarcoma), Chen and colleagues reported a statistically significant increase in positive peritoneal cytology for cancers evaluated by hysteroscopy versus D&C. The disease-specific survival for the hysteroscopy group was 60 months, compared with 71 months for the D&C group. While this finding was not statistically significant, it was clinically relevant, and the effect of hysteroscopy on prognosis with type 2 endometrial cancer is unclear.⁹

Three clinical scenarios

---

A common occurrence in the evaluation of postmenopausal bleeding (PMB) is an initial TVUS finding of an enlarged endometrium and an endometrial biopsy that is negative or reveals scant or insufficient tissue. Unfortunately, the diagnostic evaluation process often stops here, and a diagnosis for the PMB is never actually identified. Here are several clinical scenarios that highlight the need for hysteroscopy in the initial evaluation of PMB, especially when there is a discordance between transvaginal ultrasonography (TVUS) and endometrial biopsy findings.

Patient 1: Discordant TVUS and biopsy, with benign findings

The patient is a 52-year-old woman who presented to her gynecologist reporting abnormal uterine bleeding (AUB). She has a history of breast cancer, and she completed tamoxifen treatment. Pelvic ultrasonography was performed; an enlarged endometrial stripe of 1.3 cm was found (FIGURE 4A). Endometrial biopsy was performed, showing adequate tissue but with a negative result. The patient is told that she is likely perimenopausal, which is the reason for her bleeding.

At the time of referral, the patient is evaluated with in-office hysteroscopy. Diagnosis of a 5 cm x 7 cm benign endometrial polyp is made. An uneventful hysteroscopic polypectomy is performed (VIDEO 2).

Video 2

Vidyard Video

This scenario illustrates the shortcoming of initial evaluation by not performing a hysteroscopy, especially in a woman with a thickened endometrium with previous tamoxifen therapy. Subsequent visits failed to correlate bleeding etiology with discordant TVUS and endometrial biopsy results with hysteroscopy, and no hysteroscopy was performed in the operating room at the time of D&C.

Patient 2: Discordant TVUS and biopsy, with premalignant findings

The patient is a 62-year-old woman who had incidental findings of a thickened endometrium on computed tomography scan of the pelvis. TVUS confirmed a thickened endometrium measuring 17 mm, and an endometrial biopsy showed scant tissue.

At the time of referral, a diagnostic hysteroscopy was performed in the office. Endometrial atrophy, a large benign appearing polyp, and focal abnormal appearing tissue were seen (FIGURE 5). A decision for polypectomy and directed biopsy was made. Histology findings confirmed benign polyp and atypical hyperplasia (VIDEO 3).

Video 3

Vidyard Video

This scenario illustrates that while the patient was asymptomatic, there was discordance between the TVUS and endometrial biopsy. Hysteroscopy identified a benign endometrial polyp, which is common in asymptomatic postmenopausal patients with a thickened endometrium and endometrial biopsy showing scant tissue. However, addition of the diagnostic hysteroscopy identified focal precancerous tissue, removed under directed biopsy.

Patient 3: Discordant TVUS and biopsy, with malignant findings

The patient is a 68-year-old woman with PMB. TVUS showed a thickened endometrium measuring 14 mm. An endometrial biopsy was negative, showing scant tissue. No additional diagnostic evaluation or management was offered.

Video 4A

Vidyard Video

At the time of referral, the patient was evaluated with in-office diagnostic hysteroscopy, and the patient was found to have endometrial atrophy, benign appearing polyps, and focal abnormal tissue (FIGURE 6). A decision for polypectomy and directed biopsy was made. Histology confirmed benign polyps and grade 1 adenocarcinoma (VIDEOS 4A, 4B, 4C).

Video 4B

Vidyard Video

This scenario illustrates the possibility of having multiple endometrial pathologies present at the time of discordant TVUS and endometrial biopsy. Hysteroscopy plays a critical role in additional evaluation and diagnosis of endometrial carcinoma with directed biopsy, especially in a symptomatic woman with PMB.

Video 4C

Vidyard Video

 

 

Conclusion

Evaluation of PMB begins with a screening TVUS. Findings of an endometrium of ≤4 mm indicate a very low likelihood of the presence of endometrial cancer, and treatment for atrophy or changes to hormone replacement therapy regimen is reasonable first-line management; endometrial biopsy is not recommended. For patients with persistent PMB or thickened endometrium ≥4 mm on TVUS, biopsy sampling of the endometrium should be performed. If the endometrial biopsy does not explain the etiology of the PMB with atypical hyperplasia or endometrial cancer, then hysteroscopy should be performed to evaluate for focal endometrial disease and possible directed biopsy.

Postmenopausal bleeding (PMB) is the presenting sign in most cases of endometrial carcinoma. Prompt evaluation of PMB can exclude, or diagnose, endometrial carcinoma.¹ Although no general consensus exists for PMB evaluation, it involves endometrial assessment with transvaginal ultrasonography (TVUS) and subsequent endometrial biopsy when a thickened endometrium is found. When biopsy results reveal insufficient or scant tissue, further investigation into the etiology of PMB should include office hysteroscopy with possible directed biopsy. In this article I discuss the prevalence of PMB and steps for evaluation, providing clinical takeaways.

Postmenopausal bleeding: Its risk for cancer

Abnormal uterine bleeding (AUB) in a postmenopausal woman is of particular concern to the gynecologist and the patient because of the increased possibility of endometrial carcinoma in this age group. AUB is present in more than 90% of postmenopausal women with endometrial carcinoma, which leads to diagnosis in the early stages of the disease. Approximately 3% to 7% of postmenopausal women with PMB will have endometrial carcinoma.² Most women with PMB, however, experience bleeding secondary to atrophic changes of the vagina or endometrium and not to endometrial carcinoma. (FIGURE 1, VIDEO 1) In addition, women who take gonadal steroids for hormone replacement therapy (HRT) may experience breakthrough bleeding that leads to initial investigation with TVUS.

Video 1

Vidyard Video

The risk of malignancy in polyps in postmenopausal women over the age of 59 who present with PMB is approximately 12%, and hysteroscopic resection should routinely be performed. For asymptomatic patients, the risk of a malignant lesion is low—approximately 3%—and for these women intervention should be assessed individually for the risks of carcinoma and benefits of hysteroscopic removal.³

Clinical takeaway. The high possibility of endometrial carcinoma in postmenopausal women warrants that any patient who is symptomatic with PMB should be presumed to have endometrial cancer until the diagnostic evaluation process proves she does not.

Evaluation of postmenopausal bleeding

Transvaginal ultrasound

As mentioned, no general consensus exists for the evaluation of PMB; however, initial evaluation by TVUS is recommended. The American College of Obstetricians and Gynecologists (ACOG) concluded that when the endometrium measures ≤4 mm with TVUS, the likelihood that bleeding is secondary to endometrial carcinoma is less than 1% (negative predictive value 99%), and endometrial biopsy is not recommended.³ Endometrial sampling in this clinical scenario likely will result in insufficient tissue for evaluation, and it is reasonable to consider initial management for atrophy. A thickened endometrium on TVUS (>4 mm in a postmenopausal woman with PMB) warrants additional evaluation with endometrial sampling (FIGURE 2).

Clinical takeaway. A thickened endometrium on TVUS ≥4 mm in a postmenopausal woman with PMB warrants additional evaluation with endometrial sampling.

Endometrial biopsy

An endometrial biopsy is performed to determine whether endometrial cancer or precancer is present in women with AUB. ACOG recommends that endometrial biopsy be performed for women older than age 45. It is also appropriate in women younger than 45 years if they have risk factors for developing endometrial cancer, including unopposed estrogen exposure (obesity, ovulatory dysfunction), failed medical management of AUB, or persistence of AUB.⁴

Continue to: Endometrial biopsy has some...

 

 

Endometrial biopsy has some diagnostic shortcomings, however. In 2016 a systematic review and meta-analysis found that, in women with PMB, the specificity of endometrial biopsy was 98% to 100% (accurate diagnosis with a positive result). The sensitivity (ability to make an accurate diagnosis) of endometrial biopsy to identify endometrial pathology (carcinoma, atypical hyperplasia, and polyps) is lower than typically thought. These investigators found an endometrial biopsy failure rate of 11% (range, 1% to 53%) and rate of insufficient samples of 31% (range, 7% to 76%). In women with insufficient or failed samples, endometrial cancer or precancer was found in 7% (range, 0% to 18%).⁵ Therefore, a negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative. The results of endometrial biopsy are only an endpoint to the evaluation of PMB when atypical hyperplasia or endometrial cancer is identified.

Clinical takeaway. A negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative.

 

Hysteroscopy

Hysteroscopy is the gold standard for evaluating the uterine cavity, diagnosing intrauterine pathology, and operative intervention for some causes of AUB. It also is easily performed in the office. This makes the hysteroscope an essential instrument for the gynecologist. Dr. Linda Bradley, a preeminent leader in hysteroscopic surgical education, has coined the phrase, “My hysteroscope is my stethoscope.”⁶ As gynecologists, we should be as adept at using a hysteroscope in the office as the cardiologist is at using a stethoscope.

It has been known for some time that hysteroscopy improves our diagnostic capabilities over blinded procedures such as endometrial biopsy and dilation and curettage (D&C). As far back as 1989, Dr. Frank Loffer reported the increased sensitivity (ability to make an accurate diagnosis) of hysteroscopy with directed biopsy over blinded D&C (98% vs 65%) in the evaluation of AUB.⁷ Evaluation of the endometrium with D&C is no longer recommended; yet today, few gynecologists perform hysteroscopic-directed biopsy for AUB evaluation instead of blinded tissue sampling despite the clinical superiority and in-office capabilities (FIGURE 3).

Continue to: Hysteroscopy and endometrial carcinoma...

 

 

Hysteroscopy and endometrial carcinoma

The most common type of gynecologic cancer in the United States is endometrial adenocarcinoma (type 1 endometrial cancer). There is some concern about the effect of hysteroscopy on endometrial cancer prognosis and the spread of cells to the peritoneum at the time of hysteroscopy. A large meta-analysis found that hysteroscopy performed in the presence of type 1 endometrial cancer statistically significantly increased the likelihood of positive intraperitoneal cytology; however, it did not alter the clinical outcome. It was recommended that hysteroscopy not be avoided for this reason and is helpful in the diagnosis of endometrial cancer, especially in the early stages of disease.⁸

For endometrial cancer type 2 (serous carcinoma, clear cell carcinoma, and carcinosarcoma), Chen and colleagues reported a statistically significant increase in positive peritoneal cytology for cancers evaluated by hysteroscopy versus D&C. The disease-specific survival for the hysteroscopy group was 60 months, compared with 71 months for the D&C group. While this finding was not statistically significant, it was clinically relevant, and the effect of hysteroscopy on prognosis with type 2 endometrial cancer is unclear.⁹

Three clinical scenarios

---

A common occurrence in the evaluation of postmenopausal bleeding (PMB) is an initial TVUS finding of an enlarged endometrium and an endometrial biopsy that is negative or reveals scant or insufficient tissue. Unfortunately, the diagnostic evaluation process often stops here, and a diagnosis for the PMB is never actually identified. Here are several clinical scenarios that highlight the need for hysteroscopy in the initial evaluation of PMB, especially when there is a discordance between transvaginal ultrasonography (TVUS) and endometrial biopsy findings.

Patient 1: Discordant TVUS and biopsy, with benign findings

The patient is a 52-year-old woman who presented to her gynecologist reporting abnormal uterine bleeding (AUB). She has a history of breast cancer, and she completed tamoxifen treatment. Pelvic ultrasonography was performed; an enlarged endometrial stripe of 1.3 cm was found (FIGURE 4A). Endometrial biopsy was performed, showing adequate tissue but with a negative result. The patient is told that she is likely perimenopausal, which is the reason for her bleeding.

At the time of referral, the patient is evaluated with in-office hysteroscopy. Diagnosis of a 5 cm x 7 cm benign endometrial polyp is made. An uneventful hysteroscopic polypectomy is performed (VIDEO 2).

Video 2

Vidyard Video

This scenario illustrates the shortcoming of initial evaluation by not performing a hysteroscopy, especially in a woman with a thickened endometrium with previous tamoxifen therapy. Subsequent visits failed to correlate bleeding etiology with discordant TVUS and endometrial biopsy results with hysteroscopy, and no hysteroscopy was performed in the operating room at the time of D&C.

Patient 2: Discordant TVUS and biopsy, with premalignant findings

The patient is a 62-year-old woman who had incidental findings of a thickened endometrium on computed tomography scan of the pelvis. TVUS confirmed a thickened endometrium measuring 17 mm, and an endometrial biopsy showed scant tissue.

At the time of referral, a diagnostic hysteroscopy was performed in the office. Endometrial atrophy, a large benign appearing polyp, and focal abnormal appearing tissue were seen (FIGURE 5). A decision for polypectomy and directed biopsy was made. Histology findings confirmed benign polyp and atypical hyperplasia (VIDEO 3).

Video 3

Vidyard Video

This scenario illustrates that while the patient was asymptomatic, there was discordance between the TVUS and endometrial biopsy. Hysteroscopy identified a benign endometrial polyp, which is common in asymptomatic postmenopausal patients with a thickened endometrium and endometrial biopsy showing scant tissue. However, addition of the diagnostic hysteroscopy identified focal precancerous tissue, removed under directed biopsy.

Patient 3: Discordant TVUS and biopsy, with malignant findings

The patient is a 68-year-old woman with PMB. TVUS showed a thickened endometrium measuring 14 mm. An endometrial biopsy was negative, showing scant tissue. No additional diagnostic evaluation or management was offered.

Video 4A

Vidyard Video

At the time of referral, the patient was evaluated with in-office diagnostic hysteroscopy, and the patient was found to have endometrial atrophy, benign appearing polyps, and focal abnormal tissue (FIGURE 6). A decision for polypectomy and directed biopsy was made. Histology confirmed benign polyps and grade 1 adenocarcinoma (VIDEOS 4A, 4B, 4C).

Video 4B

Vidyard Video

This scenario illustrates the possibility of having multiple endometrial pathologies present at the time of discordant TVUS and endometrial biopsy. Hysteroscopy plays a critical role in additional evaluation and diagnosis of endometrial carcinoma with directed biopsy, especially in a symptomatic woman with PMB.

Video 4C

Vidyard Video

 

 

Conclusion

Evaluation of PMB begins with a screening TVUS. Findings of an endometrium of ≤4 mm indicate a very low likelihood of the presence of endometrial cancer, and treatment for atrophy or changes to hormone replacement therapy regimen is reasonable first-line management; endometrial biopsy is not recommended. For patients with persistent PMB or thickened endometrium ≥4 mm on TVUS, biopsy sampling of the endometrium should be performed. If the endometrial biopsy does not explain the etiology of the PMB with atypical hyperplasia or endometrial cancer, then hysteroscopy should be performed to evaluate for focal endometrial disease and possible directed biopsy.

Postmenopausal bleeding (PMB) is the presenting sign in most cases of endometrial carcinoma. Prompt evaluation of PMB can exclude, or diagnose, endometrial carcinoma.¹ Although no general consensus exists for PMB evaluation, it involves endometrial assessment with transvaginal ultrasonography (TVUS) and subsequent endometrial biopsy when a thickened endometrium is found. When biopsy results reveal insufficient or scant tissue, further investigation into the etiology of PMB should include office hysteroscopy with possible directed biopsy. In this article I discuss the prevalence of PMB and steps for evaluation, providing clinical takeaways.

Postmenopausal bleeding: Its risk for cancer

Abnormal uterine bleeding (AUB) in a postmenopausal woman is of particular concern to the gynecologist and the patient because of the increased possibility of endometrial carcinoma in this age group. AUB is present in more than 90% of postmenopausal women with endometrial carcinoma, which leads to diagnosis in the early stages of the disease. Approximately 3% to 7% of postmenopausal women with PMB will have endometrial carcinoma.² Most women with PMB, however, experience bleeding secondary to atrophic changes of the vagina or endometrium and not to endometrial carcinoma. (FIGURE 1, VIDEO 1) In addition, women who take gonadal steroids for hormone replacement therapy (HRT) may experience breakthrough bleeding that leads to initial investigation with TVUS.

Video 1

Vidyard Video

The risk of malignancy in polyps in postmenopausal women over the age of 59 who present with PMB is approximately 12%, and hysteroscopic resection should routinely be performed. For asymptomatic patients, the risk of a malignant lesion is low—approximately 3%—and for these women intervention should be assessed individually for the risks of carcinoma and benefits of hysteroscopic removal.³

Clinical takeaway. The high possibility of endometrial carcinoma in postmenopausal women warrants that any patient who is symptomatic with PMB should be presumed to have endometrial cancer until the diagnostic evaluation process proves she does not.

Evaluation of postmenopausal bleeding

Transvaginal ultrasound

As mentioned, no general consensus exists for the evaluation of PMB; however, initial evaluation by TVUS is recommended. The American College of Obstetricians and Gynecologists (ACOG) concluded that when the endometrium measures ≤4 mm with TVUS, the likelihood that bleeding is secondary to endometrial carcinoma is less than 1% (negative predictive value 99%), and endometrial biopsy is not recommended.³ Endometrial sampling in this clinical scenario likely will result in insufficient tissue for evaluation, and it is reasonable to consider initial management for atrophy. A thickened endometrium on TVUS (>4 mm in a postmenopausal woman with PMB) warrants additional evaluation with endometrial sampling (FIGURE 2).

Clinical takeaway. A thickened endometrium on TVUS ≥4 mm in a postmenopausal woman with PMB warrants additional evaluation with endometrial sampling.

Endometrial biopsy

An endometrial biopsy is performed to determine whether endometrial cancer or precancer is present in women with AUB. ACOG recommends that endometrial biopsy be performed for women older than age 45. It is also appropriate in women younger than 45 years if they have risk factors for developing endometrial cancer, including unopposed estrogen exposure (obesity, ovulatory dysfunction), failed medical management of AUB, or persistence of AUB.⁴

Continue to: Endometrial biopsy has some...

 

 

Endometrial biopsy has some diagnostic shortcomings, however. In 2016 a systematic review and meta-analysis found that, in women with PMB, the specificity of endometrial biopsy was 98% to 100% (accurate diagnosis with a positive result). The sensitivity (ability to make an accurate diagnosis) of endometrial biopsy to identify endometrial pathology (carcinoma, atypical hyperplasia, and polyps) is lower than typically thought. These investigators found an endometrial biopsy failure rate of 11% (range, 1% to 53%) and rate of insufficient samples of 31% (range, 7% to 76%). In women with insufficient or failed samples, endometrial cancer or precancer was found in 7% (range, 0% to 18%).⁵ Therefore, a negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative. The results of endometrial biopsy are only an endpoint to the evaluation of PMB when atypical hyperplasia or endometrial cancer is identified.

Clinical takeaway. A negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative.

 

Hysteroscopy

Hysteroscopy is the gold standard for evaluating the uterine cavity, diagnosing intrauterine pathology, and operative intervention for some causes of AUB. It also is easily performed in the office. This makes the hysteroscope an essential instrument for the gynecologist. Dr. Linda Bradley, a preeminent leader in hysteroscopic surgical education, has coined the phrase, “My hysteroscope is my stethoscope.”⁶ As gynecologists, we should be as adept at using a hysteroscope in the office as the cardiologist is at using a stethoscope.

It has been known for some time that hysteroscopy improves our diagnostic capabilities over blinded procedures such as endometrial biopsy and dilation and curettage (D&C). As far back as 1989, Dr. Frank Loffer reported the increased sensitivity (ability to make an accurate diagnosis) of hysteroscopy with directed biopsy over blinded D&C (98% vs 65%) in the evaluation of AUB.⁷ Evaluation of the endometrium with D&C is no longer recommended; yet today, few gynecologists perform hysteroscopic-directed biopsy for AUB evaluation instead of blinded tissue sampling despite the clinical superiority and in-office capabilities (FIGURE 3).

Continue to: Hysteroscopy and endometrial carcinoma...

 

 

Hysteroscopy and endometrial carcinoma

The most common type of gynecologic cancer in the United States is endometrial adenocarcinoma (type 1 endometrial cancer). There is some concern about the effect of hysteroscopy on endometrial cancer prognosis and the spread of cells to the peritoneum at the time of hysteroscopy. A large meta-analysis found that hysteroscopy performed in the presence of type 1 endometrial cancer statistically significantly increased the likelihood of positive intraperitoneal cytology; however, it did not alter the clinical outcome. It was recommended that hysteroscopy not be avoided for this reason and is helpful in the diagnosis of endometrial cancer, especially in the early stages of disease.⁸

For endometrial cancer type 2 (serous carcinoma, clear cell carcinoma, and carcinosarcoma), Chen and colleagues reported a statistically significant increase in positive peritoneal cytology for cancers evaluated by hysteroscopy versus D&C. The disease-specific survival for the hysteroscopy group was 60 months, compared with 71 months for the D&C group. While this finding was not statistically significant, it was clinically relevant, and the effect of hysteroscopy on prognosis with type 2 endometrial cancer is unclear.⁹

Three clinical scenarios

---

A common occurrence in the evaluation of postmenopausal bleeding (PMB) is an initial TVUS finding of an enlarged endometrium and an endometrial biopsy that is negative or reveals scant or insufficient tissue. Unfortunately, the diagnostic evaluation process often stops here, and a diagnosis for the PMB is never actually identified. Here are several clinical scenarios that highlight the need for hysteroscopy in the initial evaluation of PMB, especially when there is a discordance between transvaginal ultrasonography (TVUS) and endometrial biopsy findings.

Patient 1: Discordant TVUS and biopsy, with benign findings

The patient is a 52-year-old woman who presented to her gynecologist reporting abnormal uterine bleeding (AUB). She has a history of breast cancer, and she completed tamoxifen treatment. Pelvic ultrasonography was performed; an enlarged endometrial stripe of 1.3 cm was found (FIGURE 4A). Endometrial biopsy was performed, showing adequate tissue but with a negative result. The patient is told that she is likely perimenopausal, which is the reason for her bleeding.

At the time of referral, the patient is evaluated with in-office hysteroscopy. Diagnosis of a 5 cm x 7 cm benign endometrial polyp is made. An uneventful hysteroscopic polypectomy is performed (VIDEO 2).

Video 2

Vidyard Video

This scenario illustrates the shortcoming of initial evaluation by not performing a hysteroscopy, especially in a woman with a thickened endometrium with previous tamoxifen therapy. Subsequent visits failed to correlate bleeding etiology with discordant TVUS and endometrial biopsy results with hysteroscopy, and no hysteroscopy was performed in the operating room at the time of D&C.

Patient 2: Discordant TVUS and biopsy, with premalignant findings

The patient is a 62-year-old woman who had incidental findings of a thickened endometrium on computed tomography scan of the pelvis. TVUS confirmed a thickened endometrium measuring 17 mm, and an endometrial biopsy showed scant tissue.

At the time of referral, a diagnostic hysteroscopy was performed in the office. Endometrial atrophy, a large benign appearing polyp, and focal abnormal appearing tissue were seen (FIGURE 5). A decision for polypectomy and directed biopsy was made. Histology findings confirmed benign polyp and atypical hyperplasia (VIDEO 3).

Video 3

Vidyard Video

This scenario illustrates that while the patient was asymptomatic, there was discordance between the TVUS and endometrial biopsy. Hysteroscopy identified a benign endometrial polyp, which is common in asymptomatic postmenopausal patients with a thickened endometrium and endometrial biopsy showing scant tissue. However, addition of the diagnostic hysteroscopy identified focal precancerous tissue, removed under directed biopsy.

Patient 3: Discordant TVUS and biopsy, with malignant findings

The patient is a 68-year-old woman with PMB. TVUS showed a thickened endometrium measuring 14 mm. An endometrial biopsy was negative, showing scant tissue. No additional diagnostic evaluation or management was offered.

Video 4A

Vidyard Video

At the time of referral, the patient was evaluated with in-office diagnostic hysteroscopy, and the patient was found to have endometrial atrophy, benign appearing polyps, and focal abnormal tissue (FIGURE 6). A decision for polypectomy and directed biopsy was made. Histology confirmed benign polyps and grade 1 adenocarcinoma (VIDEOS 4A, 4B, 4C).

Video 4B

Vidyard Video

This scenario illustrates the possibility of having multiple endometrial pathologies present at the time of discordant TVUS and endometrial biopsy. Hysteroscopy plays a critical role in additional evaluation and diagnosis of endometrial carcinoma with directed biopsy, especially in a symptomatic woman with PMB.

Video 4C

Vidyard Video

 

 

Conclusion

Evaluation of PMB begins with a screening TVUS. Findings of an endometrium of ≤4 mm indicate a very low likelihood of the presence of endometrial cancer, and treatment for atrophy or changes to hormone replacement therapy regimen is reasonable first-line management; endometrial biopsy is not recommended. For patients with persistent PMB or thickened endometrium ≥4 mm on TVUS, biopsy sampling of the endometrium should be performed. If the endometrial biopsy does not explain the etiology of the PMB with atypical hyperplasia or endometrial cancer, then hysteroscopy should be performed to evaluate for focal endometrial disease and possible directed biopsy.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal (GI) tract and arise from the interstitial cells of Cajal of the myenteric plexus. These tumors are rare, with about 1 case per 100,000 persons diagnosed in the United States annually, but may be incidentally discovered in up to 1 in 5 autopsy specimens of older adults.^1,2 Epidemiologic risk factors include increasing age, with a peak incidence between age 60 and 65 years, male gender, black race, and non-Hispanic white ethnicity. Germline predisposition can also increase the risk of developing GISTs; molecular drivers of GIST include gain-of-function mutations in the KIT proto-oncogene and platelet-derived growth factor receptor α (PDGFRA) gene, which both encode structurally similar tyrosine kinase receptors; germline mutations of succinate dehydrogenase (SDH) subunit genes; and mutations associated with neurofibromatosis type 1.

GISTs most commonly involve the stomach, followed by the small intestine, but can arise anywhere within the GI tract (esophagus, colon, rectum, and anus). They can also develop outside the GI tract, arising from the mesentery, omentum, and retroperitoneum. The majority of cases are localized or locoregional, whereas about 20% are metastatic at presentation.¹ GISTs can occur in children, adolescents, and young adults. Pediatric GISTs represent a distinct subset marked by female predominance and gastric origin, are often multifocal, can sometimes have lymph node involvement, and typically lack mutations in the KIT and PDGFRA genes.

This review is the first of 2 articles focusing on the diagnosis and management of GISTs. Here, we review the evaluation and diagnosis of GISTs along with management of localized disease. Management of advanced disease is reviewed in a separate article.

Case Presentation

A 64-year-old African American man with progressive iron deficiency and abdominal discomfort undergoes upper and lower endoscopy and is found to have a bulging mass within his abdominal cavity. He undergoes a computed tomography (CT) evaluation of the chest, abdomen, and pelvis with contrast, which reveals the presence of a 10-cm gastric mass, with no other lesions identified. He undergoes surgical resection of the mass and presents for review of his pathology and to discuss his treatment plan.

What histopathologic features are consistent with GIST?

What factors are used for risk stratification and to predict likelihood of recurrence?

Clinical Presentation and Diagnosis

Most patients present with symptoms of overt or occult GI bleeding or abdominal discomfort, but a significant proportion of GISTs are discovered incidentally. Lymph node involvement is not typical, except for GISTs occurring in children and/or with rare syndromes. Most syndromic GISTs are multifocal and multicentric. After surgical resection, GISTs usually recur or metastasize within the abdominal cavity, including the omentum, peritoneum, or liver. These tumors rarely spread to the lungs, brain, or bones; when tumor spread does occur, it tends to be in heavily pre-treated patients with advanced disease who have been on multiple lines of therapy for a long duration of time.

The diagnosis usually can be made by histopathology. Specimens can be obtained by endoscopic ultrasound (EUS)– or CT-guided methods, the latter of which carries a very small risk of contamination from percutaneous biopsy. In terms of morphology, GISTs can be spindle cell, epithelioid, or mixed neoplasms. Epithelioid tumors are more commonly seen in the stomach and are often PDGFRA-mutated or SDH-deficient. The differential diagnosis includes other soft-tissue GI wall tumors such as leiomyosarcomas/leiomyomas, germ cell tumors, lymphomas, fibromatosis, and neuroendocrine and neurogenic tumors. A unique feature of GISTs that differentiates them from leiomyomas is near universal expression of CD117 by immunohistochemistry (IHC); this characteristic has allowed pathologists and providers to accurately distinguish true GISTs from other GI mesenchymal tumors.³ Recently, DOG1 (discovered on GIST1) immunoreactivity has been found to be helpful in identifying patients with CD117-negative GISTs. Initially identified through gene expression analysis of GISTs, DOG1 IHC can identify the common mutant c-Kit-driven CD117-positive GISTs as well as the rare CD117-negative GISTs, which are often driven by mutated PDGFRA.⁴ Importantly, IHC for KIT and DOG1 are not surrogates for mutational status, nor are they predictive of tyrosine kinase inhibitor (TKI) sensitivity. If IHC of a tumor specimen is CD117- and DOG1-negative, the specimen can be sent for KIT and PDGFRA mutational analysis to confirm the diagnosis. If analysis reveals that these genes are wild-type, then IHC staining for SDH B (SDHB) should follow to assess for an SDH-deficient GIST (negative staining).

Risk Stratification for Recurrence

The clinical behavior of GISTs can be variable. Some are indolent, while others behave more aggressively, with a greater malignant potential and a higher propensity to recur and metastasize. Clinical and pathologic features can provide important prognostic information that allows providers to risk-stratify patients. Various institutions have assessed prognostic variables for GISTs. In 2001, the National Institutes of Health (NIH) held a GIST workshop that proposed an approach to estimating metastatic risk based on tumor size and mitotic index (NIH or Fletcher criteria).⁵ Joensuu et al later proposed a modification of the NIH risk classification to include tumor location and tumor rupture (modified NIH criteria or Joensuu criteria).^6-8 Similarly, the Armed Forces Institute of Pathology (AFIP) identified tumor site as a prognostic factor, with gastric GISTs having the best prognosis (AFIP-Miettinen criteria).^9-11 Tabular schemes were designed which stratified patients into discrete groups with ranges for mitotic rate and tumor size. Nomograms for ease of use were then constructed utilizing a bimodal mitotic rate and included tumor site and size.¹² Finally, contour maps were developed, which have the advantage of evaluating mitotic rate and tumor size as continuous nonlinear variables and also include tumor site and rupture (associated with a high risk of peritoneal metastasis) separately, further improving risk assessment. These contour maps have been validated against pooled data from 10 series (2560 patients).¹³ High-risk features identified from these studies include tumor location, size, mitotic rate and tumor rupture and are now used for deciding on the use of adjuvant imatinib and as requirements to enter clinical trials assessing adjuvant therapy for resected GISTs.

Case Continued

The patient’s operative and pathology reports indicate that the tumor is a spindle cell neoplasm of the stomach that is positive for CD117, DOG1, and CD34 and negative for smooth muscle actin and S-100, consistent with a diagnosis of GIST. Resection margins are negative. There are 10 mitoses per 50 high-power fields (HPF). Per the operative report, there was no intraoperative or intraperitoneal tumor rupture. Thus, while his GIST was gastric, which generally has a more favorable prognosis, the tumor harbors high-risk features based on its size and mitotic index.

What further testing should be requested?

Molecular Alterations

It is recommended that a mutational analysis be performed as part of the diagnostic work-up of all GISTs.¹⁴ Mutational analysis can provide prognostic and predictive information for sensitivity to imatinib and should be considered standard of care. It may also be useful for confirming a GIST diagnosis, or, if negative, lead to further evaluation with an IHC stain for SDHB. The c-Kit receptor is a member of the tyrosine kinase family and, through direct interactions with stem cell factor (SCF), can upregulate the PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, and JAK-STAT pathways, resulting in transcription and translation of genes that enhance cell growth and survival.¹⁵ The cell of origin of GISTs, the interstitial cells of Cajal, are dependent on the SCF–c-Kit interaction for development.¹⁶ Likewise, the large majority of GISTs (about 70%) are driven by upregulation and constitutive activation of c-Kit, which is normally autoinhibited. About 80% of KIT mutations involve exon 11; these GISTs are most often associated with a gastric location and are associated with a favorable recurrence-free survival (RFS) rate with surgery alone.¹⁷KIT exon 9 mutations are much less common, encompassing only about 10% of GIST KIT mutations, and GISTs with these mutations are more likely to arise from the small bowel.¹⁷

About 8% of GISTs harbor gain-of-function PDGFRA driver mutations rendering constitutively active PDGFRA.¹⁸PDGFRA mutations are mutually exclusive from KIT mutations, and PDGFRA-mutated tumors most often occur in the stomach. PDGFRA mutations generally are associated with a lower mitotic rate and gastric location. Identification of the PDGFRA D842V mutation on exon 18, which is the most common, is important, as it is associated with imatinib resistance, and these patients should not be offered imatinib.¹⁹

Several other mutations associated with GISTs outside of the KIT and PDGFRA spectrum have been identified. About 10% of GISTs are wildtype for KIT and PDGFRA, and not all KIT/PDGFRA-wildtype GISTs are imatinib-sensitive and/or respond to other TKIs.¹⁸ These tumors may harbor aberrations in SDH and NF1, or less commonly, BRAF V600E, FGFR, and NTRK.^20,21 SDH subunits B, C and D play a role in the Krebs cycle and electron transport chain. Germline mutations in these SDH subunits can result in the Carney-Stratakis syndrome characterized by the dyad of multifocal GISTs and multicentric paragangliomas.²² This syndrome is most likely to manifest in the pediatric or young adult population. In contradistinction is the Carney triad, which is associated with acquired loss of function of the SDHC gene due to promoter hypermethylation. This syndrome classically occurs in young women and is characterized by an indolent-behaving triad of multicentric GISTs, non-adrenal paragangliomas, and pulmonary chondromas.²³ Like PDGFRA D842V–mutated GISTs, SDH-deficient and NF1-associated GISTs are considered imatinib resistant, and these patients should not be offered imatinib therapy.¹⁴

Case Continued

The patient’s GIST is found to harbor a KIT exon 11 single codon deletion. He appears anxious and asks to have everything done to prevent his GIST from coming back and to improve his lifespan.

Management

A multidisciplinary team approach to the management of all GISTs is essential and includes input from radiology, gastroenterology, pathology, medical and surgical oncology, nuclear medicine, and nursing.

Surgical Resection

Small esophagogastric and duodenal GISTs ≤ 2 cm can be asymptomatic and managed with serial endoscopic surveillance, typically every 6 to 12 months, with biopsies if the tumors increase in size. GISTs larger than 2 cm require surgical resection, with resection of the full pseudocapsule and an R0 resection, if possible, since larger GISTs carry a higher risk of growth and recurrence. If an R0 resection would lead to significant morbidity or functional sequelae, an R1 may suffice. Rectal GISTs are an exception, where microscopic margins have been shown to be associated with an increased risk of local failure.²⁴ It is important to explore the abdomen thoroughly for peritoneal, rectovaginal, and vesicular implants and metastasis to the liver. A formal lymph node dissection is not necessary because lymph nodes are rarely involved and should only be removed when clinically suspicious. Tumor rupture must be avoided. A laparoscopic approach should only be considered for smaller tumors, since there is a risk of tumor rupture with larger tumors.¹⁴

When is adjuvant imatinib indicated?

Adjuvant Imatinib

Among patients with local or locally advanced GISTs, the risk of death from recurrence with surgery alone can be high, with a historical 5-year overall survival (OS) of about 35%.²⁵ As a result, multiple studies have assessed the benefit of adjuvant imatinib, which is now considered standard of care for patients with imatinib-sensitive, high-risk GISTs. In addition to inhibiting BCR-ABL, imatinib mesylate inhibits multiple other receptor tyrosine kinases, including PDGFR, SCF and c-Kit. As a result, imatinib has demonstrated in vitro inhibition of cell proliferation and apoptosis and clinical activity against GISTs expressing CD117.²⁶ Importantly, adjuvant imatinib should only be offered to patients with imatinib-sensitive mutations, such as KIT exon 11 and KIT exon 9 mutations. Adjuvant imatinib should not be offered to patients with imatinib-insensitive mutations such as PDGFR 842V, NF1, or BRAF-related or SDH-deficient GISTs.

The ACOSOG Z9000 was the first study of adjuvant imatinib in patients with resected GISTs.²⁵ This was a single-arm, phase 2 study involving 106 patients with surgically resected GISTs deemed high-risk for recurrence, defined as size > 10 cm, tumor rupture, or up to 4 peritoneal implants. Patients were treated with imatinib 400 mg daily for 1 year. The primary and secondary endpoints were OS and RFS, respectively. Long-term follow-up of this study demonstrated 1-, 3-, and 5-year OS of 99%, 97%, and 83%, and 1-, 3-, and 5-year RFS of 96%, 60%, and 40%, which compared favorably with historical controls. In a multivariable analysis, increasing tumor size, small bowel location, KIT exon 9 mutation, high mitotic rate, and older age were independent risk factors for a poor RFS.²⁵ It is important to note that the benefit of adjuvant imatinib waned after discontinuation of therapy, creating a rationale to study adjuvant imatinib for longer periods of time.

As a result of the promising phase 2 data, ACOSOG opened a phase 3 randomized trial (Z9001) comparing 1 year of adjuvant imatinib to placebo among patients with surgically resected GISTs that were > 3 cm in size and that stained positive for CD117 on pathology. The trial accrued 713 patients and was stopped early at a planned interim analysis, which revealed a 1-year RFS of 98% for imatinib versus 83% for placebo (hazard ratio [HR], 0.35; P < 0.001). The 1-year OS did not differ between the 2 arms (92.2% vs 99.7%; HR, 0.66; P = 0.47).²⁷ When comparing the 2 arms, imatinib was associated with a higher RFS among patients with a KIT exon 11 deletion, but not among patients with other KIT mutation types, PDGFRA mutations, or who were KIT/PDGFRA wildtype.²⁸ Imatinib was granted approval by the US Food and Drug Administration (FDA) for the adjuvant treatment of high-risk GISTs based on the results of the ACOSOG Z9001 trial.

The EORTC 62024 study was a randomized placebo-controlled trial assessing the benefit of 2 years of adjuvant imatinib.²⁹ Patients had to be considered intermediate or high risk per the 2002 NIH consensus classification to be eligible. The trial enrolled 918 patients. The 5-year OS rate, the original primary endpoint, did not differ between the 2 groups (100% vs 99%). The 3-year and 5-year RFS rates, secondary endpoints, were significantly longer among patients treated with imatinib (84% vs 66% and 69% vs 63%, respectively). Again, it was noted that the benefit of imatinib waned over time after treatment discontinuation.

The Scandinavian Sarcoma Group (SSG XVIII) trial was a prospective randomized phase 3 trial that compared 3 years versus 1 year of adjuvant imatinib.³⁰ Patients had to be enrolled within 12 weeks of the postoperative period and had to have GISTs that were CD117-positive and with a high estimated risk of recurrence, per the modified NIH consensus criteria (size > 10 cm, > 10 mitoses per 50 HPF, diameter > 5 cm with mitotic count > 5, or tumor rupture before or at surgery). Three years of adjuvant imatinib was associated with a 54% reduction in the hazard for recurrence at 5 years (65.6% vs 47.9%; HR, 0.46; P < 0.001) and a 55% reduction in the hazard for death at 5 years (OS 92% vs 81.7%; HR, 0.45; P = 0.02). Based on the results of this study, the FDA granted approval for the use of 3 years of adjuvant imatinib in patients with high-risk resected GISTs.

The observation that a longer duration of adjuvant imatinib was associated with superior RFS and OS led to studies to further explore longer durations of adjuvant imatinib. The PERSIST-5 (Postresection Evaluation of Recurrence-free Survival for Gastrointestinal Stromal Tumors With 5 Years of Adjuvant Imatinib) was a multicenter, single-arm, phase 2 prospective study of adjuvant imatinib with a primary endpoint of RFS after 5 years.³¹ Patients had to have an intermediate or high risk of recurrence, which included GISTs at any site > 2 cm with > 5 mitoses per 50 HPF or nongastric GISTs that were ≥ 5 cm. With 91 patients enrolled, the estimated 5-year RFS was 90% and the OS was 95%. Of note, about half of the patients stopped treatment early due to a variety of reasons, including patient choice or adverse events. Importantly, there were no recurrences in patients with imatinib-sensitive mutations while on therapy. We know that in patients at high risk of relapse, adjuvant imatinib delays recurrence and improves survival, but whether any patients are cured, or their survival curves are just shifted to the right, is unknown. Only longer follow-up of existing studies, and the results of newer trials utilizing longer durations of adjuvant treatment, will help to determine the real value of adjuvant therapy for GIST patients.³² Based on this study, it would be reasonable to discuss a longer duration of imatinib with patients deemed to be at very high risk of recurrence and who are tolerating therapy well. We are awaiting the data from the randomized phase 3 Scandinavian Sarcoma Group XII trial comparing 5 years versus 3 years of adjuvant imatinib therapy, and from the French ImadGIST trial of adjuvant imatinib for 3 versus 6 years. A summary of the aforementioned key adjuvant trials is shown in the Table.

When imatinib is commenced, careful monitoring for treatment toxicities and drug interactions should ensue in order to improve compliance. Dose density should be maintained if possible, as retrospective studies suggest suboptimal plasma levels are associated with a worse outcome.³³

When should neoadjuvant imatinib be considered?

Neoadjuvant Imatinib

Neoadjuvant imatinib should be considered for patients requiring total gastrectomy, esophagectomy, or abdominoperineal resection of the rectum in order to reduce tumor size, limit subsequent surgical morbidity, mitigate tumor bleeding and rupture, and aid with organ preservation. Patients with rectal GISTs that may otherwise warrant an abdominoperineal resection should be offered a trial of imatinib in the neoadjuvant setting. There is no evidence for the use of any other TKI aside from imatinib in the neoadjuvant or adjuvant setting. With neoadjuvant imatinib, it is difficult to accurately assess the mitotic rate in the resected tumor specimen.

The RTOG 0132/ACRIN 6665 trial was a prospective phase 2 study evaluating the efficacy of imatinib 600 mg daily in the perioperative setting.³⁴ The trial enrolled 50 patients, 30 with primary GISTs (group A) and 22 with recurrent metastatic GISTs (group B). Based on data from the metastatic setting revealing a time to treatment response of about 2.5 months, patients were treated with 8 to 12 weeks of preoperative imatinib followed by 2 years of adjuvant imatinib. Imatinib was stopped 24 hours preoperatively and resumed as soon as possible postoperatively. In group A, 7% of patients achieved a partial response (PR), 83% achieved stable disease, and 2-year progression-free survival (PFS) and OS were 83% and 93%, respectively. In group B, 4.5% of patients achieved a PR, 91% achieved stable disease, and 4.5% experienced progressive disease in the preoperative period; the 2-year PFS and OS were 77% and 91%, respectively. The results of this trial demonstrated the feasibility of using perioperative imatinib with minimal effects on surgical outcomes and set the rationale to use neoadjuvant imatinib in select patients with borderline resectable or rectal GISTs. Another EORTC pooled analysis from 10 sarcoma centers revealed that after a median of 10 months of neoadjuvant imatinib, 83.2% of patients achieved an R0 resection and only 1% progressed during treatment.³⁵ After a median follow-up of 46 months, the 5-year disease-free survival and OS were 65% and 87%, respectively.

Mutational testing should be performed beforehand to ensure the tumor is imatinib-sensitive. If a KIT exon 9 mutation is identified, then 400 mg twice daily should be considered (given the benefit seen with 800 mg imatinib for advanced GIST patients), although there are no studies to confirm this practice. Neoadjuvant imatinib is recommended for a total of 6 to 12 months to ensure maximal tumor debulking, but with very close monitoring and surgical input for disease resistance and growth.¹⁴ Imatinib should be stopped 1 to 2 days preoperatively and resumed once the patient has recovered from surgery for a total of 3 years (pre-/postoperatively combined). Neoadjuvant therapy has been shown to be safe and effective, but there have been no randomized trials to assess survival.

What is appropriate surveillance for resected GISTs?

Surveillance

There have been no randomized studies to guide the management of surveillance after surgical resection and adjuvant therapy. There is no known optimal follow-up schedule, but several have been proposed.^13,36 Among high-risk patients, it is suggested to image every 3 to 6 months during adjuvant therapy, followed by every 3 months for 2 years after discontinuing therapy, then every 6 months for another 3 years and annually thereafter for an additional 5 years. High-risk patients usually relapse within 1 to 3 years after finishing adjuvant therapy, while low-risk patients can relapse later given that their disease can be slower growing. It has been recommended that low-risk patients undergo imaging every 6 months for 5 years, with follow-up individualized thereafter. Very-low-risk patients may not require more than annual imaging. Because most relapses occur within the peritoneum or liver, imaging should encompass the abdomen and pelvis. Surveillance imaging usually consists of CT scans of the abdomen and pelvis. MRI scans can be utilized for patients at lower risk or who are out several years in order to avoid excess radiation exposure. MRI is also specifically helpful for rectal and esophageal lesions. Chest CT or chest radiograph and bone scan are not routinely required for follow-up.

Case Conclusion

The patient receives adjuvant imatinib and experiences grade 2 myalgias, periorbital edema, and macrocytic anemia, which result in imatinib discontinuation after 3 years of treatment. He is seen every 3 to 6 months and a contrast CT abdomen and pelvis is obtained every 6 months for 5 years. During this 5-year follow-up period, he does not have any clinical or radiographic evidence of disease recurrence.

Further follow-up of this patient is presented in the second article in this 2-part review of management of GISTs.

Key Points

• GISTs are the most common mesenchymal neoplasms of the GI tract and can occasionally occur in extragastrointestinal locations as well.
• GISTs encompass a heterogeneous family of tumor subsets with different natural histories, mutations, and TKI responsiveness.
• Surgery is the mainstay of treatment for localized GISTs, with cure rates greater than 50%.
• For very small (< 2 cm) esophagogastric GISTs, endoscopic ultrasound evaluation and follow-up is recommended.
• For tumors ≥ 2 cm, biopsy and excision is the standard approach.
• For localized GISTs, complete surgical resection (R0) is standard treatment, with no lymphadenectomy for clinically negative lymph nodes.
• Mutational analysis should be considered standard of practice. It can be helpful for confirming the diagnosis and can be predictive and prognostic in determining specific TKI therapy and dose.
• Adjuvant imatinib at a dose of 400 mg for 3 years is standard of care for GISTs that are at high risk of relapse and are imatinib-sensitive, and it is the only TKI approved for adjuvant therapy. Patients with PDGFRA D842V, NF1, BRAF or SDH-deficient GISTs should not receive adjuvant imatinib therapy.
• Neoadjuvant therapy can be utilized for sites where extensive resection would lead to significant morbidity. It should be given for 6 to 12 months, but patients need to be monitored closely for tumor growth.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal (GI) tract and arise from the interstitial cells of Cajal of the myenteric plexus. These tumors are rare, with about 1 case per 100,000 persons diagnosed in the United States annually, but may be incidentally discovered in up to 1 in 5 autopsy specimens of older adults.^1,2 Epidemiologic risk factors include increasing age, with a peak incidence between age 60 and 65 years, male gender, black race, and non-Hispanic white ethnicity. Germline predisposition can also increase the risk of developing GISTs; molecular drivers of GIST include gain-of-function mutations in the KIT proto-oncogene and platelet-derived growth factor receptor α (PDGFRA) gene, which both encode structurally similar tyrosine kinase receptors; germline mutations of succinate dehydrogenase (SDH) subunit genes; and mutations associated with neurofibromatosis type 1.

GISTs most commonly involve the stomach, followed by the small intestine, but can arise anywhere within the GI tract (esophagus, colon, rectum, and anus). They can also develop outside the GI tract, arising from the mesentery, omentum, and retroperitoneum. The majority of cases are localized or locoregional, whereas about 20% are metastatic at presentation.¹ GISTs can occur in children, adolescents, and young adults. Pediatric GISTs represent a distinct subset marked by female predominance and gastric origin, are often multifocal, can sometimes have lymph node involvement, and typically lack mutations in the KIT and PDGFRA genes.

This review is the first of 2 articles focusing on the diagnosis and management of GISTs. Here, we review the evaluation and diagnosis of GISTs along with management of localized disease. Management of advanced disease is reviewed in a separate article.

Case Presentation

A 64-year-old African American man with progressive iron deficiency and abdominal discomfort undergoes upper and lower endoscopy and is found to have a bulging mass within his abdominal cavity. He undergoes a computed tomography (CT) evaluation of the chest, abdomen, and pelvis with contrast, which reveals the presence of a 10-cm gastric mass, with no other lesions identified. He undergoes surgical resection of the mass and presents for review of his pathology and to discuss his treatment plan.

What histopathologic features are consistent with GIST?

What factors are used for risk stratification and to predict likelihood of recurrence?

Clinical Presentation and Diagnosis

Most patients present with symptoms of overt or occult GI bleeding or abdominal discomfort, but a significant proportion of GISTs are discovered incidentally. Lymph node involvement is not typical, except for GISTs occurring in children and/or with rare syndromes. Most syndromic GISTs are multifocal and multicentric. After surgical resection, GISTs usually recur or metastasize within the abdominal cavity, including the omentum, peritoneum, or liver. These tumors rarely spread to the lungs, brain, or bones; when tumor spread does occur, it tends to be in heavily pre-treated patients with advanced disease who have been on multiple lines of therapy for a long duration of time.

The diagnosis usually can be made by histopathology. Specimens can be obtained by endoscopic ultrasound (EUS)– or CT-guided methods, the latter of which carries a very small risk of contamination from percutaneous biopsy. In terms of morphology, GISTs can be spindle cell, epithelioid, or mixed neoplasms. Epithelioid tumors are more commonly seen in the stomach and are often PDGFRA-mutated or SDH-deficient. The differential diagnosis includes other soft-tissue GI wall tumors such as leiomyosarcomas/leiomyomas, germ cell tumors, lymphomas, fibromatosis, and neuroendocrine and neurogenic tumors. A unique feature of GISTs that differentiates them from leiomyomas is near universal expression of CD117 by immunohistochemistry (IHC); this characteristic has allowed pathologists and providers to accurately distinguish true GISTs from other GI mesenchymal tumors.³ Recently, DOG1 (discovered on GIST1) immunoreactivity has been found to be helpful in identifying patients with CD117-negative GISTs. Initially identified through gene expression analysis of GISTs, DOG1 IHC can identify the common mutant c-Kit-driven CD117-positive GISTs as well as the rare CD117-negative GISTs, which are often driven by mutated PDGFRA.⁴ Importantly, IHC for KIT and DOG1 are not surrogates for mutational status, nor are they predictive of tyrosine kinase inhibitor (TKI) sensitivity. If IHC of a tumor specimen is CD117- and DOG1-negative, the specimen can be sent for KIT and PDGFRA mutational analysis to confirm the diagnosis. If analysis reveals that these genes are wild-type, then IHC staining for SDH B (SDHB) should follow to assess for an SDH-deficient GIST (negative staining).

Risk Stratification for Recurrence

The clinical behavior of GISTs can be variable. Some are indolent, while others behave more aggressively, with a greater malignant potential and a higher propensity to recur and metastasize. Clinical and pathologic features can provide important prognostic information that allows providers to risk-stratify patients. Various institutions have assessed prognostic variables for GISTs. In 2001, the National Institutes of Health (NIH) held a GIST workshop that proposed an approach to estimating metastatic risk based on tumor size and mitotic index (NIH or Fletcher criteria).⁵ Joensuu et al later proposed a modification of the NIH risk classification to include tumor location and tumor rupture (modified NIH criteria or Joensuu criteria).^6-8 Similarly, the Armed Forces Institute of Pathology (AFIP) identified tumor site as a prognostic factor, with gastric GISTs having the best prognosis (AFIP-Miettinen criteria).^9-11 Tabular schemes were designed which stratified patients into discrete groups with ranges for mitotic rate and tumor size. Nomograms for ease of use were then constructed utilizing a bimodal mitotic rate and included tumor site and size.¹² Finally, contour maps were developed, which have the advantage of evaluating mitotic rate and tumor size as continuous nonlinear variables and also include tumor site and rupture (associated with a high risk of peritoneal metastasis) separately, further improving risk assessment. These contour maps have been validated against pooled data from 10 series (2560 patients).¹³ High-risk features identified from these studies include tumor location, size, mitotic rate and tumor rupture and are now used for deciding on the use of adjuvant imatinib and as requirements to enter clinical trials assessing adjuvant therapy for resected GISTs.

Case Continued

The patient’s operative and pathology reports indicate that the tumor is a spindle cell neoplasm of the stomach that is positive for CD117, DOG1, and CD34 and negative for smooth muscle actin and S-100, consistent with a diagnosis of GIST. Resection margins are negative. There are 10 mitoses per 50 high-power fields (HPF). Per the operative report, there was no intraoperative or intraperitoneal tumor rupture. Thus, while his GIST was gastric, which generally has a more favorable prognosis, the tumor harbors high-risk features based on its size and mitotic index.

What further testing should be requested?

Molecular Alterations

It is recommended that a mutational analysis be performed as part of the diagnostic work-up of all GISTs.¹⁴ Mutational analysis can provide prognostic and predictive information for sensitivity to imatinib and should be considered standard of care. It may also be useful for confirming a GIST diagnosis, or, if negative, lead to further evaluation with an IHC stain for SDHB. The c-Kit receptor is a member of the tyrosine kinase family and, through direct interactions with stem cell factor (SCF), can upregulate the PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, and JAK-STAT pathways, resulting in transcription and translation of genes that enhance cell growth and survival.¹⁵ The cell of origin of GISTs, the interstitial cells of Cajal, are dependent on the SCF–c-Kit interaction for development.¹⁶ Likewise, the large majority of GISTs (about 70%) are driven by upregulation and constitutive activation of c-Kit, which is normally autoinhibited. About 80% of KIT mutations involve exon 11; these GISTs are most often associated with a gastric location and are associated with a favorable recurrence-free survival (RFS) rate with surgery alone.¹⁷KIT exon 9 mutations are much less common, encompassing only about 10% of GIST KIT mutations, and GISTs with these mutations are more likely to arise from the small bowel.¹⁷

About 8% of GISTs harbor gain-of-function PDGFRA driver mutations rendering constitutively active PDGFRA.¹⁸PDGFRA mutations are mutually exclusive from KIT mutations, and PDGFRA-mutated tumors most often occur in the stomach. PDGFRA mutations generally are associated with a lower mitotic rate and gastric location. Identification of the PDGFRA D842V mutation on exon 18, which is the most common, is important, as it is associated with imatinib resistance, and these patients should not be offered imatinib.¹⁹

Several other mutations associated with GISTs outside of the KIT and PDGFRA spectrum have been identified. About 10% of GISTs are wildtype for KIT and PDGFRA, and not all KIT/PDGFRA-wildtype GISTs are imatinib-sensitive and/or respond to other TKIs.¹⁸ These tumors may harbor aberrations in SDH and NF1, or less commonly, BRAF V600E, FGFR, and NTRK.^20,21 SDH subunits B, C and D play a role in the Krebs cycle and electron transport chain. Germline mutations in these SDH subunits can result in the Carney-Stratakis syndrome characterized by the dyad of multifocal GISTs and multicentric paragangliomas.²² This syndrome is most likely to manifest in the pediatric or young adult population. In contradistinction is the Carney triad, which is associated with acquired loss of function of the SDHC gene due to promoter hypermethylation. This syndrome classically occurs in young women and is characterized by an indolent-behaving triad of multicentric GISTs, non-adrenal paragangliomas, and pulmonary chondromas.²³ Like PDGFRA D842V–mutated GISTs, SDH-deficient and NF1-associated GISTs are considered imatinib resistant, and these patients should not be offered imatinib therapy.¹⁴

Case Continued

The patient’s GIST is found to harbor a KIT exon 11 single codon deletion. He appears anxious and asks to have everything done to prevent his GIST from coming back and to improve his lifespan.

Management

A multidisciplinary team approach to the management of all GISTs is essential and includes input from radiology, gastroenterology, pathology, medical and surgical oncology, nuclear medicine, and nursing.

Surgical Resection

Small esophagogastric and duodenal GISTs ≤ 2 cm can be asymptomatic and managed with serial endoscopic surveillance, typically every 6 to 12 months, with biopsies if the tumors increase in size. GISTs larger than 2 cm require surgical resection, with resection of the full pseudocapsule and an R0 resection, if possible, since larger GISTs carry a higher risk of growth and recurrence. If an R0 resection would lead to significant morbidity or functional sequelae, an R1 may suffice. Rectal GISTs are an exception, where microscopic margins have been shown to be associated with an increased risk of local failure.²⁴ It is important to explore the abdomen thoroughly for peritoneal, rectovaginal, and vesicular implants and metastasis to the liver. A formal lymph node dissection is not necessary because lymph nodes are rarely involved and should only be removed when clinically suspicious. Tumor rupture must be avoided. A laparoscopic approach should only be considered for smaller tumors, since there is a risk of tumor rupture with larger tumors.¹⁴

When is adjuvant imatinib indicated?

Adjuvant Imatinib

Among patients with local or locally advanced GISTs, the risk of death from recurrence with surgery alone can be high, with a historical 5-year overall survival (OS) of about 35%.²⁵ As a result, multiple studies have assessed the benefit of adjuvant imatinib, which is now considered standard of care for patients with imatinib-sensitive, high-risk GISTs. In addition to inhibiting BCR-ABL, imatinib mesylate inhibits multiple other receptor tyrosine kinases, including PDGFR, SCF and c-Kit. As a result, imatinib has demonstrated in vitro inhibition of cell proliferation and apoptosis and clinical activity against GISTs expressing CD117.²⁶ Importantly, adjuvant imatinib should only be offered to patients with imatinib-sensitive mutations, such as KIT exon 11 and KIT exon 9 mutations. Adjuvant imatinib should not be offered to patients with imatinib-insensitive mutations such as PDGFR 842V, NF1, or BRAF-related or SDH-deficient GISTs.

The ACOSOG Z9000 was the first study of adjuvant imatinib in patients with resected GISTs.²⁵ This was a single-arm, phase 2 study involving 106 patients with surgically resected GISTs deemed high-risk for recurrence, defined as size > 10 cm, tumor rupture, or up to 4 peritoneal implants. Patients were treated with imatinib 400 mg daily for 1 year. The primary and secondary endpoints were OS and RFS, respectively. Long-term follow-up of this study demonstrated 1-, 3-, and 5-year OS of 99%, 97%, and 83%, and 1-, 3-, and 5-year RFS of 96%, 60%, and 40%, which compared favorably with historical controls. In a multivariable analysis, increasing tumor size, small bowel location, KIT exon 9 mutation, high mitotic rate, and older age were independent risk factors for a poor RFS.²⁵ It is important to note that the benefit of adjuvant imatinib waned after discontinuation of therapy, creating a rationale to study adjuvant imatinib for longer periods of time.

As a result of the promising phase 2 data, ACOSOG opened a phase 3 randomized trial (Z9001) comparing 1 year of adjuvant imatinib to placebo among patients with surgically resected GISTs that were > 3 cm in size and that stained positive for CD117 on pathology. The trial accrued 713 patients and was stopped early at a planned interim analysis, which revealed a 1-year RFS of 98% for imatinib versus 83% for placebo (hazard ratio [HR], 0.35; P < 0.001). The 1-year OS did not differ between the 2 arms (92.2% vs 99.7%; HR, 0.66; P = 0.47).²⁷ When comparing the 2 arms, imatinib was associated with a higher RFS among patients with a KIT exon 11 deletion, but not among patients with other KIT mutation types, PDGFRA mutations, or who were KIT/PDGFRA wildtype.²⁸ Imatinib was granted approval by the US Food and Drug Administration (FDA) for the adjuvant treatment of high-risk GISTs based on the results of the ACOSOG Z9001 trial.

The EORTC 62024 study was a randomized placebo-controlled trial assessing the benefit of 2 years of adjuvant imatinib.²⁹ Patients had to be considered intermediate or high risk per the 2002 NIH consensus classification to be eligible. The trial enrolled 918 patients. The 5-year OS rate, the original primary endpoint, did not differ between the 2 groups (100% vs 99%). The 3-year and 5-year RFS rates, secondary endpoints, were significantly longer among patients treated with imatinib (84% vs 66% and 69% vs 63%, respectively). Again, it was noted that the benefit of imatinib waned over time after treatment discontinuation.

The Scandinavian Sarcoma Group (SSG XVIII) trial was a prospective randomized phase 3 trial that compared 3 years versus 1 year of adjuvant imatinib.³⁰ Patients had to be enrolled within 12 weeks of the postoperative period and had to have GISTs that were CD117-positive and with a high estimated risk of recurrence, per the modified NIH consensus criteria (size > 10 cm, > 10 mitoses per 50 HPF, diameter > 5 cm with mitotic count > 5, or tumor rupture before or at surgery). Three years of adjuvant imatinib was associated with a 54% reduction in the hazard for recurrence at 5 years (65.6% vs 47.9%; HR, 0.46; P < 0.001) and a 55% reduction in the hazard for death at 5 years (OS 92% vs 81.7%; HR, 0.45; P = 0.02). Based on the results of this study, the FDA granted approval for the use of 3 years of adjuvant imatinib in patients with high-risk resected GISTs.

The observation that a longer duration of adjuvant imatinib was associated with superior RFS and OS led to studies to further explore longer durations of adjuvant imatinib. The PERSIST-5 (Postresection Evaluation of Recurrence-free Survival for Gastrointestinal Stromal Tumors With 5 Years of Adjuvant Imatinib) was a multicenter, single-arm, phase 2 prospective study of adjuvant imatinib with a primary endpoint of RFS after 5 years.³¹ Patients had to have an intermediate or high risk of recurrence, which included GISTs at any site > 2 cm with > 5 mitoses per 50 HPF or nongastric GISTs that were ≥ 5 cm. With 91 patients enrolled, the estimated 5-year RFS was 90% and the OS was 95%. Of note, about half of the patients stopped treatment early due to a variety of reasons, including patient choice or adverse events. Importantly, there were no recurrences in patients with imatinib-sensitive mutations while on therapy. We know that in patients at high risk of relapse, adjuvant imatinib delays recurrence and improves survival, but whether any patients are cured, or their survival curves are just shifted to the right, is unknown. Only longer follow-up of existing studies, and the results of newer trials utilizing longer durations of adjuvant treatment, will help to determine the real value of adjuvant therapy for GIST patients.³² Based on this study, it would be reasonable to discuss a longer duration of imatinib with patients deemed to be at very high risk of recurrence and who are tolerating therapy well. We are awaiting the data from the randomized phase 3 Scandinavian Sarcoma Group XII trial comparing 5 years versus 3 years of adjuvant imatinib therapy, and from the French ImadGIST trial of adjuvant imatinib for 3 versus 6 years. A summary of the aforementioned key adjuvant trials is shown in the Table.

When imatinib is commenced, careful monitoring for treatment toxicities and drug interactions should ensue in order to improve compliance. Dose density should be maintained if possible, as retrospective studies suggest suboptimal plasma levels are associated with a worse outcome.³³

When should neoadjuvant imatinib be considered?

Neoadjuvant Imatinib

Neoadjuvant imatinib should be considered for patients requiring total gastrectomy, esophagectomy, or abdominoperineal resection of the rectum in order to reduce tumor size, limit subsequent surgical morbidity, mitigate tumor bleeding and rupture, and aid with organ preservation. Patients with rectal GISTs that may otherwise warrant an abdominoperineal resection should be offered a trial of imatinib in the neoadjuvant setting. There is no evidence for the use of any other TKI aside from imatinib in the neoadjuvant or adjuvant setting. With neoadjuvant imatinib, it is difficult to accurately assess the mitotic rate in the resected tumor specimen.

The RTOG 0132/ACRIN 6665 trial was a prospective phase 2 study evaluating the efficacy of imatinib 600 mg daily in the perioperative setting.³⁴ The trial enrolled 50 patients, 30 with primary GISTs (group A) and 22 with recurrent metastatic GISTs (group B). Based on data from the metastatic setting revealing a time to treatment response of about 2.5 months, patients were treated with 8 to 12 weeks of preoperative imatinib followed by 2 years of adjuvant imatinib. Imatinib was stopped 24 hours preoperatively and resumed as soon as possible postoperatively. In group A, 7% of patients achieved a partial response (PR), 83% achieved stable disease, and 2-year progression-free survival (PFS) and OS were 83% and 93%, respectively. In group B, 4.5% of patients achieved a PR, 91% achieved stable disease, and 4.5% experienced progressive disease in the preoperative period; the 2-year PFS and OS were 77% and 91%, respectively. The results of this trial demonstrated the feasibility of using perioperative imatinib with minimal effects on surgical outcomes and set the rationale to use neoadjuvant imatinib in select patients with borderline resectable or rectal GISTs. Another EORTC pooled analysis from 10 sarcoma centers revealed that after a median of 10 months of neoadjuvant imatinib, 83.2% of patients achieved an R0 resection and only 1% progressed during treatment.³⁵ After a median follow-up of 46 months, the 5-year disease-free survival and OS were 65% and 87%, respectively.

Mutational testing should be performed beforehand to ensure the tumor is imatinib-sensitive. If a KIT exon 9 mutation is identified, then 400 mg twice daily should be considered (given the benefit seen with 800 mg imatinib for advanced GIST patients), although there are no studies to confirm this practice. Neoadjuvant imatinib is recommended for a total of 6 to 12 months to ensure maximal tumor debulking, but with very close monitoring and surgical input for disease resistance and growth.¹⁴ Imatinib should be stopped 1 to 2 days preoperatively and resumed once the patient has recovered from surgery for a total of 3 years (pre-/postoperatively combined). Neoadjuvant therapy has been shown to be safe and effective, but there have been no randomized trials to assess survival.

What is appropriate surveillance for resected GISTs?

Surveillance

There have been no randomized studies to guide the management of surveillance after surgical resection and adjuvant therapy. There is no known optimal follow-up schedule, but several have been proposed.^13,36 Among high-risk patients, it is suggested to image every 3 to 6 months during adjuvant therapy, followed by every 3 months for 2 years after discontinuing therapy, then every 6 months for another 3 years and annually thereafter for an additional 5 years. High-risk patients usually relapse within 1 to 3 years after finishing adjuvant therapy, while low-risk patients can relapse later given that their disease can be slower growing. It has been recommended that low-risk patients undergo imaging every 6 months for 5 years, with follow-up individualized thereafter. Very-low-risk patients may not require more than annual imaging. Because most relapses occur within the peritoneum or liver, imaging should encompass the abdomen and pelvis. Surveillance imaging usually consists of CT scans of the abdomen and pelvis. MRI scans can be utilized for patients at lower risk or who are out several years in order to avoid excess radiation exposure. MRI is also specifically helpful for rectal and esophageal lesions. Chest CT or chest radiograph and bone scan are not routinely required for follow-up.

Case Conclusion

The patient receives adjuvant imatinib and experiences grade 2 myalgias, periorbital edema, and macrocytic anemia, which result in imatinib discontinuation after 3 years of treatment. He is seen every 3 to 6 months and a contrast CT abdomen and pelvis is obtained every 6 months for 5 years. During this 5-year follow-up period, he does not have any clinical or radiographic evidence of disease recurrence.

Further follow-up of this patient is presented in the second article in this 2-part review of management of GISTs.

Key Points

• GISTs are the most common mesenchymal neoplasms of the GI tract and can occasionally occur in extragastrointestinal locations as well.
• GISTs encompass a heterogeneous family of tumor subsets with different natural histories, mutations, and TKI responsiveness.
• Surgery is the mainstay of treatment for localized GISTs, with cure rates greater than 50%.
• For very small (< 2 cm) esophagogastric GISTs, endoscopic ultrasound evaluation and follow-up is recommended.
• For tumors ≥ 2 cm, biopsy and excision is the standard approach.
• For localized GISTs, complete surgical resection (R0) is standard treatment, with no lymphadenectomy for clinically negative lymph nodes.
• Mutational analysis should be considered standard of practice. It can be helpful for confirming the diagnosis and can be predictive and prognostic in determining specific TKI therapy and dose.
• Adjuvant imatinib at a dose of 400 mg for 3 years is standard of care for GISTs that are at high risk of relapse and are imatinib-sensitive, and it is the only TKI approved for adjuvant therapy. Patients with PDGFRA D842V, NF1, BRAF or SDH-deficient GISTs should not receive adjuvant imatinib therapy.
• Neoadjuvant therapy can be utilized for sites where extensive resection would lead to significant morbidity. It should be given for 6 to 12 months, but patients need to be monitored closely for tumor growth.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal (GI) tract and arise from the interstitial cells of Cajal of the myenteric plexus. These tumors are rare, with about 1 case per 100,000 persons diagnosed in the United States annually, but may be incidentally discovered in up to 1 in 5 autopsy specimens of older adults.^1,2 Epidemiologic risk factors include increasing age, with a peak incidence between age 60 and 65 years, male gender, black race, and non-Hispanic white ethnicity. Germline predisposition can also increase the risk of developing GISTs; molecular drivers of GIST include gain-of-function mutations in the KIT proto-oncogene and platelet-derived growth factor receptor α (PDGFRA) gene, which both encode structurally similar tyrosine kinase receptors; germline mutations of succinate dehydrogenase (SDH) subunit genes; and mutations associated with neurofibromatosis type 1.

GISTs most commonly involve the stomach, followed by the small intestine, but can arise anywhere within the GI tract (esophagus, colon, rectum, and anus). They can also develop outside the GI tract, arising from the mesentery, omentum, and retroperitoneum. The majority of cases are localized or locoregional, whereas about 20% are metastatic at presentation.¹ GISTs can occur in children, adolescents, and young adults. Pediatric GISTs represent a distinct subset marked by female predominance and gastric origin, are often multifocal, can sometimes have lymph node involvement, and typically lack mutations in the KIT and PDGFRA genes.

This review is the first of 2 articles focusing on the diagnosis and management of GISTs. Here, we review the evaluation and diagnosis of GISTs along with management of localized disease. Management of advanced disease is reviewed in a separate article.

Case Presentation

A 64-year-old African American man with progressive iron deficiency and abdominal discomfort undergoes upper and lower endoscopy and is found to have a bulging mass within his abdominal cavity. He undergoes a computed tomography (CT) evaluation of the chest, abdomen, and pelvis with contrast, which reveals the presence of a 10-cm gastric mass, with no other lesions identified. He undergoes surgical resection of the mass and presents for review of his pathology and to discuss his treatment plan.

What histopathologic features are consistent with GIST?

What factors are used for risk stratification and to predict likelihood of recurrence?

Clinical Presentation and Diagnosis

Most patients present with symptoms of overt or occult GI bleeding or abdominal discomfort, but a significant proportion of GISTs are discovered incidentally. Lymph node involvement is not typical, except for GISTs occurring in children and/or with rare syndromes. Most syndromic GISTs are multifocal and multicentric. After surgical resection, GISTs usually recur or metastasize within the abdominal cavity, including the omentum, peritoneum, or liver. These tumors rarely spread to the lungs, brain, or bones; when tumor spread does occur, it tends to be in heavily pre-treated patients with advanced disease who have been on multiple lines of therapy for a long duration of time.

The diagnosis usually can be made by histopathology. Specimens can be obtained by endoscopic ultrasound (EUS)– or CT-guided methods, the latter of which carries a very small risk of contamination from percutaneous biopsy. In terms of morphology, GISTs can be spindle cell, epithelioid, or mixed neoplasms. Epithelioid tumors are more commonly seen in the stomach and are often PDGFRA-mutated or SDH-deficient. The differential diagnosis includes other soft-tissue GI wall tumors such as leiomyosarcomas/leiomyomas, germ cell tumors, lymphomas, fibromatosis, and neuroendocrine and neurogenic tumors. A unique feature of GISTs that differentiates them from leiomyomas is near universal expression of CD117 by immunohistochemistry (IHC); this characteristic has allowed pathologists and providers to accurately distinguish true GISTs from other GI mesenchymal tumors.³ Recently, DOG1 (discovered on GIST1) immunoreactivity has been found to be helpful in identifying patients with CD117-negative GISTs. Initially identified through gene expression analysis of GISTs, DOG1 IHC can identify the common mutant c-Kit-driven CD117-positive GISTs as well as the rare CD117-negative GISTs, which are often driven by mutated PDGFRA.⁴ Importantly, IHC for KIT and DOG1 are not surrogates for mutational status, nor are they predictive of tyrosine kinase inhibitor (TKI) sensitivity. If IHC of a tumor specimen is CD117- and DOG1-negative, the specimen can be sent for KIT and PDGFRA mutational analysis to confirm the diagnosis. If analysis reveals that these genes are wild-type, then IHC staining for SDH B (SDHB) should follow to assess for an SDH-deficient GIST (negative staining).

Risk Stratification for Recurrence

The clinical behavior of GISTs can be variable. Some are indolent, while others behave more aggressively, with a greater malignant potential and a higher propensity to recur and metastasize. Clinical and pathologic features can provide important prognostic information that allows providers to risk-stratify patients. Various institutions have assessed prognostic variables for GISTs. In 2001, the National Institutes of Health (NIH) held a GIST workshop that proposed an approach to estimating metastatic risk based on tumor size and mitotic index (NIH or Fletcher criteria).⁵ Joensuu et al later proposed a modification of the NIH risk classification to include tumor location and tumor rupture (modified NIH criteria or Joensuu criteria).^6-8 Similarly, the Armed Forces Institute of Pathology (AFIP) identified tumor site as a prognostic factor, with gastric GISTs having the best prognosis (AFIP-Miettinen criteria).^9-11 Tabular schemes were designed which stratified patients into discrete groups with ranges for mitotic rate and tumor size. Nomograms for ease of use were then constructed utilizing a bimodal mitotic rate and included tumor site and size.¹² Finally, contour maps were developed, which have the advantage of evaluating mitotic rate and tumor size as continuous nonlinear variables and also include tumor site and rupture (associated with a high risk of peritoneal metastasis) separately, further improving risk assessment. These contour maps have been validated against pooled data from 10 series (2560 patients).¹³ High-risk features identified from these studies include tumor location, size, mitotic rate and tumor rupture and are now used for deciding on the use of adjuvant imatinib and as requirements to enter clinical trials assessing adjuvant therapy for resected GISTs.

Case Continued

The patient’s operative and pathology reports indicate that the tumor is a spindle cell neoplasm of the stomach that is positive for CD117, DOG1, and CD34 and negative for smooth muscle actin and S-100, consistent with a diagnosis of GIST. Resection margins are negative. There are 10 mitoses per 50 high-power fields (HPF). Per the operative report, there was no intraoperative or intraperitoneal tumor rupture. Thus, while his GIST was gastric, which generally has a more favorable prognosis, the tumor harbors high-risk features based on its size and mitotic index.

What further testing should be requested?

Molecular Alterations

It is recommended that a mutational analysis be performed as part of the diagnostic work-up of all GISTs.¹⁴ Mutational analysis can provide prognostic and predictive information for sensitivity to imatinib and should be considered standard of care. It may also be useful for confirming a GIST diagnosis, or, if negative, lead to further evaluation with an IHC stain for SDHB. The c-Kit receptor is a member of the tyrosine kinase family and, through direct interactions with stem cell factor (SCF), can upregulate the PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, and JAK-STAT pathways, resulting in transcription and translation of genes that enhance cell growth and survival.¹⁵ The cell of origin of GISTs, the interstitial cells of Cajal, are dependent on the SCF–c-Kit interaction for development.¹⁶ Likewise, the large majority of GISTs (about 70%) are driven by upregulation and constitutive activation of c-Kit, which is normally autoinhibited. About 80% of KIT mutations involve exon 11; these GISTs are most often associated with a gastric location and are associated with a favorable recurrence-free survival (RFS) rate with surgery alone.¹⁷KIT exon 9 mutations are much less common, encompassing only about 10% of GIST KIT mutations, and GISTs with these mutations are more likely to arise from the small bowel.¹⁷

About 8% of GISTs harbor gain-of-function PDGFRA driver mutations rendering constitutively active PDGFRA.¹⁸PDGFRA mutations are mutually exclusive from KIT mutations, and PDGFRA-mutated tumors most often occur in the stomach. PDGFRA mutations generally are associated with a lower mitotic rate and gastric location. Identification of the PDGFRA D842V mutation on exon 18, which is the most common, is important, as it is associated with imatinib resistance, and these patients should not be offered imatinib.¹⁹

Several other mutations associated with GISTs outside of the KIT and PDGFRA spectrum have been identified. About 10% of GISTs are wildtype for KIT and PDGFRA, and not all KIT/PDGFRA-wildtype GISTs are imatinib-sensitive and/or respond to other TKIs.¹⁸ These tumors may harbor aberrations in SDH and NF1, or less commonly, BRAF V600E, FGFR, and NTRK.^20,21 SDH subunits B, C and D play a role in the Krebs cycle and electron transport chain. Germline mutations in these SDH subunits can result in the Carney-Stratakis syndrome characterized by the dyad of multifocal GISTs and multicentric paragangliomas.²² This syndrome is most likely to manifest in the pediatric or young adult population. In contradistinction is the Carney triad, which is associated with acquired loss of function of the SDHC gene due to promoter hypermethylation. This syndrome classically occurs in young women and is characterized by an indolent-behaving triad of multicentric GISTs, non-adrenal paragangliomas, and pulmonary chondromas.²³ Like PDGFRA D842V–mutated GISTs, SDH-deficient and NF1-associated GISTs are considered imatinib resistant, and these patients should not be offered imatinib therapy.¹⁴

Case Continued

The patient’s GIST is found to harbor a KIT exon 11 single codon deletion. He appears anxious and asks to have everything done to prevent his GIST from coming back and to improve his lifespan.

Management

A multidisciplinary team approach to the management of all GISTs is essential and includes input from radiology, gastroenterology, pathology, medical and surgical oncology, nuclear medicine, and nursing.

Surgical Resection

Small esophagogastric and duodenal GISTs ≤ 2 cm can be asymptomatic and managed with serial endoscopic surveillance, typically every 6 to 12 months, with biopsies if the tumors increase in size. GISTs larger than 2 cm require surgical resection, with resection of the full pseudocapsule and an R0 resection, if possible, since larger GISTs carry a higher risk of growth and recurrence. If an R0 resection would lead to significant morbidity or functional sequelae, an R1 may suffice. Rectal GISTs are an exception, where microscopic margins have been shown to be associated with an increased risk of local failure.²⁴ It is important to explore the abdomen thoroughly for peritoneal, rectovaginal, and vesicular implants and metastasis to the liver. A formal lymph node dissection is not necessary because lymph nodes are rarely involved and should only be removed when clinically suspicious. Tumor rupture must be avoided. A laparoscopic approach should only be considered for smaller tumors, since there is a risk of tumor rupture with larger tumors.¹⁴

When is adjuvant imatinib indicated?

Adjuvant Imatinib

Among patients with local or locally advanced GISTs, the risk of death from recurrence with surgery alone can be high, with a historical 5-year overall survival (OS) of about 35%.²⁵ As a result, multiple studies have assessed the benefit of adjuvant imatinib, which is now considered standard of care for patients with imatinib-sensitive, high-risk GISTs. In addition to inhibiting BCR-ABL, imatinib mesylate inhibits multiple other receptor tyrosine kinases, including PDGFR, SCF and c-Kit. As a result, imatinib has demonstrated in vitro inhibition of cell proliferation and apoptosis and clinical activity against GISTs expressing CD117.²⁶ Importantly, adjuvant imatinib should only be offered to patients with imatinib-sensitive mutations, such as KIT exon 11 and KIT exon 9 mutations. Adjuvant imatinib should not be offered to patients with imatinib-insensitive mutations such as PDGFR 842V, NF1, or BRAF-related or SDH-deficient GISTs.

The ACOSOG Z9000 was the first study of adjuvant imatinib in patients with resected GISTs.²⁵ This was a single-arm, phase 2 study involving 106 patients with surgically resected GISTs deemed high-risk for recurrence, defined as size > 10 cm, tumor rupture, or up to 4 peritoneal implants. Patients were treated with imatinib 400 mg daily for 1 year. The primary and secondary endpoints were OS and RFS, respectively. Long-term follow-up of this study demonstrated 1-, 3-, and 5-year OS of 99%, 97%, and 83%, and 1-, 3-, and 5-year RFS of 96%, 60%, and 40%, which compared favorably with historical controls. In a multivariable analysis, increasing tumor size, small bowel location, KIT exon 9 mutation, high mitotic rate, and older age were independent risk factors for a poor RFS.²⁵ It is important to note that the benefit of adjuvant imatinib waned after discontinuation of therapy, creating a rationale to study adjuvant imatinib for longer periods of time.

As a result of the promising phase 2 data, ACOSOG opened a phase 3 randomized trial (Z9001) comparing 1 year of adjuvant imatinib to placebo among patients with surgically resected GISTs that were > 3 cm in size and that stained positive for CD117 on pathology. The trial accrued 713 patients and was stopped early at a planned interim analysis, which revealed a 1-year RFS of 98% for imatinib versus 83% for placebo (hazard ratio [HR], 0.35; P < 0.001). The 1-year OS did not differ between the 2 arms (92.2% vs 99.7%; HR, 0.66; P = 0.47).²⁷ When comparing the 2 arms, imatinib was associated with a higher RFS among patients with a KIT exon 11 deletion, but not among patients with other KIT mutation types, PDGFRA mutations, or who were KIT/PDGFRA wildtype.²⁸ Imatinib was granted approval by the US Food and Drug Administration (FDA) for the adjuvant treatment of high-risk GISTs based on the results of the ACOSOG Z9001 trial.

The EORTC 62024 study was a randomized placebo-controlled trial assessing the benefit of 2 years of adjuvant imatinib.²⁹ Patients had to be considered intermediate or high risk per the 2002 NIH consensus classification to be eligible. The trial enrolled 918 patients. The 5-year OS rate, the original primary endpoint, did not differ between the 2 groups (100% vs 99%). The 3-year and 5-year RFS rates, secondary endpoints, were significantly longer among patients treated with imatinib (84% vs 66% and 69% vs 63%, respectively). Again, it was noted that the benefit of imatinib waned over time after treatment discontinuation.

The Scandinavian Sarcoma Group (SSG XVIII) trial was a prospective randomized phase 3 trial that compared 3 years versus 1 year of adjuvant imatinib.³⁰ Patients had to be enrolled within 12 weeks of the postoperative period and had to have GISTs that were CD117-positive and with a high estimated risk of recurrence, per the modified NIH consensus criteria (size > 10 cm, > 10 mitoses per 50 HPF, diameter > 5 cm with mitotic count > 5, or tumor rupture before or at surgery). Three years of adjuvant imatinib was associated with a 54% reduction in the hazard for recurrence at 5 years (65.6% vs 47.9%; HR, 0.46; P < 0.001) and a 55% reduction in the hazard for death at 5 years (OS 92% vs 81.7%; HR, 0.45; P = 0.02). Based on the results of this study, the FDA granted approval for the use of 3 years of adjuvant imatinib in patients with high-risk resected GISTs.

The observation that a longer duration of adjuvant imatinib was associated with superior RFS and OS led to studies to further explore longer durations of adjuvant imatinib. The PERSIST-5 (Postresection Evaluation of Recurrence-free Survival for Gastrointestinal Stromal Tumors With 5 Years of Adjuvant Imatinib) was a multicenter, single-arm, phase 2 prospective study of adjuvant imatinib with a primary endpoint of RFS after 5 years.³¹ Patients had to have an intermediate or high risk of recurrence, which included GISTs at any site > 2 cm with > 5 mitoses per 50 HPF or nongastric GISTs that were ≥ 5 cm. With 91 patients enrolled, the estimated 5-year RFS was 90% and the OS was 95%. Of note, about half of the patients stopped treatment early due to a variety of reasons, including patient choice or adverse events. Importantly, there were no recurrences in patients with imatinib-sensitive mutations while on therapy. We know that in patients at high risk of relapse, adjuvant imatinib delays recurrence and improves survival, but whether any patients are cured, or their survival curves are just shifted to the right, is unknown. Only longer follow-up of existing studies, and the results of newer trials utilizing longer durations of adjuvant treatment, will help to determine the real value of adjuvant therapy for GIST patients.³² Based on this study, it would be reasonable to discuss a longer duration of imatinib with patients deemed to be at very high risk of recurrence and who are tolerating therapy well. We are awaiting the data from the randomized phase 3 Scandinavian Sarcoma Group XII trial comparing 5 years versus 3 years of adjuvant imatinib therapy, and from the French ImadGIST trial of adjuvant imatinib for 3 versus 6 years. A summary of the aforementioned key adjuvant trials is shown in the Table.

When imatinib is commenced, careful monitoring for treatment toxicities and drug interactions should ensue in order to improve compliance. Dose density should be maintained if possible, as retrospective studies suggest suboptimal plasma levels are associated with a worse outcome.³³

When should neoadjuvant imatinib be considered?

Neoadjuvant Imatinib

Neoadjuvant imatinib should be considered for patients requiring total gastrectomy, esophagectomy, or abdominoperineal resection of the rectum in order to reduce tumor size, limit subsequent surgical morbidity, mitigate tumor bleeding and rupture, and aid with organ preservation. Patients with rectal GISTs that may otherwise warrant an abdominoperineal resection should be offered a trial of imatinib in the neoadjuvant setting. There is no evidence for the use of any other TKI aside from imatinib in the neoadjuvant or adjuvant setting. With neoadjuvant imatinib, it is difficult to accurately assess the mitotic rate in the resected tumor specimen.

The RTOG 0132/ACRIN 6665 trial was a prospective phase 2 study evaluating the efficacy of imatinib 600 mg daily in the perioperative setting.³⁴ The trial enrolled 50 patients, 30 with primary GISTs (group A) and 22 with recurrent metastatic GISTs (group B). Based on data from the metastatic setting revealing a time to treatment response of about 2.5 months, patients were treated with 8 to 12 weeks of preoperative imatinib followed by 2 years of adjuvant imatinib. Imatinib was stopped 24 hours preoperatively and resumed as soon as possible postoperatively. In group A, 7% of patients achieved a partial response (PR), 83% achieved stable disease, and 2-year progression-free survival (PFS) and OS were 83% and 93%, respectively. In group B, 4.5% of patients achieved a PR, 91% achieved stable disease, and 4.5% experienced progressive disease in the preoperative period; the 2-year PFS and OS were 77% and 91%, respectively. The results of this trial demonstrated the feasibility of using perioperative imatinib with minimal effects on surgical outcomes and set the rationale to use neoadjuvant imatinib in select patients with borderline resectable or rectal GISTs. Another EORTC pooled analysis from 10 sarcoma centers revealed that after a median of 10 months of neoadjuvant imatinib, 83.2% of patients achieved an R0 resection and only 1% progressed during treatment.³⁵ After a median follow-up of 46 months, the 5-year disease-free survival and OS were 65% and 87%, respectively.

Mutational testing should be performed beforehand to ensure the tumor is imatinib-sensitive. If a KIT exon 9 mutation is identified, then 400 mg twice daily should be considered (given the benefit seen with 800 mg imatinib for advanced GIST patients), although there are no studies to confirm this practice. Neoadjuvant imatinib is recommended for a total of 6 to 12 months to ensure maximal tumor debulking, but with very close monitoring and surgical input for disease resistance and growth.¹⁴ Imatinib should be stopped 1 to 2 days preoperatively and resumed once the patient has recovered from surgery for a total of 3 years (pre-/postoperatively combined). Neoadjuvant therapy has been shown to be safe and effective, but there have been no randomized trials to assess survival.

What is appropriate surveillance for resected GISTs?

Surveillance

There have been no randomized studies to guide the management of surveillance after surgical resection and adjuvant therapy. There is no known optimal follow-up schedule, but several have been proposed.^13,36 Among high-risk patients, it is suggested to image every 3 to 6 months during adjuvant therapy, followed by every 3 months for 2 years after discontinuing therapy, then every 6 months for another 3 years and annually thereafter for an additional 5 years. High-risk patients usually relapse within 1 to 3 years after finishing adjuvant therapy, while low-risk patients can relapse later given that their disease can be slower growing. It has been recommended that low-risk patients undergo imaging every 6 months for 5 years, with follow-up individualized thereafter. Very-low-risk patients may not require more than annual imaging. Because most relapses occur within the peritoneum or liver, imaging should encompass the abdomen and pelvis. Surveillance imaging usually consists of CT scans of the abdomen and pelvis. MRI scans can be utilized for patients at lower risk or who are out several years in order to avoid excess radiation exposure. MRI is also specifically helpful for rectal and esophageal lesions. Chest CT or chest radiograph and bone scan are not routinely required for follow-up.

Case Conclusion

The patient receives adjuvant imatinib and experiences grade 2 myalgias, periorbital edema, and macrocytic anemia, which result in imatinib discontinuation after 3 years of treatment. He is seen every 3 to 6 months and a contrast CT abdomen and pelvis is obtained every 6 months for 5 years. During this 5-year follow-up period, he does not have any clinical or radiographic evidence of disease recurrence.

Further follow-up of this patient is presented in the second article in this 2-part review of management of GISTs.

Key Points

• GISTs are the most common mesenchymal neoplasms of the GI tract and can occasionally occur in extragastrointestinal locations as well.
• GISTs encompass a heterogeneous family of tumor subsets with different natural histories, mutations, and TKI responsiveness.
• Surgery is the mainstay of treatment for localized GISTs, with cure rates greater than 50%.
• For very small (< 2 cm) esophagogastric GISTs, endoscopic ultrasound evaluation and follow-up is recommended.
• For tumors ≥ 2 cm, biopsy and excision is the standard approach.
• For localized GISTs, complete surgical resection (R0) is standard treatment, with no lymphadenectomy for clinically negative lymph nodes.
• Mutational analysis should be considered standard of practice. It can be helpful for confirming the diagnosis and can be predictive and prognostic in determining specific TKI therapy and dose.
• Adjuvant imatinib at a dose of 400 mg for 3 years is standard of care for GISTs that are at high risk of relapse and are imatinib-sensitive, and it is the only TKI approved for adjuvant therapy. Patients with PDGFRA D842V, NF1, BRAF or SDH-deficient GISTs should not receive adjuvant imatinib therapy.
• Neoadjuvant therapy can be utilized for sites where extensive resection would lead to significant morbidity. It should be given for 6 to 12 months, but patients need to be monitored closely for tumor growth.

Most advanced gastrointestinal stromal tumors (GISTs) are due to a recurrence of localized disease, with only a small minority presenting with metastatic disease.¹ Compared with chemotherapy, tyrosine kinase inhibitors (TKIs) have significantly improved the natural history of the disease, with median overall survival (OS) increasing from less than 1 year to about 5 years and approximately 1 in 5 patients achieving long-term survival.² In addition, newer drugs in development and in clinical trials appear promising and have the potential to improve outcomes even further. This article reviews current evidence on options for treating metastatic or recurrent GISTs and GISTs that have progressed following initial therapy. The evaluation and diagnosis of GIST along with management of localized disease are reviewed in a separate article.

Case Presentation

A 64-year-old African American man underwent surgical resection of a 10-cm gastric mass, which pathology reported was positive for CD117, DOG1, and CD34 and negative for smooth muscle actin and S-100, consistent with a diagnosis of GIST. There were 10 mitoses per 50 HPF, and there was no intraoperative or intraperitoneal tumor rupture. The patient was treated with adjuvant imatinib, which was discontinued after 3 years due to grade 2 myalgias, periorbital edema, and macrocytic anemia. Surveillance included office visits every 3 to 6 months and a contrast CT abdomen and pelvis every 6 months. For the past 5 years, he has not had any clinical or radiographic evidence of disease recurrence. New imaging reveals multiple liver metastases and peritoneal implants. He feels fatigued and has lost about 10 lb since his last visit. He is 5 years out from his initial diagnosis and 2 years out from last receiving imatinib. His original tumor harbored a KIT exon 11 deletion.

What treatment should you recommend now?

Imatinib for Advanced GISTs

Before the first report of the efficacy of imatinib for metastatic GISTs in 2002, patients with advanced unresectable or metastatic GISTs were routinely treated with doxorubicin-based chemotherapy regimens, which were largely ineffective, with response rates (RRs) of around 5% and a median overall survival (OS) of less than 1 year.^3,4 In 2002 a landmark phase 2 study revealed imatinib’s significant efficacy profile in advanced or metastatic GISTs, resulting in its approval by the US Food and Drug Administration (FDA).⁵ In this study, 147 patients with CD117-positive GISTs were randomly assigned to receive daily imatinib 400 mg or 600 mg for up to 36 months. The RRs were similar between the 2 groups (68.5% vs 67.6%), with a median time to response of 12 weeks and median duration of response of 118 days. Results of this study were much more favorable when compared to doxorubicin, rendering imatinib the new standard of care for advanced GISTs. A long-term follow-up of this study after a median of 63 months confirmed near identical RRs, progression-free survival (PFS), and median survival of 57 months among the 2 groups.⁶

Imatinib Daily Dosing

Although 400 mg of daily imatinib proved to be efficacious, it was unclear if a dose-response relationship existed for imatinib. An EORTC phase 2 study demonstrated a benefit of using a higher dose of imatinib at 400 mg twice daily, producing a RR of 71% (4% complete , 67% partial) and 1-year PFS of 73%, which appeared favorable compared with once-daily dosing and set the framework for larger phase 3 studies.⁷ Two phase 3 studies compared imatinib 400 mg once daily versus twice daily (until disease progression or unacceptable toxicity) among patients with CD117-positive advanced or metastatic GISTs. These studies were eventually combined into a meta-analysis (metaGIST) to compare RR, PFS and OS between the treatment groups. Both studies allowed cross-over to the 800 mg dose for patients who progressed on 400 mg daily.

The first study, conducted jointly by the EORTC, Italian Sarcoma Group, and Australasian Gastro-Intestinal Trials Group (EU-AUS),⁸ randomly assigned 946 patients to 400 mg once daily or twice daily. There were no differences in response rates between the groups, but the twice-daily group had a predicted 18% reduction in the hazard for progression compared with the once-daily group (estimated HR, 0.82; P = 0.026), which came at the expense of greater toxicities warranting dose reductions (60%) and treatment interruptions (64%). Cross-over to high-dose imatinib was feasible and safe, producing a partial response in 2%, stable disease in 27%, and a median PFS of 81 days. The second study was an intergroup study conducted jointly by SWOG, CALGB, NCI-C, and ECOG (S0033, US-CDN), with a nearly identical study design as the EU-AUS trial.⁹ The trial enrolled 746 patients. After a median follow up of 4.5 years, the median PFS and OS were not statistically different (18 vs 20 months and 55 vs 51 months, respectively). There were also no differences in response rates. One third of patients initially placed on the once-daily arm who crossed over after progression achieved a treatment response or stable disease.

The combined EU-AUS and US-CDN analysis (metaGIST) included 1640 patients with a median age of 60 years and 58% of whom were men; 818 and 822 patients were assigned to the 400 mg and 800 mg total daily doses, respectively.¹⁰ The median follow-up was 37.5 months. There were no differences in OS (49 vs 48.7 months), median PFS (18.9 vs 23.2 months), or overall response rates (51.4% vs 53.9%). Patients who had crossed over (n = 347) to the 800 mg total daily dose arm had a 7.7-month average PFS while on the higher daily dose. An analysis was performed on 377 patients in the EU-AUS trial assessing the impact of mutational status on clinical outcomes among imatinib-treated patients. KIT exon 9 activating mutations were found to be a significant independent prognostic factor for death when compared with KIT exon 11 mutations. However, the adverse prognostic value of KIT exon 9 mutations was partially overcome with higher doses of imatinib, as those who received 800 mg total had a significantly better PFS, with a 61% relative risk reduction, than those who received 400 mg. Altogether, it was concluded that imatinib 400 mg once daily should be the standard-of-care first-line treatment for advanced or metastatic GISTs, unless a KIT exon 9 mutation is present, in which case imatinib 800 mg should be considered, if 400 mg is well tolerated. In addition, patients treated with frontline imatinib at 400 mg once daily, if tolerated well, should be considered for imatinib 800 mg upon progression of disease.

Despite there being problems with secondary resistance, significant progress has occurred in the treatment of metastatic disease over a short period of time. Prior to 2000, median OS for patients with metastatic GISTs was 9 months. With the introduction of imatinib and other TKIs, the median OS has increased to 5 years, with an estimated 10-year OS rate of approximately 20%.²

Since at this point, imatinib was a well-established standard of care for advanced GISTs, it was questioned whether imatinib therapy could be interrupted. At this time, treatment interruption in a stop-and-go fashion was deemed feasible in other metastatic solid tumors such as colorectal cancer (OPTIMOX1).¹¹ The BFR French trial showed that stopping imatinib therapy in patients who had a response or stable disease after 1, 3, or 5 years was generally followed by relatively rapid tumor progression (approximately 50% of patients within 6 months), even when tumors were previously removed.¹² Therefore, it is recommended that treatment in the metastatic setting should be continued indefinitely, unless there is disease progression. Hence, unlike with colorectal cancer or chronic myelogenous leukemia, as of now there is no role for imatinib interruption in metastatic GISTs.

Case Continued

The patient is started on imatinib 400 mg daily, and overall he tolerates therapy well. Interval CT imaging reveals a treatment response. Two years later, imaging reveals an increase in the tumor size and density with a new nodule present within a preexisting mass. There are no clinical trials in the area.

What defines tumor progression?

Disease Progression

When GISTs are responding to treatment, on imaging the tumors can become more cystic and less dense but with an increase in size. In addition, tumor progression may not always be associated with increased size—increased density of the tumor or a nodule within a mass that may indicate progression. If CT imaging is equivocal for progression, positron emission tomography (PET) can play a role in identifying true progression. It is critically important that tumor size and density are carefully assessed when performing interval imaging. Of note, radiofrequency ablation, cryotherapy, or chemoembolization can be used for symptomatic liver metastases or oligometastatic disease. When evaluating for progression, one needs to ask patients about compliance (ie, maintaining dose intensity related to side effects of therapy as well as the financial burden of treatment—copay toxicity).

What are mechanisms of secondary imatinib resistance?

Imatinib resistance can be subtle in patients with GISTs, manifesting with new nodular, enhancing foci enclosed within a preexisting mass (resistant clonal nodule), or can be clinically or radiographically overt.¹³ Imatinib resistance occurs through multiple mechanisms including acquisition of secondary activating KIT mutations in the intracellular ATP-binding domain (exons 13 and 14) and the activation loop (exons 17 and 18).¹⁴

What are the treatment options for this patient?

Second-line Therapy

Sunitinib malate is a multitargeted TKI that not only targets c-Kit and PDGFRA, but also has anti-angiogenic activity through inhibition of vascular endothelial growth factor receptors (VEGFR). Sunitinib gained FDA approval for the second-line treatment of advanced GISTs based on an international double-blind trial that randomized 312 patients with imatinib-resistant metastatic GISTs in a 2:1 fashion to receive sunitinib 50 mg daily for 4 weeks on and 2 weeks off or placebo.^15,16 The trial was unblinded early at the planned interim analysis, which revealed a marked benefit, producing a 66% reduction in the hazard risk of progression (27.3 vs 6.4 weeks, HR, 0.33; P < 0.001). The most common treatment-related adverse events were fatigue, diarrhea, skin discoloration, nausea, and hand-foot syndrome. Another open-label phase 2 study assessed a continuous dosing schema of sunitinib 37.5 mg daily, which has been shown to be effective with less toxicity.¹⁷ Among the 60 patients enrolled, the primary endpoint of clinical benefit rate at 24 weeks was reached in 53%, which consisted of 13% partial responses and 40% stable disease. Most toxicities were grade 1 or 2 and easily manageable through standard interventions. This has been recommended as an alternative to the initial scheduled regimen.¹⁸ Part of sunitinib’s success is its activity against GISTs harboring secondary KIT exon 13 and 14 mutations, and possibly its anti-angiogenic activity.¹⁹ Sunitinib is particularly efficacious among GISTs harboring KIT exon 9 mutations.

Patients who have progressed on prior imatinib and sunitinib can receive third-line regorafenib, a multi-TKI that differs chemically from sorafenib by a fluorouracil group (fluoro-sorafenib). FDA approval of regorafenib was based on the phase 3 GRID (GIST Regorafenib In progressive Disease) multicenter international trial.²⁰ This trial randomly assigned 199 patients in a 2:1 fashion to receive regorafenib 160 mg daily for 21 days out of 28-day cycles plus best supportive care (BSC) versus placebo plus BSC. Cross-over was allowed. Regorafenib significantly reduced the hazard risk of progression by 73% compared with placebo (4.8 vs 0.9 months; HR, 0.27; P < 0.001). There was no difference in OS, which may be because of cross-over (median OS, 17.4 months in both arms). As a result, regorafenib is now considered standard third-line treatment for patients with metastatic GISTs. It has a less favorable toxicity profile than imatinib, with hand-foot syndrome, transaminitis, hypertension and fatigue being the most common treatment toxicities. In order to avoid noncompliance, it is recommended to start at 80 mg and carefully titrate upwards to the 160 mg dose.

A list of landmark studies for advanced GISTs is provided in Table 1.

A summary of FDA-approved drugs for treating GISTs is provided in Table 2.

Clinical Trials

Clinical trial enrollment should be considered for all patients with advanced or unresectable GISTs throughout their treatment continuum. Owing to significant advances in genomic profiling through next-generation sequencing, multiple driver mutations have recently been identified, and targeted therapies are being explored in clinical trials.²¹ For example, the neurotrophic receptor tyrosine kinase (NTRK) gene appears to be mutated in a small number of advanced GISTs, and these can respond to the highly selective TRK inhibitor larotrectinib.²² Additionally, ongoing studies are assessing immunotherapies for sporadic GISTs and treatment for familial GISTs (Table 3). Some notable studies include those assessing the efficacy of agents that target KIT and PDGFR secondary mutations, including avapritinib (BLU-285) and DCC-2618, MEK inhibitors, and the multi-kinase inhibitor crenolanib for GISTs harboring the imatinib-resistant PDGFRA D842V mutation. There are also studies utilizing checkpoint inhibitors alone or in combination with imatinib.