Clinical Review

Nonmelanoma skin cancer (NMSC) is the most common malignancy worldwide, and its incidence continues to increase. More than 5 million NMSCs are estimated to occur annually in the United States alone.¹ There are more cases of basal cell carcinoma (BCC) than all other cancers combined, with squamous cell carcinoma (SCC) being the second most common cancer in the United States.^1-3 The rising incidence of NMSCs highlights the importance of investigating additional treatment options with fewer side effects, better cosmetic outcomes, and better efficacy.¹

Originally, treatment options for NMSCs largely relied on destructive and surgical methods. Basal cell carcinoma and SCC commonly are treated with cryosurgery; electrodesiccation and curettage; or more definitive surgical options, including excision and Mohs micrographic surgery (MMS). Over time, topical agents such as 5-fluorouracil, imiquimod, ingenol mebutate, and various forms of aminolevulinic acid (ALA) for photodynamic therapy (PDT) were included for superficial lesions as well as field treatment. The development of oral hedgehog (Hh) inhibitors, such as vismodegib, offered a promising alternative to patients with advanced disease. Each treatment has its own specific indications and side effects; thus, there is always room for novel therapeutic approaches. We review new and potential treatments from 2018 and beyond. Although only 5% of SCCs become locally advanced, recur, or metastasize, and 0.4% to 0.8% of BCCs progress to advanced disease, many of the newer studies target advanced NMSCs, given their life-threatening and debilitating nature.^4,5 Similarly, the incidence of nevoid basal cell carcinoma (NBCC) syndrome is as low as 1 in 57,000 to 1 in 164,000 but continues to be studied because of its morbidity and the potential to contribute new treatment options for BCC in the general population.⁶

Topical Therapy

Sonidegib
Basal cell carcinoma proliferation is a result of an unregulated Hh pathway that is initiated when the Hh ligand binds to the patched 1 protein (PTCH1).^7-11 Patched 1 protein normally inhibits the smoothened (SMO) transmembrane receptor protein, decreasing the signaling cascade. In BCCs, there is a loss of PTCH1 function, effectively increasing the Hh pathway activity. Sonidegib is an Hh inhibitor that in turn prevents inhibition of PTCH1 in an attempt to reregulate the pathway.^7-11 Although sonidegib is known for its 2015 approval by the US Food and Drug Administration (FDA) as a systemic therapy for locally advanced BCCs,¹² one study investigated a topical formulation on 8 patients with NBCC syndrome.¹³ Patients were treated twice daily with sonidegib cream 0.75% for 4 weeks in a double-blind, randomized, vehicle-controlled study. A total of 27 BCCs were randomized and treated with either vehicle or sonidegib. A biopsy was taken at the end of the study of 1 sonidegib-treated and 1 vehicle-treated BCC lesion per patient. Of the 13 sonidegib-treated BCC lesions, 3 (23.1%) showed complete response, 9 (69.2%) showed partial response, and 1 (7.7%) showed no response vs 13 of 14 (92.8%) lesions that did not respond to the vehicle. Patients tolerated the treatment well without skin irritation or signs of local or systemic side effects.¹³ Topical sonidegib should be further investigated as an adjunct or in different vehicles given the successful regression of BCCs and its minimal side-effect profile.

Systemic Therapy

Cemiplimab
Cemiplimab is a human monoclonal antibody against programmed death receptor 1 (PD-1) that was FDA approved in September 2018 for the treatment of metastatic cutaneous SCC.¹⁴ Programmed death receptor 1 is found on T lymphocytes, B lymphocytes, and macrophages, which normally assist in the immune response to tumor cells. However, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2) are found on tumor cells and bind to PD-1. Cemiplimab prevents PD-1 from binding to PD-L1 and PD-L2, allowing an appropriate immune response.^14,15 A phase 1 clinical trial of cemiplimab showed a 50% (13/26) response rate.¹⁶ The phase 2 trial included patients with advanced SCC, but the primary analysis only considered patients with metastatic SCC. Phase 2 results showed a 47.5% (28/59) response rate. Patients received intravenous cemiplimab 3 mg/kg once every 2 weeks for up to 48 weeks in phase 1 and up to 96 weeks in phase 2. Both phases of the trial showed a response to treatment lasting longer than 6 months in more than 50% of patients. The most common adverse events were diarrhea, fatigue, nausea, constipation, and rash.¹⁶

Although immune-mediated adverse reactions are rare, they can occur given cemiplimab’s mechanism of action and may range from severe to fatal. Examples of immune-mediated adverse reactions that occurred during the study included pneumonitis, colitis, hepatitis, adrenal insufficiency, hypophysitis, hypothyroidism, hyperthyroidism, type 1 diabetes mellitus, nephritis with renal dysfunction, and immune-mediated dermatologic reactions.¹⁴ It is important to monitor for immune-mediated adverse reactions and address them immediately once detected.

Other PD-1 Inhibitors
Although PD-1 inhibitors have been studied in advanced SCCs, their clinical data are limited for BCCs.¹⁷ Prior to 2018, there was a small number of case reports of patients with BCC with partial to exceptional response to PD-1 inhibitors. Recently, 2 additional case reports were published with contrasting outcomes using 2 different PD-1 inhibitors. An elderly patient with metastatic non–small cell lung cancer was treated with nivolumab after failing chemotherapy. She subsequently developed a BCC on the nose that was resected but recurred 2 months later despite continuing nivolumab.¹⁷ Another case report detailed a patient with a history of BCC on the shoulder excised 5 years prior who presented with recurrence on the sternum and clavicle.¹⁸ One year later the patient was found to have BCC metastases to the lung. After progression of disease despite vismodegib and recurrence of BCC with taladegib, the patient was then placed on pembrolizumab. At 6 weeks and 12 months, computed tomography showed resolution of multiple lung lesions. Sixteen weeks after initiation of pembrolizumab treatment, spinal metastases were found, but the treatment was continued because of the improvement in the lung metastases.¹⁸

Taladegib
Taladegib is a SMO antagonist that has been through a phase 1 trial in patients with advanced cancer, including treatment-naive and previously treated BCCs.¹⁹ Eighty-four patients were treated to examine the safety profile and determine an appropriate phase 2 dose and administration schedule. The maximum tolerable dose was determined to be 400 mg because of dose-limiting toxicities. All clinical responses were in patients with BCCs (47/84 [55.9%] patients), with a response rate of 46.8%. Eleven of 16 (68.8%) Hh-treatment–naive patients and 11 of 31 (35.5%) patients previously treated with Hh responded to taladegib. Common adverse events were dysgeusia, fatigue, nausea, and muscle spasms.¹⁹ Although vismodegib is an FDA-approved SMO antagonist since 2012, treatment resistance and tolerability issues have been continuing concerns.^20,21 Taladegib is a potential alternative that may be found to have improved pharmacodynamics and pharmacokinetics. Not only did in vitro studies show a preferable protein-binding profile with taladegib, but it also displayed dose proportionality, while vismodegib has been known to have nonlinear pharmacokinetics.¹⁹

Posaconazole
Posaconazole is a systemic antifungal agent that is a structural analogue to itraconazole.²² Itraconazole has been found to inhibit the Hh pathway as an SMO antagonist. In a study with mice, posaconazole was found to have strong activity against drug-resistant SMO mutants while inhibiting the growth of Hh-dependent BCCs in vivo. A marked decrease also was seen in the ciliary accumulation of SMO, suggesting a similar mechanism of action to itraconazole. Posaconazole’s use for BCCs currently is limited to basic science studies but may offer a potential alternative to itraconazole, which is known to have many drug-drug interactions and requires dose adjustments in renal and hepatic insufficiency. When used as an antifungal compared to itraconazole, posaconazole has a favorable long-term safety profile due to fewer drug-drug interactions and mild side effects; it also does not require dose adjustments in mild to moderate renal or hepatic insufficiency.²² Thus, posaconazole is a potentially safer alternative to itraconazole for the treatment of BCCs. Although phase 2 studies of itraconazole for BCCs have shown decreased cell proliferation, tumor size, and reduced GLI1 messenger RNA, side effects included fatigue and grade 4 heart failure.^23,24

Radiation Therapy

Radiation therapies (RTs), such as superficial RT, have been long-established treatment options.²⁵ However, there also are emerging methods of delivering RT, including electronic brachytherapy (EB). Although there is a low likelihood of residual tumor after RT given the number of sessions involved and the more aggressive nature of the treatment, these factors also can be a substantial burden on the patient. Furthermore, RT may result in subsequent scar tissue, which can hinder the use of other emerging technologies, such as noninvasive imaging devices, following RT.

Superficial RT
Superficial RT is a secondary option for the treatment of NMSC for use in special circumstances, such as when surgical intervention is contraindicated or refused, and after the benefits and risks of treatment alternatives have been discussed.²⁶ However, depending on the tumor type and anatomical location, 6 to 18 treatments may be required, with treatment frequency ranging from 1 to 5 treatments per week.²⁵ Patients may find this treatment regimen difficult to maintain given the length of time and frequency of treatments required. Side effects include radiation dermatitis and postinflammatory hypopigmentation or hyperpigmentation in patients with dark skin, and there is a risk for recurrence.^25,27

Electronic Brachytherapy
Brachytherapy is a method of delivering RT via radioactive isotopes, whereas EB uses lower-energy photons that require less shielding.²⁸ As a relatively new therapy, studies on the efficacy of EB on NMSC continue to grow but with limited data comparing EB with established treatments. Furthermore, there are limited long-term follow-up data, and future studies should expand the patient demographic to younger patients before treatment guidelines can be established.²⁸

RT With Concurrent and Adjuvant Vismodegib
Vismodegib is an SMO inhibitor that was FDA approved in 2012 for the treatment of locally advanced BCC in patients who are not candidates for surgery or RT.²⁹ Over time, studies have looked into other indications for vismodegib, such as a neoadjuvant to MMS or in patients with NBCC syndrome.¹¹ Prior to 2018, there were only 2 known case reports of concurrent vismodegib and RT used for recurrent advanced BCC.³⁰ Recently, vismodegib has been further examined in combination with RT in a case report,³¹ basic science study,³² and phase 2 trials (ClinicalTrials.gov Identifiers NCT02956889 and NCT01835626).

Prior studies showed low cure rates with vismodegib alone after RT (43%) as well as decreasing cure rates with primary RT alone as tumor size increased.^33,34 In 2018, vismodegib was used concurrently and as an adjuvant to RT in a patient with advanced multifocal BCC.³¹ The patient had multiple large BCCs on the trunk that were painful and bleeding. The patient was started on RT and 150 mg/d vismodegib concurrently, which was then continued adjuvantly for 3 months until it was discontinued because of diarrhea. The patient had complete response in all lesions with resolution of symptoms.³¹ A separate basic science study further supported the potential role of vismodegib in radiation sensitization of both BCCs and head and neck SCCs.³² There presently are 2 phase 2 trials investigating the concurrent use of vismodegib and RT, which could help determine the efficacy of the combined approach for patients with advanced BCCs who are poor surgical candidates (NCT02956889 and NCT01835626).

Photodynamic Therapy

Photodynamic therapy has been in use since the 1970s when Dougherty et al³⁵ performed one of the first studies on its use in skin cancer. Since then, PDT has been used for the treatment of actinic keratoses (AKs) and more recently BCCs. In PDT, a photosensitizer (PS) is applied and activated by a 400-nm blue light or 635-nm red light, depending on the PS used. The PS then produces highly reactive oxygen species, leading to apoptosis of the cancer cells.³⁶ In Europe, red light PDT is licensed for the treatment of AKs as well as superficial and nodular BCCs, though approved indications vary between countries. In the United States, PDT is only FDA approved for the treatment of AKs.³⁷

Aminolevulinic Acid Hydrochloride
Aminolevulinic acid hydrochloride is a red light PS used to treat AKs since 2011 and BCCs since 2017 in Europe in addition to AKs in the United States since 2016.^38,39 A phase 3 noninferiority clinical trial in Europe of 281 patients compared the treatment of nonaggressive BCCs with ALA to methyl aminolevulinate (MAL) cream.⁴⁰ The study found a complete response rate of 93.4% vs 91.8%. Superficial BCCs treated with ALA had a clearance rate of 94.7% vs 96.4% with MAL, while nodular BCCs treated with ALA had a clearance rate of 85.7% vs 76.2% with MAL. A 1-year clinical follow-up showed similar recurrence rates (8.4% for ALA vs 8.5% for MAL).⁴⁰ The results of this study led to an expanded indication in Europe to include the treatment of BCCs.³⁸ Aminolevulinic acid hydrochloride currently is undergoing phase 3 clinical trials in the United States for approval for the treatment of superficial BCCs (NCT03573401). If similar outcomes are achieved, US patients may have access to an alternative nonsurgical treatment of BCCs. The ongoing US trial is exclusively investigating the efficacy and safety for superficial BCCs, which may limit FDA approval to only superficial BCCs, accounting for only 8.4% to 24.1% of all BCCs.^35,41,42

Laser Therapy

Ablative and nonablative lasers have been used to treat NMSCs in the literature. Ablative lasers destroy tumors through vaporization of tissue water, whereas nonablative lasers target the vasculature of tumors while preserving the surrounding tissue.^43,44 Nonablative lasers include pulsed dye lasers (PDL) and Nd:YAG lasers. Examples of ablative lasers include CO₂ and erbium:YAG lasers. Given the status of lasers as an emerging treatment method, there currently is no standardized laser setting for any of the laser therapies used to treat NMSCs. Although there is the potential for optimal cosmetic outcomes and a limited side-effect profile for nonablative laser therapies, there are limited data on long-term follow-up to study recurrence rates and establish a more standardized treatment protocol.

Pulsed Dye Lasers
Although there were no studies on PDL therapy alone in 2018, a study published in 2019 evaluated a combination laser treatment using a 595-nm PDL and 1927-nm fractional laser for the treatment of 93 BCCs, yielding a 95.7% (89/93) clearance rate and 4.5% (4/89) recurrence rate over a follow-up period of up to 6 years (range, 2.53 months to 6.03 years).⁴⁵ Studies of PDL prior to 2018 had follow-ups ranging from 2 weeks to 6 months.^46-51 Although the majority were biopsy-proven BCCs, reflectance confocal microscopy also was used for same-day diagnoses. Long-term follow-up included clinical examinations, dermoscopy, and optical coherence tomography.⁴⁵ The clearance rate (95.7%) using noninvasive imaging in conjunction with the combination laser treatment was superior to both histologic and clinical clearance rates of prior PDL-only studies, which ranged from 25% to 95%.^46-51 To have long-term follow-up data, the study used noninvasive imaging with clinical follow-up because histology would not be viable for long-term follow-up. This study was retrospective rather than prospective, which was a limitation.⁴⁵

Nd:YAG Lasers
The majority of studies utilizing Nd:YAG lasers investigated their efficacy in treating BCCs, with the exception of 1 study of facial SCCs. This major study in 2009 of 627 BCCs showed a 2.5% recurrence rate after a follow-up time of 3 months to 5 years.⁵² Nd:YAG lasers continue to be investigated, including a more recent study of 31 extrafacial, biopsy-proven BCCs that were treated with the 1064-nm Nd:YAG laser, which showed a 90% histologic clearance on 1-month follow-up after a single treatment.⁵³ In 2019, a retrospective review of 16 BCC lesions on the head, neck, trunk, and extremities showed 100% clearance after 1 treatment, with an average follow-up period of 9 months (range, 6–15 months).⁵⁴ In a retrospective review, Markowitz and Psomadakis⁵⁵ contributed data supporting the further investigation and use of the 1064-nm Nd:YAG laser for BCC treatment while leveraging noninvasive imaging to demonstrate a same-day management model. Seventeen BCC lesions on the face and body were diagnosed by reflectance confocal microscopy and treated with an Nd:YAG laser, and clearance was monitored clinically, dermoscopically, and by optical coherence tomography. There was 100% clearance of the lesions in the study, with 82.4% (14/17) clearing after 1 treatment; mean follow-up was 103 days (range, 48–371 days).⁵⁵ These studies were limited by their short follow-up time; long-term data are needed to determine true rates of recurrence.

Ablative Lasers
Ablative lasers also have been used in the treatment of NMSCs. In addition to the potentially increased healing time compared to nonablative lasers, other limitations of ablative laser therapy include residual tumor burden or recurrence that may not be easily visualized in scarred tissue after nonablative management.⁴⁴

Conclusion

Although MMS remains the gold standard for invasive management of NMSCs, studies from 2018 and beyond (eTable) expanded not only on MMS topics such as increased patient access and improved techniques but also on the increasing potential of noninvasive treatments. Some of the noninvasive therapies were entirely new compounds, whereas others were already in use for a different disease indication. Furthering our knowledge and expanding our repertoire of management options will prepare us as the number of patients affected by NMSCs increases.

Nonmelanoma skin cancer (NMSC) is the most common malignancy worldwide, and its incidence continues to increase. More than 5 million NMSCs are estimated to occur annually in the United States alone.¹ There are more cases of basal cell carcinoma (BCC) than all other cancers combined, with squamous cell carcinoma (SCC) being the second most common cancer in the United States.^1-3 The rising incidence of NMSCs highlights the importance of investigating additional treatment options with fewer side effects, better cosmetic outcomes, and better efficacy.¹

Originally, treatment options for NMSCs largely relied on destructive and surgical methods. Basal cell carcinoma and SCC commonly are treated with cryosurgery; electrodesiccation and curettage; or more definitive surgical options, including excision and Mohs micrographic surgery (MMS). Over time, topical agents such as 5-fluorouracil, imiquimod, ingenol mebutate, and various forms of aminolevulinic acid (ALA) for photodynamic therapy (PDT) were included for superficial lesions as well as field treatment. The development of oral hedgehog (Hh) inhibitors, such as vismodegib, offered a promising alternative to patients with advanced disease. Each treatment has its own specific indications and side effects; thus, there is always room for novel therapeutic approaches. We review new and potential treatments from 2018 and beyond. Although only 5% of SCCs become locally advanced, recur, or metastasize, and 0.4% to 0.8% of BCCs progress to advanced disease, many of the newer studies target advanced NMSCs, given their life-threatening and debilitating nature.^4,5 Similarly, the incidence of nevoid basal cell carcinoma (NBCC) syndrome is as low as 1 in 57,000 to 1 in 164,000 but continues to be studied because of its morbidity and the potential to contribute new treatment options for BCC in the general population.⁶

Topical Therapy

Sonidegib
Basal cell carcinoma proliferation is a result of an unregulated Hh pathway that is initiated when the Hh ligand binds to the patched 1 protein (PTCH1).^7-11 Patched 1 protein normally inhibits the smoothened (SMO) transmembrane receptor protein, decreasing the signaling cascade. In BCCs, there is a loss of PTCH1 function, effectively increasing the Hh pathway activity. Sonidegib is an Hh inhibitor that in turn prevents inhibition of PTCH1 in an attempt to reregulate the pathway.^7-11 Although sonidegib is known for its 2015 approval by the US Food and Drug Administration (FDA) as a systemic therapy for locally advanced BCCs,¹² one study investigated a topical formulation on 8 patients with NBCC syndrome.¹³ Patients were treated twice daily with sonidegib cream 0.75% for 4 weeks in a double-blind, randomized, vehicle-controlled study. A total of 27 BCCs were randomized and treated with either vehicle or sonidegib. A biopsy was taken at the end of the study of 1 sonidegib-treated and 1 vehicle-treated BCC lesion per patient. Of the 13 sonidegib-treated BCC lesions, 3 (23.1%) showed complete response, 9 (69.2%) showed partial response, and 1 (7.7%) showed no response vs 13 of 14 (92.8%) lesions that did not respond to the vehicle. Patients tolerated the treatment well without skin irritation or signs of local or systemic side effects.¹³ Topical sonidegib should be further investigated as an adjunct or in different vehicles given the successful regression of BCCs and its minimal side-effect profile.

Systemic Therapy

Cemiplimab
Cemiplimab is a human monoclonal antibody against programmed death receptor 1 (PD-1) that was FDA approved in September 2018 for the treatment of metastatic cutaneous SCC.¹⁴ Programmed death receptor 1 is found on T lymphocytes, B lymphocytes, and macrophages, which normally assist in the immune response to tumor cells. However, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2) are found on tumor cells and bind to PD-1. Cemiplimab prevents PD-1 from binding to PD-L1 and PD-L2, allowing an appropriate immune response.^14,15 A phase 1 clinical trial of cemiplimab showed a 50% (13/26) response rate.¹⁶ The phase 2 trial included patients with advanced SCC, but the primary analysis only considered patients with metastatic SCC. Phase 2 results showed a 47.5% (28/59) response rate. Patients received intravenous cemiplimab 3 mg/kg once every 2 weeks for up to 48 weeks in phase 1 and up to 96 weeks in phase 2. Both phases of the trial showed a response to treatment lasting longer than 6 months in more than 50% of patients. The most common adverse events were diarrhea, fatigue, nausea, constipation, and rash.¹⁶

Although immune-mediated adverse reactions are rare, they can occur given cemiplimab’s mechanism of action and may range from severe to fatal. Examples of immune-mediated adverse reactions that occurred during the study included pneumonitis, colitis, hepatitis, adrenal insufficiency, hypophysitis, hypothyroidism, hyperthyroidism, type 1 diabetes mellitus, nephritis with renal dysfunction, and immune-mediated dermatologic reactions.¹⁴ It is important to monitor for immune-mediated adverse reactions and address them immediately once detected.

Other PD-1 Inhibitors
Although PD-1 inhibitors have been studied in advanced SCCs, their clinical data are limited for BCCs.¹⁷ Prior to 2018, there was a small number of case reports of patients with BCC with partial to exceptional response to PD-1 inhibitors. Recently, 2 additional case reports were published with contrasting outcomes using 2 different PD-1 inhibitors. An elderly patient with metastatic non–small cell lung cancer was treated with nivolumab after failing chemotherapy. She subsequently developed a BCC on the nose that was resected but recurred 2 months later despite continuing nivolumab.¹⁷ Another case report detailed a patient with a history of BCC on the shoulder excised 5 years prior who presented with recurrence on the sternum and clavicle.¹⁸ One year later the patient was found to have BCC metastases to the lung. After progression of disease despite vismodegib and recurrence of BCC with taladegib, the patient was then placed on pembrolizumab. At 6 weeks and 12 months, computed tomography showed resolution of multiple lung lesions. Sixteen weeks after initiation of pembrolizumab treatment, spinal metastases were found, but the treatment was continued because of the improvement in the lung metastases.¹⁸

Taladegib
Taladegib is a SMO antagonist that has been through a phase 1 trial in patients with advanced cancer, including treatment-naive and previously treated BCCs.¹⁹ Eighty-four patients were treated to examine the safety profile and determine an appropriate phase 2 dose and administration schedule. The maximum tolerable dose was determined to be 400 mg because of dose-limiting toxicities. All clinical responses were in patients with BCCs (47/84 [55.9%] patients), with a response rate of 46.8%. Eleven of 16 (68.8%) Hh-treatment–naive patients and 11 of 31 (35.5%) patients previously treated with Hh responded to taladegib. Common adverse events were dysgeusia, fatigue, nausea, and muscle spasms.¹⁹ Although vismodegib is an FDA-approved SMO antagonist since 2012, treatment resistance and tolerability issues have been continuing concerns.^20,21 Taladegib is a potential alternative that may be found to have improved pharmacodynamics and pharmacokinetics. Not only did in vitro studies show a preferable protein-binding profile with taladegib, but it also displayed dose proportionality, while vismodegib has been known to have nonlinear pharmacokinetics.¹⁹

Posaconazole
Posaconazole is a systemic antifungal agent that is a structural analogue to itraconazole.²² Itraconazole has been found to inhibit the Hh pathway as an SMO antagonist. In a study with mice, posaconazole was found to have strong activity against drug-resistant SMO mutants while inhibiting the growth of Hh-dependent BCCs in vivo. A marked decrease also was seen in the ciliary accumulation of SMO, suggesting a similar mechanism of action to itraconazole. Posaconazole’s use for BCCs currently is limited to basic science studies but may offer a potential alternative to itraconazole, which is known to have many drug-drug interactions and requires dose adjustments in renal and hepatic insufficiency. When used as an antifungal compared to itraconazole, posaconazole has a favorable long-term safety profile due to fewer drug-drug interactions and mild side effects; it also does not require dose adjustments in mild to moderate renal or hepatic insufficiency.²² Thus, posaconazole is a potentially safer alternative to itraconazole for the treatment of BCCs. Although phase 2 studies of itraconazole for BCCs have shown decreased cell proliferation, tumor size, and reduced GLI1 messenger RNA, side effects included fatigue and grade 4 heart failure.^23,24

Radiation Therapy

Radiation therapies (RTs), such as superficial RT, have been long-established treatment options.²⁵ However, there also are emerging methods of delivering RT, including electronic brachytherapy (EB). Although there is a low likelihood of residual tumor after RT given the number of sessions involved and the more aggressive nature of the treatment, these factors also can be a substantial burden on the patient. Furthermore, RT may result in subsequent scar tissue, which can hinder the use of other emerging technologies, such as noninvasive imaging devices, following RT.

Superficial RT
Superficial RT is a secondary option for the treatment of NMSC for use in special circumstances, such as when surgical intervention is contraindicated or refused, and after the benefits and risks of treatment alternatives have been discussed.²⁶ However, depending on the tumor type and anatomical location, 6 to 18 treatments may be required, with treatment frequency ranging from 1 to 5 treatments per week.²⁵ Patients may find this treatment regimen difficult to maintain given the length of time and frequency of treatments required. Side effects include radiation dermatitis and postinflammatory hypopigmentation or hyperpigmentation in patients with dark skin, and there is a risk for recurrence.^25,27

Electronic Brachytherapy
Brachytherapy is a method of delivering RT via radioactive isotopes, whereas EB uses lower-energy photons that require less shielding.²⁸ As a relatively new therapy, studies on the efficacy of EB on NMSC continue to grow but with limited data comparing EB with established treatments. Furthermore, there are limited long-term follow-up data, and future studies should expand the patient demographic to younger patients before treatment guidelines can be established.²⁸

RT With Concurrent and Adjuvant Vismodegib
Vismodegib is an SMO inhibitor that was FDA approved in 2012 for the treatment of locally advanced BCC in patients who are not candidates for surgery or RT.²⁹ Over time, studies have looked into other indications for vismodegib, such as a neoadjuvant to MMS or in patients with NBCC syndrome.¹¹ Prior to 2018, there were only 2 known case reports of concurrent vismodegib and RT used for recurrent advanced BCC.³⁰ Recently, vismodegib has been further examined in combination with RT in a case report,³¹ basic science study,³² and phase 2 trials (ClinicalTrials.gov Identifiers NCT02956889 and NCT01835626).

Prior studies showed low cure rates with vismodegib alone after RT (43%) as well as decreasing cure rates with primary RT alone as tumor size increased.^33,34 In 2018, vismodegib was used concurrently and as an adjuvant to RT in a patient with advanced multifocal BCC.³¹ The patient had multiple large BCCs on the trunk that were painful and bleeding. The patient was started on RT and 150 mg/d vismodegib concurrently, which was then continued adjuvantly for 3 months until it was discontinued because of diarrhea. The patient had complete response in all lesions with resolution of symptoms.³¹ A separate basic science study further supported the potential role of vismodegib in radiation sensitization of both BCCs and head and neck SCCs.³² There presently are 2 phase 2 trials investigating the concurrent use of vismodegib and RT, which could help determine the efficacy of the combined approach for patients with advanced BCCs who are poor surgical candidates (NCT02956889 and NCT01835626).

Photodynamic Therapy

Photodynamic therapy has been in use since the 1970s when Dougherty et al³⁵ performed one of the first studies on its use in skin cancer. Since then, PDT has been used for the treatment of actinic keratoses (AKs) and more recently BCCs. In PDT, a photosensitizer (PS) is applied and activated by a 400-nm blue light or 635-nm red light, depending on the PS used. The PS then produces highly reactive oxygen species, leading to apoptosis of the cancer cells.³⁶ In Europe, red light PDT is licensed for the treatment of AKs as well as superficial and nodular BCCs, though approved indications vary between countries. In the United States, PDT is only FDA approved for the treatment of AKs.³⁷

Aminolevulinic Acid Hydrochloride
Aminolevulinic acid hydrochloride is a red light PS used to treat AKs since 2011 and BCCs since 2017 in Europe in addition to AKs in the United States since 2016.^38,39 A phase 3 noninferiority clinical trial in Europe of 281 patients compared the treatment of nonaggressive BCCs with ALA to methyl aminolevulinate (MAL) cream.⁴⁰ The study found a complete response rate of 93.4% vs 91.8%. Superficial BCCs treated with ALA had a clearance rate of 94.7% vs 96.4% with MAL, while nodular BCCs treated with ALA had a clearance rate of 85.7% vs 76.2% with MAL. A 1-year clinical follow-up showed similar recurrence rates (8.4% for ALA vs 8.5% for MAL).⁴⁰ The results of this study led to an expanded indication in Europe to include the treatment of BCCs.³⁸ Aminolevulinic acid hydrochloride currently is undergoing phase 3 clinical trials in the United States for approval for the treatment of superficial BCCs (NCT03573401). If similar outcomes are achieved, US patients may have access to an alternative nonsurgical treatment of BCCs. The ongoing US trial is exclusively investigating the efficacy and safety for superficial BCCs, which may limit FDA approval to only superficial BCCs, accounting for only 8.4% to 24.1% of all BCCs.^35,41,42

Laser Therapy

Ablative and nonablative lasers have been used to treat NMSCs in the literature. Ablative lasers destroy tumors through vaporization of tissue water, whereas nonablative lasers target the vasculature of tumors while preserving the surrounding tissue.^43,44 Nonablative lasers include pulsed dye lasers (PDL) and Nd:YAG lasers. Examples of ablative lasers include CO₂ and erbium:YAG lasers. Given the status of lasers as an emerging treatment method, there currently is no standardized laser setting for any of the laser therapies used to treat NMSCs. Although there is the potential for optimal cosmetic outcomes and a limited side-effect profile for nonablative laser therapies, there are limited data on long-term follow-up to study recurrence rates and establish a more standardized treatment protocol.

Pulsed Dye Lasers
Although there were no studies on PDL therapy alone in 2018, a study published in 2019 evaluated a combination laser treatment using a 595-nm PDL and 1927-nm fractional laser for the treatment of 93 BCCs, yielding a 95.7% (89/93) clearance rate and 4.5% (4/89) recurrence rate over a follow-up period of up to 6 years (range, 2.53 months to 6.03 years).⁴⁵ Studies of PDL prior to 2018 had follow-ups ranging from 2 weeks to 6 months.^46-51 Although the majority were biopsy-proven BCCs, reflectance confocal microscopy also was used for same-day diagnoses. Long-term follow-up included clinical examinations, dermoscopy, and optical coherence tomography.⁴⁵ The clearance rate (95.7%) using noninvasive imaging in conjunction with the combination laser treatment was superior to both histologic and clinical clearance rates of prior PDL-only studies, which ranged from 25% to 95%.^46-51 To have long-term follow-up data, the study used noninvasive imaging with clinical follow-up because histology would not be viable for long-term follow-up. This study was retrospective rather than prospective, which was a limitation.⁴⁵

Nd:YAG Lasers
The majority of studies utilizing Nd:YAG lasers investigated their efficacy in treating BCCs, with the exception of 1 study of facial SCCs. This major study in 2009 of 627 BCCs showed a 2.5% recurrence rate after a follow-up time of 3 months to 5 years.⁵² Nd:YAG lasers continue to be investigated, including a more recent study of 31 extrafacial, biopsy-proven BCCs that were treated with the 1064-nm Nd:YAG laser, which showed a 90% histologic clearance on 1-month follow-up after a single treatment.⁵³ In 2019, a retrospective review of 16 BCC lesions on the head, neck, trunk, and extremities showed 100% clearance after 1 treatment, with an average follow-up period of 9 months (range, 6–15 months).⁵⁴ In a retrospective review, Markowitz and Psomadakis⁵⁵ contributed data supporting the further investigation and use of the 1064-nm Nd:YAG laser for BCC treatment while leveraging noninvasive imaging to demonstrate a same-day management model. Seventeen BCC lesions on the face and body were diagnosed by reflectance confocal microscopy and treated with an Nd:YAG laser, and clearance was monitored clinically, dermoscopically, and by optical coherence tomography. There was 100% clearance of the lesions in the study, with 82.4% (14/17) clearing after 1 treatment; mean follow-up was 103 days (range, 48–371 days).⁵⁵ These studies were limited by their short follow-up time; long-term data are needed to determine true rates of recurrence.

Ablative Lasers
Ablative lasers also have been used in the treatment of NMSCs. In addition to the potentially increased healing time compared to nonablative lasers, other limitations of ablative laser therapy include residual tumor burden or recurrence that may not be easily visualized in scarred tissue after nonablative management.⁴⁴

Conclusion

Although MMS remains the gold standard for invasive management of NMSCs, studies from 2018 and beyond (eTable) expanded not only on MMS topics such as increased patient access and improved techniques but also on the increasing potential of noninvasive treatments. Some of the noninvasive therapies were entirely new compounds, whereas others were already in use for a different disease indication. Furthering our knowledge and expanding our repertoire of management options will prepare us as the number of patients affected by NMSCs increases.

Nonmelanoma skin cancer (NMSC) is the most common malignancy worldwide, and its incidence continues to increase. More than 5 million NMSCs are estimated to occur annually in the United States alone.¹ There are more cases of basal cell carcinoma (BCC) than all other cancers combined, with squamous cell carcinoma (SCC) being the second most common cancer in the United States.^1-3 The rising incidence of NMSCs highlights the importance of investigating additional treatment options with fewer side effects, better cosmetic outcomes, and better efficacy.¹

Originally, treatment options for NMSCs largely relied on destructive and surgical methods. Basal cell carcinoma and SCC commonly are treated with cryosurgery; electrodesiccation and curettage; or more definitive surgical options, including excision and Mohs micrographic surgery (MMS). Over time, topical agents such as 5-fluorouracil, imiquimod, ingenol mebutate, and various forms of aminolevulinic acid (ALA) for photodynamic therapy (PDT) were included for superficial lesions as well as field treatment. The development of oral hedgehog (Hh) inhibitors, such as vismodegib, offered a promising alternative to patients with advanced disease. Each treatment has its own specific indications and side effects; thus, there is always room for novel therapeutic approaches. We review new and potential treatments from 2018 and beyond. Although only 5% of SCCs become locally advanced, recur, or metastasize, and 0.4% to 0.8% of BCCs progress to advanced disease, many of the newer studies target advanced NMSCs, given their life-threatening and debilitating nature.^4,5 Similarly, the incidence of nevoid basal cell carcinoma (NBCC) syndrome is as low as 1 in 57,000 to 1 in 164,000 but continues to be studied because of its morbidity and the potential to contribute new treatment options for BCC in the general population.⁶

Topical Therapy

Sonidegib
Basal cell carcinoma proliferation is a result of an unregulated Hh pathway that is initiated when the Hh ligand binds to the patched 1 protein (PTCH1).^7-11 Patched 1 protein normally inhibits the smoothened (SMO) transmembrane receptor protein, decreasing the signaling cascade. In BCCs, there is a loss of PTCH1 function, effectively increasing the Hh pathway activity. Sonidegib is an Hh inhibitor that in turn prevents inhibition of PTCH1 in an attempt to reregulate the pathway.^7-11 Although sonidegib is known for its 2015 approval by the US Food and Drug Administration (FDA) as a systemic therapy for locally advanced BCCs,¹² one study investigated a topical formulation on 8 patients with NBCC syndrome.¹³ Patients were treated twice daily with sonidegib cream 0.75% for 4 weeks in a double-blind, randomized, vehicle-controlled study. A total of 27 BCCs were randomized and treated with either vehicle or sonidegib. A biopsy was taken at the end of the study of 1 sonidegib-treated and 1 vehicle-treated BCC lesion per patient. Of the 13 sonidegib-treated BCC lesions, 3 (23.1%) showed complete response, 9 (69.2%) showed partial response, and 1 (7.7%) showed no response vs 13 of 14 (92.8%) lesions that did not respond to the vehicle. Patients tolerated the treatment well without skin irritation or signs of local or systemic side effects.¹³ Topical sonidegib should be further investigated as an adjunct or in different vehicles given the successful regression of BCCs and its minimal side-effect profile.

Systemic Therapy

Cemiplimab
Cemiplimab is a human monoclonal antibody against programmed death receptor 1 (PD-1) that was FDA approved in September 2018 for the treatment of metastatic cutaneous SCC.¹⁴ Programmed death receptor 1 is found on T lymphocytes, B lymphocytes, and macrophages, which normally assist in the immune response to tumor cells. However, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2) are found on tumor cells and bind to PD-1. Cemiplimab prevents PD-1 from binding to PD-L1 and PD-L2, allowing an appropriate immune response.^14,15 A phase 1 clinical trial of cemiplimab showed a 50% (13/26) response rate.¹⁶ The phase 2 trial included patients with advanced SCC, but the primary analysis only considered patients with metastatic SCC. Phase 2 results showed a 47.5% (28/59) response rate. Patients received intravenous cemiplimab 3 mg/kg once every 2 weeks for up to 48 weeks in phase 1 and up to 96 weeks in phase 2. Both phases of the trial showed a response to treatment lasting longer than 6 months in more than 50% of patients. The most common adverse events were diarrhea, fatigue, nausea, constipation, and rash.¹⁶

Although immune-mediated adverse reactions are rare, they can occur given cemiplimab’s mechanism of action and may range from severe to fatal. Examples of immune-mediated adverse reactions that occurred during the study included pneumonitis, colitis, hepatitis, adrenal insufficiency, hypophysitis, hypothyroidism, hyperthyroidism, type 1 diabetes mellitus, nephritis with renal dysfunction, and immune-mediated dermatologic reactions.¹⁴ It is important to monitor for immune-mediated adverse reactions and address them immediately once detected.

Other PD-1 Inhibitors
Although PD-1 inhibitors have been studied in advanced SCCs, their clinical data are limited for BCCs.¹⁷ Prior to 2018, there was a small number of case reports of patients with BCC with partial to exceptional response to PD-1 inhibitors. Recently, 2 additional case reports were published with contrasting outcomes using 2 different PD-1 inhibitors. An elderly patient with metastatic non–small cell lung cancer was treated with nivolumab after failing chemotherapy. She subsequently developed a BCC on the nose that was resected but recurred 2 months later despite continuing nivolumab.¹⁷ Another case report detailed a patient with a history of BCC on the shoulder excised 5 years prior who presented with recurrence on the sternum and clavicle.¹⁸ One year later the patient was found to have BCC metastases to the lung. After progression of disease despite vismodegib and recurrence of BCC with taladegib, the patient was then placed on pembrolizumab. At 6 weeks and 12 months, computed tomography showed resolution of multiple lung lesions. Sixteen weeks after initiation of pembrolizumab treatment, spinal metastases were found, but the treatment was continued because of the improvement in the lung metastases.¹⁸

Taladegib
Taladegib is a SMO antagonist that has been through a phase 1 trial in patients with advanced cancer, including treatment-naive and previously treated BCCs.¹⁹ Eighty-four patients were treated to examine the safety profile and determine an appropriate phase 2 dose and administration schedule. The maximum tolerable dose was determined to be 400 mg because of dose-limiting toxicities. All clinical responses were in patients with BCCs (47/84 [55.9%] patients), with a response rate of 46.8%. Eleven of 16 (68.8%) Hh-treatment–naive patients and 11 of 31 (35.5%) patients previously treated with Hh responded to taladegib. Common adverse events were dysgeusia, fatigue, nausea, and muscle spasms.¹⁹ Although vismodegib is an FDA-approved SMO antagonist since 2012, treatment resistance and tolerability issues have been continuing concerns.^20,21 Taladegib is a potential alternative that may be found to have improved pharmacodynamics and pharmacokinetics. Not only did in vitro studies show a preferable protein-binding profile with taladegib, but it also displayed dose proportionality, while vismodegib has been known to have nonlinear pharmacokinetics.¹⁹

Posaconazole
Posaconazole is a systemic antifungal agent that is a structural analogue to itraconazole.²² Itraconazole has been found to inhibit the Hh pathway as an SMO antagonist. In a study with mice, posaconazole was found to have strong activity against drug-resistant SMO mutants while inhibiting the growth of Hh-dependent BCCs in vivo. A marked decrease also was seen in the ciliary accumulation of SMO, suggesting a similar mechanism of action to itraconazole. Posaconazole’s use for BCCs currently is limited to basic science studies but may offer a potential alternative to itraconazole, which is known to have many drug-drug interactions and requires dose adjustments in renal and hepatic insufficiency. When used as an antifungal compared to itraconazole, posaconazole has a favorable long-term safety profile due to fewer drug-drug interactions and mild side effects; it also does not require dose adjustments in mild to moderate renal or hepatic insufficiency.²² Thus, posaconazole is a potentially safer alternative to itraconazole for the treatment of BCCs. Although phase 2 studies of itraconazole for BCCs have shown decreased cell proliferation, tumor size, and reduced GLI1 messenger RNA, side effects included fatigue and grade 4 heart failure.^23,24

Radiation Therapy

Radiation therapies (RTs), such as superficial RT, have been long-established treatment options.²⁵ However, there also are emerging methods of delivering RT, including electronic brachytherapy (EB). Although there is a low likelihood of residual tumor after RT given the number of sessions involved and the more aggressive nature of the treatment, these factors also can be a substantial burden on the patient. Furthermore, RT may result in subsequent scar tissue, which can hinder the use of other emerging technologies, such as noninvasive imaging devices, following RT.

Superficial RT
Superficial RT is a secondary option for the treatment of NMSC for use in special circumstances, such as when surgical intervention is contraindicated or refused, and after the benefits and risks of treatment alternatives have been discussed.²⁶ However, depending on the tumor type and anatomical location, 6 to 18 treatments may be required, with treatment frequency ranging from 1 to 5 treatments per week.²⁵ Patients may find this treatment regimen difficult to maintain given the length of time and frequency of treatments required. Side effects include radiation dermatitis and postinflammatory hypopigmentation or hyperpigmentation in patients with dark skin, and there is a risk for recurrence.^25,27

Electronic Brachytherapy
Brachytherapy is a method of delivering RT via radioactive isotopes, whereas EB uses lower-energy photons that require less shielding.²⁸ As a relatively new therapy, studies on the efficacy of EB on NMSC continue to grow but with limited data comparing EB with established treatments. Furthermore, there are limited long-term follow-up data, and future studies should expand the patient demographic to younger patients before treatment guidelines can be established.²⁸

RT With Concurrent and Adjuvant Vismodegib
Vismodegib is an SMO inhibitor that was FDA approved in 2012 for the treatment of locally advanced BCC in patients who are not candidates for surgery or RT.²⁹ Over time, studies have looked into other indications for vismodegib, such as a neoadjuvant to MMS or in patients with NBCC syndrome.¹¹ Prior to 2018, there were only 2 known case reports of concurrent vismodegib and RT used for recurrent advanced BCC.³⁰ Recently, vismodegib has been further examined in combination with RT in a case report,³¹ basic science study,³² and phase 2 trials (ClinicalTrials.gov Identifiers NCT02956889 and NCT01835626).

Prior studies showed low cure rates with vismodegib alone after RT (43%) as well as decreasing cure rates with primary RT alone as tumor size increased.^33,34 In 2018, vismodegib was used concurrently and as an adjuvant to RT in a patient with advanced multifocal BCC.³¹ The patient had multiple large BCCs on the trunk that were painful and bleeding. The patient was started on RT and 150 mg/d vismodegib concurrently, which was then continued adjuvantly for 3 months until it was discontinued because of diarrhea. The patient had complete response in all lesions with resolution of symptoms.³¹ A separate basic science study further supported the potential role of vismodegib in radiation sensitization of both BCCs and head and neck SCCs.³² There presently are 2 phase 2 trials investigating the concurrent use of vismodegib and RT, which could help determine the efficacy of the combined approach for patients with advanced BCCs who are poor surgical candidates (NCT02956889 and NCT01835626).

Photodynamic Therapy

Photodynamic therapy has been in use since the 1970s when Dougherty et al³⁵ performed one of the first studies on its use in skin cancer. Since then, PDT has been used for the treatment of actinic keratoses (AKs) and more recently BCCs. In PDT, a photosensitizer (PS) is applied and activated by a 400-nm blue light or 635-nm red light, depending on the PS used. The PS then produces highly reactive oxygen species, leading to apoptosis of the cancer cells.³⁶ In Europe, red light PDT is licensed for the treatment of AKs as well as superficial and nodular BCCs, though approved indications vary between countries. In the United States, PDT is only FDA approved for the treatment of AKs.³⁷

Aminolevulinic Acid Hydrochloride
Aminolevulinic acid hydrochloride is a red light PS used to treat AKs since 2011 and BCCs since 2017 in Europe in addition to AKs in the United States since 2016.^38,39 A phase 3 noninferiority clinical trial in Europe of 281 patients compared the treatment of nonaggressive BCCs with ALA to methyl aminolevulinate (MAL) cream.⁴⁰ The study found a complete response rate of 93.4% vs 91.8%. Superficial BCCs treated with ALA had a clearance rate of 94.7% vs 96.4% with MAL, while nodular BCCs treated with ALA had a clearance rate of 85.7% vs 76.2% with MAL. A 1-year clinical follow-up showed similar recurrence rates (8.4% for ALA vs 8.5% for MAL).⁴⁰ The results of this study led to an expanded indication in Europe to include the treatment of BCCs.³⁸ Aminolevulinic acid hydrochloride currently is undergoing phase 3 clinical trials in the United States for approval for the treatment of superficial BCCs (NCT03573401). If similar outcomes are achieved, US patients may have access to an alternative nonsurgical treatment of BCCs. The ongoing US trial is exclusively investigating the efficacy and safety for superficial BCCs, which may limit FDA approval to only superficial BCCs, accounting for only 8.4% to 24.1% of all BCCs.^35,41,42

Laser Therapy

Ablative and nonablative lasers have been used to treat NMSCs in the literature. Ablative lasers destroy tumors through vaporization of tissue water, whereas nonablative lasers target the vasculature of tumors while preserving the surrounding tissue.^43,44 Nonablative lasers include pulsed dye lasers (PDL) and Nd:YAG lasers. Examples of ablative lasers include CO₂ and erbium:YAG lasers. Given the status of lasers as an emerging treatment method, there currently is no standardized laser setting for any of the laser therapies used to treat NMSCs. Although there is the potential for optimal cosmetic outcomes and a limited side-effect profile for nonablative laser therapies, there are limited data on long-term follow-up to study recurrence rates and establish a more standardized treatment protocol.

Pulsed Dye Lasers
Although there were no studies on PDL therapy alone in 2018, a study published in 2019 evaluated a combination laser treatment using a 595-nm PDL and 1927-nm fractional laser for the treatment of 93 BCCs, yielding a 95.7% (89/93) clearance rate and 4.5% (4/89) recurrence rate over a follow-up period of up to 6 years (range, 2.53 months to 6.03 years).⁴⁵ Studies of PDL prior to 2018 had follow-ups ranging from 2 weeks to 6 months.^46-51 Although the majority were biopsy-proven BCCs, reflectance confocal microscopy also was used for same-day diagnoses. Long-term follow-up included clinical examinations, dermoscopy, and optical coherence tomography.⁴⁵ The clearance rate (95.7%) using noninvasive imaging in conjunction with the combination laser treatment was superior to both histologic and clinical clearance rates of prior PDL-only studies, which ranged from 25% to 95%.^46-51 To have long-term follow-up data, the study used noninvasive imaging with clinical follow-up because histology would not be viable for long-term follow-up. This study was retrospective rather than prospective, which was a limitation.⁴⁵

Nd:YAG Lasers
The majority of studies utilizing Nd:YAG lasers investigated their efficacy in treating BCCs, with the exception of 1 study of facial SCCs. This major study in 2009 of 627 BCCs showed a 2.5% recurrence rate after a follow-up time of 3 months to 5 years.⁵² Nd:YAG lasers continue to be investigated, including a more recent study of 31 extrafacial, biopsy-proven BCCs that were treated with the 1064-nm Nd:YAG laser, which showed a 90% histologic clearance on 1-month follow-up after a single treatment.⁵³ In 2019, a retrospective review of 16 BCC lesions on the head, neck, trunk, and extremities showed 100% clearance after 1 treatment, with an average follow-up period of 9 months (range, 6–15 months).⁵⁴ In a retrospective review, Markowitz and Psomadakis⁵⁵ contributed data supporting the further investigation and use of the 1064-nm Nd:YAG laser for BCC treatment while leveraging noninvasive imaging to demonstrate a same-day management model. Seventeen BCC lesions on the face and body were diagnosed by reflectance confocal microscopy and treated with an Nd:YAG laser, and clearance was monitored clinically, dermoscopically, and by optical coherence tomography. There was 100% clearance of the lesions in the study, with 82.4% (14/17) clearing after 1 treatment; mean follow-up was 103 days (range, 48–371 days).⁵⁵ These studies were limited by their short follow-up time; long-term data are needed to determine true rates of recurrence.

Ablative Lasers
Ablative lasers also have been used in the treatment of NMSCs. In addition to the potentially increased healing time compared to nonablative lasers, other limitations of ablative laser therapy include residual tumor burden or recurrence that may not be easily visualized in scarred tissue after nonablative management.⁴⁴

Conclusion

Although MMS remains the gold standard for invasive management of NMSCs, studies from 2018 and beyond (eTable) expanded not only on MMS topics such as increased patient access and improved techniques but also on the increasing potential of noninvasive treatments. Some of the noninvasive therapies were entirely new compounds, whereas others were already in use for a different disease indication. Furthering our knowledge and expanding our repertoire of management options will prepare us as the number of patients affected by NMSCs increases.

Rotator cuff disease accounts for as many as 65% of shoulder-related visits to physicians’ offices,¹ yet the natural course of rotator cuff tears is still not well understood.² Treatment options are controversial because both conservative and surgical management have been successful. Physical therapy is a durable and reliable treatment option, but there are concerns about long-term progression of the tear.³ Surgical arthroscopic techniques, which result in less morbidity than open surgery, have improved overall surgical care; as such, the rate of rotator cuff procedures has increased significantly.⁴

Our goal in this article is to provide clinical guidance to the primary care provider. We review management options for rotator cuff injury; summarize considerations for proceeding with conservative or surgical management; and discuss surgical risks and complications.

Conservative management: Who is most likely to benefit?

The choice of treatment for rotator cuff injury depends on a host of variables, including shoulder dominance, duration of symptoms, type of tear (partial or full), age, demands (activity level, occupation, sport), and comorbidities (diabetes, tobacco use). Treatment goals include resolution of pain, normalized range of motion and strength, and restored arm and shoulder function.⁵

Initial nonoperative management is indicated in patients who

• have a partial-thickness tear (a notable exception is young patients with traumatic injury),⁶
• have lower functional demands and moderate symptoms, or
• refuse surgery.⁷

Patients who respond to nonoperative management will, typically, do so within 6 to 12 weeks.^5,8

Few randomized, controlled trials have compared conservative and surgical management of rotator cuff tears; furthermore, the findings of these studies have been mixed. Nonoperative management has been shown to be the favored initial treatment for isolated, symptomatic, nontraumatic, supraspinatus tears in older patients.⁹ In a recent study,¹⁰ 5-year outcomes were examined in a prospective cohort enrolled in a rotator cuff treatment program: Approximately 75% of patients remained successfully treated with nonoperative management, and clinical outcomes of the operative and nonoperative groups were not significantly different at 5-year follow-up. Investigators concluded that nonoperative treatment is effective for many patients who have a chronic, full-­thickness rotator cuff tear. 

In a study investigating the treatment of degenerative rotator cuff tear, patients were randomly treated using an operative or nonoperative protocol. No differences in functional outcomes were observed at 1 year after treatment; however, surgical treatment significantly improved subjective parameters of pain and disability.¹¹ A similar study suggested statistically significant improvement in outcomes for patients managed operatively, compared with those treated nonoperatively, but differences in shoulder outcome and the visual analog pain score were small and failed to meet thresholds considered clinically significant. Larger studies, with longer follow-up, are required to determine whether clinical differences between these types of treatment become more evident over time.¹²

Continue to: A look at nonoperative options and outcomes

Surveillance. Rotator cuff disease of the supraspinatus tendon often results from a degenerative process that progresses to partial and, eventually, full-thickness tearing.⁸ Once a tear develops, progression is difficult to predict. Many rotator cuff tears grow larger over time; this progression is commonly associated with new or increased pain and weakness, or both. Although asymptomatic progression of a tear is uncommon, many patients—and physicians—are apprehensive about proceeding with nonoperative treatment for a full-thickness tear.⁸

Simple analgesics are a low-risk firstline option for pain in rotator cuff injury. Avoid opioids, except during the immediate postoperative period.

To diminish such fears, surveillance can include regular assessment of shoulder motion and strength, with consideration of repeat imaging until surgery is performed or the patient is no longer a surgical candidate or interested in surgical treatment.⁷ Patients and providers need to remain vigilant because tears that are initially graded as repairable can become irreparable if the tendon retracts or there is fatty infiltration of the muscle belly. Results of secondary surgical repair following failed prolonged nonoperative treatment tend to be inferior to results seen in patients who undergo primary tendon repair.⁷

Analgesics. Simple analgesics, such as acetaminophen, are a low-risk first-line option for pain relief; however, there are limited data on the efficacy of acetaminophen in rotator cuff disease. A topical or oral nonsteroidal anti-inflammatory drug (NSAID), or both, can be considered, but potential contraindications, such as gastrointestinal, renal, and cardiovascular risks, should be monitored.¹³ Avoid opioids, given the potential for abuse, except during the immediate postoperative period.⁵

Glucocorticoid injection. Injection of a glucocorticoid drug into the subacromial space should be considered in patients whose pain interferes with sleep, limits activities of daily living, or hinders the ability to participate in physical therapy.⁵ A recent systematic review demonstrated that NSAIDs and glucocorticoids brought similar pain relief and active abduction at 4 to 6 weeks, but that glucocorticoids were significantly better at achieving remission of symptoms.¹⁴ There are no data comparing glucocorticoid preparations (ie, different glucocorticoids or anesthetics, dosages, volumes), and ultrasound guidance does not appear to be necessary for short-term pain relief.¹⁵ Note: Repeated injection has been shown to decrease the durability of surgically repaired tendons¹⁶; if a patient is a candidate for surgery, repeat injections should be carefully considered—and avoided if possible.

Physical therapy. The goals of physical therapy are activity modification, stretching the shoulder capsule, and strengthening the surrounding musculature (periscapular, rotator cuff, and deltoid). Patients advance through 3 phases of recovery: shoulder mobility, strengthening, and function (ie, joint reactivation to improve shoulder proprioception and coordination).

Continue to: A recent meta-analysis...

A recent meta-analysis¹⁷ found comparative evidence on treating rotator cuff tears with physical therapy to be inconclusive. At 1-year follow-up, there was no clinically significant difference between surgery and active physical therapy in either improving the Constant Shoulder Score (an assessment of function) or reducing pain caused by a rotator cuff tear. Therefore, the authors proposed, given the low risk of harm, a conservative approach should be the initial treatment modality for a tear.

Consider injection of a glucocorticoid drug into the subacromial space in a patient whose pain interferes with sleep, limits activities of daily living, or hinders physical therapy.

A Cochrane review¹⁸ examined 60 eligible trials, in which the mean age of patients was 51 years and the mean duration of symptoms, 11 months. Overall, the review concluded that the effects of manual therapy and exercise might be similar to those of glucocorticoid injection and arthroscopic subacromial decompression. The authors noted that this conclusion is based on low-quality evidence, with only 1 study in the review that compared the combination of manual therapy and exercise to placebo.

Other conservative options. Ultrasound, topical nitroglycerin, topical ­lidocaine, glucocorticoid iontophoresis, transcutaneous electrical nerve stimulation, massage, acupuncture, extracorporeal shockwave therapy, hyaluronic acid, and platelet-rich plasma have been used to treat rotator cuff disease. These modalities require further study, however, to determine their effectiveness for this indication.^7,19

Who is a candidate for surgical management?

Although nonoperative treatment is preferred for rotator cuff tendinitis or tendinosis and partial-thickness tears, appropriate management of full-thickness tears is debatable.²⁰ Some surgeons advocate early operative intervention of repairable full-thickness tears to prevent further progression and reduce the risk of long-term dysfunction.

The decision to pursue operative repair depends on

• patient characteristics (age, activity level, comorbidities),
• patient function (amount of disability caused by the tear),
• characteristics of the tear (length, depth, retraction), and
• chronicity of the tear (acuity).

Continue to: TABLE 1...

TABLE 1^21,22 highlights variables that influence the decision to proceed, or not to proceed, with operative intervention. Because enlargement of a tear usually exacerbates symptoms,²³ patients with a tear who are successfully managed nonoperatively should be counseled on the potential of the tear to progress.

What are the surgical options?

Little clinical evidence favors one exposure technique over another. This equivalency has been demonstrated by a systematic review of randomized controlled trials comparing arthroscopic and mini-open rotator cuff repair, which showed no difference in function, pain, or range of motion.²⁴ That conclusion notwithstanding, arthroscopic repair is increasingly popular because it results in less pain, initially, and faster return to work.²⁰

There is controversy among surgeons regarding the choice of fixation technique: Tendons can be secured using 1 or 2 rows of anchors (FIGURE). Advocates of single-row repair cite shorter surgical time, decreased cost, and equivalent outcomes; surgeons who favor double-row, or so-called transosseous-equivalent, repair claim that it provides better restoration of normal anatomy and biomechanical superiority.^25,26

Regardless of technique, most patients are immobilized for 4 to 6 weeks postoperatively.²⁷ Physical therapy usually commences within the first week or 2 postop, limited to passive motion for 6 to 12 weeks. Active motion and strengthening of rotator-cuff muscles often is initiated by 3 months postop, although this phase is sometimes delayed because of concern over slow tendon ­healing. Typically, patients make a full return to sports and manual work at 6 months postop. Patients experience most symptomatic improvement during the first 6 months following surgery, although functional gains can be realized for as long as 2 years after surgery.²⁸

If a patient is going to respond to nonoperative management at all, they typically do so in 6 to 12 weeks.

Most torn rotator cuffs can be fixed back to the greater tuberosity, but some chronic, massive, retracted tears lack the mobility to be repaired, or re-tear shortly after repair. Over time, the humeral head in a rotator cuff–deficient shoulder can migrate superiorly to abut the undersurface of the acromion, which can lead to significant glenohumeral osteoarthritis. To prevent or remedy elevation of the humeral head, salvage procedures—debridement, partial repair, spanning graft, tendon transfer, superior capsule reconstruction, balloon arthroplasty, reverse total shoulder replacement—can be used to alleviate pain and restore function. These procedures have significant limitations, however, and usually provide less favorable outcomes than standard repair.^29-35

Continue to: Surgical outcomes

Pain, function, and patient satisfaction outcomes following rotator cuff repair are generally favorable: 90% of patients are “happy” 6 months postop.²⁸ Younger populations often have traumatic rotator cuff tears; they generally are interested in returning to sporting activities following their injury. Nearly 85% of younger patients who undergo rotator cuff repair return to sports, and 65.9% return to an equivalent level of play.³⁶

Variables associated with an unfavorable outcome include increasing age, smoking, increased size of the tear, poor tendon quality, hyperlipidemia, workers’ compensation status, fatty infiltration of muscle, obesity, diabetes, and additional procedures to the biceps tendon and acromioclavicular joint performed at the time of rotator cuff repair.^37-39 Interestingly, a study concluded that, if a patient expects a good surgical outcome, they are more likely to go on to report a favorable outcome—suggesting that a patient’s expectations might influence their actual outcome.⁴⁰

Risks and complications

Although rotator cuff surgery has much lower morbidity than other orthopedic surgeries, it is not without risk of complications. If re-tears are excluded, postop complications have been reported in approximately 10% of patients.⁴¹ Common complications and their anticipated rate of occurrence are listed in TABLE 2.^42-49

Re-tear of the surgically repaired tendon is the most common postop complication. Published re-tear rates range from 20% to 96%^42,43 and generally correlate with initial tear size: A small tear is twice as likely to heal as a massive tear.⁵⁰ That large range—a span of 76%—results from using a variety of methods to measure re-tear and might not have clinical meaning. A meta-analysis that examined more than 8000 shoulder surgeries reported an overall re-tear rate of 26.6%; however, both patients whose tendons healed and those who re-tore demonstrated clinical improvement.⁵¹ In a separate study, patients reported improvement in pain, function, range of motion, and satisfaction regardless of the integrity of the tendon; however, significant improvement in strength was seen only in those whose repair had healed.⁵²

Postop stiffness is more common with arthroscopic repair than with open surgery, and with smaller rather than larger tears.⁵³ Patient variables associated with an increased risk of postop adhesive capsulitis include workers’ compensation insurance, age < 50 years, and preoperative calcific tendonitis or adhesive capsulitis.⁵³ Stiffness generally responds to physical therapy and rarely requires surgical lysis of adhesions or capsular release.

Continue to: Significant injury...

Significant injury to the deltoid muscle has become increasingly uncommon with the advancement of arthroscopic surgery. In traditional open surgery, detachment of the deltoid (and subsequent repair) is required to improve visualization; however, doing so can lead to atrophy and muscle rupture and dehiscence. Deltoid damage occurs in ≤ 60% of open surgeries but is negligible in arthroscopic and mini-open repairs, which involve splitting deltoid fibers to gain exposure of the underlying rotator cuff.⁵⁴

CORRESPONDENCE
Cayce Onks, DO, MS, ATC, Penn State Health Milton S. Hershey Medical Center, Penn State College of Medicine, Family and Community Medicine H154, 500 University Drive, PO Box 850, Hershey, PA 17033-0850; [email protected].

Rotator cuff disease accounts for as many as 65% of shoulder-related visits to physicians’ offices,¹ yet the natural course of rotator cuff tears is still not well understood.² Treatment options are controversial because both conservative and surgical management have been successful. Physical therapy is a durable and reliable treatment option, but there are concerns about long-term progression of the tear.³ Surgical arthroscopic techniques, which result in less morbidity than open surgery, have improved overall surgical care; as such, the rate of rotator cuff procedures has increased significantly.⁴

Our goal in this article is to provide clinical guidance to the primary care provider. We review management options for rotator cuff injury; summarize considerations for proceeding with conservative or surgical management; and discuss surgical risks and complications.

Conservative management: Who is most likely to benefit?

The choice of treatment for rotator cuff injury depends on a host of variables, including shoulder dominance, duration of symptoms, type of tear (partial or full), age, demands (activity level, occupation, sport), and comorbidities (diabetes, tobacco use). Treatment goals include resolution of pain, normalized range of motion and strength, and restored arm and shoulder function.⁵

Initial nonoperative management is indicated in patients who

• have a partial-thickness tear (a notable exception is young patients with traumatic injury),⁶
• have lower functional demands and moderate symptoms, or
• refuse surgery.⁷

Patients who respond to nonoperative management will, typically, do so within 6 to 12 weeks.^5,8

Few randomized, controlled trials have compared conservative and surgical management of rotator cuff tears; furthermore, the findings of these studies have been mixed. Nonoperative management has been shown to be the favored initial treatment for isolated, symptomatic, nontraumatic, supraspinatus tears in older patients.⁹ In a recent study,¹⁰ 5-year outcomes were examined in a prospective cohort enrolled in a rotator cuff treatment program: Approximately 75% of patients remained successfully treated with nonoperative management, and clinical outcomes of the operative and nonoperative groups were not significantly different at 5-year follow-up. Investigators concluded that nonoperative treatment is effective for many patients who have a chronic, full-­thickness rotator cuff tear. 

In a study investigating the treatment of degenerative rotator cuff tear, patients were randomly treated using an operative or nonoperative protocol. No differences in functional outcomes were observed at 1 year after treatment; however, surgical treatment significantly improved subjective parameters of pain and disability.¹¹ A similar study suggested statistically significant improvement in outcomes for patients managed operatively, compared with those treated nonoperatively, but differences in shoulder outcome and the visual analog pain score were small and failed to meet thresholds considered clinically significant. Larger studies, with longer follow-up, are required to determine whether clinical differences between these types of treatment become more evident over time.¹²

Continue to: A look at nonoperative options and outcomes

Surveillance. Rotator cuff disease of the supraspinatus tendon often results from a degenerative process that progresses to partial and, eventually, full-thickness tearing.⁸ Once a tear develops, progression is difficult to predict. Many rotator cuff tears grow larger over time; this progression is commonly associated with new or increased pain and weakness, or both. Although asymptomatic progression of a tear is uncommon, many patients—and physicians—are apprehensive about proceeding with nonoperative treatment for a full-thickness tear.⁸

Simple analgesics are a low-risk firstline option for pain in rotator cuff injury. Avoid opioids, except during the immediate postoperative period.

To diminish such fears, surveillance can include regular assessment of shoulder motion and strength, with consideration of repeat imaging until surgery is performed or the patient is no longer a surgical candidate or interested in surgical treatment.⁷ Patients and providers need to remain vigilant because tears that are initially graded as repairable can become irreparable if the tendon retracts or there is fatty infiltration of the muscle belly. Results of secondary surgical repair following failed prolonged nonoperative treatment tend to be inferior to results seen in patients who undergo primary tendon repair.⁷

Analgesics. Simple analgesics, such as acetaminophen, are a low-risk first-line option for pain relief; however, there are limited data on the efficacy of acetaminophen in rotator cuff disease. A topical or oral nonsteroidal anti-inflammatory drug (NSAID), or both, can be considered, but potential contraindications, such as gastrointestinal, renal, and cardiovascular risks, should be monitored.¹³ Avoid opioids, given the potential for abuse, except during the immediate postoperative period.⁵

Glucocorticoid injection. Injection of a glucocorticoid drug into the subacromial space should be considered in patients whose pain interferes with sleep, limits activities of daily living, or hinders the ability to participate in physical therapy.⁵ A recent systematic review demonstrated that NSAIDs and glucocorticoids brought similar pain relief and active abduction at 4 to 6 weeks, but that glucocorticoids were significantly better at achieving remission of symptoms.¹⁴ There are no data comparing glucocorticoid preparations (ie, different glucocorticoids or anesthetics, dosages, volumes), and ultrasound guidance does not appear to be necessary for short-term pain relief.¹⁵ Note: Repeated injection has been shown to decrease the durability of surgically repaired tendons¹⁶; if a patient is a candidate for surgery, repeat injections should be carefully considered—and avoided if possible.

Physical therapy. The goals of physical therapy are activity modification, stretching the shoulder capsule, and strengthening the surrounding musculature (periscapular, rotator cuff, and deltoid). Patients advance through 3 phases of recovery: shoulder mobility, strengthening, and function (ie, joint reactivation to improve shoulder proprioception and coordination).

Continue to: A recent meta-analysis...

A recent meta-analysis¹⁷ found comparative evidence on treating rotator cuff tears with physical therapy to be inconclusive. At 1-year follow-up, there was no clinically significant difference between surgery and active physical therapy in either improving the Constant Shoulder Score (an assessment of function) or reducing pain caused by a rotator cuff tear. Therefore, the authors proposed, given the low risk of harm, a conservative approach should be the initial treatment modality for a tear.

Consider injection of a glucocorticoid drug into the subacromial space in a patient whose pain interferes with sleep, limits activities of daily living, or hinders physical therapy.

A Cochrane review¹⁸ examined 60 eligible trials, in which the mean age of patients was 51 years and the mean duration of symptoms, 11 months. Overall, the review concluded that the effects of manual therapy and exercise might be similar to those of glucocorticoid injection and arthroscopic subacromial decompression. The authors noted that this conclusion is based on low-quality evidence, with only 1 study in the review that compared the combination of manual therapy and exercise to placebo.

Other conservative options. Ultrasound, topical nitroglycerin, topical ­lidocaine, glucocorticoid iontophoresis, transcutaneous electrical nerve stimulation, massage, acupuncture, extracorporeal shockwave therapy, hyaluronic acid, and platelet-rich plasma have been used to treat rotator cuff disease. These modalities require further study, however, to determine their effectiveness for this indication.^7,19

Who is a candidate for surgical management?

Although nonoperative treatment is preferred for rotator cuff tendinitis or tendinosis and partial-thickness tears, appropriate management of full-thickness tears is debatable.²⁰ Some surgeons advocate early operative intervention of repairable full-thickness tears to prevent further progression and reduce the risk of long-term dysfunction.

The decision to pursue operative repair depends on

• patient characteristics (age, activity level, comorbidities),
• patient function (amount of disability caused by the tear),
• characteristics of the tear (length, depth, retraction), and
• chronicity of the tear (acuity).

Continue to: TABLE 1...

TABLE 1^21,22 highlights variables that influence the decision to proceed, or not to proceed, with operative intervention. Because enlargement of a tear usually exacerbates symptoms,²³ patients with a tear who are successfully managed nonoperatively should be counseled on the potential of the tear to progress.

What are the surgical options?

Little clinical evidence favors one exposure technique over another. This equivalency has been demonstrated by a systematic review of randomized controlled trials comparing arthroscopic and mini-open rotator cuff repair, which showed no difference in function, pain, or range of motion.²⁴ That conclusion notwithstanding, arthroscopic repair is increasingly popular because it results in less pain, initially, and faster return to work.²⁰

There is controversy among surgeons regarding the choice of fixation technique: Tendons can be secured using 1 or 2 rows of anchors (FIGURE). Advocates of single-row repair cite shorter surgical time, decreased cost, and equivalent outcomes; surgeons who favor double-row, or so-called transosseous-equivalent, repair claim that it provides better restoration of normal anatomy and biomechanical superiority.^25,26

Regardless of technique, most patients are immobilized for 4 to 6 weeks postoperatively.²⁷ Physical therapy usually commences within the first week or 2 postop, limited to passive motion for 6 to 12 weeks. Active motion and strengthening of rotator-cuff muscles often is initiated by 3 months postop, although this phase is sometimes delayed because of concern over slow tendon ­healing. Typically, patients make a full return to sports and manual work at 6 months postop. Patients experience most symptomatic improvement during the first 6 months following surgery, although functional gains can be realized for as long as 2 years after surgery.²⁸

If a patient is going to respond to nonoperative management at all, they typically do so in 6 to 12 weeks.

Most torn rotator cuffs can be fixed back to the greater tuberosity, but some chronic, massive, retracted tears lack the mobility to be repaired, or re-tear shortly after repair. Over time, the humeral head in a rotator cuff–deficient shoulder can migrate superiorly to abut the undersurface of the acromion, which can lead to significant glenohumeral osteoarthritis. To prevent or remedy elevation of the humeral head, salvage procedures—debridement, partial repair, spanning graft, tendon transfer, superior capsule reconstruction, balloon arthroplasty, reverse total shoulder replacement—can be used to alleviate pain and restore function. These procedures have significant limitations, however, and usually provide less favorable outcomes than standard repair.^29-35

Continue to: Surgical outcomes

Pain, function, and patient satisfaction outcomes following rotator cuff repair are generally favorable: 90% of patients are “happy” 6 months postop.²⁸ Younger populations often have traumatic rotator cuff tears; they generally are interested in returning to sporting activities following their injury. Nearly 85% of younger patients who undergo rotator cuff repair return to sports, and 65.9% return to an equivalent level of play.³⁶

Variables associated with an unfavorable outcome include increasing age, smoking, increased size of the tear, poor tendon quality, hyperlipidemia, workers’ compensation status, fatty infiltration of muscle, obesity, diabetes, and additional procedures to the biceps tendon and acromioclavicular joint performed at the time of rotator cuff repair.^37-39 Interestingly, a study concluded that, if a patient expects a good surgical outcome, they are more likely to go on to report a favorable outcome—suggesting that a patient’s expectations might influence their actual outcome.⁴⁰

Risks and complications

Although rotator cuff surgery has much lower morbidity than other orthopedic surgeries, it is not without risk of complications. If re-tears are excluded, postop complications have been reported in approximately 10% of patients.⁴¹ Common complications and their anticipated rate of occurrence are listed in TABLE 2.^42-49

Re-tear of the surgically repaired tendon is the most common postop complication. Published re-tear rates range from 20% to 96%^42,43 and generally correlate with initial tear size: A small tear is twice as likely to heal as a massive tear.⁵⁰ That large range—a span of 76%—results from using a variety of methods to measure re-tear and might not have clinical meaning. A meta-analysis that examined more than 8000 shoulder surgeries reported an overall re-tear rate of 26.6%; however, both patients whose tendons healed and those who re-tore demonstrated clinical improvement.⁵¹ In a separate study, patients reported improvement in pain, function, range of motion, and satisfaction regardless of the integrity of the tendon; however, significant improvement in strength was seen only in those whose repair had healed.⁵²

Postop stiffness is more common with arthroscopic repair than with open surgery, and with smaller rather than larger tears.⁵³ Patient variables associated with an increased risk of postop adhesive capsulitis include workers’ compensation insurance, age < 50 years, and preoperative calcific tendonitis or adhesive capsulitis.⁵³ Stiffness generally responds to physical therapy and rarely requires surgical lysis of adhesions or capsular release.

Continue to: Significant injury...

Significant injury to the deltoid muscle has become increasingly uncommon with the advancement of arthroscopic surgery. In traditional open surgery, detachment of the deltoid (and subsequent repair) is required to improve visualization; however, doing so can lead to atrophy and muscle rupture and dehiscence. Deltoid damage occurs in ≤ 60% of open surgeries but is negligible in arthroscopic and mini-open repairs, which involve splitting deltoid fibers to gain exposure of the underlying rotator cuff.⁵⁴

CORRESPONDENCE
Cayce Onks, DO, MS, ATC, Penn State Health Milton S. Hershey Medical Center, Penn State College of Medicine, Family and Community Medicine H154, 500 University Drive, PO Box 850, Hershey, PA 17033-0850; [email protected].

Rotator cuff disease accounts for as many as 65% of shoulder-related visits to physicians’ offices,¹ yet the natural course of rotator cuff tears is still not well understood.² Treatment options are controversial because both conservative and surgical management have been successful. Physical therapy is a durable and reliable treatment option, but there are concerns about long-term progression of the tear.³ Surgical arthroscopic techniques, which result in less morbidity than open surgery, have improved overall surgical care; as such, the rate of rotator cuff procedures has increased significantly.⁴

Our goal in this article is to provide clinical guidance to the primary care provider. We review management options for rotator cuff injury; summarize considerations for proceeding with conservative or surgical management; and discuss surgical risks and complications.

Conservative management: Who is most likely to benefit?

The choice of treatment for rotator cuff injury depends on a host of variables, including shoulder dominance, duration of symptoms, type of tear (partial or full), age, demands (activity level, occupation, sport), and comorbidities (diabetes, tobacco use). Treatment goals include resolution of pain, normalized range of motion and strength, and restored arm and shoulder function.⁵

Initial nonoperative management is indicated in patients who

• have a partial-thickness tear (a notable exception is young patients with traumatic injury),⁶
• have lower functional demands and moderate symptoms, or
• refuse surgery.⁷

Patients who respond to nonoperative management will, typically, do so within 6 to 12 weeks.^5,8

Few randomized, controlled trials have compared conservative and surgical management of rotator cuff tears; furthermore, the findings of these studies have been mixed. Nonoperative management has been shown to be the favored initial treatment for isolated, symptomatic, nontraumatic, supraspinatus tears in older patients.⁹ In a recent study,¹⁰ 5-year outcomes were examined in a prospective cohort enrolled in a rotator cuff treatment program: Approximately 75% of patients remained successfully treated with nonoperative management, and clinical outcomes of the operative and nonoperative groups were not significantly different at 5-year follow-up. Investigators concluded that nonoperative treatment is effective for many patients who have a chronic, full-­thickness rotator cuff tear. 

In a study investigating the treatment of degenerative rotator cuff tear, patients were randomly treated using an operative or nonoperative protocol. No differences in functional outcomes were observed at 1 year after treatment; however, surgical treatment significantly improved subjective parameters of pain and disability.¹¹ A similar study suggested statistically significant improvement in outcomes for patients managed operatively, compared with those treated nonoperatively, but differences in shoulder outcome and the visual analog pain score were small and failed to meet thresholds considered clinically significant. Larger studies, with longer follow-up, are required to determine whether clinical differences between these types of treatment become more evident over time.¹²

Continue to: A look at nonoperative options and outcomes

Surveillance. Rotator cuff disease of the supraspinatus tendon often results from a degenerative process that progresses to partial and, eventually, full-thickness tearing.⁸ Once a tear develops, progression is difficult to predict. Many rotator cuff tears grow larger over time; this progression is commonly associated with new or increased pain and weakness, or both. Although asymptomatic progression of a tear is uncommon, many patients—and physicians—are apprehensive about proceeding with nonoperative treatment for a full-thickness tear.⁸

Simple analgesics are a low-risk firstline option for pain in rotator cuff injury. Avoid opioids, except during the immediate postoperative period.

To diminish such fears, surveillance can include regular assessment of shoulder motion and strength, with consideration of repeat imaging until surgery is performed or the patient is no longer a surgical candidate or interested in surgical treatment.⁷ Patients and providers need to remain vigilant because tears that are initially graded as repairable can become irreparable if the tendon retracts or there is fatty infiltration of the muscle belly. Results of secondary surgical repair following failed prolonged nonoperative treatment tend to be inferior to results seen in patients who undergo primary tendon repair.⁷

Analgesics. Simple analgesics, such as acetaminophen, are a low-risk first-line option for pain relief; however, there are limited data on the efficacy of acetaminophen in rotator cuff disease. A topical or oral nonsteroidal anti-inflammatory drug (NSAID), or both, can be considered, but potential contraindications, such as gastrointestinal, renal, and cardiovascular risks, should be monitored.¹³ Avoid opioids, given the potential for abuse, except during the immediate postoperative period.⁵

Glucocorticoid injection. Injection of a glucocorticoid drug into the subacromial space should be considered in patients whose pain interferes with sleep, limits activities of daily living, or hinders the ability to participate in physical therapy.⁵ A recent systematic review demonstrated that NSAIDs and glucocorticoids brought similar pain relief and active abduction at 4 to 6 weeks, but that glucocorticoids were significantly better at achieving remission of symptoms.¹⁴ There are no data comparing glucocorticoid preparations (ie, different glucocorticoids or anesthetics, dosages, volumes), and ultrasound guidance does not appear to be necessary for short-term pain relief.¹⁵ Note: Repeated injection has been shown to decrease the durability of surgically repaired tendons¹⁶; if a patient is a candidate for surgery, repeat injections should be carefully considered—and avoided if possible.

Physical therapy. The goals of physical therapy are activity modification, stretching the shoulder capsule, and strengthening the surrounding musculature (periscapular, rotator cuff, and deltoid). Patients advance through 3 phases of recovery: shoulder mobility, strengthening, and function (ie, joint reactivation to improve shoulder proprioception and coordination).

Continue to: A recent meta-analysis...

A recent meta-analysis¹⁷ found comparative evidence on treating rotator cuff tears with physical therapy to be inconclusive. At 1-year follow-up, there was no clinically significant difference between surgery and active physical therapy in either improving the Constant Shoulder Score (an assessment of function) or reducing pain caused by a rotator cuff tear. Therefore, the authors proposed, given the low risk of harm, a conservative approach should be the initial treatment modality for a tear.

Consider injection of a glucocorticoid drug into the subacromial space in a patient whose pain interferes with sleep, limits activities of daily living, or hinders physical therapy.

A Cochrane review¹⁸ examined 60 eligible trials, in which the mean age of patients was 51 years and the mean duration of symptoms, 11 months. Overall, the review concluded that the effects of manual therapy and exercise might be similar to those of glucocorticoid injection and arthroscopic subacromial decompression. The authors noted that this conclusion is based on low-quality evidence, with only 1 study in the review that compared the combination of manual therapy and exercise to placebo.

Other conservative options. Ultrasound, topical nitroglycerin, topical ­lidocaine, glucocorticoid iontophoresis, transcutaneous electrical nerve stimulation, massage, acupuncture, extracorporeal shockwave therapy, hyaluronic acid, and platelet-rich plasma have been used to treat rotator cuff disease. These modalities require further study, however, to determine their effectiveness for this indication.^7,19

Who is a candidate for surgical management?

Although nonoperative treatment is preferred for rotator cuff tendinitis or tendinosis and partial-thickness tears, appropriate management of full-thickness tears is debatable.²⁰ Some surgeons advocate early operative intervention of repairable full-thickness tears to prevent further progression and reduce the risk of long-term dysfunction.

The decision to pursue operative repair depends on

• patient characteristics (age, activity level, comorbidities),
• patient function (amount of disability caused by the tear),
• characteristics of the tear (length, depth, retraction), and
• chronicity of the tear (acuity).

Continue to: TABLE 1...

TABLE 1^21,22 highlights variables that influence the decision to proceed, or not to proceed, with operative intervention. Because enlargement of a tear usually exacerbates symptoms,²³ patients with a tear who are successfully managed nonoperatively should be counseled on the potential of the tear to progress.

What are the surgical options?

Little clinical evidence favors one exposure technique over another. This equivalency has been demonstrated by a systematic review of randomized controlled trials comparing arthroscopic and mini-open rotator cuff repair, which showed no difference in function, pain, or range of motion.²⁴ That conclusion notwithstanding, arthroscopic repair is increasingly popular because it results in less pain, initially, and faster return to work.²⁰

There is controversy among surgeons regarding the choice of fixation technique: Tendons can be secured using 1 or 2 rows of anchors (FIGURE). Advocates of single-row repair cite shorter surgical time, decreased cost, and equivalent outcomes; surgeons who favor double-row, or so-called transosseous-equivalent, repair claim that it provides better restoration of normal anatomy and biomechanical superiority.^25,26

Regardless of technique, most patients are immobilized for 4 to 6 weeks postoperatively.²⁷ Physical therapy usually commences within the first week or 2 postop, limited to passive motion for 6 to 12 weeks. Active motion and strengthening of rotator-cuff muscles often is initiated by 3 months postop, although this phase is sometimes delayed because of concern over slow tendon ­healing. Typically, patients make a full return to sports and manual work at 6 months postop. Patients experience most symptomatic improvement during the first 6 months following surgery, although functional gains can be realized for as long as 2 years after surgery.²⁸

If a patient is going to respond to nonoperative management at all, they typically do so in 6 to 12 weeks.

Most torn rotator cuffs can be fixed back to the greater tuberosity, but some chronic, massive, retracted tears lack the mobility to be repaired, or re-tear shortly after repair. Over time, the humeral head in a rotator cuff–deficient shoulder can migrate superiorly to abut the undersurface of the acromion, which can lead to significant glenohumeral osteoarthritis. To prevent or remedy elevation of the humeral head, salvage procedures—debridement, partial repair, spanning graft, tendon transfer, superior capsule reconstruction, balloon arthroplasty, reverse total shoulder replacement—can be used to alleviate pain and restore function. These procedures have significant limitations, however, and usually provide less favorable outcomes than standard repair.^29-35

Continue to: Surgical outcomes

Pain, function, and patient satisfaction outcomes following rotator cuff repair are generally favorable: 90% of patients are “happy” 6 months postop.²⁸ Younger populations often have traumatic rotator cuff tears; they generally are interested in returning to sporting activities following their injury. Nearly 85% of younger patients who undergo rotator cuff repair return to sports, and 65.9% return to an equivalent level of play.³⁶

Variables associated with an unfavorable outcome include increasing age, smoking, increased size of the tear, poor tendon quality, hyperlipidemia, workers’ compensation status, fatty infiltration of muscle, obesity, diabetes, and additional procedures to the biceps tendon and acromioclavicular joint performed at the time of rotator cuff repair.^37-39 Interestingly, a study concluded that, if a patient expects a good surgical outcome, they are more likely to go on to report a favorable outcome—suggesting that a patient’s expectations might influence their actual outcome.⁴⁰

Risks and complications

Although rotator cuff surgery has much lower morbidity than other orthopedic surgeries, it is not without risk of complications. If re-tears are excluded, postop complications have been reported in approximately 10% of patients.⁴¹ Common complications and their anticipated rate of occurrence are listed in TABLE 2.^42-49

Re-tear of the surgically repaired tendon is the most common postop complication. Published re-tear rates range from 20% to 96%^42,43 and generally correlate with initial tear size: A small tear is twice as likely to heal as a massive tear.⁵⁰ That large range—a span of 76%—results from using a variety of methods to measure re-tear and might not have clinical meaning. A meta-analysis that examined more than 8000 shoulder surgeries reported an overall re-tear rate of 26.6%; however, both patients whose tendons healed and those who re-tore demonstrated clinical improvement.⁵¹ In a separate study, patients reported improvement in pain, function, range of motion, and satisfaction regardless of the integrity of the tendon; however, significant improvement in strength was seen only in those whose repair had healed.⁵²

Postop stiffness is more common with arthroscopic repair than with open surgery, and with smaller rather than larger tears.⁵³ Patient variables associated with an increased risk of postop adhesive capsulitis include workers’ compensation insurance, age < 50 years, and preoperative calcific tendonitis or adhesive capsulitis.⁵³ Stiffness generally responds to physical therapy and rarely requires surgical lysis of adhesions or capsular release.

Continue to: Significant injury...

Significant injury to the deltoid muscle has become increasingly uncommon with the advancement of arthroscopic surgery. In traditional open surgery, detachment of the deltoid (and subsequent repair) is required to improve visualization; however, doing so can lead to atrophy and muscle rupture and dehiscence. Deltoid damage occurs in ≤ 60% of open surgeries but is negligible in arthroscopic and mini-open repairs, which involve splitting deltoid fibers to gain exposure of the underlying rotator cuff.⁵⁴

CORRESPONDENCE
Cayce Onks, DO, MS, ATC, Penn State Health Milton S. Hershey Medical Center, Penn State College of Medicine, Family and Community Medicine H154, 500 University Drive, PO Box 850, Hershey, PA 17033-0850; [email protected].

Condylomata acuminata

Condylomata acuminata (CA), or anogenital warts, are the cutaneous manifestation of infection by human papillomavirus (HPV). The virus is transmitted primarily via sexual contact with infected skin or mucosa, although it also may result from nonsexual contact or vertical transmission during vaginal delivery.¹ More than 200 types of HPV have been identified; however, genotypes 6 and 11 are most commonly implicated in the development of CA and are associated with a low risk for oncogenesis. Nevertheless, CA pose a tremendous economic and psychological burden on the health care system and those affected, respectively, representing the most common sexually transmitted viral disease in the United States.²

Clinical presentation

CA present as discrete or clustered smooth, papillomatous, sessile, exophytic papules or plaques, often lacking the thick, horny scale seen in common warts, and they may be broad based or pedunculated.² The anogenital region is affected, including the external genitalia, perineum, perianal area, and adjacent skin such as the mons pubis and inguinal folds. Extension into the urethra or vaginal, cervical, and anal canals is possible, although rarely beyond the dentate line.^2,3 Lesions typically are asymptomatic but may be extensive or disfiguring, often noticed by patients upon self-inspection and leading to significant distress. Symptoms such as pruritus, pain, bleeding, or discharge may develop in traumatized or secondarily infected lesions.^1,3

Diagnosis

Although CA can be diagnosed clinically, biopsy facilitates definitive diagnosis in less clear-cut cases.^1,3 Histologically, CA are characterized by hyperkeratosis, parakeratosis, acanthosis, and papillomatosis, with the presence of koilocytes in the epidermis.²

Treatment

Treatment of CA is challenging, as there are currently no antiviral therapies available to cure the condition. Treatment options include destructive, immunomodulatory, and antiproliferative therapies, either alone or in combination. There is no first-line therapy indicated for CA, and treatment selection is dependent on multiple patient-specific factors, including the size, number, and anatomic location of the lesions, as well as ease of treatment and adverse effects.²

Topical therapies. For external CA, there are several treatments that may be applied by patients themselves, including topical podophyllotoxin, imiquimod, and sinecatechins (TABLE).¹ Podophyllotoxin (brand name Condylox) is an antiproliferative agent available as a 0.15% cream or 0.5% solution.^1,2 It should be applied twice daily for 3 consecutive days per week for up to 4 weeks. Podophyllotoxin is contraindicated in pregnancy and may cause local irritation.²

Imiquimod (brand names Aldara and Zyclara) is an immunomodulatory, available as a 5% and 3.75% cream. For external genital warts, the cream should be applied 3 times per week for up to 16 weeks; for perianal warts it should be applied daily for up to 8 weeks. Adverse effects of imiquimod include local irritation and systemic flu-like symptoms and are prominent with the 3.75% formulation, reducing adherence.^1,2,4

Sinecatechins (brand name Veregen; 10% or 15% ointment) is an active ingredient in green tea and has reported antioxidant, antiviral, and antitumor properties. It is applied 3 times daily for up to 16 weeks.^2,4 Local reactions may occur and, rarely, severe reactions such as vulvovaginitis and pelvic pain, have been reported in women.^2,4

In-office treatment options include cryotherapy, trichloroacetic acid (TCA), intralesional immunotherapy, laser therapy, phototherapy, and surgical options.² Liquid nitrogen is cost-effective, efficacious, and safe for use in pregnancy; it is used in 2 to 3 freeze/thaw cycles per cryotherapy session to induce cellular damage.^1,2 Its disadvantages include adverse effects, such as blistering, ulceration, dyspigmentation, and scarring. In addition, subclinical lesions in adjacent skin are not addressed during treatment.²

TCA is a caustic agent applied in the office once weekly or every 2 to 3 weeks for a maximum of 3 to 4 months, with similar benefits to cryotherapy in terms of ease of application and safety in pregnancy. There is the risk of blistering and ulceration in treated lesions as well as in inadvertently treated adjacent skin.¹

Intralesional immunotherapy with Candida antigen (brand name Candin) is used in 3 sessions 4 to 6 weeks apart and is safe, with minimal adverse effects.²

Laser therapy treatment options include carbon dioxide laser therapy and ND:YAG laser. Their use is limited, however, by availability and cost.^1,2

CA may be removed surgically via shave excision, scissor excision, curettage, and electrosurgery. These procedures can be painful, however, requiring local anesthesia and having a prolonged healing course.^1,2

CA recurrence

CA unfortunately has a high rate of recurrence despite treatment, and patients require extensive counseling. Patients should be screened for other sexually transmitted infections and advised to notify their sexual partners. If followed properly, safe sexual practices, including condom use and limiting sexual partners, may prevent further transmission.¹ The quadrivalent HPV vaccine (effective for the prevention of infection with HPV genotypes 6, 11, 16, and 18 in unexposed individuals) is ineffective in treating patients with pre-existing CA but can protect against the acquisition of other HPV genotypes included in the vaccine.^1,5

Arriving at the diagnosis

Acrochordons are a common skin finding in the groin, but the onset is more gradual and the individual lesions tend to be more pedunculated. Molluscum is also on the differential and can affect the genitalia. Molluscum lesions have a characteristic central dimple or dell, which is absent in CA.

CASE Treatment course

The patient was treated with successive sessions of cryotherapy in combination with a course of topical imiquimod followed by several injections with Candida antigen, with persistence of some lesions as well as recurrence.

Condylomata acuminata

Condylomata acuminata (CA), or anogenital warts, are the cutaneous manifestation of infection by human papillomavirus (HPV). The virus is transmitted primarily via sexual contact with infected skin or mucosa, although it also may result from nonsexual contact or vertical transmission during vaginal delivery.¹ More than 200 types of HPV have been identified; however, genotypes 6 and 11 are most commonly implicated in the development of CA and are associated with a low risk for oncogenesis. Nevertheless, CA pose a tremendous economic and psychological burden on the health care system and those affected, respectively, representing the most common sexually transmitted viral disease in the United States.²

Clinical presentation

CA present as discrete or clustered smooth, papillomatous, sessile, exophytic papules or plaques, often lacking the thick, horny scale seen in common warts, and they may be broad based or pedunculated.² The anogenital region is affected, including the external genitalia, perineum, perianal area, and adjacent skin such as the mons pubis and inguinal folds. Extension into the urethra or vaginal, cervical, and anal canals is possible, although rarely beyond the dentate line.^2,3 Lesions typically are asymptomatic but may be extensive or disfiguring, often noticed by patients upon self-inspection and leading to significant distress. Symptoms such as pruritus, pain, bleeding, or discharge may develop in traumatized or secondarily infected lesions.^1,3

Diagnosis

Although CA can be diagnosed clinically, biopsy facilitates definitive diagnosis in less clear-cut cases.^1,3 Histologically, CA are characterized by hyperkeratosis, parakeratosis, acanthosis, and papillomatosis, with the presence of koilocytes in the epidermis.²

Treatment

Treatment of CA is challenging, as there are currently no antiviral therapies available to cure the condition. Treatment options include destructive, immunomodulatory, and antiproliferative therapies, either alone or in combination. There is no first-line therapy indicated for CA, and treatment selection is dependent on multiple patient-specific factors, including the size, number, and anatomic location of the lesions, as well as ease of treatment and adverse effects.²

Topical therapies. For external CA, there are several treatments that may be applied by patients themselves, including topical podophyllotoxin, imiquimod, and sinecatechins (TABLE).¹ Podophyllotoxin (brand name Condylox) is an antiproliferative agent available as a 0.15% cream or 0.5% solution.^1,2 It should be applied twice daily for 3 consecutive days per week for up to 4 weeks. Podophyllotoxin is contraindicated in pregnancy and may cause local irritation.²

Imiquimod (brand names Aldara and Zyclara) is an immunomodulatory, available as a 5% and 3.75% cream. For external genital warts, the cream should be applied 3 times per week for up to 16 weeks; for perianal warts it should be applied daily for up to 8 weeks. Adverse effects of imiquimod include local irritation and systemic flu-like symptoms and are prominent with the 3.75% formulation, reducing adherence.^1,2,4

Sinecatechins (brand name Veregen; 10% or 15% ointment) is an active ingredient in green tea and has reported antioxidant, antiviral, and antitumor properties. It is applied 3 times daily for up to 16 weeks.^2,4 Local reactions may occur and, rarely, severe reactions such as vulvovaginitis and pelvic pain, have been reported in women.^2,4

In-office treatment options include cryotherapy, trichloroacetic acid (TCA), intralesional immunotherapy, laser therapy, phototherapy, and surgical options.² Liquid nitrogen is cost-effective, efficacious, and safe for use in pregnancy; it is used in 2 to 3 freeze/thaw cycles per cryotherapy session to induce cellular damage.^1,2 Its disadvantages include adverse effects, such as blistering, ulceration, dyspigmentation, and scarring. In addition, subclinical lesions in adjacent skin are not addressed during treatment.²

TCA is a caustic agent applied in the office once weekly or every 2 to 3 weeks for a maximum of 3 to 4 months, with similar benefits to cryotherapy in terms of ease of application and safety in pregnancy. There is the risk of blistering and ulceration in treated lesions as well as in inadvertently treated adjacent skin.¹

Intralesional immunotherapy with Candida antigen (brand name Candin) is used in 3 sessions 4 to 6 weeks apart and is safe, with minimal adverse effects.²

Laser therapy treatment options include carbon dioxide laser therapy and ND:YAG laser. Their use is limited, however, by availability and cost.^1,2

CA may be removed surgically via shave excision, scissor excision, curettage, and electrosurgery. These procedures can be painful, however, requiring local anesthesia and having a prolonged healing course.^1,2

CA recurrence

CA unfortunately has a high rate of recurrence despite treatment, and patients require extensive counseling. Patients should be screened for other sexually transmitted infections and advised to notify their sexual partners. If followed properly, safe sexual practices, including condom use and limiting sexual partners, may prevent further transmission.¹ The quadrivalent HPV vaccine (effective for the prevention of infection with HPV genotypes 6, 11, 16, and 18 in unexposed individuals) is ineffective in treating patients with pre-existing CA but can protect against the acquisition of other HPV genotypes included in the vaccine.^1,5

Arriving at the diagnosis

Acrochordons are a common skin finding in the groin, but the onset is more gradual and the individual lesions tend to be more pedunculated. Molluscum is also on the differential and can affect the genitalia. Molluscum lesions have a characteristic central dimple or dell, which is absent in CA.

CASE Treatment course

The patient was treated with successive sessions of cryotherapy in combination with a course of topical imiquimod followed by several injections with Candida antigen, with persistence of some lesions as well as recurrence.

Condylomata acuminata

Condylomata acuminata (CA), or anogenital warts, are the cutaneous manifestation of infection by human papillomavirus (HPV). The virus is transmitted primarily via sexual contact with infected skin or mucosa, although it also may result from nonsexual contact or vertical transmission during vaginal delivery.¹ More than 200 types of HPV have been identified; however, genotypes 6 and 11 are most commonly implicated in the development of CA and are associated with a low risk for oncogenesis. Nevertheless, CA pose a tremendous economic and psychological burden on the health care system and those affected, respectively, representing the most common sexually transmitted viral disease in the United States.²

Clinical presentation

CA present as discrete or clustered smooth, papillomatous, sessile, exophytic papules or plaques, often lacking the thick, horny scale seen in common warts, and they may be broad based or pedunculated.² The anogenital region is affected, including the external genitalia, perineum, perianal area, and adjacent skin such as the mons pubis and inguinal folds. Extension into the urethra or vaginal, cervical, and anal canals is possible, although rarely beyond the dentate line.^2,3 Lesions typically are asymptomatic but may be extensive or disfiguring, often noticed by patients upon self-inspection and leading to significant distress. Symptoms such as pruritus, pain, bleeding, or discharge may develop in traumatized or secondarily infected lesions.^1,3

Diagnosis

Although CA can be diagnosed clinically, biopsy facilitates definitive diagnosis in less clear-cut cases.^1,3 Histologically, CA are characterized by hyperkeratosis, parakeratosis, acanthosis, and papillomatosis, with the presence of koilocytes in the epidermis.²

Treatment

Treatment of CA is challenging, as there are currently no antiviral therapies available to cure the condition. Treatment options include destructive, immunomodulatory, and antiproliferative therapies, either alone or in combination. There is no first-line therapy indicated for CA, and treatment selection is dependent on multiple patient-specific factors, including the size, number, and anatomic location of the lesions, as well as ease of treatment and adverse effects.²

Topical therapies. For external CA, there are several treatments that may be applied by patients themselves, including topical podophyllotoxin, imiquimod, and sinecatechins (TABLE).¹ Podophyllotoxin (brand name Condylox) is an antiproliferative agent available as a 0.15% cream or 0.5% solution.^1,2 It should be applied twice daily for 3 consecutive days per week for up to 4 weeks. Podophyllotoxin is contraindicated in pregnancy and may cause local irritation.²

Imiquimod (brand names Aldara and Zyclara) is an immunomodulatory, available as a 5% and 3.75% cream. For external genital warts, the cream should be applied 3 times per week for up to 16 weeks; for perianal warts it should be applied daily for up to 8 weeks. Adverse effects of imiquimod include local irritation and systemic flu-like symptoms and are prominent with the 3.75% formulation, reducing adherence.^1,2,4

Sinecatechins (brand name Veregen; 10% or 15% ointment) is an active ingredient in green tea and has reported antioxidant, antiviral, and antitumor properties. It is applied 3 times daily for up to 16 weeks.^2,4 Local reactions may occur and, rarely, severe reactions such as vulvovaginitis and pelvic pain, have been reported in women.^2,4

In-office treatment options include cryotherapy, trichloroacetic acid (TCA), intralesional immunotherapy, laser therapy, phototherapy, and surgical options.² Liquid nitrogen is cost-effective, efficacious, and safe for use in pregnancy; it is used in 2 to 3 freeze/thaw cycles per cryotherapy session to induce cellular damage.^1,2 Its disadvantages include adverse effects, such as blistering, ulceration, dyspigmentation, and scarring. In addition, subclinical lesions in adjacent skin are not addressed during treatment.²

TCA is a caustic agent applied in the office once weekly or every 2 to 3 weeks for a maximum of 3 to 4 months, with similar benefits to cryotherapy in terms of ease of application and safety in pregnancy. There is the risk of blistering and ulceration in treated lesions as well as in inadvertently treated adjacent skin.¹

Intralesional immunotherapy with Candida antigen (brand name Candin) is used in 3 sessions 4 to 6 weeks apart and is safe, with minimal adverse effects.²

Laser therapy treatment options include carbon dioxide laser therapy and ND:YAG laser. Their use is limited, however, by availability and cost.^1,2

CA may be removed surgically via shave excision, scissor excision, curettage, and electrosurgery. These procedures can be painful, however, requiring local anesthesia and having a prolonged healing course.^1,2

CA recurrence

CA unfortunately has a high rate of recurrence despite treatment, and patients require extensive counseling. Patients should be screened for other sexually transmitted infections and advised to notify their sexual partners. If followed properly, safe sexual practices, including condom use and limiting sexual partners, may prevent further transmission.¹ The quadrivalent HPV vaccine (effective for the prevention of infection with HPV genotypes 6, 11, 16, and 18 in unexposed individuals) is ineffective in treating patients with pre-existing CA but can protect against the acquisition of other HPV genotypes included in the vaccine.^1,5

Arriving at the diagnosis

Acrochordons are a common skin finding in the groin, but the onset is more gradual and the individual lesions tend to be more pedunculated. Molluscum is also on the differential and can affect the genitalia. Molluscum lesions have a characteristic central dimple or dell, which is absent in CA.

CASE Treatment course

The patient was treated with successive sessions of cryotherapy in combination with a course of topical imiquimod followed by several injections with Candida antigen, with persistence of some lesions as well as recurrence.

Although we are not able to cover all of the important developments in fertility medicine over the past year, there were 3 important articles published in the past 12 months that we highlight here. First, we discuss an American College of Obstetricians and Gynecologists (ACOG) committee opinion on genetic carrier screening that was reaffirmed in 2019. Second, we explore an interesting retrospective analysis of time-lapse videos and clinical outcomes of more than 10,000 embryos from 8 IVF clinics, across 4 countries. The authors assessed whether a deep learning model could predict the probability of pregnancy with fetal heart from time-lapse videos in the hopes that their research can improve prioritization of the most viable embryo for single embryo transfer. Last, we consider a review of the data on obstetric and reproductive health effects of preconception and prenatal exposure to several environmental toxicants, including heavy metals, endocrine-disrupting chemicals, pesticides, and air pollution.

Preconception genetic carrier screening: Standardize your counseling approach 

American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 690: carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129:e35-e40. 

With the rapid development of advanced and high throughput platforms for DNA sequencing in the past several years, the cost of genetic testing has decreased dramatically. Women's health care providers in general, and fertility specialists in particular, are uniquely positioned to take advantage of these novel and yet affordable technologies by counseling prospective parents during the preconception counseling, or early prenatal period, about the availability of genetic carrier screening and its potential to provide actionable information in a timely manner. The ultimate objective of genetic carrier screening is to enable individuals to make an informed decision regarding their reproductive choices based on their personal values. In a study by Larsen and colleagues, the uptake of genetic carrier screening was significantly higher when offered in the preconception period (68.7%), compared with during pregnancy (35.1%), which highlights the significance of early counseling.¹  

Based on the Centers for Disease Control and Prevention's Birth/Infant Death Data set, birth defects affect 1 in every 33 (about 3%) of all babies born in the United States each year and account for 20% of infant mortality.² About 20% of birth defects are caused by single-gene (monogenic) disorders, and although some of these are due to dominant conditions or de novo mutations, a significant proportion are due to autosomal recessive, or X-chromosome linked conditions that are commonly assessed by genetic carrier screening.  

ACOG published a committee opinion on "Carrier Screening in the Age of Genomic Medicine" in March 2017, which was reaffirmed in 2019.³  

Residual risk. Several points discussed in this document are of paramount importance, including the need for pretest and posttest counseling and consent, as well as a discussion of "residual risk." Newer platforms employ sequencing techniques that potentially can detect most, if not all, of the disease-causing variants in the tested genes, such as the gene for cystic fibrosis and, therefore, have a higher detection rate compared with the older PCR-based techniques for a limited number of specific mutations included in the panel. Due to a variety of technical and biological limitations, however, such as allelic dropouts and the occurrence of de novo mutations, the detection rate is not 100%; there is always a residual risk that needs to be estimated and provided to individuals based on the existing knowledge on frequency of gene, penetrance of phenotype, and prevalence of condition in the general and specific ethnic populations.  

Continue to: Expanded vs panethnic screening...

Expanded vs panethnic screening. Furthermore, although sequencing technology has made "expanded carrier screening" for several hundred conditions, simultaneous to and independent of ethnicity and family history, more easily available and affordable, ethnic-specific and panethnic screening for a more limited number of conditions are still acceptable approaches. Having said this, when the first partner screened is identified to be a carrier, his/her reproductive partners must be offered next-generation sequencing to identify less common disease-causing variants.⁴  

A cautionary point to consider when expanded carrier screening panels are requested is the significant variability among commercial laboratories with regard to the conditions included in their panels. In addition, consider the absence of a well-defined or predictable phenotype for some of the included conditions.  

Perhaps the most important matter when it comes to genetic carrier screening is to have a standard counseling approach that is persistently followed and offers the opportunity for individuals to know about their genetic testing options and available reproductive choices, including the use of donor gametes, preimplantation genetic testing for monogenic disease (PGT-M, formerly known as preimplantation genetic diagnosis, or PGD), prenatal testing, and pregnancy management options. For couples and/or individuals who decide to proceed with an affected pregnancy, earlier diagnosis can assist with postnatal management.  

Medicolegal responsibility. Genetic carrier screening also is of specific relevance to the field of fertility medicine and assisted reproductive technology (ART) as a potential liability issue. Couples and individuals who are undergoing fertility treatment with in vitro fertilization (IVF) for a variety of medical or personal reasons are a specific group that certainly should be offered genetic carrier screening, as they have the option of "adding on" PGT-M (PGD) to their existing treatment plan at a fraction of the cost and treatment burden that would have otherwise been needed if they were not undergoing IVF. After counseling, some individuals and couples may ultimately opt out of genetic carrier screening. The counseling discussion needs to be clearly documented in the medical chart.

Continue to: Artificial intelligence and embryo selection...

Artificial intelligence and embryo selection  

With continued improvements in embryo culture conditions and cryopreservation technology, there has been a tremendous amount of interest in developing better methods for embryo selection. These efforts are aimed at encouraging elective single embryo transfer (eSET) for women of all ages, thereby lowering the risk of multiple pregnancy and its associated adverse neonatal and obstetric outcomes—without compromising the pregnancy rates per transfer or lengthening the time to pregnancy.  

One of the most extensively studied methods for this purpose is preimplantation genetic testing for aneuploidy (PGT-A, formerly known as PGS), but emerging data from large multicenter randomized clinical trials (RCTs) have again cast significant doubt on PGT-A's efficacy and utility.⁵ Meanwhile, alternative methods for embryo selection are currently under investigation, including noninvasive PGT-A and morphokinetic assessment of embryo development via analysis of images obtained by time-lapse imaging.  

The potential of time-lapse imaging 

Despite the initial promising results from time-lapse imaging, subsequent RCTs have not shown a significant clinical benefit.⁶ However, these early methods of morphokinetic assessment are mainly dependent on the embryologists' subjective assessment of individual static frames and "annotation" of observed spatial and temporal features of embryo development. In addition to being a very time-consuming task, this process is subject to significant interobserver and intraobserver variability.  

Considering these limitations, even machine-based algorithms that incorporate these annotations along with such other clinical variables as parental age and prior obstetric history, have a low predictive power for the outcome of embryo transfer, with an area under the curve (AUC) of the ROC curve of 0.65 to 0.74. (An AUC of 0.5 represents completely random prediction and an AUC of 1.0 suggests perfect prediction.)⁷ 

A recent study by Tran and colleagues has employed a deep learning (neural network) model to analyze the entire raw time-lapse videos in an automated manner without prior annotation by embryologists. After analysis of 10,638 embryos from 8 different IVF clinics in 4 different countries, they have reported an AUC of 0.93 (95% confidence interval, 0.92-0.94) for prediction of fetal heart rate activity detected at 7 weeks of gestation or beyond. Although these data are very preliminary and have not yet been validated prospectively in larger datasets for live birth, it may herald the beginning of a new era for the automation and standardization of embryo assessment with artificial intelligence—similar to the rapidly increasing role of facial recognition technology for various applications.

Continue to: Environmental toxicants: The hidden danger...

Environmental toxicants: The hidden danger 

Segal TR, Giudice LC. Before the beginning: environmental exposures and reproductive and obstetrical outcomes. Fertil Steril. 2019;112:613-621. 

We receive news daily about the existential risk to humans of climate change. However, a risk that is likely as serious goes almost unseen by the public and most health care providers. That risk is environmental toxicants.⁸ 

More than 80,000 chemicals are registered in the United States, most in the last 75 years. These chemicals are ubiquitous. All of us are continuously exposed to and suffused with these toxicants and their metabolites. Air pollution adds insult to injury. Since this exposure has especially significant implications for fertility, infertility, pregnancy, perinatal health, childhood development, adult diseases, and later generational reproduction, it is imperative that reproductive health professionals take responsibility for helping mitigate this environmental crisis. 

The problem is exceptionally complicated  

The risks posed by environmental toxicants are much less visible than those for climate change, so the public, policymakers, and providers are largely unaware or may even seem uncaring. Few health professionals have sufficient knowledge to deliver care in this area, know which questions to ask, or have adequate information/medical record tools to assist them in care—and what are the possible interventions? 

Addressing risk posed by individual toxicants 

Addressing the problem clinically requires asking patients questions about exposure and recommending interventions. Toxicant chemicals include the neurotoxin mercury, which can be addressed by limiting intake of fish, especially certain types. 

Lead was used before 1978 in paint, it also was used in gas and in water pipes. People living in older homes may be exposed, as well as those in occupations exposed to lead. Others with lead exposure risk include immigrants from areas without lead regulations and people using pica- or lead-glazed pottery. Lead exposure has been associated with multiple pregnancy complications and permanently impaired intellectual development in children. If lead testing reveals high levels, chelation therapy can help. 

Cadmium is a heavy metal used in rechargeable batteries, paint pigment, and plastic production. Exposure results from food intake, smoking, and second-hand smoke. Cadmium accumulates in the liver, kidneys, testes, ovaries, and placenta. Exposure causes itai-itai disease, which is characterized by osteomalacia and renal tubular dysfunction as well as epigenetic changes in placental DNA and damage to the reproductive system. Eating organic food and reducing industrial exposure to cadmium are preventive strategies. 

Pesticides are ubiquitous, with 90% of the US population having detectable levels. Exposure during the preconception period can lead to intrauterine growth restriction, low birth weight, subsequent cancers, and other problems. Eating organic food can reduce risk, as can frequent hand washing when exposed to pesticides, using protective gear, and removing shoes in the home. 

Endocrine-disrupting chemicals (EDCs) are chemicals that can mimic or block endogenous hormones, which leads to adverse health outcomes. In addition to heavy metals, 3 important EDCs are bisphenol A (BPA), phthalates, and polybrominated diethyl ethers (PBDEs). Exposure is ubiquitous from industrial food processing, personal care products, cosmetics, and dust. Phthalates and BPA have short half-lives of hours to days, while PBDEs can persist in adipose tissue for months. Abnormal urogenital and neurologic development and thyroid disruption can result. Eating organic food, eating at home, and decreasing processed food intake can reduce exposure. 

BPA is used in plastics, canned food liners, cash register receipts, and epoxy resins. Exposure is through inhalation, ingestion, and dermal absorption and affects semen quality, fertilization, placentation, and early reproduction. Limiting the use of plastic containers, not microwaving food in plastic, and avoiding thermal paper cash register receipts can reduce exposure. 

Phthalates are synthetically derived and used as plasticizers in personal and medical products. The major source of phthalate exposure is food; exposure causes sperm, egg, and DNA damage. Phthalate avoidance involves replacing plastic bottles with glass or stainless steel, avoiding reheating food in plastic containers, and choosing "fragrance free" products. 

PBDEs are used in flame retardants on upholstery, textiles, carpeting, and some electronics. Most PBDEs have been replaced by alternatives; however, their half-life is up to 12 years. Complications caused by PBDEs include thyroid disruption, resulting in abnormal fetal brain development. Avoiding dust and furniture that contain PBDEs, as well as hand washing, reduces exposure risk. 

Air pollutants are associated with adverse obstetric outcomes and lower cognitive function in children. Avoiding areas with heavy traffic, staying indoors when air is heavily polluted, and using a HEPA filter in the home can reduce chemicals from air pollution. 

Recommendations 

The magnitude of the problem that environmental toxicant exposure creates requires health care providers to take action. The table in the publication by Segal and Giudice can be used as a tool that patients can answer first themselves before review by their provider.² It can be added to your electronic health record and/or patient portal. Even making general comments to raise awareness, asking questions regarding exposure, and making recommendations can be helpful (TABLES 1 and 2). When possible, we also should advocate for public awareness and policy changes that address this significant health issue. 

Although we are not able to cover all of the important developments in fertility medicine over the past year, there were 3 important articles published in the past 12 months that we highlight here. First, we discuss an American College of Obstetricians and Gynecologists (ACOG) committee opinion on genetic carrier screening that was reaffirmed in 2019. Second, we explore an interesting retrospective analysis of time-lapse videos and clinical outcomes of more than 10,000 embryos from 8 IVF clinics, across 4 countries. The authors assessed whether a deep learning model could predict the probability of pregnancy with fetal heart from time-lapse videos in the hopes that their research can improve prioritization of the most viable embryo for single embryo transfer. Last, we consider a review of the data on obstetric and reproductive health effects of preconception and prenatal exposure to several environmental toxicants, including heavy metals, endocrine-disrupting chemicals, pesticides, and air pollution.

Preconception genetic carrier screening: Standardize your counseling approach 

American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 690: carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129:e35-e40. 

With the rapid development of advanced and high throughput platforms for DNA sequencing in the past several years, the cost of genetic testing has decreased dramatically. Women's health care providers in general, and fertility specialists in particular, are uniquely positioned to take advantage of these novel and yet affordable technologies by counseling prospective parents during the preconception counseling, or early prenatal period, about the availability of genetic carrier screening and its potential to provide actionable information in a timely manner. The ultimate objective of genetic carrier screening is to enable individuals to make an informed decision regarding their reproductive choices based on their personal values. In a study by Larsen and colleagues, the uptake of genetic carrier screening was significantly higher when offered in the preconception period (68.7%), compared with during pregnancy (35.1%), which highlights the significance of early counseling.¹  

Based on the Centers for Disease Control and Prevention's Birth/Infant Death Data set, birth defects affect 1 in every 33 (about 3%) of all babies born in the United States each year and account for 20% of infant mortality.² About 20% of birth defects are caused by single-gene (monogenic) disorders, and although some of these are due to dominant conditions or de novo mutations, a significant proportion are due to autosomal recessive, or X-chromosome linked conditions that are commonly assessed by genetic carrier screening.  

ACOG published a committee opinion on "Carrier Screening in the Age of Genomic Medicine" in March 2017, which was reaffirmed in 2019.³  

Residual risk. Several points discussed in this document are of paramount importance, including the need for pretest and posttest counseling and consent, as well as a discussion of "residual risk." Newer platforms employ sequencing techniques that potentially can detect most, if not all, of the disease-causing variants in the tested genes, such as the gene for cystic fibrosis and, therefore, have a higher detection rate compared with the older PCR-based techniques for a limited number of specific mutations included in the panel. Due to a variety of technical and biological limitations, however, such as allelic dropouts and the occurrence of de novo mutations, the detection rate is not 100%; there is always a residual risk that needs to be estimated and provided to individuals based on the existing knowledge on frequency of gene, penetrance of phenotype, and prevalence of condition in the general and specific ethnic populations.  

Continue to: Expanded vs panethnic screening...

Expanded vs panethnic screening. Furthermore, although sequencing technology has made "expanded carrier screening" for several hundred conditions, simultaneous to and independent of ethnicity and family history, more easily available and affordable, ethnic-specific and panethnic screening for a more limited number of conditions are still acceptable approaches. Having said this, when the first partner screened is identified to be a carrier, his/her reproductive partners must be offered next-generation sequencing to identify less common disease-causing variants.⁴  

A cautionary point to consider when expanded carrier screening panels are requested is the significant variability among commercial laboratories with regard to the conditions included in their panels. In addition, consider the absence of a well-defined or predictable phenotype for some of the included conditions.  

Perhaps the most important matter when it comes to genetic carrier screening is to have a standard counseling approach that is persistently followed and offers the opportunity for individuals to know about their genetic testing options and available reproductive choices, including the use of donor gametes, preimplantation genetic testing for monogenic disease (PGT-M, formerly known as preimplantation genetic diagnosis, or PGD), prenatal testing, and pregnancy management options. For couples and/or individuals who decide to proceed with an affected pregnancy, earlier diagnosis can assist with postnatal management.  

Medicolegal responsibility. Genetic carrier screening also is of specific relevance to the field of fertility medicine and assisted reproductive technology (ART) as a potential liability issue. Couples and individuals who are undergoing fertility treatment with in vitro fertilization (IVF) for a variety of medical or personal reasons are a specific group that certainly should be offered genetic carrier screening, as they have the option of "adding on" PGT-M (PGD) to their existing treatment plan at a fraction of the cost and treatment burden that would have otherwise been needed if they were not undergoing IVF. After counseling, some individuals and couples may ultimately opt out of genetic carrier screening. The counseling discussion needs to be clearly documented in the medical chart.

Continue to: Artificial intelligence and embryo selection...

Artificial intelligence and embryo selection  

With continued improvements in embryo culture conditions and cryopreservation technology, there has been a tremendous amount of interest in developing better methods for embryo selection. These efforts are aimed at encouraging elective single embryo transfer (eSET) for women of all ages, thereby lowering the risk of multiple pregnancy and its associated adverse neonatal and obstetric outcomes—without compromising the pregnancy rates per transfer or lengthening the time to pregnancy.  

One of the most extensively studied methods for this purpose is preimplantation genetic testing for aneuploidy (PGT-A, formerly known as PGS), but emerging data from large multicenter randomized clinical trials (RCTs) have again cast significant doubt on PGT-A's efficacy and utility.⁵ Meanwhile, alternative methods for embryo selection are currently under investigation, including noninvasive PGT-A and morphokinetic assessment of embryo development via analysis of images obtained by time-lapse imaging.  

The potential of time-lapse imaging 

Despite the initial promising results from time-lapse imaging, subsequent RCTs have not shown a significant clinical benefit.⁶ However, these early methods of morphokinetic assessment are mainly dependent on the embryologists' subjective assessment of individual static frames and "annotation" of observed spatial and temporal features of embryo development. In addition to being a very time-consuming task, this process is subject to significant interobserver and intraobserver variability.  

Considering these limitations, even machine-based algorithms that incorporate these annotations along with such other clinical variables as parental age and prior obstetric history, have a low predictive power for the outcome of embryo transfer, with an area under the curve (AUC) of the ROC curve of 0.65 to 0.74. (An AUC of 0.5 represents completely random prediction and an AUC of 1.0 suggests perfect prediction.)⁷ 

A recent study by Tran and colleagues has employed a deep learning (neural network) model to analyze the entire raw time-lapse videos in an automated manner without prior annotation by embryologists. After analysis of 10,638 embryos from 8 different IVF clinics in 4 different countries, they have reported an AUC of 0.93 (95% confidence interval, 0.92-0.94) for prediction of fetal heart rate activity detected at 7 weeks of gestation or beyond. Although these data are very preliminary and have not yet been validated prospectively in larger datasets for live birth, it may herald the beginning of a new era for the automation and standardization of embryo assessment with artificial intelligence—similar to the rapidly increasing role of facial recognition technology for various applications.

Continue to: Environmental toxicants: The hidden danger...

Environmental toxicants: The hidden danger 

Segal TR, Giudice LC. Before the beginning: environmental exposures and reproductive and obstetrical outcomes. Fertil Steril. 2019;112:613-621. 

We receive news daily about the existential risk to humans of climate change. However, a risk that is likely as serious goes almost unseen by the public and most health care providers. That risk is environmental toxicants.⁸ 

More than 80,000 chemicals are registered in the United States, most in the last 75 years. These chemicals are ubiquitous. All of us are continuously exposed to and suffused with these toxicants and their metabolites. Air pollution adds insult to injury. Since this exposure has especially significant implications for fertility, infertility, pregnancy, perinatal health, childhood development, adult diseases, and later generational reproduction, it is imperative that reproductive health professionals take responsibility for helping mitigate this environmental crisis. 

The problem is exceptionally complicated  

The risks posed by environmental toxicants are much less visible than those for climate change, so the public, policymakers, and providers are largely unaware or may even seem uncaring. Few health professionals have sufficient knowledge to deliver care in this area, know which questions to ask, or have adequate information/medical record tools to assist them in care—and what are the possible interventions? 

Addressing risk posed by individual toxicants 

Addressing the problem clinically requires asking patients questions about exposure and recommending interventions. Toxicant chemicals include the neurotoxin mercury, which can be addressed by limiting intake of fish, especially certain types. 

Lead was used before 1978 in paint, it also was used in gas and in water pipes. People living in older homes may be exposed, as well as those in occupations exposed to lead. Others with lead exposure risk include immigrants from areas without lead regulations and people using pica- or lead-glazed pottery. Lead exposure has been associated with multiple pregnancy complications and permanently impaired intellectual development in children. If lead testing reveals high levels, chelation therapy can help. 

Cadmium is a heavy metal used in rechargeable batteries, paint pigment, and plastic production. Exposure results from food intake, smoking, and second-hand smoke. Cadmium accumulates in the liver, kidneys, testes, ovaries, and placenta. Exposure causes itai-itai disease, which is characterized by osteomalacia and renal tubular dysfunction as well as epigenetic changes in placental DNA and damage to the reproductive system. Eating organic food and reducing industrial exposure to cadmium are preventive strategies. 

Pesticides are ubiquitous, with 90% of the US population having detectable levels. Exposure during the preconception period can lead to intrauterine growth restriction, low birth weight, subsequent cancers, and other problems. Eating organic food can reduce risk, as can frequent hand washing when exposed to pesticides, using protective gear, and removing shoes in the home. 

Endocrine-disrupting chemicals (EDCs) are chemicals that can mimic or block endogenous hormones, which leads to adverse health outcomes. In addition to heavy metals, 3 important EDCs are bisphenol A (BPA), phthalates, and polybrominated diethyl ethers (PBDEs). Exposure is ubiquitous from industrial food processing, personal care products, cosmetics, and dust. Phthalates and BPA have short half-lives of hours to days, while PBDEs can persist in adipose tissue for months. Abnormal urogenital and neurologic development and thyroid disruption can result. Eating organic food, eating at home, and decreasing processed food intake can reduce exposure. 

BPA is used in plastics, canned food liners, cash register receipts, and epoxy resins. Exposure is through inhalation, ingestion, and dermal absorption and affects semen quality, fertilization, placentation, and early reproduction. Limiting the use of plastic containers, not microwaving food in plastic, and avoiding thermal paper cash register receipts can reduce exposure. 

Phthalates are synthetically derived and used as plasticizers in personal and medical products. The major source of phthalate exposure is food; exposure causes sperm, egg, and DNA damage. Phthalate avoidance involves replacing plastic bottles with glass or stainless steel, avoiding reheating food in plastic containers, and choosing "fragrance free" products. 

PBDEs are used in flame retardants on upholstery, textiles, carpeting, and some electronics. Most PBDEs have been replaced by alternatives; however, their half-life is up to 12 years. Complications caused by PBDEs include thyroid disruption, resulting in abnormal fetal brain development. Avoiding dust and furniture that contain PBDEs, as well as hand washing, reduces exposure risk. 

Air pollutants are associated with adverse obstetric outcomes and lower cognitive function in children. Avoiding areas with heavy traffic, staying indoors when air is heavily polluted, and using a HEPA filter in the home can reduce chemicals from air pollution. 

Recommendations 

The magnitude of the problem that environmental toxicant exposure creates requires health care providers to take action. The table in the publication by Segal and Giudice can be used as a tool that patients can answer first themselves before review by their provider.² It can be added to your electronic health record and/or patient portal. Even making general comments to raise awareness, asking questions regarding exposure, and making recommendations can be helpful (TABLES 1 and 2). When possible, we also should advocate for public awareness and policy changes that address this significant health issue. 

Although we are not able to cover all of the important developments in fertility medicine over the past year, there were 3 important articles published in the past 12 months that we highlight here. First, we discuss an American College of Obstetricians and Gynecologists (ACOG) committee opinion on genetic carrier screening that was reaffirmed in 2019. Second, we explore an interesting retrospective analysis of time-lapse videos and clinical outcomes of more than 10,000 embryos from 8 IVF clinics, across 4 countries. The authors assessed whether a deep learning model could predict the probability of pregnancy with fetal heart from time-lapse videos in the hopes that their research can improve prioritization of the most viable embryo for single embryo transfer. Last, we consider a review of the data on obstetric and reproductive health effects of preconception and prenatal exposure to several environmental toxicants, including heavy metals, endocrine-disrupting chemicals, pesticides, and air pollution.

Preconception genetic carrier screening: Standardize your counseling approach 

American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 690: carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129:e35-e40. 

With the rapid development of advanced and high throughput platforms for DNA sequencing in the past several years, the cost of genetic testing has decreased dramatically. Women's health care providers in general, and fertility specialists in particular, are uniquely positioned to take advantage of these novel and yet affordable technologies by counseling prospective parents during the preconception counseling, or early prenatal period, about the availability of genetic carrier screening and its potential to provide actionable information in a timely manner. The ultimate objective of genetic carrier screening is to enable individuals to make an informed decision regarding their reproductive choices based on their personal values. In a study by Larsen and colleagues, the uptake of genetic carrier screening was significantly higher when offered in the preconception period (68.7%), compared with during pregnancy (35.1%), which highlights the significance of early counseling.¹  

Based on the Centers for Disease Control and Prevention's Birth/Infant Death Data set, birth defects affect 1 in every 33 (about 3%) of all babies born in the United States each year and account for 20% of infant mortality.² About 20% of birth defects are caused by single-gene (monogenic) disorders, and although some of these are due to dominant conditions or de novo mutations, a significant proportion are due to autosomal recessive, or X-chromosome linked conditions that are commonly assessed by genetic carrier screening.  

ACOG published a committee opinion on "Carrier Screening in the Age of Genomic Medicine" in March 2017, which was reaffirmed in 2019.³  

Residual risk. Several points discussed in this document are of paramount importance, including the need for pretest and posttest counseling and consent, as well as a discussion of "residual risk." Newer platforms employ sequencing techniques that potentially can detect most, if not all, of the disease-causing variants in the tested genes, such as the gene for cystic fibrosis and, therefore, have a higher detection rate compared with the older PCR-based techniques for a limited number of specific mutations included in the panel. Due to a variety of technical and biological limitations, however, such as allelic dropouts and the occurrence of de novo mutations, the detection rate is not 100%; there is always a residual risk that needs to be estimated and provided to individuals based on the existing knowledge on frequency of gene, penetrance of phenotype, and prevalence of condition in the general and specific ethnic populations.  

Continue to: Expanded vs panethnic screening...

Expanded vs panethnic screening. Furthermore, although sequencing technology has made "expanded carrier screening" for several hundred conditions, simultaneous to and independent of ethnicity and family history, more easily available and affordable, ethnic-specific and panethnic screening for a more limited number of conditions are still acceptable approaches. Having said this, when the first partner screened is identified to be a carrier, his/her reproductive partners must be offered next-generation sequencing to identify less common disease-causing variants.⁴  

A cautionary point to consider when expanded carrier screening panels are requested is the significant variability among commercial laboratories with regard to the conditions included in their panels. In addition, consider the absence of a well-defined or predictable phenotype for some of the included conditions.  

Perhaps the most important matter when it comes to genetic carrier screening is to have a standard counseling approach that is persistently followed and offers the opportunity for individuals to know about their genetic testing options and available reproductive choices, including the use of donor gametes, preimplantation genetic testing for monogenic disease (PGT-M, formerly known as preimplantation genetic diagnosis, or PGD), prenatal testing, and pregnancy management options. For couples and/or individuals who decide to proceed with an affected pregnancy, earlier diagnosis can assist with postnatal management.  

Medicolegal responsibility. Genetic carrier screening also is of specific relevance to the field of fertility medicine and assisted reproductive technology (ART) as a potential liability issue. Couples and individuals who are undergoing fertility treatment with in vitro fertilization (IVF) for a variety of medical or personal reasons are a specific group that certainly should be offered genetic carrier screening, as they have the option of "adding on" PGT-M (PGD) to their existing treatment plan at a fraction of the cost and treatment burden that would have otherwise been needed if they were not undergoing IVF. After counseling, some individuals and couples may ultimately opt out of genetic carrier screening. The counseling discussion needs to be clearly documented in the medical chart.

Continue to: Artificial intelligence and embryo selection...

Artificial intelligence and embryo selection  

With continued improvements in embryo culture conditions and cryopreservation technology, there has been a tremendous amount of interest in developing better methods for embryo selection. These efforts are aimed at encouraging elective single embryo transfer (eSET) for women of all ages, thereby lowering the risk of multiple pregnancy and its associated adverse neonatal and obstetric outcomes—without compromising the pregnancy rates per transfer or lengthening the time to pregnancy.  

One of the most extensively studied methods for this purpose is preimplantation genetic testing for aneuploidy (PGT-A, formerly known as PGS), but emerging data from large multicenter randomized clinical trials (RCTs) have again cast significant doubt on PGT-A's efficacy and utility.⁵ Meanwhile, alternative methods for embryo selection are currently under investigation, including noninvasive PGT-A and morphokinetic assessment of embryo development via analysis of images obtained by time-lapse imaging.  

The potential of time-lapse imaging 

Despite the initial promising results from time-lapse imaging, subsequent RCTs have not shown a significant clinical benefit.⁶ However, these early methods of morphokinetic assessment are mainly dependent on the embryologists' subjective assessment of individual static frames and "annotation" of observed spatial and temporal features of embryo development. In addition to being a very time-consuming task, this process is subject to significant interobserver and intraobserver variability.  

Considering these limitations, even machine-based algorithms that incorporate these annotations along with such other clinical variables as parental age and prior obstetric history, have a low predictive power for the outcome of embryo transfer, with an area under the curve (AUC) of the ROC curve of 0.65 to 0.74. (An AUC of 0.5 represents completely random prediction and an AUC of 1.0 suggests perfect prediction.)⁷ 

A recent study by Tran and colleagues has employed a deep learning (neural network) model to analyze the entire raw time-lapse videos in an automated manner without prior annotation by embryologists. After analysis of 10,638 embryos from 8 different IVF clinics in 4 different countries, they have reported an AUC of 0.93 (95% confidence interval, 0.92-0.94) for prediction of fetal heart rate activity detected at 7 weeks of gestation or beyond. Although these data are very preliminary and have not yet been validated prospectively in larger datasets for live birth, it may herald the beginning of a new era for the automation and standardization of embryo assessment with artificial intelligence—similar to the rapidly increasing role of facial recognition technology for various applications.

Continue to: Environmental toxicants: The hidden danger...

Environmental toxicants: The hidden danger 

Segal TR, Giudice LC. Before the beginning: environmental exposures and reproductive and obstetrical outcomes. Fertil Steril. 2019;112:613-621. 

We receive news daily about the existential risk to humans of climate change. However, a risk that is likely as serious goes almost unseen by the public and most health care providers. That risk is environmental toxicants.⁸ 

More than 80,000 chemicals are registered in the United States, most in the last 75 years. These chemicals are ubiquitous. All of us are continuously exposed to and suffused with these toxicants and their metabolites. Air pollution adds insult to injury. Since this exposure has especially significant implications for fertility, infertility, pregnancy, perinatal health, childhood development, adult diseases, and later generational reproduction, it is imperative that reproductive health professionals take responsibility for helping mitigate this environmental crisis. 

The problem is exceptionally complicated  

The risks posed by environmental toxicants are much less visible than those for climate change, so the public, policymakers, and providers are largely unaware or may even seem uncaring. Few health professionals have sufficient knowledge to deliver care in this area, know which questions to ask, or have adequate information/medical record tools to assist them in care—and what are the possible interventions? 

Addressing risk posed by individual toxicants 

Addressing the problem clinically requires asking patients questions about exposure and recommending interventions. Toxicant chemicals include the neurotoxin mercury, which can be addressed by limiting intake of fish, especially certain types. 

Lead was used before 1978 in paint, it also was used in gas and in water pipes. People living in older homes may be exposed, as well as those in occupations exposed to lead. Others with lead exposure risk include immigrants from areas without lead regulations and people using pica- or lead-glazed pottery. Lead exposure has been associated with multiple pregnancy complications and permanently impaired intellectual development in children. If lead testing reveals high levels, chelation therapy can help. 

Cadmium is a heavy metal used in rechargeable batteries, paint pigment, and plastic production. Exposure results from food intake, smoking, and second-hand smoke. Cadmium accumulates in the liver, kidneys, testes, ovaries, and placenta. Exposure causes itai-itai disease, which is characterized by osteomalacia and renal tubular dysfunction as well as epigenetic changes in placental DNA and damage to the reproductive system. Eating organic food and reducing industrial exposure to cadmium are preventive strategies. 

Pesticides are ubiquitous, with 90% of the US population having detectable levels. Exposure during the preconception period can lead to intrauterine growth restriction, low birth weight, subsequent cancers, and other problems. Eating organic food can reduce risk, as can frequent hand washing when exposed to pesticides, using protective gear, and removing shoes in the home. 

Endocrine-disrupting chemicals (EDCs) are chemicals that can mimic or block endogenous hormones, which leads to adverse health outcomes. In addition to heavy metals, 3 important EDCs are bisphenol A (BPA), phthalates, and polybrominated diethyl ethers (PBDEs). Exposure is ubiquitous from industrial food processing, personal care products, cosmetics, and dust. Phthalates and BPA have short half-lives of hours to days, while PBDEs can persist in adipose tissue for months. Abnormal urogenital and neurologic development and thyroid disruption can result. Eating organic food, eating at home, and decreasing processed food intake can reduce exposure. 

BPA is used in plastics, canned food liners, cash register receipts, and epoxy resins. Exposure is through inhalation, ingestion, and dermal absorption and affects semen quality, fertilization, placentation, and early reproduction. Limiting the use of plastic containers, not microwaving food in plastic, and avoiding thermal paper cash register receipts can reduce exposure. 

Phthalates are synthetically derived and used as plasticizers in personal and medical products. The major source of phthalate exposure is food; exposure causes sperm, egg, and DNA damage. Phthalate avoidance involves replacing plastic bottles with glass or stainless steel, avoiding reheating food in plastic containers, and choosing "fragrance free" products. 

PBDEs are used in flame retardants on upholstery, textiles, carpeting, and some electronics. Most PBDEs have been replaced by alternatives; however, their half-life is up to 12 years. Complications caused by PBDEs include thyroid disruption, resulting in abnormal fetal brain development. Avoiding dust and furniture that contain PBDEs, as well as hand washing, reduces exposure risk. 

Air pollutants are associated with adverse obstetric outcomes and lower cognitive function in children. Avoiding areas with heavy traffic, staying indoors when air is heavily polluted, and using a HEPA filter in the home can reduce chemicals from air pollution. 

Recommendations 

The magnitude of the problem that environmental toxicant exposure creates requires health care providers to take action. The table in the publication by Segal and Giudice can be used as a tool that patients can answer first themselves before review by their provider.² It can be added to your electronic health record and/or patient portal. Even making general comments to raise awareness, asking questions regarding exposure, and making recommendations can be helpful (TABLES 1 and 2). When possible, we also should advocate for public awareness and policy changes that address this significant health issue. 

In this second in a series of 3 articles discussing medical malpractice and the ObGyn we look at the reasons for malpractice claims and liability, what happens to malpractice claims, and the direction and future of medical malpractice. The first article dealt with 2 sources of major malpractice damages: the “big verdict” and physicians with multiple malpractice paid claims. Next month we look at the place of apology in medicine, in cases in which error, including negligence, may have caused a patient injury.

CASE 1 Long-term brachial plexus injury

Right upper extremity injury occurs in the neonate at delivery with sequela of long-term brachial plexus injury (which is diagnosed around 6 months of age). Physical therapy and orthopedic assessment are rendered. Despite continued treatment, discrepancy in arm lengths (ie, affected side arm is noticeably shorter than opposite side) remains. The child cannot play basketball with his older brother and is the victim of ridicule, the plaintiff’s attorney emphasizes. He is unable to properly pronate or supinate the affected arm.

The defendant ObGyn maintains that there was “no shoulder dystocia [at delivery] and the shoulder did not get obstructed in the pelvis; shoulder was delivered 15 seconds after delivery of the head.” The nursing staff testifies that if shoulder dystocia had been the problem they would have launched upon a series of procedures to address such, in accord with the delivering obstetrician. The defense expert witness testifies that a brachial plexus injury can happen without shoulder dystocia.

A defense verdict is rendered by the Florida jury.¹
 

CASE 2 Shoulder dystocia

During delivery, the obstetrician notes a shoulder dystocia (“turtle sign”). After initial attempts to release the shoulder were unsuccessful, the physician applies traction several times to the head of the child, and the baby is delivered. There is permanent injury to the right brachial plexus. The defendant ObGyn says that traction was necessary to dislodge the shoulder, and that the injury was the result of the forces of labor (not the traction). The expert witness for the plaintiff testifies that the medical standard of care did not permit traction under these circumstances, and that the traction was the likely cause of the injury.

The Virginia jury awards $2.32 million in damages.²

Note: The above vignettes are drawn from actual cases but are only outlines of those cases and are not complete descriptions of the claims in the cases. Because the information comes from informal sources, not formal court records, the facts may be inaccurate and incomplete. They should be viewed as illustrations only.

The trend in malpractice

It has been clear for many years that medical malpractice claims are not randomly or evenly distributed among physicians. Notably, the variation among specialties has, and continues to be, substantial (FIGURE 1).³ Recent data suggest that, although paid claims per “1,000 physician-years” averages 14 paid claims per 1,000 physician years, it ranges from 4 or 5 in 1,000 (psychiatry and pediatrics) to 53 and 49 claims per 1,000 (neurology and plastic surgery, respectively). Obstetrics and gynecology has the fourth highest rate at 42.5 paid claims per 1,000 physician years.⁴ (These data are for the years 1992–2014.)

Continue to: The number of ObGyn paid malpractice claims has decreased over time...

The number of ObGyn paid malpractice claims has decreased over time. Although large verdicts and physicians with multiple paid malpractice claims receive a good deal of attention (as we noted in part 1 of our series), in fact, paid medical malpractice claims have trended downward in recent decades.⁵ When the data above are disaggregated by 5-year periods, for example, in obstetrics and gynecology, there has been a consistent reduction in paid malpractice claims from 1992 to 2014. Paid claims went from 58 per 1,000 physician-years in 1992–1996 to 25 per 1,000 in 2009–2014 (FIGURE 2).^4,6 In short, the rate dropped by half over approximately 20 years.⁴

It is reasonable to expect that such a decline in the cost of malpractice insurance premiums would follow. Robert L. Barbieri, MD, who practices in Boston, Massachusetts, in his excellent recent editorial in OBG Management⁶ reported that his professional liability insurance premiums decreased 18% from 2014 to 2019, and his colleague reported a 22% reduction during the same time period.⁶ An American Medical Association report of 7 states or metropolitan areas for 2008 to 2017 found considerable variance. The study looked at the rates and the trend of rates for malpractice insurance in several areas of the United States (FIGURE 3).⁷ For ObGyns, one of these jurisdictions experienced increased rates; in one other, rates stayed the same, and in 5 jurisdictions, the rates went down. The premiums varied across the country, however. In 2017, Los Angeles/Orange had an average rate of $49,804, and in Nassau and Suffolk counties, New York, the rate was $214,999. The median rate was approximately $170,000.⁷

Why have malpractice payouts declined overall?

Have medical errors declined?

It would be wonderful if the reduction in malpractice claims represented a significant decrease in medical errors. Attention to medical errors was driven by the first widely noticed study of medical error deaths. The Institute of Medicine (IOM) study in 2000, put the number of deaths annually at 44,000 to 98,000.⁸ There have been many efforts to reduce such errors, and it is possible that those efforts have indeed reduced errors somewhat.⁴ Barbieri provided a helpful digest of many of the error-reduction suggestions for ObGyn practice (TABLE 1).⁶ But the number of medical errors remains high. More recent studies have suggested that the IOM’s reported number of injuries may have been low.⁹ In 2013, one study suggested that 210,000 deaths annually were “associated with preventable harm” in hospitals. Because of how the data were gathered the authors estimated that the actual number of preventable deaths was closer to 400,000 annually. Serious harm to patients was estimated at 10 to 20 times the IOM rate.⁹

Therefore, a dramatic reduction in preventable medical errors does not appear to explain the reduction in malpractice claims. Some portion of it may be explained by malpractice reforms—see "The medical reform factor" section below.

The collective accountability factor

The way malpractice claims are paid (FIGURE 4),¹⁰ reported, and handled may explain some of the apparent reduction in overall paid claims. Perhaps the advent of “collective accountability,” in which patient care is rendered by teams and responsibility accepted at a team level, can alleviate a significant amount of individual physician medical malpractice claims.¹¹ This “enterprise liability” may shift the burden of medical error from physicians to health care organizations.¹² Collective accountability may, therefore, focus on institutional responsibility rather than individual physician negligence.^11,13 Institutions frequently hire multiple specialists and cover their medical malpractice costs as well as stand to be named in suits.

Continue to: The institutional involvement in malpractice cases also may affect...

The institutional involvement in malpractice cases also may affect apparent malpractice rates in another way. The National Practitioner Data Bank, which is the source of information for many malpractice studies, only requires reporting about individual physicians, not institutions.¹⁴ If, therefore, claims are settled on behalf of an institution, without implicating the physician, the number of physician malpractice cases may appear to decline without any real change in malpractice rates.¹⁴ In addition, institutions have taken the lead in informal resolution of injuries that occur in the institution, and these programs may reduce the direct malpractice claims against physicians. (These “disclosure, apology, and offer,” and similar programs, are discussed in the upcoming third part of this series.)

The medical reform factor

As noted, annual rates paid for medical malpractice in our specialty are trending downward. Many commentators look to malpractice reforms as the reason for the drop in malpractice rates.^15-17 Because medical malpractice is essentially a matter of state law, the medical malpractice reform has occurred primarily at the state level.¹⁸ There have been many different reforms tried—limits on expert witnesses, review panels, and a variety of procedural limitations.¹⁹ Perhaps the most effective reform has been caps being placed on noneconomic damages (generally pain and suffering).²⁰ These caps vary by state (FIGURE 5)^21,22 and, of course, affect the “big verdict” cases. (As we saw in the second case scenario above, Virginia is an example of a state with a cap on malpractice awards.) They also have the secondary effect of reducing the number of malpractice cases. They make malpractice cases less attractive to some attorneys because they reduce the opportunity of large contingency fees from large verdicts. (Virtually all medical malpractice cases in the United States are tried on a contingency-fee basis, meaning that the plaintiff does not pay the attorney handling the case but rather the attorney takes a percentage of any recovery—typically in the neighborhood of 35%.) The reform process continues, although, presently, there is less pressure to act on the malpractice crisis.

Medical malpractice cases are emotional and costly

Another reason for the relatively low rate of paid claims is that medical malpractice cases are difficult, emotionally challenging, time consuming, and expensive to pursue.²³ They typically drag on for years, require extensive and expensive expert consultants as well as witnesses, and face stiff defense (compared with many other torts). The settlement of medical malpractice cases, for example, is less likely than other kinds of personal injury cases.

The contingency-fee basis does mean that injured patients do not have to pay attorney fees up front; however, plaintiffs may have to pay substantial costs along the way. The other side of this coin is that lawyers can be reluctant to take malpractice cases in which the damages are likely to be small, or where the legal uncertainty reduces the odds of achieving any damages. Thus, many potential malpractice cases are never filed.

A word of caution

The news of a reduction in malpractice paid claims may not be permanent. The numbers can conceivably be cyclical, and political reforms achieved can be changed. In addition, new technology will likely bring new kinds of malpractice claims. That appears to be the case, for example, with electronic health records (EHRs). One insurer reports that EHR malpractice claims have increased over the last 8 years.²⁴ The most common injury in these claims was death (25%), as well as a magnitude of less serious injuries. EHR-related claims result from system failures, copy-paste inaccuracies, faulty drop-down menu use, and uncorrected “auto-populated” fields. Obstetrics is tied for fifth on the list of 14 specialties with claims related to EHRs, and gynecology is tied for eighth place.²⁴

Continue to: A federal court ruled that a hospital that changed from...

A federal court ruled that a hospital that changed from paper records to EHRs for test results had a duty to “‘implement a reasonable procedure during the transition phase’ to ensure the timely delivery of test results” to health care providers.²⁵ We will address this in a future “What’s the Verdict?”.

Rates of harm, malpractice cases, and the disposition of cases

There are many surprises when looking at medical malpractice claims data generally. The first surprise is how few claims are filed relative to the number of error-related injuries. Given the estimate of 210,000 to 400,000 deaths “associated with preventable harm” in hospitals, plus 10 to 20 times that number of serious injuries, it would be reasonable to expect claims of many hundreds of thousands per year. Compare the probability of a malpractice claim from an error-related injury, for example, with the probability of other personal injuries—eg, of traffic deaths associated with preventable harm.

The second key observation is how many of the claims filed are not successful—even when there was evidence in the record of errors associated with the injury. Studies slice the data in different ways but collectively suggest that only a small proportion of malpractice claims filed (a claim is generally regarded as some written demand for compensation for injuries) result in payments, either through settlement or by trial. A 2006 study by Studdert and colleagues determined that 63% of formal malpractice claims filed did involve injuries resulting from errors.²⁶ The study found that in 16% of the claims (not injuries) there was no payment even though there was error. In 10% of the claims there was payment, even in the absence of error.

Overall, in this study, 56% of the claims received some compensation.²⁶ That is higher than a more recent study by Jena and others, which found only 22% of claims resulted in compensation.³

How malpractice claims are decided is also interesting. Jena and colleagues found that only 55% of claims resulted in litigation.²⁷ Presumably, the other 45% may have resulted in the plaintiff dropping the case, or in some form of settlement. Of the claims that were litigated, 54% were dismissed by the court, and another 35% were settled before a trial verdict. The cases that went to trial (about 10%), overwhelmingly (80%) resulted in verdicts for the defense.^3,27 A different study found that only 9% of cases went to trial, and 87% were a defense verdict.²⁸ The high level of defense verdicts may suggest that malpractice defense lawyers, and their client physicians, do a good job of assessing cases they are likely to lose, and settling them before trial.

ObGyns generally have larger numbers of claims and among the largest payment amounts when there is payment. Fewer of their cases are dismissed by the courts, so more go to trial. At trial, however, ObGyns prevail at a remarkably high rate.²⁷ As for the probability of payment of a malpractice claim for ObGyns, one study suggested that there is approximately a 16% annual probability of a claim being filed, but only a 3% annual probability of a payment being made (suggesting about a 20% probability of payment per claim).³

Continue to: The purposes and effects of the medical malpractice system...

The purposes and effects of the medical malpractice system

The essential goals of tort law (including medical malpractice) include compensation for those who are injured and deterrence of future injuries (TABLE 2). What are the overall effects to the medical malpractice system? Unfortunately, the answer is that the law delivers disappointing results at best. It has a fairly high error rate. Many people who deserve some compensation for their injuries never seek compensation, and many deserving injured patients fail in efforts to receive compensation. At the same time, a few of the injured receive huge recoveries (even windfalls), and at least a small fraction receive compensation when there was no medical error. In addition to the high error rate, the system is inefficient and very expensive. Both defendants (through their insurance carriers) and plaintiffs spend a lot of money, years of time, and untold emotional pain dealing with these cases. The system also exacts high emotional and personal costs on plaintiffs and defendants.

Malpractice reform has not really addressed these issues—it has generally been focused on ways to reduce the cost of malpractice insurance. The most effective reform in reducing rates—caps—has had the effect of compensating the most seriously injured as though they were more modestly injured, and dissuading attorneys from taking the cases of those less seriously injured.

The medical and legal professions exist to help patients (the public). It does not seem that we have arrived at a system that does that very fairly or efficiently when a patient is injured because of preventable medical error.

Watch for the third and final article in this series next month, as we are going to look at “apology in medicine and a proactive response” to communication regarding a complication.

In this second in a series of 3 articles discussing medical malpractice and the ObGyn we look at the reasons for malpractice claims and liability, what happens to malpractice claims, and the direction and future of medical malpractice. The first article dealt with 2 sources of major malpractice damages: the “big verdict” and physicians with multiple malpractice paid claims. Next month we look at the place of apology in medicine, in cases in which error, including negligence, may have caused a patient injury.

CASE 1 Long-term brachial plexus injury

Right upper extremity injury occurs in the neonate at delivery with sequela of long-term brachial plexus injury (which is diagnosed around 6 months of age). Physical therapy and orthopedic assessment are rendered. Despite continued treatment, discrepancy in arm lengths (ie, affected side arm is noticeably shorter than opposite side) remains. The child cannot play basketball with his older brother and is the victim of ridicule, the plaintiff’s attorney emphasizes. He is unable to properly pronate or supinate the affected arm.

The defendant ObGyn maintains that there was “no shoulder dystocia [at delivery] and the shoulder did not get obstructed in the pelvis; shoulder was delivered 15 seconds after delivery of the head.” The nursing staff testifies that if shoulder dystocia had been the problem they would have launched upon a series of procedures to address such, in accord with the delivering obstetrician. The defense expert witness testifies that a brachial plexus injury can happen without shoulder dystocia.

A defense verdict is rendered by the Florida jury.¹
 

CASE 2 Shoulder dystocia

During delivery, the obstetrician notes a shoulder dystocia (“turtle sign”). After initial attempts to release the shoulder were unsuccessful, the physician applies traction several times to the head of the child, and the baby is delivered. There is permanent injury to the right brachial plexus. The defendant ObGyn says that traction was necessary to dislodge the shoulder, and that the injury was the result of the forces of labor (not the traction). The expert witness for the plaintiff testifies that the medical standard of care did not permit traction under these circumstances, and that the traction was the likely cause of the injury.

The Virginia jury awards $2.32 million in damages.²

Note: The above vignettes are drawn from actual cases but are only outlines of those cases and are not complete descriptions of the claims in the cases. Because the information comes from informal sources, not formal court records, the facts may be inaccurate and incomplete. They should be viewed as illustrations only.

The trend in malpractice

It has been clear for many years that medical malpractice claims are not randomly or evenly distributed among physicians. Notably, the variation among specialties has, and continues to be, substantial (FIGURE 1).³ Recent data suggest that, although paid claims per “1,000 physician-years” averages 14 paid claims per 1,000 physician years, it ranges from 4 or 5 in 1,000 (psychiatry and pediatrics) to 53 and 49 claims per 1,000 (neurology and plastic surgery, respectively). Obstetrics and gynecology has the fourth highest rate at 42.5 paid claims per 1,000 physician years.⁴ (These data are for the years 1992–2014.)

Continue to: The number of ObGyn paid malpractice claims has decreased over time...

The number of ObGyn paid malpractice claims has decreased over time. Although large verdicts and physicians with multiple paid malpractice claims receive a good deal of attention (as we noted in part 1 of our series), in fact, paid medical malpractice claims have trended downward in recent decades.⁵ When the data above are disaggregated by 5-year periods, for example, in obstetrics and gynecology, there has been a consistent reduction in paid malpractice claims from 1992 to 2014. Paid claims went from 58 per 1,000 physician-years in 1992–1996 to 25 per 1,000 in 2009–2014 (FIGURE 2).^4,6 In short, the rate dropped by half over approximately 20 years.⁴

It is reasonable to expect that such a decline in the cost of malpractice insurance premiums would follow. Robert L. Barbieri, MD, who practices in Boston, Massachusetts, in his excellent recent editorial in OBG Management⁶ reported that his professional liability insurance premiums decreased 18% from 2014 to 2019, and his colleague reported a 22% reduction during the same time period.⁶ An American Medical Association report of 7 states or metropolitan areas for 2008 to 2017 found considerable variance. The study looked at the rates and the trend of rates for malpractice insurance in several areas of the United States (FIGURE 3).⁷ For ObGyns, one of these jurisdictions experienced increased rates; in one other, rates stayed the same, and in 5 jurisdictions, the rates went down. The premiums varied across the country, however. In 2017, Los Angeles/Orange had an average rate of $49,804, and in Nassau and Suffolk counties, New York, the rate was $214,999. The median rate was approximately $170,000.⁷

Why have malpractice payouts declined overall?

Have medical errors declined?

It would be wonderful if the reduction in malpractice claims represented a significant decrease in medical errors. Attention to medical errors was driven by the first widely noticed study of medical error deaths. The Institute of Medicine (IOM) study in 2000, put the number of deaths annually at 44,000 to 98,000.⁸ There have been many efforts to reduce such errors, and it is possible that those efforts have indeed reduced errors somewhat.⁴ Barbieri provided a helpful digest of many of the error-reduction suggestions for ObGyn practice (TABLE 1).⁶ But the number of medical errors remains high. More recent studies have suggested that the IOM’s reported number of injuries may have been low.⁹ In 2013, one study suggested that 210,000 deaths annually were “associated with preventable harm” in hospitals. Because of how the data were gathered the authors estimated that the actual number of preventable deaths was closer to 400,000 annually. Serious harm to patients was estimated at 10 to 20 times the IOM rate.⁹

Therefore, a dramatic reduction in preventable medical errors does not appear to explain the reduction in malpractice claims. Some portion of it may be explained by malpractice reforms—see "The medical reform factor" section below.

The collective accountability factor

The way malpractice claims are paid (FIGURE 4),¹⁰ reported, and handled may explain some of the apparent reduction in overall paid claims. Perhaps the advent of “collective accountability,” in which patient care is rendered by teams and responsibility accepted at a team level, can alleviate a significant amount of individual physician medical malpractice claims.¹¹ This “enterprise liability” may shift the burden of medical error from physicians to health care organizations.¹² Collective accountability may, therefore, focus on institutional responsibility rather than individual physician negligence.^11,13 Institutions frequently hire multiple specialists and cover their medical malpractice costs as well as stand to be named in suits.

Continue to: The institutional involvement in malpractice cases also may affect...

The institutional involvement in malpractice cases also may affect apparent malpractice rates in another way. The National Practitioner Data Bank, which is the source of information for many malpractice studies, only requires reporting about individual physicians, not institutions.¹⁴ If, therefore, claims are settled on behalf of an institution, without implicating the physician, the number of physician malpractice cases may appear to decline without any real change in malpractice rates.¹⁴ In addition, institutions have taken the lead in informal resolution of injuries that occur in the institution, and these programs may reduce the direct malpractice claims against physicians. (These “disclosure, apology, and offer,” and similar programs, are discussed in the upcoming third part of this series.)

The medical reform factor

As noted, annual rates paid for medical malpractice in our specialty are trending downward. Many commentators look to malpractice reforms as the reason for the drop in malpractice rates.^15-17 Because medical malpractice is essentially a matter of state law, the medical malpractice reform has occurred primarily at the state level.¹⁸ There have been many different reforms tried—limits on expert witnesses, review panels, and a variety of procedural limitations.¹⁹ Perhaps the most effective reform has been caps being placed on noneconomic damages (generally pain and suffering).²⁰ These caps vary by state (FIGURE 5)^21,22 and, of course, affect the “big verdict” cases. (As we saw in the second case scenario above, Virginia is an example of a state with a cap on malpractice awards.) They also have the secondary effect of reducing the number of malpractice cases. They make malpractice cases less attractive to some attorneys because they reduce the opportunity of large contingency fees from large verdicts. (Virtually all medical malpractice cases in the United States are tried on a contingency-fee basis, meaning that the plaintiff does not pay the attorney handling the case but rather the attorney takes a percentage of any recovery—typically in the neighborhood of 35%.) The reform process continues, although, presently, there is less pressure to act on the malpractice crisis.

Medical malpractice cases are emotional and costly

Another reason for the relatively low rate of paid claims is that medical malpractice cases are difficult, emotionally challenging, time consuming, and expensive to pursue.²³ They typically drag on for years, require extensive and expensive expert consultants as well as witnesses, and face stiff defense (compared with many other torts). The settlement of medical malpractice cases, for example, is less likely than other kinds of personal injury cases.

The contingency-fee basis does mean that injured patients do not have to pay attorney fees up front; however, plaintiffs may have to pay substantial costs along the way. The other side of this coin is that lawyers can be reluctant to take malpractice cases in which the damages are likely to be small, or where the legal uncertainty reduces the odds of achieving any damages. Thus, many potential malpractice cases are never filed.

A word of caution

The news of a reduction in malpractice paid claims may not be permanent. The numbers can conceivably be cyclical, and political reforms achieved can be changed. In addition, new technology will likely bring new kinds of malpractice claims. That appears to be the case, for example, with electronic health records (EHRs). One insurer reports that EHR malpractice claims have increased over the last 8 years.²⁴ The most common injury in these claims was death (25%), as well as a magnitude of less serious injuries. EHR-related claims result from system failures, copy-paste inaccuracies, faulty drop-down menu use, and uncorrected “auto-populated” fields. Obstetrics is tied for fifth on the list of 14 specialties with claims related to EHRs, and gynecology is tied for eighth place.²⁴

Continue to: A federal court ruled that a hospital that changed from...

A federal court ruled that a hospital that changed from paper records to EHRs for test results had a duty to “‘implement a reasonable procedure during the transition phase’ to ensure the timely delivery of test results” to health care providers.²⁵ We will address this in a future “What’s the Verdict?”.

Rates of harm, malpractice cases, and the disposition of cases

There are many surprises when looking at medical malpractice claims data generally. The first surprise is how few claims are filed relative to the number of error-related injuries. Given the estimate of 210,000 to 400,000 deaths “associated with preventable harm” in hospitals, plus 10 to 20 times that number of serious injuries, it would be reasonable to expect claims of many hundreds of thousands per year. Compare the probability of a malpractice claim from an error-related injury, for example, with the probability of other personal injuries—eg, of traffic deaths associated with preventable harm.

The second key observation is how many of the claims filed are not successful—even when there was evidence in the record of errors associated with the injury. Studies slice the data in different ways but collectively suggest that only a small proportion of malpractice claims filed (a claim is generally regarded as some written demand for compensation for injuries) result in payments, either through settlement or by trial. A 2006 study by Studdert and colleagues determined that 63% of formal malpractice claims filed did involve injuries resulting from errors.²⁶ The study found that in 16% of the claims (not injuries) there was no payment even though there was error. In 10% of the claims there was payment, even in the absence of error.

Overall, in this study, 56% of the claims received some compensation.²⁶ That is higher than a more recent study by Jena and others, which found only 22% of claims resulted in compensation.³

How malpractice claims are decided is also interesting. Jena and colleagues found that only 55% of claims resulted in litigation.²⁷ Presumably, the other 45% may have resulted in the plaintiff dropping the case, or in some form of settlement. Of the claims that were litigated, 54% were dismissed by the court, and another 35% were settled before a trial verdict. The cases that went to trial (about 10%), overwhelmingly (80%) resulted in verdicts for the defense.^3,27 A different study found that only 9% of cases went to trial, and 87% were a defense verdict.²⁸ The high level of defense verdicts may suggest that malpractice defense lawyers, and their client physicians, do a good job of assessing cases they are likely to lose, and settling them before trial.

ObGyns generally have larger numbers of claims and among the largest payment amounts when there is payment. Fewer of their cases are dismissed by the courts, so more go to trial. At trial, however, ObGyns prevail at a remarkably high rate.²⁷ As for the probability of payment of a malpractice claim for ObGyns, one study suggested that there is approximately a 16% annual probability of a claim being filed, but only a 3% annual probability of a payment being made (suggesting about a 20% probability of payment per claim).³

Continue to: The purposes and effects of the medical malpractice system...

The purposes and effects of the medical malpractice system

The essential goals of tort law (including medical malpractice) include compensation for those who are injured and deterrence of future injuries (TABLE 2). What are the overall effects to the medical malpractice system? Unfortunately, the answer is that the law delivers disappointing results at best. It has a fairly high error rate. Many people who deserve some compensation for their injuries never seek compensation, and many deserving injured patients fail in efforts to receive compensation. At the same time, a few of the injured receive huge recoveries (even windfalls), and at least a small fraction receive compensation when there was no medical error. In addition to the high error rate, the system is inefficient and very expensive. Both defendants (through their insurance carriers) and plaintiffs spend a lot of money, years of time, and untold emotional pain dealing with these cases. The system also exacts high emotional and personal costs on plaintiffs and defendants.

Malpractice reform has not really addressed these issues—it has generally been focused on ways to reduce the cost of malpractice insurance. The most effective reform in reducing rates—caps—has had the effect of compensating the most seriously injured as though they were more modestly injured, and dissuading attorneys from taking the cases of those less seriously injured.

The medical and legal professions exist to help patients (the public). It does not seem that we have arrived at a system that does that very fairly or efficiently when a patient is injured because of preventable medical error.

Watch for the third and final article in this series next month, as we are going to look at “apology in medicine and a proactive response” to communication regarding a complication.

In this second in a series of 3 articles discussing medical malpractice and the ObGyn we look at the reasons for malpractice claims and liability, what happens to malpractice claims, and the direction and future of medical malpractice. The first article dealt with 2 sources of major malpractice damages: the “big verdict” and physicians with multiple malpractice paid claims. Next month we look at the place of apology in medicine, in cases in which error, including negligence, may have caused a patient injury.

CASE 1 Long-term brachial plexus injury

Right upper extremity injury occurs in the neonate at delivery with sequela of long-term brachial plexus injury (which is diagnosed around 6 months of age). Physical therapy and orthopedic assessment are rendered. Despite continued treatment, discrepancy in arm lengths (ie, affected side arm is noticeably shorter than opposite side) remains. The child cannot play basketball with his older brother and is the victim of ridicule, the plaintiff’s attorney emphasizes. He is unable to properly pronate or supinate the affected arm.

The defendant ObGyn maintains that there was “no shoulder dystocia [at delivery] and the shoulder did not get obstructed in the pelvis; shoulder was delivered 15 seconds after delivery of the head.” The nursing staff testifies that if shoulder dystocia had been the problem they would have launched upon a series of procedures to address such, in accord with the delivering obstetrician. The defense expert witness testifies that a brachial plexus injury can happen without shoulder dystocia.

A defense verdict is rendered by the Florida jury.¹
 

CASE 2 Shoulder dystocia

During delivery, the obstetrician notes a shoulder dystocia (“turtle sign”). After initial attempts to release the shoulder were unsuccessful, the physician applies traction several times to the head of the child, and the baby is delivered. There is permanent injury to the right brachial plexus. The defendant ObGyn says that traction was necessary to dislodge the shoulder, and that the injury was the result of the forces of labor (not the traction). The expert witness for the plaintiff testifies that the medical standard of care did not permit traction under these circumstances, and that the traction was the likely cause of the injury.

The Virginia jury awards $2.32 million in damages.²

Note: The above vignettes are drawn from actual cases but are only outlines of those cases and are not complete descriptions of the claims in the cases. Because the information comes from informal sources, not formal court records, the facts may be inaccurate and incomplete. They should be viewed as illustrations only.

The trend in malpractice

It has been clear for many years that medical malpractice claims are not randomly or evenly distributed among physicians. Notably, the variation among specialties has, and continues to be, substantial (FIGURE 1).³ Recent data suggest that, although paid claims per “1,000 physician-years” averages 14 paid claims per 1,000 physician years, it ranges from 4 or 5 in 1,000 (psychiatry and pediatrics) to 53 and 49 claims per 1,000 (neurology and plastic surgery, respectively). Obstetrics and gynecology has the fourth highest rate at 42.5 paid claims per 1,000 physician years.⁴ (These data are for the years 1992–2014.)

Continue to: The number of ObGyn paid malpractice claims has decreased over time...

The number of ObGyn paid malpractice claims has decreased over time. Although large verdicts and physicians with multiple paid malpractice claims receive a good deal of attention (as we noted in part 1 of our series), in fact, paid medical malpractice claims have trended downward in recent decades.⁵ When the data above are disaggregated by 5-year periods, for example, in obstetrics and gynecology, there has been a consistent reduction in paid malpractice claims from 1992 to 2014. Paid claims went from 58 per 1,000 physician-years in 1992–1996 to 25 per 1,000 in 2009–2014 (FIGURE 2).^4,6 In short, the rate dropped by half over approximately 20 years.⁴

It is reasonable to expect that such a decline in the cost of malpractice insurance premiums would follow. Robert L. Barbieri, MD, who practices in Boston, Massachusetts, in his excellent recent editorial in OBG Management⁶ reported that his professional liability insurance premiums decreased 18% from 2014 to 2019, and his colleague reported a 22% reduction during the same time period.⁶ An American Medical Association report of 7 states or metropolitan areas for 2008 to 2017 found considerable variance. The study looked at the rates and the trend of rates for malpractice insurance in several areas of the United States (FIGURE 3).⁷ For ObGyns, one of these jurisdictions experienced increased rates; in one other, rates stayed the same, and in 5 jurisdictions, the rates went down. The premiums varied across the country, however. In 2017, Los Angeles/Orange had an average rate of $49,804, and in Nassau and Suffolk counties, New York, the rate was $214,999. The median rate was approximately $170,000.⁷

Why have malpractice payouts declined overall?

Have medical errors declined?

It would be wonderful if the reduction in malpractice claims represented a significant decrease in medical errors. Attention to medical errors was driven by the first widely noticed study of medical error deaths. The Institute of Medicine (IOM) study in 2000, put the number of deaths annually at 44,000 to 98,000.⁸ There have been many efforts to reduce such errors, and it is possible that those efforts have indeed reduced errors somewhat.⁴ Barbieri provided a helpful digest of many of the error-reduction suggestions for ObGyn practice (TABLE 1).⁶ But the number of medical errors remains high. More recent studies have suggested that the IOM’s reported number of injuries may have been low.⁹ In 2013, one study suggested that 210,000 deaths annually were “associated with preventable harm” in hospitals. Because of how the data were gathered the authors estimated that the actual number of preventable deaths was closer to 400,000 annually. Serious harm to patients was estimated at 10 to 20 times the IOM rate.⁹

Therefore, a dramatic reduction in preventable medical errors does not appear to explain the reduction in malpractice claims. Some portion of it may be explained by malpractice reforms—see "The medical reform factor" section below.

The collective accountability factor

The way malpractice claims are paid (FIGURE 4),¹⁰ reported, and handled may explain some of the apparent reduction in overall paid claims. Perhaps the advent of “collective accountability,” in which patient care is rendered by teams and responsibility accepted at a team level, can alleviate a significant amount of individual physician medical malpractice claims.¹¹ This “enterprise liability” may shift the burden of medical error from physicians to health care organizations.¹² Collective accountability may, therefore, focus on institutional responsibility rather than individual physician negligence.^11,13 Institutions frequently hire multiple specialists and cover their medical malpractice costs as well as stand to be named in suits.

Continue to: The institutional involvement in malpractice cases also may affect...

The institutional involvement in malpractice cases also may affect apparent malpractice rates in another way. The National Practitioner Data Bank, which is the source of information for many malpractice studies, only requires reporting about individual physicians, not institutions.¹⁴ If, therefore, claims are settled on behalf of an institution, without implicating the physician, the number of physician malpractice cases may appear to decline without any real change in malpractice rates.¹⁴ In addition, institutions have taken the lead in informal resolution of injuries that occur in the institution, and these programs may reduce the direct malpractice claims against physicians. (These “disclosure, apology, and offer,” and similar programs, are discussed in the upcoming third part of this series.)

The medical reform factor

As noted, annual rates paid for medical malpractice in our specialty are trending downward. Many commentators look to malpractice reforms as the reason for the drop in malpractice rates.^15-17 Because medical malpractice is essentially a matter of state law, the medical malpractice reform has occurred primarily at the state level.¹⁸ There have been many different reforms tried—limits on expert witnesses, review panels, and a variety of procedural limitations.¹⁹ Perhaps the most effective reform has been caps being placed on noneconomic damages (generally pain and suffering).²⁰ These caps vary by state (FIGURE 5)^21,22 and, of course, affect the “big verdict” cases. (As we saw in the second case scenario above, Virginia is an example of a state with a cap on malpractice awards.) They also have the secondary effect of reducing the number of malpractice cases. They make malpractice cases less attractive to some attorneys because they reduce the opportunity of large contingency fees from large verdicts. (Virtually all medical malpractice cases in the United States are tried on a contingency-fee basis, meaning that the plaintiff does not pay the attorney handling the case but rather the attorney takes a percentage of any recovery—typically in the neighborhood of 35%.) The reform process continues, although, presently, there is less pressure to act on the malpractice crisis.

Medical malpractice cases are emotional and costly

Another reason for the relatively low rate of paid claims is that medical malpractice cases are difficult, emotionally challenging, time consuming, and expensive to pursue.²³ They typically drag on for years, require extensive and expensive expert consultants as well as witnesses, and face stiff defense (compared with many other torts). The settlement of medical malpractice cases, for example, is less likely than other kinds of personal injury cases.

The contingency-fee basis does mean that injured patients do not have to pay attorney fees up front; however, plaintiffs may have to pay substantial costs along the way. The other side of this coin is that lawyers can be reluctant to take malpractice cases in which the damages are likely to be small, or where the legal uncertainty reduces the odds of achieving any damages. Thus, many potential malpractice cases are never filed.

A word of caution

The news of a reduction in malpractice paid claims may not be permanent. The numbers can conceivably be cyclical, and political reforms achieved can be changed. In addition, new technology will likely bring new kinds of malpractice claims. That appears to be the case, for example, with electronic health records (EHRs). One insurer reports that EHR malpractice claims have increased over the last 8 years.²⁴ The most common injury in these claims was death (25%), as well as a magnitude of less serious injuries. EHR-related claims result from system failures, copy-paste inaccuracies, faulty drop-down menu use, and uncorrected “auto-populated” fields. Obstetrics is tied for fifth on the list of 14 specialties with claims related to EHRs, and gynecology is tied for eighth place.²⁴

Continue to: A federal court ruled that a hospital that changed from...

A federal court ruled that a hospital that changed from paper records to EHRs for test results had a duty to “‘implement a reasonable procedure during the transition phase’ to ensure the timely delivery of test results” to health care providers.²⁵ We will address this in a future “What’s the Verdict?”.

Rates of harm, malpractice cases, and the disposition of cases

There are many surprises when looking at medical malpractice claims data generally. The first surprise is how few claims are filed relative to the number of error-related injuries. Given the estimate of 210,000 to 400,000 deaths “associated with preventable harm” in hospitals, plus 10 to 20 times that number of serious injuries, it would be reasonable to expect claims of many hundreds of thousands per year. Compare the probability of a malpractice claim from an error-related injury, for example, with the probability of other personal injuries—eg, of traffic deaths associated with preventable harm.

The second key observation is how many of the claims filed are not successful—even when there was evidence in the record of errors associated with the injury. Studies slice the data in different ways but collectively suggest that only a small proportion of malpractice claims filed (a claim is generally regarded as some written demand for compensation for injuries) result in payments, either through settlement or by trial. A 2006 study by Studdert and colleagues determined that 63% of formal malpractice claims filed did involve injuries resulting from errors.²⁶ The study found that in 16% of the claims (not injuries) there was no payment even though there was error. In 10% of the claims there was payment, even in the absence of error.

Overall, in this study, 56% of the claims received some compensation.²⁶ That is higher than a more recent study by Jena and others, which found only 22% of claims resulted in compensation.³

How malpractice claims are decided is also interesting. Jena and colleagues found that only 55% of claims resulted in litigation.²⁷ Presumably, the other 45% may have resulted in the plaintiff dropping the case, or in some form of settlement. Of the claims that were litigated, 54% were dismissed by the court, and another 35% were settled before a trial verdict. The cases that went to trial (about 10%), overwhelmingly (80%) resulted in verdicts for the defense.^3,27 A different study found that only 9% of cases went to trial, and 87% were a defense verdict.²⁸ The high level of defense verdicts may suggest that malpractice defense lawyers, and their client physicians, do a good job of assessing cases they are likely to lose, and settling them before trial.

ObGyns generally have larger numbers of claims and among the largest payment amounts when there is payment. Fewer of their cases are dismissed by the courts, so more go to trial. At trial, however, ObGyns prevail at a remarkably high rate.²⁷ As for the probability of payment of a malpractice claim for ObGyns, one study suggested that there is approximately a 16% annual probability of a claim being filed, but only a 3% annual probability of a payment being made (suggesting about a 20% probability of payment per claim).³

Continue to: The purposes and effects of the medical malpractice system...

The purposes and effects of the medical malpractice system

The essential goals of tort law (including medical malpractice) include compensation for those who are injured and deterrence of future injuries (TABLE 2). What are the overall effects to the medical malpractice system? Unfortunately, the answer is that the law delivers disappointing results at best. It has a fairly high error rate. Many people who deserve some compensation for their injuries never seek compensation, and many deserving injured patients fail in efforts to receive compensation. At the same time, a few of the injured receive huge recoveries (even windfalls), and at least a small fraction receive compensation when there was no medical error. In addition to the high error rate, the system is inefficient and very expensive. Both defendants (through their insurance carriers) and plaintiffs spend a lot of money, years of time, and untold emotional pain dealing with these cases. The system also exacts high emotional and personal costs on plaintiffs and defendants.

Malpractice reform has not really addressed these issues—it has generally been focused on ways to reduce the cost of malpractice insurance. The most effective reform in reducing rates—caps—has had the effect of compensating the most seriously injured as though they were more modestly injured, and dissuading attorneys from taking the cases of those less seriously injured.

The medical and legal professions exist to help patients (the public). It does not seem that we have arrived at a system that does that very fairly or efficiently when a patient is injured because of preventable medical error.

Watch for the third and final article in this series next month, as we are going to look at “apology in medicine and a proactive response” to communication regarding a complication.

Over the years, there has been growing concern about the relationship between physicians and pharmaceutical companies. Many studies have demonstrated that pharmaceutical interactions and incentives can influence physicians’ prescribing habits.^1-3 As a result, many academic centers have adopted policies that attempt to limit the pharmaceutical industry’s influence on faculty and in-training physicians. Although these policies can vary greatly, they generally limit access of pharmaceutical representatives to providers and restrict pharmaceutical samples.^4,5 This policy shift has even been reported in private practice.⁶

At the heart of the matter is the question: What really influences physicians to write a prescription for a particular medication? Is it cost, efficacy, or representatives pushing a product? Prior studies illustrate that generic medications are equivalent to their brand-name counterparts. In fact, current regulations require no more than 5% to 7% difference in bioequivalence.^7-9 Although most generic medications are bioequivalent, it may not be universal.¹⁰

Garrison and Levin¹¹ distributed a survey to US-based prescribers in family practice, psychiatry, and internal medicine and found that prescribers deemed patient response and success as the highest priority when determining which drugs to prescribe. In contrast, drug representatives and free samples only slightly contributed.¹¹ Considering the minimum duration for efficacy of a medication such as an antidepressant vs a topical steroid, this pattern may differ with samples in dermatologic settings. Interestingly, another survey concluded that samples were associated with “sticky” prescribing habits, noting that physicians would prescribe a brand-name medication after using a sample, despite increased cost to the patient.¹² Further, it has been suggested that recipients of free samples may experience increased costs in the long run, which contrasts a stated goal of affordability to patients.^12,13

Physician interaction with pharmaceutical companies begins as early as medical school,¹⁴ with physicians reporting interactions as often as 4 times each month.^14-18 Interactions can include meetings with pharmaceutical representatives, sponsored meals, gifts, continuing medical education sponsorship, funding for travel, pharmaceutical representative speakers, research funding, and drug samples.³

A 2014 study reported that prescribing habits are influenced by the free drug samples provided by nongeneric pharmaceutical companies.¹⁹ Nationally, the number of brand-name and branded generic medications constitute 79% of prescriptions, yet together they only comprise 17% of medications prescribed at an academic medical clinic that does not provide samples. The number of medications with samples being prescribed by dermatologists increased by 15% over 9 years, which may correlate with the wider availability of medication samples, more specifically an increase in branded generic samples.¹⁹ This potential interaction is the reason why institutions question the current influence of pharmaceutical companies. Samples may appear convenient, allowing a patient to test the medication prior to committing; however, with brand-name samples being provided to the physician, he/she may become more inclined to prescribe the branded medication.^12,15,19-22 Because brand-name medications are more expensive than generic medications, this practice can increase the cost of health care.¹³ One study found that over 1 year, the overuse of nongeneric medications led to a loss of potential savings throughout 49 states, equating to $229 million just through Medicaid; interestingly, it was noted that in some states, a maximum reimbursement is set by Medicaid, regardless of whether the generic or branded medication is dispensed. The authors also noted variability in the potential savings by state, which may be a function of the state-by-state maximum reimbursements for certain medications.²³ Another study on oral combination medications estimated Medicare spending on branded drugs relative to the cost if generic combinations had been purchased instead. This study examined branded medications for which the active components were available as over-the-counter (OTC), generic, or same-class generic, and the authors estimated that $925 million could have been saved in 2016 by purchasing a generic substitute.²⁴ The overuse of nongeneric medications when generic alternatives are available becomes an issue that not only financially impacts patients but all taxpayers. However, this pattern may differ if limited only to dermatologic medications, which was not the focus of the prior studies.

To limit conflicts of interest in interactions with the pharmaceutical, medical device, and biotechnology industries, the University of South Florida (USF) Morsani College of Medicine (COM)(Tampa, Florida) implemented its own set of regulations that eliminated in-office pharmaceutical samples, in addition to other restrictions. This study aimed to investigate if there was a change in the prescribing habits of academic dermatologists after their medical school implemented these new policies.

We hypothesized that the number of brand-name drugs prescribed by physicians in the Department of Dermatology & Cutaneous Surgery would change following USF Morsani COM pharmaceutical policy changes. We sought to determine how physician prescribing practices within the Department of Dermatology & Cutaneous Surgery changed following USF Morsani COM pharmaceutical policy changes.

Methods

Data Collection
A retrospective review of medical records was conducted to investigate the effect of the USF Morsani COM pharmaceutical policy changes on physician prescribing practices within the Department of Dermatology & Cutaneous Surgery. Medical records of patients seen for common dermatology diagnoses before (January 1, 2010, to May 30, 2010) and after (August 1, 2011, to December 31, 2011) the pharmaceutical policy changes were reviewed, and all medications prescribed were recorded. Data were collected from medical records within the USF Health electronic medical record system and included visits with each of the department’s 3 attending dermatologists. The diagnoses included in the study—acne vulgaris, atopic dermatitis, onychomycosis, psoriasis, and rosacea—were chosen because in-office samples were available. Prescribing data from the first 100 consecutive medical records were collected from each time period, and a medical record was included only if it contained at least 1 of the following diagnoses: acne vulgaris, atopic dermatitis, onychomycosis, psoriasis, or rosacea. The assessment and plan of each progress note were reviewed, and the exact medication name and associated diagnosis were recorded for each prescription. Subsequently, each medication was reviewed and placed in 1 of 3 categories: brand name, generic, and OTC. The total number of prescriptions for each diagnosis (per visit/note); the specific number of brand, generic, and OTC medications prescribed (per visit/note); and the percentage of brand, generic, and OTC medications prescribed (per visit/note and per diagnosis in total) were calculated. To ensure only intended medications were included, each medication recorded in the medical record note was cross-referenced with the prescribed medication in the electronic medical record. The primary objective of this study was to capture the prescribing physician’s intent as proxied by the pattern of prescription. Thus, changes made in prescriptions after the initial plan—whether insurance related or otherwise—were not relevant to this investigation.

The data were collected to compare the percentage of brand vs generic or OTC prescriptions per diagnosis to see if there was a difference in the prescribing habits before and after the pharmaceutical policy changes. Of note, several other pieces of data were collected from each medical record, including age, race, class of insurance (ie, Medicare, Medicaid, private health maintenance organization, private preferred provider organization), subtype diagnoses, and whether the prescription was new or a refill. The information gathered from the written record on the assessment and plan was verified using prescriptions ordered in the Allscripts electronic record, and any difference was noted. No identifying information that could be used to easily identify study participants was recorded.

Differences in prescribing habits across diagnoses before and after the policy changes were ascertained using a Fisher exact test and were further assessed using a mixed effects ordinal logistic regression model that accounted for within-provider clustering and baseline patient characteristics. An ordinal model was chosen to recognize differences in average cost among brand-name, generic, and OTC medications.

Results

In total, 200 medical records were collected. For the period analyzed before the policy change, 252 brand-name medications were prescribed compared to 231 prescribed for the period analyzed after the policy changes. There was insufficient evidence of an overall difference in brand-name medications prescribed before and after the policy changes (P=.145; Fisher exact test)(Table 1). There also was insufficient evidence of an overall difference in generic prescriptions, which totaled 153 before and 134 after the policy changes (P=.872; Fisher exact test)(Table 2). Over-the-counter prescriptions totaled 49 before and 69 after the policy changes. There was insufficient evidence of an overall difference before and after the policy changes for OTC medications (P=.192; Fisher exact test)(Table 3).

The mixed effects ordinal logistic regression model for the dependent variable—prescription type (branded, generic, or OTC)—showed an odds ratio (OR) of 1.27 for prescribing habits before and after the policy changes (OR, 1.27; 95% confidence interval, 0.97-1.67; P=.08) after accounting for provider and baseline characteristics. Despite the P value exceeding the predefined significance level, the confidence interval suggests anywhere from a 3% decrease, no change, and up to a 67% increase in postpolicy odds relative to the prepolicy odds, with a point estimate of a 27% increase in postpolicy odds over prepolicy odds. As an observational study, this suggests moderate evidence of a change based on the odds after the policy change relative to the odds before implementation (Figure).

Comment

Although some medical institutions are diligently working to limit the potential influence pharmaceutical companies have on physician prescribing habits,^4,5,25 the effect on physician prescribing habits is only now being established.¹⁵ Prior studies^12,19,21 have found evidence that medication samples may lead to overuse of brand-name medications, but these findings do not hold true for the USF dermatologists included in this study, perhaps due to the difference in pharmaceutical company interactions or physicians maintaining prior prescription habits that were unrelated to the policy. Although this study focused on policy changes for in-office samples, prior studies either included other forms of interaction²¹ or did not include samples.²²

Pharmaceutical samples allow patients to try a medication before committing to a long-term course of treatment with a particular medication, which has utility for physicians and patients. Although brand-name prescriptions may cost more, a trial period may assist the patient in deciding whether the medication is worth purchasing. Furthermore, physicians may feel more comfortable prescribing a medication once the individual patient has demonstrated a benefit from the sample, which may be particularly true in a specialty such as dermatology in which many branded topical medications contain a different vehicle than generic formulations, resulting in notable variations in active medication delivery and efficacy. Given the higher cost of branded topical medications, proving efficacy in patients through samples can provide a useful tool to the physician to determine the need for a branded formulation.

The benefits described are subjective but should not be disregarded. Although Hurley et al¹⁹ found that the number of brand-name medications prescribed increases as more samples are given out, our study demonstrated that after eliminating medication samples, there was no significant difference in the percentage of brand-name medications prescribed compared to generic and OTC medications.

Physician education concerning the price of each brand-name medication prescribed in office may be one method of reducing the amount of such prescriptions. Physicians generally are uninformed of the cost of the medications being prescribed²⁶ and may not recognize the financial burden one medication may have compared to its alternative. However, educating physicians will empower them to make the conscious decision to prefer or not prefer a brand-name medication. With some generic medications shown to have a difference in bioequivalence compared to their brand-name counterparts, a physician may find more success prescribing the brand-name medications, regardless of pharmaceutical company influence, which is an alternative solution to policy changes that eliminate samples entirely. Although this study found insufficient evidence that removing samples decreases brand-name medication prescriptions, it is imperative that solutions are established to reduce the country’s increasing burden of medical costs.

Possible shortfalls of this study include the short period of time between which prepolicy data and postpolicy data were collected. It is possible that providers did not have enough time to adjust their prescribing habits or that providers would not have changed a prescribing pattern or preference simply because of a policy change. Future studies could allow a time period greater than 2 years to compare prepolicy and postpolicy prescribing habits, or a future study might make comparisons of prescriber patterns at different institutions that have different policies. Another possible shortfall is that providers and patients were limited to those at the Department of Dermatology & Cutaneous Surgery at the USF Morsani COM. Although this study has found insufficient evidence of a difference in prescribing habits, it may be beneficial to conduct a larger study that encompasses multiple academic institutions with similar policy changes. Most importantly, this study only investigated the influence of in-office pharmaceutical samples on prescribing patterns. This study did not look at the many other ways in which providers may be influenced by pharmaceutical companies, which likely is a significant confounding variable in this study. Continued additional studies that specifically examine other methods through which providers may be influenced would be helpful in further examining the many ways in which physician prescription habits are influenced.

Conclusion

Changes in pharmaceutical policy in 2011 at USF Morsani COM specifically banned in-office samples. The totality of evidence in this study shows modest observational evidence of a change in the postpolicy odds relative to prepolicy odds, but the data also are compatible with no change between prescribing habits before and after the policy changes. Further study is needed to fully understand this relationship.

Over the years, there has been growing concern about the relationship between physicians and pharmaceutical companies. Many studies have demonstrated that pharmaceutical interactions and incentives can influence physicians’ prescribing habits.^1-3 As a result, many academic centers have adopted policies that attempt to limit the pharmaceutical industry’s influence on faculty and in-training physicians. Although these policies can vary greatly, they generally limit access of pharmaceutical representatives to providers and restrict pharmaceutical samples.^4,5 This policy shift has even been reported in private practice.⁶

At the heart of the matter is the question: What really influences physicians to write a prescription for a particular medication? Is it cost, efficacy, or representatives pushing a product? Prior studies illustrate that generic medications are equivalent to their brand-name counterparts. In fact, current regulations require no more than 5% to 7% difference in bioequivalence.^7-9 Although most generic medications are bioequivalent, it may not be universal.¹⁰

Garrison and Levin¹¹ distributed a survey to US-based prescribers in family practice, psychiatry, and internal medicine and found that prescribers deemed patient response and success as the highest priority when determining which drugs to prescribe. In contrast, drug representatives and free samples only slightly contributed.¹¹ Considering the minimum duration for efficacy of a medication such as an antidepressant vs a topical steroid, this pattern may differ with samples in dermatologic settings. Interestingly, another survey concluded that samples were associated with “sticky” prescribing habits, noting that physicians would prescribe a brand-name medication after using a sample, despite increased cost to the patient.¹² Further, it has been suggested that recipients of free samples may experience increased costs in the long run, which contrasts a stated goal of affordability to patients.^12,13

Physician interaction with pharmaceutical companies begins as early as medical school,¹⁴ with physicians reporting interactions as often as 4 times each month.^14-18 Interactions can include meetings with pharmaceutical representatives, sponsored meals, gifts, continuing medical education sponsorship, funding for travel, pharmaceutical representative speakers, research funding, and drug samples.³

A 2014 study reported that prescribing habits are influenced by the free drug samples provided by nongeneric pharmaceutical companies.¹⁹ Nationally, the number of brand-name and branded generic medications constitute 79% of prescriptions, yet together they only comprise 17% of medications prescribed at an academic medical clinic that does not provide samples. The number of medications with samples being prescribed by dermatologists increased by 15% over 9 years, which may correlate with the wider availability of medication samples, more specifically an increase in branded generic samples.¹⁹ This potential interaction is the reason why institutions question the current influence of pharmaceutical companies. Samples may appear convenient, allowing a patient to test the medication prior to committing; however, with brand-name samples being provided to the physician, he/she may become more inclined to prescribe the branded medication.^12,15,19-22 Because brand-name medications are more expensive than generic medications, this practice can increase the cost of health care.¹³ One study found that over 1 year, the overuse of nongeneric medications led to a loss of potential savings throughout 49 states, equating to $229 million just through Medicaid; interestingly, it was noted that in some states, a maximum reimbursement is set by Medicaid, regardless of whether the generic or branded medication is dispensed. The authors also noted variability in the potential savings by state, which may be a function of the state-by-state maximum reimbursements for certain medications.²³ Another study on oral combination medications estimated Medicare spending on branded drugs relative to the cost if generic combinations had been purchased instead. This study examined branded medications for which the active components were available as over-the-counter (OTC), generic, or same-class generic, and the authors estimated that $925 million could have been saved in 2016 by purchasing a generic substitute.²⁴ The overuse of nongeneric medications when generic alternatives are available becomes an issue that not only financially impacts patients but all taxpayers. However, this pattern may differ if limited only to dermatologic medications, which was not the focus of the prior studies.

To limit conflicts of interest in interactions with the pharmaceutical, medical device, and biotechnology industries, the University of South Florida (USF) Morsani College of Medicine (COM)(Tampa, Florida) implemented its own set of regulations that eliminated in-office pharmaceutical samples, in addition to other restrictions. This study aimed to investigate if there was a change in the prescribing habits of academic dermatologists after their medical school implemented these new policies.

We hypothesized that the number of brand-name drugs prescribed by physicians in the Department of Dermatology & Cutaneous Surgery would change following USF Morsani COM pharmaceutical policy changes. We sought to determine how physician prescribing practices within the Department of Dermatology & Cutaneous Surgery changed following USF Morsani COM pharmaceutical policy changes.

Methods

Data Collection
A retrospective review of medical records was conducted to investigate the effect of the USF Morsani COM pharmaceutical policy changes on physician prescribing practices within the Department of Dermatology & Cutaneous Surgery. Medical records of patients seen for common dermatology diagnoses before (January 1, 2010, to May 30, 2010) and after (August 1, 2011, to December 31, 2011) the pharmaceutical policy changes were reviewed, and all medications prescribed were recorded. Data were collected from medical records within the USF Health electronic medical record system and included visits with each of the department’s 3 attending dermatologists. The diagnoses included in the study—acne vulgaris, atopic dermatitis, onychomycosis, psoriasis, and rosacea—were chosen because in-office samples were available. Prescribing data from the first 100 consecutive medical records were collected from each time period, and a medical record was included only if it contained at least 1 of the following diagnoses: acne vulgaris, atopic dermatitis, onychomycosis, psoriasis, or rosacea. The assessment and plan of each progress note were reviewed, and the exact medication name and associated diagnosis were recorded for each prescription. Subsequently, each medication was reviewed and placed in 1 of 3 categories: brand name, generic, and OTC. The total number of prescriptions for each diagnosis (per visit/note); the specific number of brand, generic, and OTC medications prescribed (per visit/note); and the percentage of brand, generic, and OTC medications prescribed (per visit/note and per diagnosis in total) were calculated. To ensure only intended medications were included, each medication recorded in the medical record note was cross-referenced with the prescribed medication in the electronic medical record. The primary objective of this study was to capture the prescribing physician’s intent as proxied by the pattern of prescription. Thus, changes made in prescriptions after the initial plan—whether insurance related or otherwise—were not relevant to this investigation.

The data were collected to compare the percentage of brand vs generic or OTC prescriptions per diagnosis to see if there was a difference in the prescribing habits before and after the pharmaceutical policy changes. Of note, several other pieces of data were collected from each medical record, including age, race, class of insurance (ie, Medicare, Medicaid, private health maintenance organization, private preferred provider organization), subtype diagnoses, and whether the prescription was new or a refill. The information gathered from the written record on the assessment and plan was verified using prescriptions ordered in the Allscripts electronic record, and any difference was noted. No identifying information that could be used to easily identify study participants was recorded.

Differences in prescribing habits across diagnoses before and after the policy changes were ascertained using a Fisher exact test and were further assessed using a mixed effects ordinal logistic regression model that accounted for within-provider clustering and baseline patient characteristics. An ordinal model was chosen to recognize differences in average cost among brand-name, generic, and OTC medications.

Results

In total, 200 medical records were collected. For the period analyzed before the policy change, 252 brand-name medications were prescribed compared to 231 prescribed for the period analyzed after the policy changes. There was insufficient evidence of an overall difference in brand-name medications prescribed before and after the policy changes (P=.145; Fisher exact test)(Table 1). There also was insufficient evidence of an overall difference in generic prescriptions, which totaled 153 before and 134 after the policy changes (P=.872; Fisher exact test)(Table 2). Over-the-counter prescriptions totaled 49 before and 69 after the policy changes. There was insufficient evidence of an overall difference before and after the policy changes for OTC medications (P=.192; Fisher exact test)(Table 3).

The mixed effects ordinal logistic regression model for the dependent variable—prescription type (branded, generic, or OTC)—showed an odds ratio (OR) of 1.27 for prescribing habits before and after the policy changes (OR, 1.27; 95% confidence interval, 0.97-1.67; P=.08) after accounting for provider and baseline characteristics. Despite the P value exceeding the predefined significance level, the confidence interval suggests anywhere from a 3% decrease, no change, and up to a 67% increase in postpolicy odds relative to the prepolicy odds, with a point estimate of a 27% increase in postpolicy odds over prepolicy odds. As an observational study, this suggests moderate evidence of a change based on the odds after the policy change relative to the odds before implementation (Figure).

Comment

Although some medical institutions are diligently working to limit the potential influence pharmaceutical companies have on physician prescribing habits,^4,5,25 the effect on physician prescribing habits is only now being established.¹⁵ Prior studies^12,19,21 have found evidence that medication samples may lead to overuse of brand-name medications, but these findings do not hold true for the USF dermatologists included in this study, perhaps due to the difference in pharmaceutical company interactions or physicians maintaining prior prescription habits that were unrelated to the policy. Although this study focused on policy changes for in-office samples, prior studies either included other forms of interaction²¹ or did not include samples.²²

Pharmaceutical samples allow patients to try a medication before committing to a long-term course of treatment with a particular medication, which has utility for physicians and patients. Although brand-name prescriptions may cost more, a trial period may assist the patient in deciding whether the medication is worth purchasing. Furthermore, physicians may feel more comfortable prescribing a medication once the individual patient has demonstrated a benefit from the sample, which may be particularly true in a specialty such as dermatology in which many branded topical medications contain a different vehicle than generic formulations, resulting in notable variations in active medication delivery and efficacy. Given the higher cost of branded topical medications, proving efficacy in patients through samples can provide a useful tool to the physician to determine the need for a branded formulation.

The benefits described are subjective but should not be disregarded. Although Hurley et al¹⁹ found that the number of brand-name medications prescribed increases as more samples are given out, our study demonstrated that after eliminating medication samples, there was no significant difference in the percentage of brand-name medications prescribed compared to generic and OTC medications.

Physician education concerning the price of each brand-name medication prescribed in office may be one method of reducing the amount of such prescriptions. Physicians generally are uninformed of the cost of the medications being prescribed²⁶ and may not recognize the financial burden one medication may have compared to its alternative. However, educating physicians will empower them to make the conscious decision to prefer or not prefer a brand-name medication. With some generic medications shown to have a difference in bioequivalence compared to their brand-name counterparts, a physician may find more success prescribing the brand-name medications, regardless of pharmaceutical company influence, which is an alternative solution to policy changes that eliminate samples entirely. Although this study found insufficient evidence that removing samples decreases brand-name medication prescriptions, it is imperative that solutions are established to reduce the country’s increasing burden of medical costs.

Possible shortfalls of this study include the short period of time between which prepolicy data and postpolicy data were collected. It is possible that providers did not have enough time to adjust their prescribing habits or that providers would not have changed a prescribing pattern or preference simply because of a policy change. Future studies could allow a time period greater than 2 years to compare prepolicy and postpolicy prescribing habits, or a future study might make comparisons of prescriber patterns at different institutions that have different policies. Another possible shortfall is that providers and patients were limited to those at the Department of Dermatology & Cutaneous Surgery at the USF Morsani COM. Although this study has found insufficient evidence of a difference in prescribing habits, it may be beneficial to conduct a larger study that encompasses multiple academic institutions with similar policy changes. Most importantly, this study only investigated the influence of in-office pharmaceutical samples on prescribing patterns. This study did not look at the many other ways in which providers may be influenced by pharmaceutical companies, which likely is a significant confounding variable in this study. Continued additional studies that specifically examine other methods through which providers may be influenced would be helpful in further examining the many ways in which physician prescription habits are influenced.

Conclusion

Changes in pharmaceutical policy in 2011 at USF Morsani COM specifically banned in-office samples. The totality of evidence in this study shows modest observational evidence of a change in the postpolicy odds relative to prepolicy odds, but the data also are compatible with no change between prescribing habits before and after the policy changes. Further study is needed to fully understand this relationship.

Over the years, there has been growing concern about the relationship between physicians and pharmaceutical companies. Many studies have demonstrated that pharmaceutical interactions and incentives can influence physicians’ prescribing habits.^1-3 As a result, many academic centers have adopted policies that attempt to limit the pharmaceutical industry’s influence on faculty and in-training physicians. Although these policies can vary greatly, they generally limit access of pharmaceutical representatives to providers and restrict pharmaceutical samples.^4,5 This policy shift has even been reported in private practice.⁶

At the heart of the matter is the question: What really influences physicians to write a prescription for a particular medication? Is it cost, efficacy, or representatives pushing a product? Prior studies illustrate that generic medications are equivalent to their brand-name counterparts. In fact, current regulations require no more than 5% to 7% difference in bioequivalence.^7-9 Although most generic medications are bioequivalent, it may not be universal.¹⁰

Garrison and Levin¹¹ distributed a survey to US-based prescribers in family practice, psychiatry, and internal medicine and found that prescribers deemed patient response and success as the highest priority when determining which drugs to prescribe. In contrast, drug representatives and free samples only slightly contributed.¹¹ Considering the minimum duration for efficacy of a medication such as an antidepressant vs a topical steroid, this pattern may differ with samples in dermatologic settings. Interestingly, another survey concluded that samples were associated with “sticky” prescribing habits, noting that physicians would prescribe a brand-name medication after using a sample, despite increased cost to the patient.¹² Further, it has been suggested that recipients of free samples may experience increased costs in the long run, which contrasts a stated goal of affordability to patients.^12,13

Physician interaction with pharmaceutical companies begins as early as medical school,¹⁴ with physicians reporting interactions as often as 4 times each month.^14-18 Interactions can include meetings with pharmaceutical representatives, sponsored meals, gifts, continuing medical education sponsorship, funding for travel, pharmaceutical representative speakers, research funding, and drug samples.³

A 2014 study reported that prescribing habits are influenced by the free drug samples provided by nongeneric pharmaceutical companies.¹⁹ Nationally, the number of brand-name and branded generic medications constitute 79% of prescriptions, yet together they only comprise 17% of medications prescribed at an academic medical clinic that does not provide samples. The number of medications with samples being prescribed by dermatologists increased by 15% over 9 years, which may correlate with the wider availability of medication samples, more specifically an increase in branded generic samples.¹⁹ This potential interaction is the reason why institutions question the current influence of pharmaceutical companies. Samples may appear convenient, allowing a patient to test the medication prior to committing; however, with brand-name samples being provided to the physician, he/she may become more inclined to prescribe the branded medication.^12,15,19-22 Because brand-name medications are more expensive than generic medications, this practice can increase the cost of health care.¹³ One study found that over 1 year, the overuse of nongeneric medications led to a loss of potential savings throughout 49 states, equating to $229 million just through Medicaid; interestingly, it was noted that in some states, a maximum reimbursement is set by Medicaid, regardless of whether the generic or branded medication is dispensed. The authors also noted variability in the potential savings by state, which may be a function of the state-by-state maximum reimbursements for certain medications.²³ Another study on oral combination medications estimated Medicare spending on branded drugs relative to the cost if generic combinations had been purchased instead. This study examined branded medications for which the active components were available as over-the-counter (OTC), generic, or same-class generic, and the authors estimated that $925 million could have been saved in 2016 by purchasing a generic substitute.²⁴ The overuse of nongeneric medications when generic alternatives are available becomes an issue that not only financially impacts patients but all taxpayers. However, this pattern may differ if limited only to dermatologic medications, which was not the focus of the prior studies.

To limit conflicts of interest in interactions with the pharmaceutical, medical device, and biotechnology industries, the University of South Florida (USF) Morsani College of Medicine (COM)(Tampa, Florida) implemented its own set of regulations that eliminated in-office pharmaceutical samples, in addition to other restrictions. This study aimed to investigate if there was a change in the prescribing habits of academic dermatologists after their medical school implemented these new policies.

We hypothesized that the number of brand-name drugs prescribed by physicians in the Department of Dermatology & Cutaneous Surgery would change following USF Morsani COM pharmaceutical policy changes. We sought to determine how physician prescribing practices within the Department of Dermatology & Cutaneous Surgery changed following USF Morsani COM pharmaceutical policy changes.

Methods

Data Collection
A retrospective review of medical records was conducted to investigate the effect of the USF Morsani COM pharmaceutical policy changes on physician prescribing practices within the Department of Dermatology & Cutaneous Surgery. Medical records of patients seen for common dermatology diagnoses before (January 1, 2010, to May 30, 2010) and after (August 1, 2011, to December 31, 2011) the pharmaceutical policy changes were reviewed, and all medications prescribed were recorded. Data were collected from medical records within the USF Health electronic medical record system and included visits with each of the department’s 3 attending dermatologists. The diagnoses included in the study—acne vulgaris, atopic dermatitis, onychomycosis, psoriasis, and rosacea—were chosen because in-office samples were available. Prescribing data from the first 100 consecutive medical records were collected from each time period, and a medical record was included only if it contained at least 1 of the following diagnoses: acne vulgaris, atopic dermatitis, onychomycosis, psoriasis, or rosacea. The assessment and plan of each progress note were reviewed, and the exact medication name and associated diagnosis were recorded for each prescription. Subsequently, each medication was reviewed and placed in 1 of 3 categories: brand name, generic, and OTC. The total number of prescriptions for each diagnosis (per visit/note); the specific number of brand, generic, and OTC medications prescribed (per visit/note); and the percentage of brand, generic, and OTC medications prescribed (per visit/note and per diagnosis in total) were calculated. To ensure only intended medications were included, each medication recorded in the medical record note was cross-referenced with the prescribed medication in the electronic medical record. The primary objective of this study was to capture the prescribing physician’s intent as proxied by the pattern of prescription. Thus, changes made in prescriptions after the initial plan—whether insurance related or otherwise—were not relevant to this investigation.

The data were collected to compare the percentage of brand vs generic or OTC prescriptions per diagnosis to see if there was a difference in the prescribing habits before and after the pharmaceutical policy changes. Of note, several other pieces of data were collected from each medical record, including age, race, class of insurance (ie, Medicare, Medicaid, private health maintenance organization, private preferred provider organization), subtype diagnoses, and whether the prescription was new or a refill. The information gathered from the written record on the assessment and plan was verified using prescriptions ordered in the Allscripts electronic record, and any difference was noted. No identifying information that could be used to easily identify study participants was recorded.

Differences in prescribing habits across diagnoses before and after the policy changes were ascertained using a Fisher exact test and were further assessed using a mixed effects ordinal logistic regression model that accounted for within-provider clustering and baseline patient characteristics. An ordinal model was chosen to recognize differences in average cost among brand-name, generic, and OTC medications.

Results

In total, 200 medical records were collected. For the period analyzed before the policy change, 252 brand-name medications were prescribed compared to 231 prescribed for the period analyzed after the policy changes. There was insufficient evidence of an overall difference in brand-name medications prescribed before and after the policy changes (P=.145; Fisher exact test)(Table 1). There also was insufficient evidence of an overall difference in generic prescriptions, which totaled 153 before and 134 after the policy changes (P=.872; Fisher exact test)(Table 2). Over-the-counter prescriptions totaled 49 before and 69 after the policy changes. There was insufficient evidence of an overall difference before and after the policy changes for OTC medications (P=.192; Fisher exact test)(Table 3).

The mixed effects ordinal logistic regression model for the dependent variable—prescription type (branded, generic, or OTC)—showed an odds ratio (OR) of 1.27 for prescribing habits before and after the policy changes (OR, 1.27; 95% confidence interval, 0.97-1.67; P=.08) after accounting for provider and baseline characteristics. Despite the P value exceeding the predefined significance level, the confidence interval suggests anywhere from a 3% decrease, no change, and up to a 67% increase in postpolicy odds relative to the prepolicy odds, with a point estimate of a 27% increase in postpolicy odds over prepolicy odds. As an observational study, this suggests moderate evidence of a change based on the odds after the policy change relative to the odds before implementation (Figure).

Comment

Although some medical institutions are diligently working to limit the potential influence pharmaceutical companies have on physician prescribing habits,^4,5,25 the effect on physician prescribing habits is only now being established.¹⁵ Prior studies^12,19,21 have found evidence that medication samples may lead to overuse of brand-name medications, but these findings do not hold true for the USF dermatologists included in this study, perhaps due to the difference in pharmaceutical company interactions or physicians maintaining prior prescription habits that were unrelated to the policy. Although this study focused on policy changes for in-office samples, prior studies either included other forms of interaction²¹ or did not include samples.²²

Pharmaceutical samples allow patients to try a medication before committing to a long-term course of treatment with a particular medication, which has utility for physicians and patients. Although brand-name prescriptions may cost more, a trial period may assist the patient in deciding whether the medication is worth purchasing. Furthermore, physicians may feel more comfortable prescribing a medication once the individual patient has demonstrated a benefit from the sample, which may be particularly true in a specialty such as dermatology in which many branded topical medications contain a different vehicle than generic formulations, resulting in notable variations in active medication delivery and efficacy. Given the higher cost of branded topical medications, proving efficacy in patients through samples can provide a useful tool to the physician to determine the need for a branded formulation.

The benefits described are subjective but should not be disregarded. Although Hurley et al¹⁹ found that the number of brand-name medications prescribed increases as more samples are given out, our study demonstrated that after eliminating medication samples, there was no significant difference in the percentage of brand-name medications prescribed compared to generic and OTC medications.

Physician education concerning the price of each brand-name medication prescribed in office may be one method of reducing the amount of such prescriptions. Physicians generally are uninformed of the cost of the medications being prescribed²⁶ and may not recognize the financial burden one medication may have compared to its alternative. However, educating physicians will empower them to make the conscious decision to prefer or not prefer a brand-name medication. With some generic medications shown to have a difference in bioequivalence compared to their brand-name counterparts, a physician may find more success prescribing the brand-name medications, regardless of pharmaceutical company influence, which is an alternative solution to policy changes that eliminate samples entirely. Although this study found insufficient evidence that removing samples decreases brand-name medication prescriptions, it is imperative that solutions are established to reduce the country’s increasing burden of medical costs.

Possible shortfalls of this study include the short period of time between which prepolicy data and postpolicy data were collected. It is possible that providers did not have enough time to adjust their prescribing habits or that providers would not have changed a prescribing pattern or preference simply because of a policy change. Future studies could allow a time period greater than 2 years to compare prepolicy and postpolicy prescribing habits, or a future study might make comparisons of prescriber patterns at different institutions that have different policies. Another possible shortfall is that providers and patients were limited to those at the Department of Dermatology & Cutaneous Surgery at the USF Morsani COM. Although this study has found insufficient evidence of a difference in prescribing habits, it may be beneficial to conduct a larger study that encompasses multiple academic institutions with similar policy changes. Most importantly, this study only investigated the influence of in-office pharmaceutical samples on prescribing patterns. This study did not look at the many other ways in which providers may be influenced by pharmaceutical companies, which likely is a significant confounding variable in this study. Continued additional studies that specifically examine other methods through which providers may be influenced would be helpful in further examining the many ways in which physician prescription habits are influenced.

Conclusion

Changes in pharmaceutical policy in 2011 at USF Morsani COM specifically banned in-office samples. The totality of evidence in this study shows modest observational evidence of a change in the postpolicy odds relative to prepolicy odds, but the data also are compatible with no change between prescribing habits before and after the policy changes. Further study is needed to fully understand this relationship.

In clinical practice, for the majority of patients with psoriasis superpotent topical corticosteroids (TCSs) are used as initial therapy as well as ongoing breakthrough therapy to achieve quick resolution of target lesions. However, safe and effective long-term treatment and maintenance options are required for managing the chronic nature of psoriasis to improve patient satisfaction, adherence, and quality of life, especially given that package inserts advise no more than 2 to 4 weeks of continuous use to limit side effects. The long-term use of superpotent TCSs can have a multitude of unwanted cutaneous side effects, such as skin atrophy, telangiectases, striae, and allergic vehicle responses.^1,2 Tachyphylaxis, a decreased response to treatment over time, has been more controversial and may not occur with halobetasol propionate (HP) ointment 0.05%.³ In addition, TCSs are associated with relapse or rebound on withdrawal, which can be problematic but are poorly characterized.

We review the clinical data on HP, a superpotent TCS, in the treatment of psoriasis. We also explore both recent formulation developments and fixed-combination approaches to providing optimal treatment.

Clinical Experience With HP 0.05% in Various Formulations

Halobetasol propionate is a superpotent TCS with extensive clinical experience in treating psoriasis spanning nearly 30 years.^1,2,3-7 Most recently, a twice-daily HP lotion 0.05% formulation was evaluated in patients with moderate to severe disease.⁸ Halobetasol propionate lotion 0.05% applied morning and night was shown to be significantly more effective than vehicle after 2 weeks of treatment (P<.001) in 2 parallel-group studies of 443 patients.⁹ Treatment success (ie, at least a 2-grade improvement in investigator global assessment [IGA] and IGA score of clear or almost clear) was achieved in 44.5% of patients treated with HP lotion 0.05% compared to 6.3% and 7.1% in the 2 vehicle arms. Treatment-related adverse events (AEs) were uncommon, with application-site pain reported in 2 patients treated with HP lotion 0.05% compared to 5 patients treated with vehicle.⁹

Several earlier studies have evaluated the short-term efficacy of twice-daily HP cream 0.05% and HP ointment 0.05% in the treatment of plaque psoriasis, but only 2 placebo-controlled trials have been reported, and data are limited.

Two 2-week studies of twice-daily HP ointment 0.05% (paired-comparison and parallel-group designs) in 204 patients with moderate plaque psoriasis reported improvement in plaque elevation, erythema, and scaling compared to vehicle. Patient global responses and physician global evaluation favored HP ointment 0.05%, and reports of stinging and burning were similar with active treatment and vehicle.⁴

Similarly, HP cream 0.05% applied twice daily was shown to be significantly superior to vehicle in reducing overall disease severity, erythema, plaque elevation, and scaling after 1 and 2 weeks of treatment in a paired-comparison study of 110 patients (P=.0001).⁵ A clinically significant reduction (at least a 1-grade improvement) in erythema, plaque elevation, pruritus, and scaling was noted in 81% to 92% of patients (P=.0001). Patients’ self-assessment of effectiveness rated HP cream 0.05% as excellent, very good, or good in 69% of patients compared to 20% for vehicle. Treatment-related AEs were reported by 4 patients.⁵

A small, noncontrolled, 2-week pediatric study (N=11) demonstrated the efficacy of combined therapy with HP cream 0.05% every morning and HP ointment 0.05% every night due to the then-perceived preference for creams as being more pleasant to apply during the day and ointments being more efficacious. Reported side effects were relatively mild, with application-site burning being the most common.¹⁰

Potential local AEs associated with HP are similar to those seen with other superpotent TCSs. Overall, they were reported in 0% to 13% of patients. The most common AEs were burning, pruritus, erythema, hypopigmentation, dryness, and folliculitis.^5-8,10-14 Isolated cases of moderate telangiectasia and mild atrophy also have been reported.^8,10

Comparative Studies With Other TCSs

In comparative studies of patients with severe localized plaque psoriasis, HP ointment 0.05% applied twice daily for up to 4 weeks was significantly superior compared to clobetasol propionate ointment 0.05% for the number of patients with none or mild disease (P=.023⁷) or comparisons of global evaluation scores (P=.013¹⁵) at week 2, or compared to betamethasone valerate ointment 0.1% (P=.02).⁶ It also was more effective than betamethasone dipropionate ointment 0.05% with healing seen in 40% of patients treated with HP ointment 0.05% within 24 days compared to 25% of patients treated with betamethasone dipropionate ointment 0.05%.⁸ Patient acceptance of HP ointment 0.05% based on cosmetic acceptability and ease of application was better (very good in 90% vs 80% of patients⁷) or significantly better compared to clobetasol propionate ointment 0.05% (P=.042 and P=.019¹⁵) and betamethasone dipropionate ointment 0.05% (P=.02).⁸

Evolving Management Strategies

A number of management strategies have been proposed to improve the safety and efficacy of long-term therapy with TCSs, including weekend-only or pulse therapy, dose reduction, rotating to another therapy, or combining with other topical therapies. Maintenance efficacy data are sparse. A small double-blind study in 44 patients with mild to moderate psoriasis was conducted wherein patients were treated with calcipotriene ointment in the morning and HP ointment in the evening for 2 weeks.¹⁶ Those patients who achieved at least a 50% improvement in disease severity (N=40) were randomized to receive HP ointment twice daily on weekends and calcipotriene ointment or placebo twice daily on weekdays for 6 months. Seventy-six percent of those patients treated with a HP/calcipotriene pulsed therapy maintained remission (achieving and maintaining a 75% improvement in physician global assessment) compared to 40% of those patients treated with HP only (P=.045). Mild AEs were reported in 4 patients treated with the combination regimen and 1 patient treated with HP only. No AE-related discontinuations occurred.¹⁶

In a real-world setting, a maintenance regimen that is less complicated enhances the potential for increased patient adherence and successful outcomes.¹⁷ After an initial 2-week regimen of twice-daily HP ointment 0.05% in combination with ammonium lactate lotion in patients with mild to moderate psoriasis (N=55), those rated clear or almost clear (41/55 [74.6%]) entered a maintenance phase, applying ammonium lactate lotion twice daily and either HP or placebo ointment twice daily on weekends. The probability of disease worsening by week 14 was 29% in the HP-treated group compared to 100% in the placebo group (P<.0001). By week 24, 12 patients (29.2%) remained clear or almost clear.¹⁷

Development of HP Lotion 0.01%

There are numerous examples in dermatology where advances in formulation development have made it possible to reduce the strength of active ingredients without compromising efficacy. Formulation advances also afford improved safety profiles that can extend a product’s utility. The vehicle affects not only the potency of an agent but also patient compliance, which is crucial for adequate response. Patients prefer lighter vehicles, such as lotions, over heavy ointments and creams.^18,19

Recently, a polymeric honeycomb matrix (carbomer cross-linked polymers), which helps structure the oil emulsion and provide a uniform distribution of both active and moisturizing/hydrating ingredients (ie, sorbitol, light mineral oil, diethyl sebacate) at the surface of the skin, has been deployed for topical delivery of HP (eFigure 1). Ninety percent of the oil droplets containing solubilized halobetasol are 13 µm or smaller, an ideal size for penetration through follicular openings (unpublished data, Bausch Health, 2018).

Comparison of Skin Penetration of HP Lotion 0.01% vs HP Cream 0.05%

Comparative percutaneous absorption of 2 HP formulations—0.01% lotion and 0.05% cream—was evaluated in vitro using human tissue from a single donor mounted on Bronaugh flow-through diffusion cells. Receptor phase samples were collected over the 24-hour study period and HP content assessed using liquid chromatography–mass spectrometry analysis. Halobetasol propionate lotion 0.01% demonstrated faster tissue permeation, with receptor phase levels of 0.91% of the applied dose at 24 hours compared to 0.28% of the applied dose with HP cream 0.05%. Although there was little differentiation of cumulative receptor fluid levels of HP at 6 hours, there was significant differentiation at 12 hours. Levels of HP were lowest in the receptor phase and highest in the epidermal layers of the skin, indicating limited permeation through the epidermis to the dermis. The mean (SD) for epidermal deposition of HP following the 24-hour duration of exposure was 6.17% (2.07%) and 1.72% (0.76%) for the 0.01% lotion and 0.05% cream, respectively (Figure 1)(unpublished data, Bausch Health, 2018).

Efficacy and Safety of HP Lotion 0.01% in Moderate to Severe Plaque Psoriasis

Two articles have been published on the use of HP lotion 0.01% in moderate to severe psoriasis: 2 pivotal studies comparing once-daily application with vehicle lotion over 8 weeks (N=430),²⁰ and a comparative “label-restricted” 2-week study with HP lotion 0.01% and HP cream 0.05% (N=150).²¹

HP Lotion 0.01% Compared to Vehicle
Two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies investigated the safety and efficacy of once-daily HP lotion 0.01% in moderate to severe plaque psoriasis (N=430).²⁰ Patients were treated with HP lotion 0.01% or vehicle (randomized in a 2:1 ratio) for 8 weeks, with a 4-week posttreatment follow-up. Treatment success (defined as at least a 2-grade improvement in baseline IGA score and a score equating to clear or almost clear) was significantly greater with HP lotion 0.01% at all assessment points (Figure 2)(P=.003 for week 2; P<.001 for other time points). At week 8, 37.4% of patients receiving HP lotion 0.01% were treatment successes compared to 10.0% of patients receiving vehicle (P<.001). Additionally, a 2-grade improvement from baseline for each psoriasis sign—erythema, plaque elevation, and scaling—was achieved by 42.2% of patients receiving HP lotion 0.01% at week 8 compared to 11.4% of patients receiving vehicle (P<.001). Good efficacy was maintained posttreatment that was significant compared to vehicle (P<.001).²⁰

There were corresponding reductions in body surface area (BSA) affected following treatment with HP lotion 0.01%.²⁰ At baseline, the mean BSA was 6.1 (range, 3–12). By week 8, there was a 35.2% reduction in BSA compared to 5.9% with vehicle. Again, a significant reduction in BSA was maintained posttreatment compared to vehicle (P<.001).²⁰

Halobetasol propionate lotion 0.01% was well tolerated with few treatment-related AEs.²⁰ Most AEs were application-site reactions such as dermatitis (0.7%), infection, pruritus, and discoloration (0.4% each). Mild to moderate itching, dryness, burning, and stinging present at baseline all improved with treatment, and severity of local skin reactions was significantly lower than with vehicle at week 8 (P<.001). Quality-of-life data also highlighted the benefits of active treatment compared to vehicle for cutaneous tolerability. The Dermatology Life Quality Index (DLQI) is a 10-item patient-reported questionnaire consisting of questions concerning symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment.²² Change from baseline for DLQI (how itchy, sore, painful, stinging) was significantly greater with HP lotion 0.01% at weeks 4 and 8 (P<.001). Changes in the overall DLQI score also were significantly greater with HP lotion 0.01% at both study visits (P=.006 and P=.014 at week 4 and P=.001 and P=.004 at week 8 for study 1 and study 2, respectively).²⁰

HP Lotion 0.01% Compared to HP Cream 0.05%
Treatment success with HP lotion 0.01% also was shown to be comparable to the higher-concentration HP cream 0.05% in patients with moderate to severe psoriasis over a 2-week “label-restricted” treatment period (Figure 3). Both products were well tolerated over the 2-week treatment period. One patient reported application-site dermatitis (1.7%) with HP lotion 0.01%.²¹

Conclusion

Halobetasol propionate 0.05%—cream, ointment, and lotion—has been shown to be a highly effective short-term topical treatment for psoriasis. Longer-term treatment strategies using HP, which are important when considering management of a chronic condition, have been limited by safety concerns and labelling. However, there are data to suggest weekend or pulsed therapy may be an option.

A novel formulation of HP lotion 0.01% has been developed using a polymerized matrix with active ingredients and moisturizing excipients suspended in oil droplets. The polymerized honeycomb matrix and vehicle formulation form a barrier by reducing epidermal water loss and improving skin hydration. The oil droplets deliver uniform amounts of active ingredient in an optimal size for follicular penetration. Skin penetration has been shown to be quicker with greater retention in the epidermis with HP lotion 0.01% compared to HP cream 0.05%, with corresponding considerably lower penetration into the dermis.

Although there have been a number of clinical studies of HP for psoriasis, until recently there have been no comparative trials, with studies label restricted to a 2- to 4-week duration. Three clinical studies with HP lotion 0.01% have now been reported.Not only has HP lotion 0.01% been shown to be as effective as HP cream 0.05% in a 2-week comparative study (despite having one-fifth the concentration of HP), it also has been shown to be very effective and well tolerated following 8 weeks of daily use.^20,21 Further studies involving longer treatment durations are required to better elucidate AEs, but HP lotion 0.01% may provide the first longer-term TCS treatment solution for moderate to severe psoriasis.

Acknowledgments
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of the manuscript. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.

In clinical practice, for the majority of patients with psoriasis superpotent topical corticosteroids (TCSs) are used as initial therapy as well as ongoing breakthrough therapy to achieve quick resolution of target lesions. However, safe and effective long-term treatment and maintenance options are required for managing the chronic nature of psoriasis to improve patient satisfaction, adherence, and quality of life, especially given that package inserts advise no more than 2 to 4 weeks of continuous use to limit side effects. The long-term use of superpotent TCSs can have a multitude of unwanted cutaneous side effects, such as skin atrophy, telangiectases, striae, and allergic vehicle responses.^1,2 Tachyphylaxis, a decreased response to treatment over time, has been more controversial and may not occur with halobetasol propionate (HP) ointment 0.05%.³ In addition, TCSs are associated with relapse or rebound on withdrawal, which can be problematic but are poorly characterized.

We review the clinical data on HP, a superpotent TCS, in the treatment of psoriasis. We also explore both recent formulation developments and fixed-combination approaches to providing optimal treatment.

Clinical Experience With HP 0.05% in Various Formulations

Halobetasol propionate is a superpotent TCS with extensive clinical experience in treating psoriasis spanning nearly 30 years.^1,2,3-7 Most recently, a twice-daily HP lotion 0.05% formulation was evaluated in patients with moderate to severe disease.⁸ Halobetasol propionate lotion 0.05% applied morning and night was shown to be significantly more effective than vehicle after 2 weeks of treatment (P<.001) in 2 parallel-group studies of 443 patients.⁹ Treatment success (ie, at least a 2-grade improvement in investigator global assessment [IGA] and IGA score of clear or almost clear) was achieved in 44.5% of patients treated with HP lotion 0.05% compared to 6.3% and 7.1% in the 2 vehicle arms. Treatment-related adverse events (AEs) were uncommon, with application-site pain reported in 2 patients treated with HP lotion 0.05% compared to 5 patients treated with vehicle.⁹

Several earlier studies have evaluated the short-term efficacy of twice-daily HP cream 0.05% and HP ointment 0.05% in the treatment of plaque psoriasis, but only 2 placebo-controlled trials have been reported, and data are limited.

Two 2-week studies of twice-daily HP ointment 0.05% (paired-comparison and parallel-group designs) in 204 patients with moderate plaque psoriasis reported improvement in plaque elevation, erythema, and scaling compared to vehicle. Patient global responses and physician global evaluation favored HP ointment 0.05%, and reports of stinging and burning were similar with active treatment and vehicle.⁴

Similarly, HP cream 0.05% applied twice daily was shown to be significantly superior to vehicle in reducing overall disease severity, erythema, plaque elevation, and scaling after 1 and 2 weeks of treatment in a paired-comparison study of 110 patients (P=.0001).⁵ A clinically significant reduction (at least a 1-grade improvement) in erythema, plaque elevation, pruritus, and scaling was noted in 81% to 92% of patients (P=.0001). Patients’ self-assessment of effectiveness rated HP cream 0.05% as excellent, very good, or good in 69% of patients compared to 20% for vehicle. Treatment-related AEs were reported by 4 patients.⁵

A small, noncontrolled, 2-week pediatric study (N=11) demonstrated the efficacy of combined therapy with HP cream 0.05% every morning and HP ointment 0.05% every night due to the then-perceived preference for creams as being more pleasant to apply during the day and ointments being more efficacious. Reported side effects were relatively mild, with application-site burning being the most common.¹⁰

Potential local AEs associated with HP are similar to those seen with other superpotent TCSs. Overall, they were reported in 0% to 13% of patients. The most common AEs were burning, pruritus, erythema, hypopigmentation, dryness, and folliculitis.^5-8,10-14 Isolated cases of moderate telangiectasia and mild atrophy also have been reported.^8,10

Comparative Studies With Other TCSs

In comparative studies of patients with severe localized plaque psoriasis, HP ointment 0.05% applied twice daily for up to 4 weeks was significantly superior compared to clobetasol propionate ointment 0.05% for the number of patients with none or mild disease (P=.023⁷) or comparisons of global evaluation scores (P=.013¹⁵) at week 2, or compared to betamethasone valerate ointment 0.1% (P=.02).⁶ It also was more effective than betamethasone dipropionate ointment 0.05% with healing seen in 40% of patients treated with HP ointment 0.05% within 24 days compared to 25% of patients treated with betamethasone dipropionate ointment 0.05%.⁸ Patient acceptance of HP ointment 0.05% based on cosmetic acceptability and ease of application was better (very good in 90% vs 80% of patients⁷) or significantly better compared to clobetasol propionate ointment 0.05% (P=.042 and P=.019¹⁵) and betamethasone dipropionate ointment 0.05% (P=.02).⁸

Evolving Management Strategies

A number of management strategies have been proposed to improve the safety and efficacy of long-term therapy with TCSs, including weekend-only or pulse therapy, dose reduction, rotating to another therapy, or combining with other topical therapies. Maintenance efficacy data are sparse. A small double-blind study in 44 patients with mild to moderate psoriasis was conducted wherein patients were treated with calcipotriene ointment in the morning and HP ointment in the evening for 2 weeks.¹⁶ Those patients who achieved at least a 50% improvement in disease severity (N=40) were randomized to receive HP ointment twice daily on weekends and calcipotriene ointment or placebo twice daily on weekdays for 6 months. Seventy-six percent of those patients treated with a HP/calcipotriene pulsed therapy maintained remission (achieving and maintaining a 75% improvement in physician global assessment) compared to 40% of those patients treated with HP only (P=.045). Mild AEs were reported in 4 patients treated with the combination regimen and 1 patient treated with HP only. No AE-related discontinuations occurred.¹⁶

In a real-world setting, a maintenance regimen that is less complicated enhances the potential for increased patient adherence and successful outcomes.¹⁷ After an initial 2-week regimen of twice-daily HP ointment 0.05% in combination with ammonium lactate lotion in patients with mild to moderate psoriasis (N=55), those rated clear or almost clear (41/55 [74.6%]) entered a maintenance phase, applying ammonium lactate lotion twice daily and either HP or placebo ointment twice daily on weekends. The probability of disease worsening by week 14 was 29% in the HP-treated group compared to 100% in the placebo group (P<.0001). By week 24, 12 patients (29.2%) remained clear or almost clear.¹⁷

Development of HP Lotion 0.01%

There are numerous examples in dermatology where advances in formulation development have made it possible to reduce the strength of active ingredients without compromising efficacy. Formulation advances also afford improved safety profiles that can extend a product’s utility. The vehicle affects not only the potency of an agent but also patient compliance, which is crucial for adequate response. Patients prefer lighter vehicles, such as lotions, over heavy ointments and creams.^18,19

Recently, a polymeric honeycomb matrix (carbomer cross-linked polymers), which helps structure the oil emulsion and provide a uniform distribution of both active and moisturizing/hydrating ingredients (ie, sorbitol, light mineral oil, diethyl sebacate) at the surface of the skin, has been deployed for topical delivery of HP (eFigure 1). Ninety percent of the oil droplets containing solubilized halobetasol are 13 µm or smaller, an ideal size for penetration through follicular openings (unpublished data, Bausch Health, 2018).

Comparison of Skin Penetration of HP Lotion 0.01% vs HP Cream 0.05%

Comparative percutaneous absorption of 2 HP formulations—0.01% lotion and 0.05% cream—was evaluated in vitro using human tissue from a single donor mounted on Bronaugh flow-through diffusion cells. Receptor phase samples were collected over the 24-hour study period and HP content assessed using liquid chromatography–mass spectrometry analysis. Halobetasol propionate lotion 0.01% demonstrated faster tissue permeation, with receptor phase levels of 0.91% of the applied dose at 24 hours compared to 0.28% of the applied dose with HP cream 0.05%. Although there was little differentiation of cumulative receptor fluid levels of HP at 6 hours, there was significant differentiation at 12 hours. Levels of HP were lowest in the receptor phase and highest in the epidermal layers of the skin, indicating limited permeation through the epidermis to the dermis. The mean (SD) for epidermal deposition of HP following the 24-hour duration of exposure was 6.17% (2.07%) and 1.72% (0.76%) for the 0.01% lotion and 0.05% cream, respectively (Figure 1)(unpublished data, Bausch Health, 2018).

Efficacy and Safety of HP Lotion 0.01% in Moderate to Severe Plaque Psoriasis

Two articles have been published on the use of HP lotion 0.01% in moderate to severe psoriasis: 2 pivotal studies comparing once-daily application with vehicle lotion over 8 weeks (N=430),²⁰ and a comparative “label-restricted” 2-week study with HP lotion 0.01% and HP cream 0.05% (N=150).²¹

HP Lotion 0.01% Compared to Vehicle
Two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies investigated the safety and efficacy of once-daily HP lotion 0.01% in moderate to severe plaque psoriasis (N=430).²⁰ Patients were treated with HP lotion 0.01% or vehicle (randomized in a 2:1 ratio) for 8 weeks, with a 4-week posttreatment follow-up. Treatment success (defined as at least a 2-grade improvement in baseline IGA score and a score equating to clear or almost clear) was significantly greater with HP lotion 0.01% at all assessment points (Figure 2)(P=.003 for week 2; P<.001 for other time points). At week 8, 37.4% of patients receiving HP lotion 0.01% were treatment successes compared to 10.0% of patients receiving vehicle (P<.001). Additionally, a 2-grade improvement from baseline for each psoriasis sign—erythema, plaque elevation, and scaling—was achieved by 42.2% of patients receiving HP lotion 0.01% at week 8 compared to 11.4% of patients receiving vehicle (P<.001). Good efficacy was maintained posttreatment that was significant compared to vehicle (P<.001).²⁰

There were corresponding reductions in body surface area (BSA) affected following treatment with HP lotion 0.01%.²⁰ At baseline, the mean BSA was 6.1 (range, 3–12). By week 8, there was a 35.2% reduction in BSA compared to 5.9% with vehicle. Again, a significant reduction in BSA was maintained posttreatment compared to vehicle (P<.001).²⁰

Halobetasol propionate lotion 0.01% was well tolerated with few treatment-related AEs.²⁰ Most AEs were application-site reactions such as dermatitis (0.7%), infection, pruritus, and discoloration (0.4% each). Mild to moderate itching, dryness, burning, and stinging present at baseline all improved with treatment, and severity of local skin reactions was significantly lower than with vehicle at week 8 (P<.001). Quality-of-life data also highlighted the benefits of active treatment compared to vehicle for cutaneous tolerability. The Dermatology Life Quality Index (DLQI) is a 10-item patient-reported questionnaire consisting of questions concerning symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment.²² Change from baseline for DLQI (how itchy, sore, painful, stinging) was significantly greater with HP lotion 0.01% at weeks 4 and 8 (P<.001). Changes in the overall DLQI score also were significantly greater with HP lotion 0.01% at both study visits (P=.006 and P=.014 at week 4 and P=.001 and P=.004 at week 8 for study 1 and study 2, respectively).²⁰

HP Lotion 0.01% Compared to HP Cream 0.05%
Treatment success with HP lotion 0.01% also was shown to be comparable to the higher-concentration HP cream 0.05% in patients with moderate to severe psoriasis over a 2-week “label-restricted” treatment period (Figure 3). Both products were well tolerated over the 2-week treatment period. One patient reported application-site dermatitis (1.7%) with HP lotion 0.01%.²¹

Conclusion

Halobetasol propionate 0.05%—cream, ointment, and lotion—has been shown to be a highly effective short-term topical treatment for psoriasis. Longer-term treatment strategies using HP, which are important when considering management of a chronic condition, have been limited by safety concerns and labelling. However, there are data to suggest weekend or pulsed therapy may be an option.

A novel formulation of HP lotion 0.01% has been developed using a polymerized matrix with active ingredients and moisturizing excipients suspended in oil droplets. The polymerized honeycomb matrix and vehicle formulation form a barrier by reducing epidermal water loss and improving skin hydration. The oil droplets deliver uniform amounts of active ingredient in an optimal size for follicular penetration. Skin penetration has been shown to be quicker with greater retention in the epidermis with HP lotion 0.01% compared to HP cream 0.05%, with corresponding considerably lower penetration into the dermis.

Although there have been a number of clinical studies of HP for psoriasis, until recently there have been no comparative trials, with studies label restricted to a 2- to 4-week duration. Three clinical studies with HP lotion 0.01% have now been reported.Not only has HP lotion 0.01% been shown to be as effective as HP cream 0.05% in a 2-week comparative study (despite having one-fifth the concentration of HP), it also has been shown to be very effective and well tolerated following 8 weeks of daily use.^20,21 Further studies involving longer treatment durations are required to better elucidate AEs, but HP lotion 0.01% may provide the first longer-term TCS treatment solution for moderate to severe psoriasis.

Acknowledgments
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of the manuscript. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.

In clinical practice, for the majority of patients with psoriasis superpotent topical corticosteroids (TCSs) are used as initial therapy as well as ongoing breakthrough therapy to achieve quick resolution of target lesions. However, safe and effective long-term treatment and maintenance options are required for managing the chronic nature of psoriasis to improve patient satisfaction, adherence, and quality of life, especially given that package inserts advise no more than 2 to 4 weeks of continuous use to limit side effects. The long-term use of superpotent TCSs can have a multitude of unwanted cutaneous side effects, such as skin atrophy, telangiectases, striae, and allergic vehicle responses.^1,2 Tachyphylaxis, a decreased response to treatment over time, has been more controversial and may not occur with halobetasol propionate (HP) ointment 0.05%.³ In addition, TCSs are associated with relapse or rebound on withdrawal, which can be problematic but are poorly characterized.

We review the clinical data on HP, a superpotent TCS, in the treatment of psoriasis. We also explore both recent formulation developments and fixed-combination approaches to providing optimal treatment.

Clinical Experience With HP 0.05% in Various Formulations

Halobetasol propionate is a superpotent TCS with extensive clinical experience in treating psoriasis spanning nearly 30 years.^1,2,3-7 Most recently, a twice-daily HP lotion 0.05% formulation was evaluated in patients with moderate to severe disease.⁸ Halobetasol propionate lotion 0.05% applied morning and night was shown to be significantly more effective than vehicle after 2 weeks of treatment (P<.001) in 2 parallel-group studies of 443 patients.⁹ Treatment success (ie, at least a 2-grade improvement in investigator global assessment [IGA] and IGA score of clear or almost clear) was achieved in 44.5% of patients treated with HP lotion 0.05% compared to 6.3% and 7.1% in the 2 vehicle arms. Treatment-related adverse events (AEs) were uncommon, with application-site pain reported in 2 patients treated with HP lotion 0.05% compared to 5 patients treated with vehicle.⁹

Several earlier studies have evaluated the short-term efficacy of twice-daily HP cream 0.05% and HP ointment 0.05% in the treatment of plaque psoriasis, but only 2 placebo-controlled trials have been reported, and data are limited.

Two 2-week studies of twice-daily HP ointment 0.05% (paired-comparison and parallel-group designs) in 204 patients with moderate plaque psoriasis reported improvement in plaque elevation, erythema, and scaling compared to vehicle. Patient global responses and physician global evaluation favored HP ointment 0.05%, and reports of stinging and burning were similar with active treatment and vehicle.⁴

Similarly, HP cream 0.05% applied twice daily was shown to be significantly superior to vehicle in reducing overall disease severity, erythema, plaque elevation, and scaling after 1 and 2 weeks of treatment in a paired-comparison study of 110 patients (P=.0001).⁵ A clinically significant reduction (at least a 1-grade improvement) in erythema, plaque elevation, pruritus, and scaling was noted in 81% to 92% of patients (P=.0001). Patients’ self-assessment of effectiveness rated HP cream 0.05% as excellent, very good, or good in 69% of patients compared to 20% for vehicle. Treatment-related AEs were reported by 4 patients.⁵

A small, noncontrolled, 2-week pediatric study (N=11) demonstrated the efficacy of combined therapy with HP cream 0.05% every morning and HP ointment 0.05% every night due to the then-perceived preference for creams as being more pleasant to apply during the day and ointments being more efficacious. Reported side effects were relatively mild, with application-site burning being the most common.¹⁰

Potential local AEs associated with HP are similar to those seen with other superpotent TCSs. Overall, they were reported in 0% to 13% of patients. The most common AEs were burning, pruritus, erythema, hypopigmentation, dryness, and folliculitis.^5-8,10-14 Isolated cases of moderate telangiectasia and mild atrophy also have been reported.^8,10

Comparative Studies With Other TCSs

In comparative studies of patients with severe localized plaque psoriasis, HP ointment 0.05% applied twice daily for up to 4 weeks was significantly superior compared to clobetasol propionate ointment 0.05% for the number of patients with none or mild disease (P=.023⁷) or comparisons of global evaluation scores (P=.013¹⁵) at week 2, or compared to betamethasone valerate ointment 0.1% (P=.02).⁶ It also was more effective than betamethasone dipropionate ointment 0.05% with healing seen in 40% of patients treated with HP ointment 0.05% within 24 days compared to 25% of patients treated with betamethasone dipropionate ointment 0.05%.⁸ Patient acceptance of HP ointment 0.05% based on cosmetic acceptability and ease of application was better (very good in 90% vs 80% of patients⁷) or significantly better compared to clobetasol propionate ointment 0.05% (P=.042 and P=.019¹⁵) and betamethasone dipropionate ointment 0.05% (P=.02).⁸

Evolving Management Strategies

A number of management strategies have been proposed to improve the safety and efficacy of long-term therapy with TCSs, including weekend-only or pulse therapy, dose reduction, rotating to another therapy, or combining with other topical therapies. Maintenance efficacy data are sparse. A small double-blind study in 44 patients with mild to moderate psoriasis was conducted wherein patients were treated with calcipotriene ointment in the morning and HP ointment in the evening for 2 weeks.¹⁶ Those patients who achieved at least a 50% improvement in disease severity (N=40) were randomized to receive HP ointment twice daily on weekends and calcipotriene ointment or placebo twice daily on weekdays for 6 months. Seventy-six percent of those patients treated with a HP/calcipotriene pulsed therapy maintained remission (achieving and maintaining a 75% improvement in physician global assessment) compared to 40% of those patients treated with HP only (P=.045). Mild AEs were reported in 4 patients treated with the combination regimen and 1 patient treated with HP only. No AE-related discontinuations occurred.¹⁶

In a real-world setting, a maintenance regimen that is less complicated enhances the potential for increased patient adherence and successful outcomes.¹⁷ After an initial 2-week regimen of twice-daily HP ointment 0.05% in combination with ammonium lactate lotion in patients with mild to moderate psoriasis (N=55), those rated clear or almost clear (41/55 [74.6%]) entered a maintenance phase, applying ammonium lactate lotion twice daily and either HP or placebo ointment twice daily on weekends. The probability of disease worsening by week 14 was 29% in the HP-treated group compared to 100% in the placebo group (P<.0001). By week 24, 12 patients (29.2%) remained clear or almost clear.¹⁷

Development of HP Lotion 0.01%

There are numerous examples in dermatology where advances in formulation development have made it possible to reduce the strength of active ingredients without compromising efficacy. Formulation advances also afford improved safety profiles that can extend a product’s utility. The vehicle affects not only the potency of an agent but also patient compliance, which is crucial for adequate response. Patients prefer lighter vehicles, such as lotions, over heavy ointments and creams.^18,19

Recently, a polymeric honeycomb matrix (carbomer cross-linked polymers), which helps structure the oil emulsion and provide a uniform distribution of both active and moisturizing/hydrating ingredients (ie, sorbitol, light mineral oil, diethyl sebacate) at the surface of the skin, has been deployed for topical delivery of HP (eFigure 1). Ninety percent of the oil droplets containing solubilized halobetasol are 13 µm or smaller, an ideal size for penetration through follicular openings (unpublished data, Bausch Health, 2018).

Comparison of Skin Penetration of HP Lotion 0.01% vs HP Cream 0.05%

Comparative percutaneous absorption of 2 HP formulations—0.01% lotion and 0.05% cream—was evaluated in vitro using human tissue from a single donor mounted on Bronaugh flow-through diffusion cells. Receptor phase samples were collected over the 24-hour study period and HP content assessed using liquid chromatography–mass spectrometry analysis. Halobetasol propionate lotion 0.01% demonstrated faster tissue permeation, with receptor phase levels of 0.91% of the applied dose at 24 hours compared to 0.28% of the applied dose with HP cream 0.05%. Although there was little differentiation of cumulative receptor fluid levels of HP at 6 hours, there was significant differentiation at 12 hours. Levels of HP were lowest in the receptor phase and highest in the epidermal layers of the skin, indicating limited permeation through the epidermis to the dermis. The mean (SD) for epidermal deposition of HP following the 24-hour duration of exposure was 6.17% (2.07%) and 1.72% (0.76%) for the 0.01% lotion and 0.05% cream, respectively (Figure 1)(unpublished data, Bausch Health, 2018).

Efficacy and Safety of HP Lotion 0.01% in Moderate to Severe Plaque Psoriasis

Two articles have been published on the use of HP lotion 0.01% in moderate to severe psoriasis: 2 pivotal studies comparing once-daily application with vehicle lotion over 8 weeks (N=430),²⁰ and a comparative “label-restricted” 2-week study with HP lotion 0.01% and HP cream 0.05% (N=150).²¹

HP Lotion 0.01% Compared to Vehicle
Two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies investigated the safety and efficacy of once-daily HP lotion 0.01% in moderate to severe plaque psoriasis (N=430).²⁰ Patients were treated with HP lotion 0.01% or vehicle (randomized in a 2:1 ratio) for 8 weeks, with a 4-week posttreatment follow-up. Treatment success (defined as at least a 2-grade improvement in baseline IGA score and a score equating to clear or almost clear) was significantly greater with HP lotion 0.01% at all assessment points (Figure 2)(P=.003 for week 2; P<.001 for other time points). At week 8, 37.4% of patients receiving HP lotion 0.01% were treatment successes compared to 10.0% of patients receiving vehicle (P<.001). Additionally, a 2-grade improvement from baseline for each psoriasis sign—erythema, plaque elevation, and scaling—was achieved by 42.2% of patients receiving HP lotion 0.01% at week 8 compared to 11.4% of patients receiving vehicle (P<.001). Good efficacy was maintained posttreatment that was significant compared to vehicle (P<.001).²⁰

There were corresponding reductions in body surface area (BSA) affected following treatment with HP lotion 0.01%.²⁰ At baseline, the mean BSA was 6.1 (range, 3–12). By week 8, there was a 35.2% reduction in BSA compared to 5.9% with vehicle. Again, a significant reduction in BSA was maintained posttreatment compared to vehicle (P<.001).²⁰

Halobetasol propionate lotion 0.01% was well tolerated with few treatment-related AEs.²⁰ Most AEs were application-site reactions such as dermatitis (0.7%), infection, pruritus, and discoloration (0.4% each). Mild to moderate itching, dryness, burning, and stinging present at baseline all improved with treatment, and severity of local skin reactions was significantly lower than with vehicle at week 8 (P<.001). Quality-of-life data also highlighted the benefits of active treatment compared to vehicle for cutaneous tolerability. The Dermatology Life Quality Index (DLQI) is a 10-item patient-reported questionnaire consisting of questions concerning symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment.²² Change from baseline for DLQI (how itchy, sore, painful, stinging) was significantly greater with HP lotion 0.01% at weeks 4 and 8 (P<.001). Changes in the overall DLQI score also were significantly greater with HP lotion 0.01% at both study visits (P=.006 and P=.014 at week 4 and P=.001 and P=.004 at week 8 for study 1 and study 2, respectively).²⁰

HP Lotion 0.01% Compared to HP Cream 0.05%
Treatment success with HP lotion 0.01% also was shown to be comparable to the higher-concentration HP cream 0.05% in patients with moderate to severe psoriasis over a 2-week “label-restricted” treatment period (Figure 3). Both products were well tolerated over the 2-week treatment period. One patient reported application-site dermatitis (1.7%) with HP lotion 0.01%.²¹

Conclusion

Halobetasol propionate 0.05%—cream, ointment, and lotion—has been shown to be a highly effective short-term topical treatment for psoriasis. Longer-term treatment strategies using HP, which are important when considering management of a chronic condition, have been limited by safety concerns and labelling. However, there are data to suggest weekend or pulsed therapy may be an option.

A novel formulation of HP lotion 0.01% has been developed using a polymerized matrix with active ingredients and moisturizing excipients suspended in oil droplets. The polymerized honeycomb matrix and vehicle formulation form a barrier by reducing epidermal water loss and improving skin hydration. The oil droplets deliver uniform amounts of active ingredient in an optimal size for follicular penetration. Skin penetration has been shown to be quicker with greater retention in the epidermis with HP lotion 0.01% compared to HP cream 0.05%, with corresponding considerably lower penetration into the dermis.

Although there have been a number of clinical studies of HP for psoriasis, until recently there have been no comparative trials, with studies label restricted to a 2- to 4-week duration. Three clinical studies with HP lotion 0.01% have now been reported.Not only has HP lotion 0.01% been shown to be as effective as HP cream 0.05% in a 2-week comparative study (despite having one-fifth the concentration of HP), it also has been shown to be very effective and well tolerated following 8 weeks of daily use.^20,21 Further studies involving longer treatment durations are required to better elucidate AEs, but HP lotion 0.01% may provide the first longer-term TCS treatment solution for moderate to severe psoriasis.

Acknowledgments
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of the manuscript. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.

Prostate cancer is the most frequently diagnosed cancer in men and the third leading cause of cancer death in men worldwide.¹ An estimated 174,650 new cases are diagnosed each year in the United States; 31,620 American men die annually from the disease.² Although prostate cancer can be a serious disease, many men do not die from it. In fact, 2.9 million men who were diagnosed with prostate cancer at some point are alive today.³

Risk factors. Prostate cancer develops mainly in men ages ≥ 65 years and rarely occurs before age 40. In addition to age, family history and African American ethnicity are the major nonmodifiable risk factors for prostate cancer.⁴ From the 1970s to the most recent statistical analysis of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, African American men have continued to have significantly higher incidence of, and mortality rates from, prostate cancer than their European American counterparts. African American men are also more likely than men of European ancestry to have aggressive prostate cancers.⁵ Other risk factors include geographic location (higher risk in Northern Europe, North America, and Australia; lower risk in Asia, Africa, and South and Central America), mutations in the BRCA2 gene, and hereditary non-polyposis colon cancer syndrome.⁴

Prostate-specific antigen (PSA) was first used as a screening tool for prostate cancer in 1991.⁶ Prostate cancer incidence, especially organ-confined disease, has dramatically increased since then.⁷ PSA testing has a low sensitivity and specificity for the detection of prostate cancer, and there is no clear threshold at which biopsy can or should be offered. The most commonly used cutoff value of 4 ng/mL has a false-positive rate of about 70%.⁸

Benign prostatic conditions such as hypertrophy and infection can elevate PSA levels. In addition, the PSA test does not distinguish between aggressive and slow-growing cancers, and about 15% of patients with prostate cancer have a normal PSA level.⁹

A word about the digital rectal exam. While PSA testing has been the mainstay of prostate cancer screening, a few studies have included digital rectal exam (DRE) in their protocols. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial showed that DRE captured an additional 2% of men with prostate cancer in the setting of a normal PSA test result.¹⁰ In the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, the overall detection rate for prostate cancer was found to be better when DRE was combined with PSA and prostate biopsy than when DRE was used alone (4.5% vs 2.5%).¹¹ Nevertheless, generally speaking, DRE can be omitted in the era of PSA screening.

Screening guidelines vary

Recommendations for prostate cancer screening vary by organization and are summarized in TABLE 1.^9,12-14 In 2012, the US Preventive Services Task Force (USPSTF) recommended against PSA-based screening for prostate cancer (Category D).¹⁵ In 2018, ­USPSTF provided an update with a new recommendation that clinicians inform men ages 55 to 69 years about the potential benefits and harms of PSA-based screening (Category C).¹⁴ The USPSTF continues to recommend against PSA-based screening for men ages ≥ 70 years (Category D).¹⁴

Does PSA-based screening improve patient-centered outcomes?

Several randomized controlled trials (RCTs) such as the Quebec Prospective Randomized Controlled Trial,¹⁶ the Norrköping Sweden Study,¹⁷ ERSPC,¹¹ and PLCO¹⁰ have been conducted to assess the benefits of PSA testing. PLCO and ERSPC have contributed significantly to our understanding of prostate cancer screening even though their 13-year follow-up results are conflicting (TABLE 2).^10,11,18

Continue to: In the ERSPC 13-year follow-up publication...

In the ERSPC 13-year follow-up publication, the authors concluded that a substantial reduction in prostate cancer mortality is attributable to testing with PSA.¹⁸ Despite limitations in the study design (eg, France entered after 2 years, screening intervals varied between 2 and 4 years, biopsy indications varied, and screening was discontinued at different times), PSA screening detected more prostate cancer than was detected in the control arm (10.2% vs 6.8%).

In the initial 11 years of follow-up, the study group experienced a 21% reduction in prostate cancer mortality, even though the absolute decrease ranged from only 0.6% (545 per 89,352) to 0.5% (355 per 72,891). The updated absolute risk reduction of death from prostate cancer at 13 years of follow-up showed a larger benefit: 0.11 per 1000 person-years or 1.28 per 1000 men randomized, which is equivalent to 1 prostate cancer death averted per 781 (95% confidence interval [CI], 490-1929) men invited for screening, or 1 per 27 (17-66) additional prostate cancers detected.

The PLCO trial did not show any significant difference in prostate cancer detection (11.1% screened vs 9.9% control), and there was no improvement in prostate cancer mortality (3.7 vs 3.4 death per 10,000 person-years).¹⁰ However, the PLCO trial suffered from issues of contamination, which may have influenced the overall results. About 52% of men in the control (usual care) group received a PSA test at some point during the study. And more than two-thirds of the men who had a prostate biopsy because of a positive PSA test did not have prostate cancer.

Community standards for the PSA threshold for biopsy were applied in various centers (> 4 ng/ml in general) in PLCO, whereas in ­ERSPC, a cut-off PSA value ≥ 3 ng/mL was used for biopsy. Because of the lower PSA threshold, ERSPC may have identified cancers that would have had good outcomes without any intervention.

The harms of PSA screening

While it is unclear whether PSA screening results in any improvement in patient-centered outcomes, it does lead to downstream intervention due to overdiagnosis, which precipitates unnecessary anxiety, biopsies, and overtreatment (eg, excess radiation, overuse of androgen deprivation therapy).¹⁹ Biopsies carry the risk of hematuria (22.6%), hematospermia (50.4%), and urinary tract infection.²⁰ Data from SEER-Medicare showed that prostate biopsy was associated with a 2.65-fold increased risk of hospitalization within 30 days of the procedure compared to a control population.²¹

Continue to: Overdiagnosis leads to overtreatment...

Overdiagnosis leads to overtreatment of low-risk prostate cancer. Both traditional treatment options for prostate cancer—radical prostatectomy and radiotherapy—are associated with urinary incontinence, erectile dysfunction, and issues with bowel function.^22,23

The Prostate Cancer Intervention vs Observation Trial (PIVOT),²⁴ the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4),²⁵ and the Prostate Testing for Cancer and Treatment (ProtecT) trial,^22,23 are the major RCTs that looked at the outcomes of treatment modalities for localized prostate cancer in the modern era of PSA testing.

PIVOT compared passive observation with radical prostatectomy.²⁴ After 20 years of follow-up on 731 patients, the researchers concluded that radical prostatectomy did not reduce all-cause or prostate cancer–related mortality (TABLE 3).²⁴

SPCG-4 showed survival benefits for men who underwent radical prostatectomy compared with men in a watchful waiting group, but only 5% of the study cohort had cancer detected by PSA screening (TABLE 4).²⁵ The rest had either palpable tumors or symptoms of a tumor.

ProtecT, which followed patients with localized prostate cancer for more than 10 years,compared the outcomes and adverse effects of active surveillance, radical prostatectomy, and radiotherapy.²³ Prostate cancer–specific mortality was low irrespective of the treatment,²³ and there was no significant difference in all-cause mortality or prostate cancer–specific mortality between the 3 treatment groups.²³ The active surveillance group had considerably fewer adverse events.^22,23 The incidence rates of erectile dysfunction and urinary incontinence at the 1- and 6-year follow-up marks are outlined in TABLE 5.²²

Continue to: The purpose of active monitoring...

The purpose of active monitoring is to minimize overtreatment by avoiding immediate radical intervention. Radical treatments with curative intent can be undertaken at any point while patients are being actively monitored. It is important to note that the active monitoring that took place in ProtecT²³ was very different from the passive surveillance of PIVOT²⁴ and SPCG-4.²⁵ In ProtecT, once an elevated serum PSA level was noted, PSA levels were monitored every 3 months in the first year and every 6 to 12 months thereafter.²³ Triggers to reassess patients and consider a change in clinical management were based largely on changes in PSA levels. Participants with an increase of at least 50% in PSA level during the previous 12 months were offered either continued monitoring or treatment after further testing.

Making individualized decisions about prostate cancer screening

Traditionally, the goal of cancer screening has been to maximize the number of people screened. Generally, the information provided to patients about cancer screening emphasizes the benefits and minimizes the harms. Recently, however, there has been a shift in communication about cancer screening with the emphasis now being placed on informed decision-making and encouraging patients to make individual decisions about screening participation.²⁶

Although current guidelines regarding PSA screening differ by organization, generally speaking, PSA screening should be offered only to men with a life expectancy > 10 years.

The treatment option of active surveillance, with its lower incidence of adverse outcomes, is an important reason for patients to make individualized decisions about prostate cancer screening.

Another reason relates to 5-alpha-­reductase inhibitors. Although their role in the management of prostate cancer is currently not well defined, a reduction of almost 25% in the risk of prostate cancer and improvement in the performance of PSA has been reported.²⁷

The PSA test has low sensitivity and specificity and lacks a clear cut-off value that warrants prostate biopsy.

And yet another reason is that there are alternate strategies to manage the majority of patients who have been diagnosed with low-risk disease through transrectal ultrasound biopsy. The ERSPC study mentions multiparametric magnetic resonance imaging combined with targeted biopsy to identify high-grade disease.^28,29 Genetic and epigenetic assays of the biopsied tissue can help grade disease based on aggressiveness.³⁰ Transperineal mapping biopsy using a mapping software program can identify specific disease sites within the prostate gland, so that patients can be offered the option of targeted therapy.³⁰

Continue to: Applying shared decision-making to prostate cancer screening

Balancing errors of omission with errors of commission is challenging. Shared decision-making (SDM) is an approach whereby clinicians and patients share the best available evidence when faced with the task of medical decision-making and in which patients are supported while they consider their options and achieve their preferences.³¹ SDM is well supported by evidence from a number of RCTs and results in increased knowledge, involvement, and confidence on the part of patients.³² An individualized approach using the schematic diagram (FIGURE 1^3,18) may be helpful.

Barriers to SDM success. Many factors can interfere with the success of SDM including limited or poor communication; lack of time during busy office visits; and patients’ cultural, informational, and/or emotional needs. To improve patient-centered communication, we can: (1) make information understandable and available to patients and families; (2) prioritize training in communication; (3) use decision aid tools to facilitate communication; and (4) work to improve the payment model to incentivize patient-centered communication. Tools that facilitate SDM include videotapes, patient group discussions, brief scripts read to patients, and informational pamphlets. One such tool is the American Society for Clinical Oncology’s decision aid tool for PSA testing.³³

Limited knowledge among patients. Decisions regarding treatment among men diagnosed with localized prostate cancer can be difficult because there are several treatment options with similar prognoses, but there are differences in adverse effects. One population-based cohort study of men with newly diagnosed localized prostate cancer found that most men had significant knowledge deficits regarding the survival benefits of the 2 major treatment options—surgery and radiation.³⁴ In a large population-based study, 38% of men with localized prostate cancer reported receiving help from their primary care providers in the decision-making process for treatment.³⁵

Learning to employ SDM. Elwyn et al proposed a 3-step model to incorporate SDM into clinical practice.³¹ They described key steps that include: choice talk (making sure patients are informed about the reasonable options), option talk (providing more detailed information about the options), and decision talk (supporting the work of patients considering their preferences and deciding what is best). Properly employing these methods requires training using simulations.³¹

The bottom line

Although current guidelines regarding PSA screening differ by organization, generally speaking PSA screening should be offered only to men with a life expectancy > 10 years. The PSA test has low sensitivity and specificity and lacks a clear cut-off value that warrants prostate biopsy. Men who choose to have PSA testing increase their chances of detecting prostate cancer, but most prostate cancers are slow growing and do not cause death. The decision to undergo PSA screening should be made by both the provider and the patient, after a discussion of the limited benefits and associated harms. The interval of follow-up screening may vary from 2 to 4 years depending on patient age, level of PSA, and whether a patient is taking medications such as 5-alpha-reductase inhibitors.

CORRESPONDENCE
Jaividhya Dasarathy, MD, FAAFP, 2500 Metro Health Medical Drive, Cleveland, Ohio 44109; [email protected].

Prostate cancer is the most frequently diagnosed cancer in men and the third leading cause of cancer death in men worldwide.¹ An estimated 174,650 new cases are diagnosed each year in the United States; 31,620 American men die annually from the disease.² Although prostate cancer can be a serious disease, many men do not die from it. In fact, 2.9 million men who were diagnosed with prostate cancer at some point are alive today.³

Risk factors. Prostate cancer develops mainly in men ages ≥ 65 years and rarely occurs before age 40. In addition to age, family history and African American ethnicity are the major nonmodifiable risk factors for prostate cancer.⁴ From the 1970s to the most recent statistical analysis of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, African American men have continued to have significantly higher incidence of, and mortality rates from, prostate cancer than their European American counterparts. African American men are also more likely than men of European ancestry to have aggressive prostate cancers.⁵ Other risk factors include geographic location (higher risk in Northern Europe, North America, and Australia; lower risk in Asia, Africa, and South and Central America), mutations in the BRCA2 gene, and hereditary non-polyposis colon cancer syndrome.⁴

Prostate-specific antigen (PSA) was first used as a screening tool for prostate cancer in 1991.⁶ Prostate cancer incidence, especially organ-confined disease, has dramatically increased since then.⁷ PSA testing has a low sensitivity and specificity for the detection of prostate cancer, and there is no clear threshold at which biopsy can or should be offered. The most commonly used cutoff value of 4 ng/mL has a false-positive rate of about 70%.⁸

Benign prostatic conditions such as hypertrophy and infection can elevate PSA levels. In addition, the PSA test does not distinguish between aggressive and slow-growing cancers, and about 15% of patients with prostate cancer have a normal PSA level.⁹

A word about the digital rectal exam. While PSA testing has been the mainstay of prostate cancer screening, a few studies have included digital rectal exam (DRE) in their protocols. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial showed that DRE captured an additional 2% of men with prostate cancer in the setting of a normal PSA test result.¹⁰ In the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, the overall detection rate for prostate cancer was found to be better when DRE was combined with PSA and prostate biopsy than when DRE was used alone (4.5% vs 2.5%).¹¹ Nevertheless, generally speaking, DRE can be omitted in the era of PSA screening.

Screening guidelines vary

Recommendations for prostate cancer screening vary by organization and are summarized in TABLE 1.^9,12-14 In 2012, the US Preventive Services Task Force (USPSTF) recommended against PSA-based screening for prostate cancer (Category D).¹⁵ In 2018, ­USPSTF provided an update with a new recommendation that clinicians inform men ages 55 to 69 years about the potential benefits and harms of PSA-based screening (Category C).¹⁴ The USPSTF continues to recommend against PSA-based screening for men ages ≥ 70 years (Category D).¹⁴

Does PSA-based screening improve patient-centered outcomes?

Several randomized controlled trials (RCTs) such as the Quebec Prospective Randomized Controlled Trial,¹⁶ the Norrköping Sweden Study,¹⁷ ERSPC,¹¹ and PLCO¹⁰ have been conducted to assess the benefits of PSA testing. PLCO and ERSPC have contributed significantly to our understanding of prostate cancer screening even though their 13-year follow-up results are conflicting (TABLE 2).^10,11,18

Continue to: In the ERSPC 13-year follow-up publication...

In the ERSPC 13-year follow-up publication, the authors concluded that a substantial reduction in prostate cancer mortality is attributable to testing with PSA.¹⁸ Despite limitations in the study design (eg, France entered after 2 years, screening intervals varied between 2 and 4 years, biopsy indications varied, and screening was discontinued at different times), PSA screening detected more prostate cancer than was detected in the control arm (10.2% vs 6.8%).

In the initial 11 years of follow-up, the study group experienced a 21% reduction in prostate cancer mortality, even though the absolute decrease ranged from only 0.6% (545 per 89,352) to 0.5% (355 per 72,891). The updated absolute risk reduction of death from prostate cancer at 13 years of follow-up showed a larger benefit: 0.11 per 1000 person-years or 1.28 per 1000 men randomized, which is equivalent to 1 prostate cancer death averted per 781 (95% confidence interval [CI], 490-1929) men invited for screening, or 1 per 27 (17-66) additional prostate cancers detected.

The PLCO trial did not show any significant difference in prostate cancer detection (11.1% screened vs 9.9% control), and there was no improvement in prostate cancer mortality (3.7 vs 3.4 death per 10,000 person-years).¹⁰ However, the PLCO trial suffered from issues of contamination, which may have influenced the overall results. About 52% of men in the control (usual care) group received a PSA test at some point during the study. And more than two-thirds of the men who had a prostate biopsy because of a positive PSA test did not have prostate cancer.

Community standards for the PSA threshold for biopsy were applied in various centers (> 4 ng/ml in general) in PLCO, whereas in ­ERSPC, a cut-off PSA value ≥ 3 ng/mL was used for biopsy. Because of the lower PSA threshold, ERSPC may have identified cancers that would have had good outcomes without any intervention.

The harms of PSA screening

While it is unclear whether PSA screening results in any improvement in patient-centered outcomes, it does lead to downstream intervention due to overdiagnosis, which precipitates unnecessary anxiety, biopsies, and overtreatment (eg, excess radiation, overuse of androgen deprivation therapy).¹⁹ Biopsies carry the risk of hematuria (22.6%), hematospermia (50.4%), and urinary tract infection.²⁰ Data from SEER-Medicare showed that prostate biopsy was associated with a 2.65-fold increased risk of hospitalization within 30 days of the procedure compared to a control population.²¹

Continue to: Overdiagnosis leads to overtreatment...

Overdiagnosis leads to overtreatment of low-risk prostate cancer. Both traditional treatment options for prostate cancer—radical prostatectomy and radiotherapy—are associated with urinary incontinence, erectile dysfunction, and issues with bowel function.^22,23

The Prostate Cancer Intervention vs Observation Trial (PIVOT),²⁴ the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4),²⁵ and the Prostate Testing for Cancer and Treatment (ProtecT) trial,^22,23 are the major RCTs that looked at the outcomes of treatment modalities for localized prostate cancer in the modern era of PSA testing.

PIVOT compared passive observation with radical prostatectomy.²⁴ After 20 years of follow-up on 731 patients, the researchers concluded that radical prostatectomy did not reduce all-cause or prostate cancer–related mortality (TABLE 3).²⁴

SPCG-4 showed survival benefits for men who underwent radical prostatectomy compared with men in a watchful waiting group, but only 5% of the study cohort had cancer detected by PSA screening (TABLE 4).²⁵ The rest had either palpable tumors or symptoms of a tumor.

ProtecT, which followed patients with localized prostate cancer for more than 10 years,compared the outcomes and adverse effects of active surveillance, radical prostatectomy, and radiotherapy.²³ Prostate cancer–specific mortality was low irrespective of the treatment,²³ and there was no significant difference in all-cause mortality or prostate cancer–specific mortality between the 3 treatment groups.²³ The active surveillance group had considerably fewer adverse events.^22,23 The incidence rates of erectile dysfunction and urinary incontinence at the 1- and 6-year follow-up marks are outlined in TABLE 5.²²

Continue to: The purpose of active monitoring...

The purpose of active monitoring is to minimize overtreatment by avoiding immediate radical intervention. Radical treatments with curative intent can be undertaken at any point while patients are being actively monitored. It is important to note that the active monitoring that took place in ProtecT²³ was very different from the passive surveillance of PIVOT²⁴ and SPCG-4.²⁵ In ProtecT, once an elevated serum PSA level was noted, PSA levels were monitored every 3 months in the first year and every 6 to 12 months thereafter.²³ Triggers to reassess patients and consider a change in clinical management were based largely on changes in PSA levels. Participants with an increase of at least 50% in PSA level during the previous 12 months were offered either continued monitoring or treatment after further testing.

Making individualized decisions about prostate cancer screening

Traditionally, the goal of cancer screening has been to maximize the number of people screened. Generally, the information provided to patients about cancer screening emphasizes the benefits and minimizes the harms. Recently, however, there has been a shift in communication about cancer screening with the emphasis now being placed on informed decision-making and encouraging patients to make individual decisions about screening participation.²⁶

Although current guidelines regarding PSA screening differ by organization, generally speaking, PSA screening should be offered only to men with a life expectancy > 10 years.

The treatment option of active surveillance, with its lower incidence of adverse outcomes, is an important reason for patients to make individualized decisions about prostate cancer screening.

Another reason relates to 5-alpha-­reductase inhibitors. Although their role in the management of prostate cancer is currently not well defined, a reduction of almost 25% in the risk of prostate cancer and improvement in the performance of PSA has been reported.²⁷

The PSA test has low sensitivity and specificity and lacks a clear cut-off value that warrants prostate biopsy.

And yet another reason is that there are alternate strategies to manage the majority of patients who have been diagnosed with low-risk disease through transrectal ultrasound biopsy. The ERSPC study mentions multiparametric magnetic resonance imaging combined with targeted biopsy to identify high-grade disease.^28,29 Genetic and epigenetic assays of the biopsied tissue can help grade disease based on aggressiveness.³⁰ Transperineal mapping biopsy using a mapping software program can identify specific disease sites within the prostate gland, so that patients can be offered the option of targeted therapy.³⁰

Continue to: Applying shared decision-making to prostate cancer screening

Balancing errors of omission with errors of commission is challenging. Shared decision-making (SDM) is an approach whereby clinicians and patients share the best available evidence when faced with the task of medical decision-making and in which patients are supported while they consider their options and achieve their preferences.³¹ SDM is well supported by evidence from a number of RCTs and results in increased knowledge, involvement, and confidence on the part of patients.³² An individualized approach using the schematic diagram (FIGURE 1^3,18) may be helpful.

Barriers to SDM success. Many factors can interfere with the success of SDM including limited or poor communication; lack of time during busy office visits; and patients’ cultural, informational, and/or emotional needs. To improve patient-centered communication, we can: (1) make information understandable and available to patients and families; (2) prioritize training in communication; (3) use decision aid tools to facilitate communication; and (4) work to improve the payment model to incentivize patient-centered communication. Tools that facilitate SDM include videotapes, patient group discussions, brief scripts read to patients, and informational pamphlets. One such tool is the American Society for Clinical Oncology’s decision aid tool for PSA testing.³³

Limited knowledge among patients. Decisions regarding treatment among men diagnosed with localized prostate cancer can be difficult because there are several treatment options with similar prognoses, but there are differences in adverse effects. One population-based cohort study of men with newly diagnosed localized prostate cancer found that most men had significant knowledge deficits regarding the survival benefits of the 2 major treatment options—surgery and radiation.³⁴ In a large population-based study, 38% of men with localized prostate cancer reported receiving help from their primary care providers in the decision-making process for treatment.³⁵

Learning to employ SDM. Elwyn et al proposed a 3-step model to incorporate SDM into clinical practice.³¹ They described key steps that include: choice talk (making sure patients are informed about the reasonable options), option talk (providing more detailed information about the options), and decision talk (supporting the work of patients considering their preferences and deciding what is best). Properly employing these methods requires training using simulations.³¹

The bottom line

Although current guidelines regarding PSA screening differ by organization, generally speaking PSA screening should be offered only to men with a life expectancy > 10 years. The PSA test has low sensitivity and specificity and lacks a clear cut-off value that warrants prostate biopsy. Men who choose to have PSA testing increase their chances of detecting prostate cancer, but most prostate cancers are slow growing and do not cause death. The decision to undergo PSA screening should be made by both the provider and the patient, after a discussion of the limited benefits and associated harms. The interval of follow-up screening may vary from 2 to 4 years depending on patient age, level of PSA, and whether a patient is taking medications such as 5-alpha-reductase inhibitors.

CORRESPONDENCE
Jaividhya Dasarathy, MD, FAAFP, 2500 Metro Health Medical Drive, Cleveland, Ohio 44109; [email protected].

Prostate cancer is the most frequently diagnosed cancer in men and the third leading cause of cancer death in men worldwide.¹ An estimated 174,650 new cases are diagnosed each year in the United States; 31,620 American men die annually from the disease.² Although prostate cancer can be a serious disease, many men do not die from it. In fact, 2.9 million men who were diagnosed with prostate cancer at some point are alive today.³

Risk factors. Prostate cancer develops mainly in men ages ≥ 65 years and rarely occurs before age 40. In addition to age, family history and African American ethnicity are the major nonmodifiable risk factors for prostate cancer.⁴ From the 1970s to the most recent statistical analysis of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, African American men have continued to have significantly higher incidence of, and mortality rates from, prostate cancer than their European American counterparts. African American men are also more likely than men of European ancestry to have aggressive prostate cancers.⁵ Other risk factors include geographic location (higher risk in Northern Europe, North America, and Australia; lower risk in Asia, Africa, and South and Central America), mutations in the BRCA2 gene, and hereditary non-polyposis colon cancer syndrome.⁴

Prostate-specific antigen (PSA) was first used as a screening tool for prostate cancer in 1991.⁶ Prostate cancer incidence, especially organ-confined disease, has dramatically increased since then.⁷ PSA testing has a low sensitivity and specificity for the detection of prostate cancer, and there is no clear threshold at which biopsy can or should be offered. The most commonly used cutoff value of 4 ng/mL has a false-positive rate of about 70%.⁸

Benign prostatic conditions such as hypertrophy and infection can elevate PSA levels. In addition, the PSA test does not distinguish between aggressive and slow-growing cancers, and about 15% of patients with prostate cancer have a normal PSA level.⁹

A word about the digital rectal exam. While PSA testing has been the mainstay of prostate cancer screening, a few studies have included digital rectal exam (DRE) in their protocols. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial showed that DRE captured an additional 2% of men with prostate cancer in the setting of a normal PSA test result.¹⁰ In the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, the overall detection rate for prostate cancer was found to be better when DRE was combined with PSA and prostate biopsy than when DRE was used alone (4.5% vs 2.5%).¹¹ Nevertheless, generally speaking, DRE can be omitted in the era of PSA screening.

Screening guidelines vary

Recommendations for prostate cancer screening vary by organization and are summarized in TABLE 1.^9,12-14 In 2012, the US Preventive Services Task Force (USPSTF) recommended against PSA-based screening for prostate cancer (Category D).¹⁵ In 2018, ­USPSTF provided an update with a new recommendation that clinicians inform men ages 55 to 69 years about the potential benefits and harms of PSA-based screening (Category C).¹⁴ The USPSTF continues to recommend against PSA-based screening for men ages ≥ 70 years (Category D).¹⁴

Does PSA-based screening improve patient-centered outcomes?

Several randomized controlled trials (RCTs) such as the Quebec Prospective Randomized Controlled Trial,¹⁶ the Norrköping Sweden Study,¹⁷ ERSPC,¹¹ and PLCO¹⁰ have been conducted to assess the benefits of PSA testing. PLCO and ERSPC have contributed significantly to our understanding of prostate cancer screening even though their 13-year follow-up results are conflicting (TABLE 2).^10,11,18

Continue to: In the ERSPC 13-year follow-up publication...

In the ERSPC 13-year follow-up publication, the authors concluded that a substantial reduction in prostate cancer mortality is attributable to testing with PSA.¹⁸ Despite limitations in the study design (eg, France entered after 2 years, screening intervals varied between 2 and 4 years, biopsy indications varied, and screening was discontinued at different times), PSA screening detected more prostate cancer than was detected in the control arm (10.2% vs 6.8%).

In the initial 11 years of follow-up, the study group experienced a 21% reduction in prostate cancer mortality, even though the absolute decrease ranged from only 0.6% (545 per 89,352) to 0.5% (355 per 72,891). The updated absolute risk reduction of death from prostate cancer at 13 years of follow-up showed a larger benefit: 0.11 per 1000 person-years or 1.28 per 1000 men randomized, which is equivalent to 1 prostate cancer death averted per 781 (95% confidence interval [CI], 490-1929) men invited for screening, or 1 per 27 (17-66) additional prostate cancers detected.

The PLCO trial did not show any significant difference in prostate cancer detection (11.1% screened vs 9.9% control), and there was no improvement in prostate cancer mortality (3.7 vs 3.4 death per 10,000 person-years).¹⁰ However, the PLCO trial suffered from issues of contamination, which may have influenced the overall results. About 52% of men in the control (usual care) group received a PSA test at some point during the study. And more than two-thirds of the men who had a prostate biopsy because of a positive PSA test did not have prostate cancer.

Community standards for the PSA threshold for biopsy were applied in various centers (> 4 ng/ml in general) in PLCO, whereas in ­ERSPC, a cut-off PSA value ≥ 3 ng/mL was used for biopsy. Because of the lower PSA threshold, ERSPC may have identified cancers that would have had good outcomes without any intervention.

The harms of PSA screening

While it is unclear whether PSA screening results in any improvement in patient-centered outcomes, it does lead to downstream intervention due to overdiagnosis, which precipitates unnecessary anxiety, biopsies, and overtreatment (eg, excess radiation, overuse of androgen deprivation therapy).¹⁹ Biopsies carry the risk of hematuria (22.6%), hematospermia (50.4%), and urinary tract infection.²⁰ Data from SEER-Medicare showed that prostate biopsy was associated with a 2.65-fold increased risk of hospitalization within 30 days of the procedure compared to a control population.²¹

Continue to: Overdiagnosis leads to overtreatment...

Overdiagnosis leads to overtreatment of low-risk prostate cancer. Both traditional treatment options for prostate cancer—radical prostatectomy and radiotherapy—are associated with urinary incontinence, erectile dysfunction, and issues with bowel function.^22,23

The Prostate Cancer Intervention vs Observation Trial (PIVOT),²⁴ the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4),²⁵ and the Prostate Testing for Cancer and Treatment (ProtecT) trial,^22,23 are the major RCTs that looked at the outcomes of treatment modalities for localized prostate cancer in the modern era of PSA testing.

PIVOT compared passive observation with radical prostatectomy.²⁴ After 20 years of follow-up on 731 patients, the researchers concluded that radical prostatectomy did not reduce all-cause or prostate cancer–related mortality (TABLE 3).²⁴

SPCG-4 showed survival benefits for men who underwent radical prostatectomy compared with men in a watchful waiting group, but only 5% of the study cohort had cancer detected by PSA screening (TABLE 4).²⁵ The rest had either palpable tumors or symptoms of a tumor.

ProtecT, which followed patients with localized prostate cancer for more than 10 years,compared the outcomes and adverse effects of active surveillance, radical prostatectomy, and radiotherapy.²³ Prostate cancer–specific mortality was low irrespective of the treatment,²³ and there was no significant difference in all-cause mortality or prostate cancer–specific mortality between the 3 treatment groups.²³ The active surveillance group had considerably fewer adverse events.^22,23 The incidence rates of erectile dysfunction and urinary incontinence at the 1- and 6-year follow-up marks are outlined in TABLE 5.²²

Continue to: The purpose of active monitoring...

The purpose of active monitoring is to minimize overtreatment by avoiding immediate radical intervention. Radical treatments with curative intent can be undertaken at any point while patients are being actively monitored. It is important to note that the active monitoring that took place in ProtecT²³ was very different from the passive surveillance of PIVOT²⁴ and SPCG-4.²⁵ In ProtecT, once an elevated serum PSA level was noted, PSA levels were monitored every 3 months in the first year and every 6 to 12 months thereafter.²³ Triggers to reassess patients and consider a change in clinical management were based largely on changes in PSA levels. Participants with an increase of at least 50% in PSA level during the previous 12 months were offered either continued monitoring or treatment after further testing.

Making individualized decisions about prostate cancer screening

Traditionally, the goal of cancer screening has been to maximize the number of people screened. Generally, the information provided to patients about cancer screening emphasizes the benefits and minimizes the harms. Recently, however, there has been a shift in communication about cancer screening with the emphasis now being placed on informed decision-making and encouraging patients to make individual decisions about screening participation.²⁶

Although current guidelines regarding PSA screening differ by organization, generally speaking, PSA screening should be offered only to men with a life expectancy > 10 years.

The treatment option of active surveillance, with its lower incidence of adverse outcomes, is an important reason for patients to make individualized decisions about prostate cancer screening.

Another reason relates to 5-alpha-­reductase inhibitors. Although their role in the management of prostate cancer is currently not well defined, a reduction of almost 25% in the risk of prostate cancer and improvement in the performance of PSA has been reported.²⁷

The PSA test has low sensitivity and specificity and lacks a clear cut-off value that warrants prostate biopsy.

And yet another reason is that there are alternate strategies to manage the majority of patients who have been diagnosed with low-risk disease through transrectal ultrasound biopsy. The ERSPC study mentions multiparametric magnetic resonance imaging combined with targeted biopsy to identify high-grade disease.^28,29 Genetic and epigenetic assays of the biopsied tissue can help grade disease based on aggressiveness.³⁰ Transperineal mapping biopsy using a mapping software program can identify specific disease sites within the prostate gland, so that patients can be offered the option of targeted therapy.³⁰

Continue to: Applying shared decision-making to prostate cancer screening

Balancing errors of omission with errors of commission is challenging. Shared decision-making (SDM) is an approach whereby clinicians and patients share the best available evidence when faced with the task of medical decision-making and in which patients are supported while they consider their options and achieve their preferences.³¹ SDM is well supported by evidence from a number of RCTs and results in increased knowledge, involvement, and confidence on the part of patients.³² An individualized approach using the schematic diagram (FIGURE 1^3,18) may be helpful.

Barriers to SDM success. Many factors can interfere with the success of SDM including limited or poor communication; lack of time during busy office visits; and patients’ cultural, informational, and/or emotional needs. To improve patient-centered communication, we can: (1) make information understandable and available to patients and families; (2) prioritize training in communication; (3) use decision aid tools to facilitate communication; and (4) work to improve the payment model to incentivize patient-centered communication. Tools that facilitate SDM include videotapes, patient group discussions, brief scripts read to patients, and informational pamphlets. One such tool is the American Society for Clinical Oncology’s decision aid tool for PSA testing.³³

Limited knowledge among patients. Decisions regarding treatment among men diagnosed with localized prostate cancer can be difficult because there are several treatment options with similar prognoses, but there are differences in adverse effects. One population-based cohort study of men with newly diagnosed localized prostate cancer found that most men had significant knowledge deficits regarding the survival benefits of the 2 major treatment options—surgery and radiation.³⁴ In a large population-based study, 38% of men with localized prostate cancer reported receiving help from their primary care providers in the decision-making process for treatment.³⁵

Learning to employ SDM. Elwyn et al proposed a 3-step model to incorporate SDM into clinical practice.³¹ They described key steps that include: choice talk (making sure patients are informed about the reasonable options), option talk (providing more detailed information about the options), and decision talk (supporting the work of patients considering their preferences and deciding what is best). Properly employing these methods requires training using simulations.³¹

The bottom line

Although current guidelines regarding PSA screening differ by organization, generally speaking PSA screening should be offered only to men with a life expectancy > 10 years. The PSA test has low sensitivity and specificity and lacks a clear cut-off value that warrants prostate biopsy. Men who choose to have PSA testing increase their chances of detecting prostate cancer, but most prostate cancers are slow growing and do not cause death. The decision to undergo PSA screening should be made by both the provider and the patient, after a discussion of the limited benefits and associated harms. The interval of follow-up screening may vary from 2 to 4 years depending on patient age, level of PSA, and whether a patient is taking medications such as 5-alpha-reductase inhibitors.

CORRESPONDENCE
Jaividhya Dasarathy, MD, FAAFP, 2500 Metro Health Medical Drive, Cleveland, Ohio 44109; [email protected].

Attributed to the ancient Greek philosopher Heraclitus, and often quoted in contemporary times, is the expression “the only constant is change.” This sentiment rings true for the field of obstetrics this past year, as several bread-and-butter guidelines for managing common obstetric conditions were either challenged or altered.

The publication of the PROLONG trial called into question the use of intramuscular progesterone for the prevention of preterm birth. Prophylaxis guidelines for group B streptococcal disease were updated, including several significant clinical practice changes. Finally, there was a comprehensive overhaul of the guidelines for hypertensive disorders of pregnancy, which replaced a landmark Task Force document from the American College of Obstetricians and Gynecologists (ACOG) that was published only a few years ago.

Change is constant, and in obstetrics it is vital to keep up with the changing guidelines that result as new data become available for digestion and implementation into everyday clinical practice.

Results from the PROLONG trial may shake up treatment options for recurrent preterm birth 

Blackwell SC, Gyamfi-Bannerman C, Biggio JR Jr, et al. 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG study): a multicenter, international, randomized double-blind trial. Am J Perinatol. 2019. doi: 10.1055/s-0039-3400227. 

The drug 17 α-hydroxyprogesterone caproate (17-OHPC, or 17P; Makena) was approved by the US Food and Drug Administration (FDA) in 2011 for the prevention of spontaneous preterm birth (PTB) in women with a singleton pregnancy and a history of singleton spontaneous PTB. The results of the trial by Meis and colleagues of 17-OHPC played a major role in achieving that approval, as it demonstrated a 34% reduction in recurrent PTB and a reduction in some neonatal morbidities.¹ Following the drug's approval, both ACOG and the Society for Maternal-Fetal Medicine (SMFM) published guidelines recommending progesterone therapy, including 17-OHPC, for the prevention of recurrent spontaneous PTB.²   

The FDA approval of 17-OHPC was granted under an accelerated conditional pathway that required a confirmatory trial evaluating efficacy, safety, and long-term infant follow-up to be performed by the sponsor. That trial, Progestin's Role in Optimizing Neonatal Gestation (PROLONG), was started in 2009, and its results were published on October 25, 2019.³ 

Continue to: Design of the trial...

Design of the trial 

PROLONG was a multicenter (93 sites), randomized, placebo-controlled, double-blind study conducted in 9 countries (23% of participants were in the United States, 60% were in Russia and Ukraine). The co-primary outcome was PTB < 35 weeks and a composite neonatal morbidity and mortality index. The primary safety outcome was fetal/early infant death. 

The study was designed to have 98% power to detect a 30% reduction in PTB < 35 weeks, and 90% power to detect a 35% reduction in the neonatal composite index. It included 1,708 participants (1,130 were treated with 17-OHPC, and 578 received placebo). 

Trial outcomes. There was no difference in PTB < 35 weeks between the 17-OHPC and the placebo groups (11.0% vs 11.5%; relative risk [RR], 0.95; 95% confidence interval [CI], 0.71-1.26). There was no difference in PTB < 32 or < 37 weeks. 

The study revealed also that there was no difference between groups in the neonatal composite index (5.6% for 17-OHPC vs 5.0% for placebo; RR, 1.12; 95% CI, 0.68-1.61). In addition, there was no difference in fetal/early infant death between the 17-OHPC and placebo groups (1.7% vs 1.9%; RR, 0.87; 95% CI, 0.4-1.81). 

Conclusions. The trial investigators concluded that 17-OHPC did not demonstrate a reduction in recurrent PTB and did not decrease neonatal morbidity. 

Study limitations included underpowering and selection bias 

The investigators noted that the PTB rate in PROLONG was unexpectedly almost 50% lower than that in the Meis trial, and that therefore the PROLONG trial was underpowered to assess the primary outcomes. 

Further, the study populations of the 2 trials were very different: The Meis trial included women at higher baseline risk for PTB (> 1 prior PTB and at least 1 other risk factor for PTB). Additionally, while the PROLONG trial included mostly white (90%), married (90%), nonsmoking women (8% smoked), the Meis trial population was 59% black and 50% married, and 20% were smokers.  

The availability and common use of 17-OHPC in the United States likely led to a selection bias for the PROLONG trial population, as the highest-risk patients were most likely already receiving treatment and were therefore excluded from the PROLONG trial. 

Society, and FDA, responses to the new data 

The results of the PROLONG trial call into question what has become standard practice for patients with a history of spontaneous PTB in the United States. While the safety profile of 17-OHPC has not been cited as a concern, whether or not the drug should be used at all has—as has its current FDA-approved status. 

In response to the publication of the PROLONG trial results, ACOG released a Practice Advisory that acknowledged the study's findings but did not alter the current recommendations to continue to offer progesterone for the prevention of preterm birth, upholding ACOG's current Practice Bulletin guidance.^2,4 Additional considerations for offering 17-OHPC use include the patients' preferences, available resources, and the setting for the intervention.  

SMFM's response was more specific, stating that it is reasonable to continue to use 17-OHPC in high-risk patient populations consistent with those in the Meis trial.⁵ In the rest of the general population at risk for recurrent PTB, SMFM recommends that, due to uncertain benefit with 17-OHPC, the high cost, patient discomfort, and increased visits should be taken into account.  

Four days after the publication of the PROLONG study, the FDA Bone, Reproductive, and Urologic Drugs Advisory Committee voted 9-7 to withdraw approval for 17-OHPC.⁶ In response, SMFM released a statement supporting continued access to 17-OHPC.⁷ The FDA's final decision on the status of the drug is expected within the next several months from this writing. 

Continue to: ACOG updates guidance on preventing early-onset GBS disease...

ACOG updates guidance on preventing early-onset GBS disease 

American College of Obstetricians and Gynecologists—Committee on Obstetric Practice. ACOG committee opinion no. 782: prevention of early-onset group B streptococcal disease in newborns. Obstet Gynecol. 2019;134:e19-e40. 

Group B streptococcus (GBS) is the leading cause of newborn infection and is associated with maternal infections as well as preterm labor and stillbirth. Early-onset GBS disease occurs within 7 days of birth and is linked to vertical transmission via maternal colonization of the genitourinary or gastrointestinal tract and fetal/neonatal aspiration at birth.  

Preventing early-onset GBS disease with maternal screening and intrapartum prophylaxis according to the Centers for Disease Control and Prevention (CDC) guidelines has reduced early-onset disease by 80% since the 1990s. By contrast, late-onset GBS infection, which occurs 7 days to 3 months after birth, usually is associated with horizontal maternal transmission or hospital or community infections, and it is not prevented by intrapartum treatment. 

In 2018, the CDC transferred responsibility for GBS prophylaxis guidelines to ACOG and the American Academy of Pediatrics (AAP). In July 2019, ACOG released its Committee Opinion on preventing early-onset GBS disease in newborns.⁸ This guidance replaces and updates the previous guidelines, with 3 notable changes.  

The screening timing has changed 

In the CDC's 2010 guidelines, GBS screening was recommended to start at 35 weeks' gestation. The new guidelines recommend universal vaginal-rectal screening at 36 to 37 6/7 weeks' gestation. The new timing of culture will shift the expected 5-week window in which GBS cultures are considered valid up to at least 41 weeks' gestation. The rationale  for this change is that any GBS-unknown patient who previously would have been cultured under 37 weeks' would be an automatic candidate for empiric therapy and the lower rate of birth in the 35th versus the 41st week of gestation. 

Identifying candidates for intrapartum treatment 

The usual indications for intrapartum antibiotic prophylaxis include a GBS-positive culture at 36 weeks or beyond, GBS bacteriuria at any point in pregnancy, a prior GBS-affected child, or unknown GBS status with any of the following: < 37 weeks, rupture of membranes ≥ 18 hours or temperature ≥ 100.4°F (38°C), and a positive rapid GBS culture in labor. In addition, antibiotics now should be considered for patients at term with unknown GBS status but with a history of GBS colonization in a prior pregnancy.  

This represents a major practice change for women at ≥ 37 weeks with unknown GBS status and no other traditional risk factors. The rationale for this recommendation is that women who have been positive for GBS in a prior pregnancy have a 50% chance of being colonized in the current pregnancy, and their newborns are therefore at higher risk for early-onset GBS disease.  

Managing patients with penicillin allergy 

Intravenous penicillin (or ampicillin) remains the antibiotic of choice for intrapartum prophylaxis against GBS due to its efficacy and specific, narrow coverage of gram-positive organisms. The updated recommendations emphasize that it is important to carefully evaluate patients with reported penicillin allergies for several reasons: determining risk of anaphylaxis and clindamycin susceptibility testing in GBS evaluations are often overlooked by obstetric providers, the need for antibiotic stewardship to reduce the development of antibiotic resistance, and clarification of allergy status for future health care needs. 

Three recommendations are made: 

• Laboratory requisitions for cultures should specifically note a penicillin allergy so that clindamycin susceptibility testing can be performed. 
• Penicillin allergy skin testing should be considered for patients at unknown or low risk for anaphylaxis, as it is considered safe in pregnancy and most patients (80%-90%) who report a penicillin allergy are actually penicillin tolerant. 
• For patients at high risk for anaphylaxis to penicillin, the recommended vancomycin dosing has been changed from 1 g IV every 12 hours to 20 mg/kg IV every 8 hours (maximum single dose, 2 g). Renal function should be assessed prior to dosing. This weight- and renal function-based dosing increased neonatal therapeutic levels in several studies of different doses.

Continue to: Managing hypertension in pregnancy: New recommendations...

Managing hypertension in pregnancy: New recommendations  

American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 202. Gestational hypertension and preeclampsia. Obstet Gynecol. 2019;133:e1-e25. 

In 2013, ACOG released "Hypertension in pregnancy," a 99-page comprehensive document developed by their Task Force on Hypertension in Pregnancy, to summarize knowledge on the subject, provide guidelines for management, and identify needed areas of research.⁹ I summarized key points from that document in the 2014 "Update on Obstetrics" (OBG Manag. 2013;26[1]:28-36). Now, ACOG has released 2 Practice Bulletins—"Gestational hypertension and preeclampsia" and "Chronic hypertension in pregnancy"—that replace the 2013 document.^10,11 These Practice Bulletins are quite comprehensive and warrant a thorough read. Several noteworthy changes relevant to the practicing obstetrician are summarized below. 

Highlights of revised guidance 

Expectant management vs early delivery in preeclampsia with fetal growth restriction. Fetal growth restriction, which was removed from the definition of preeclampsia with severe features in 2013, is no longer an indication for delivery in preeclampsia with severe features (previously, if the estimated fetal weight was < 5th percentile for gestational age, delivery after steroid administration was recommended). Rather, expectant management is reasonable if fetal antenatal testing, amniotic fluid, and Doppler ultrasound studies are reassuring. Abnormal umbilical artery Doppler studies continue to be an indication for earlier delivery. 

Postpartum NSAID use in hypertension. The 2013 document cautioned against nonsteroidal anti-inflammatory drug (NSAID) use postpartum in women with hypertensive disorders of pregnancy because of concern for exacerbating hypertension. The updated Practice Bulletins recommend NSAIDs as the preferred choice over opioid analgesics as data have not shown these drugs to increase blood pressure, antihypertensive requirements, or other adverse events in postpartum patients with blood pressure issues. 

More women will be diagnosed with chronic hypertension. Recently, the American College of Cardiology and the American Heart Association changed the definition of hypertension. Stage 1 hypertension is now defined as a systolic blood pressure of 130-139 mm Hg or a diastolic blood pressure of 80-89 mm Hg. Treatment of stage 1 hypertension is recommended for nonpregnant adults with risk factors for current or future cardiovascular disease. The potential impact is that more women will enter pregnancy with a diagnosis of chronic hypertension, and more may be on prepregnancy antihypertensive therapy that will need to be addressed during the pregnancy.  

Blood pressure goals. The target blood pressure range for pregnant women with chronic hypertension is recommended to be ≥ 120/80 mm Hg and < 160/110 mm Hg (this represents a slight change, as previously diastolic blood pressure was to be < 105 mm Hg). Postpartum blood pressure goals of < 150/100 mm Hg remain the same. 

Managing acute hypertensive emergencies. Both Practice Bulletins emphasize the importance of aggressive management of acute hypertensive emergency, with options for 3 protocols: labetalol, nifedipine, and hydralazine. The goal is to administer antihypertensive therapy within 30 to 60 minutes, but administration as soon as feasibly possible after diagnosis of severe hypertension is ideal. 

Timing of delivery. Recommended delivery timing in patients with chronic hypertension was slightly altered (previous recommendations included a range of 37 to 39 6/7 weeks). The lower limit of gestational age for recommended delivery timing in chronic hypertension has not changed—it remains not before 38 weeks if no antihypertensive therapy and stable, and not before 37 weeks if antihypertensive therapy and stable.  

The upper limit of 39 6/7 weeks is challenged, however, because data support that induction of labor at either 38 or 39 weeks reduces the risk of severe hypertensive complications (such as superimposed preeclampsia and eclampsia) without increasing the risk of cesarean delivery. Therefore, for patients with chronic hypertension, expectant management beyond 39 weeks is cautioned, to be done only with careful consideration of risks and with close surveillance. 

Attributed to the ancient Greek philosopher Heraclitus, and often quoted in contemporary times, is the expression “the only constant is change.” This sentiment rings true for the field of obstetrics this past year, as several bread-and-butter guidelines for managing common obstetric conditions were either challenged or altered.

The publication of the PROLONG trial called into question the use of intramuscular progesterone for the prevention of preterm birth. Prophylaxis guidelines for group B streptococcal disease were updated, including several significant clinical practice changes. Finally, there was a comprehensive overhaul of the guidelines for hypertensive disorders of pregnancy, which replaced a landmark Task Force document from the American College of Obstetricians and Gynecologists (ACOG) that was published only a few years ago.

Change is constant, and in obstetrics it is vital to keep up with the changing guidelines that result as new data become available for digestion and implementation into everyday clinical practice.

Results from the PROLONG trial may shake up treatment options for recurrent preterm birth 

Blackwell SC, Gyamfi-Bannerman C, Biggio JR Jr, et al. 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG study): a multicenter, international, randomized double-blind trial. Am J Perinatol. 2019. doi: 10.1055/s-0039-3400227. 

The drug 17 α-hydroxyprogesterone caproate (17-OHPC, or 17P; Makena) was approved by the US Food and Drug Administration (FDA) in 2011 for the prevention of spontaneous preterm birth (PTB) in women with a singleton pregnancy and a history of singleton spontaneous PTB. The results of the trial by Meis and colleagues of 17-OHPC played a major role in achieving that approval, as it demonstrated a 34% reduction in recurrent PTB and a reduction in some neonatal morbidities.¹ Following the drug's approval, both ACOG and the Society for Maternal-Fetal Medicine (SMFM) published guidelines recommending progesterone therapy, including 17-OHPC, for the prevention of recurrent spontaneous PTB.²   

The FDA approval of 17-OHPC was granted under an accelerated conditional pathway that required a confirmatory trial evaluating efficacy, safety, and long-term infant follow-up to be performed by the sponsor. That trial, Progestin's Role in Optimizing Neonatal Gestation (PROLONG), was started in 2009, and its results were published on October 25, 2019.³ 

Continue to: Design of the trial...

Design of the trial 

PROLONG was a multicenter (93 sites), randomized, placebo-controlled, double-blind study conducted in 9 countries (23% of participants were in the United States, 60% were in Russia and Ukraine). The co-primary outcome was PTB < 35 weeks and a composite neonatal morbidity and mortality index. The primary safety outcome was fetal/early infant death. 

The study was designed to have 98% power to detect a 30% reduction in PTB < 35 weeks, and 90% power to detect a 35% reduction in the neonatal composite index. It included 1,708 participants (1,130 were treated with 17-OHPC, and 578 received placebo). 

Trial outcomes. There was no difference in PTB < 35 weeks between the 17-OHPC and the placebo groups (11.0% vs 11.5%; relative risk [RR], 0.95; 95% confidence interval [CI], 0.71-1.26). There was no difference in PTB < 32 or < 37 weeks. 

The study revealed also that there was no difference between groups in the neonatal composite index (5.6% for 17-OHPC vs 5.0% for placebo; RR, 1.12; 95% CI, 0.68-1.61). In addition, there was no difference in fetal/early infant death between the 17-OHPC and placebo groups (1.7% vs 1.9%; RR, 0.87; 95% CI, 0.4-1.81). 

Conclusions. The trial investigators concluded that 17-OHPC did not demonstrate a reduction in recurrent PTB and did not decrease neonatal morbidity. 

Study limitations included underpowering and selection bias 

The investigators noted that the PTB rate in PROLONG was unexpectedly almost 50% lower than that in the Meis trial, and that therefore the PROLONG trial was underpowered to assess the primary outcomes. 

Further, the study populations of the 2 trials were very different: The Meis trial included women at higher baseline risk for PTB (> 1 prior PTB and at least 1 other risk factor for PTB). Additionally, while the PROLONG trial included mostly white (90%), married (90%), nonsmoking women (8% smoked), the Meis trial population was 59% black and 50% married, and 20% were smokers.  

The availability and common use of 17-OHPC in the United States likely led to a selection bias for the PROLONG trial population, as the highest-risk patients were most likely already receiving treatment and were therefore excluded from the PROLONG trial. 

Society, and FDA, responses to the new data 

The results of the PROLONG trial call into question what has become standard practice for patients with a history of spontaneous PTB in the United States. While the safety profile of 17-OHPC has not been cited as a concern, whether or not the drug should be used at all has—as has its current FDA-approved status. 

In response to the publication of the PROLONG trial results, ACOG released a Practice Advisory that acknowledged the study's findings but did not alter the current recommendations to continue to offer progesterone for the prevention of preterm birth, upholding ACOG's current Practice Bulletin guidance.^2,4 Additional considerations for offering 17-OHPC use include the patients' preferences, available resources, and the setting for the intervention.  

SMFM's response was more specific, stating that it is reasonable to continue to use 17-OHPC in high-risk patient populations consistent with those in the Meis trial.⁵ In the rest of the general population at risk for recurrent PTB, SMFM recommends that, due to uncertain benefit with 17-OHPC, the high cost, patient discomfort, and increased visits should be taken into account.  

Four days after the publication of the PROLONG study, the FDA Bone, Reproductive, and Urologic Drugs Advisory Committee voted 9-7 to withdraw approval for 17-OHPC.⁶ In response, SMFM released a statement supporting continued access to 17-OHPC.⁷ The FDA's final decision on the status of the drug is expected within the next several months from this writing. 

Continue to: ACOG updates guidance on preventing early-onset GBS disease...

ACOG updates guidance on preventing early-onset GBS disease 

American College of Obstetricians and Gynecologists—Committee on Obstetric Practice. ACOG committee opinion no. 782: prevention of early-onset group B streptococcal disease in newborns. Obstet Gynecol. 2019;134:e19-e40. 

Group B streptococcus (GBS) is the leading cause of newborn infection and is associated with maternal infections as well as preterm labor and stillbirth. Early-onset GBS disease occurs within 7 days of birth and is linked to vertical transmission via maternal colonization of the genitourinary or gastrointestinal tract and fetal/neonatal aspiration at birth.  

Preventing early-onset GBS disease with maternal screening and intrapartum prophylaxis according to the Centers for Disease Control and Prevention (CDC) guidelines has reduced early-onset disease by 80% since the 1990s. By contrast, late-onset GBS infection, which occurs 7 days to 3 months after birth, usually is associated with horizontal maternal transmission or hospital or community infections, and it is not prevented by intrapartum treatment. 

In 2018, the CDC transferred responsibility for GBS prophylaxis guidelines to ACOG and the American Academy of Pediatrics (AAP). In July 2019, ACOG released its Committee Opinion on preventing early-onset GBS disease in newborns.⁸ This guidance replaces and updates the previous guidelines, with 3 notable changes.  

The screening timing has changed 

In the CDC's 2010 guidelines, GBS screening was recommended to start at 35 weeks' gestation. The new guidelines recommend universal vaginal-rectal screening at 36 to 37 6/7 weeks' gestation. The new timing of culture will shift the expected 5-week window in which GBS cultures are considered valid up to at least 41 weeks' gestation. The rationale  for this change is that any GBS-unknown patient who previously would have been cultured under 37 weeks' would be an automatic candidate for empiric therapy and the lower rate of birth in the 35th versus the 41st week of gestation. 

Identifying candidates for intrapartum treatment 

The usual indications for intrapartum antibiotic prophylaxis include a GBS-positive culture at 36 weeks or beyond, GBS bacteriuria at any point in pregnancy, a prior GBS-affected child, or unknown GBS status with any of the following: < 37 weeks, rupture of membranes ≥ 18 hours or temperature ≥ 100.4°F (38°C), and a positive rapid GBS culture in labor. In addition, antibiotics now should be considered for patients at term with unknown GBS status but with a history of GBS colonization in a prior pregnancy.  

This represents a major practice change for women at ≥ 37 weeks with unknown GBS status and no other traditional risk factors. The rationale for this recommendation is that women who have been positive for GBS in a prior pregnancy have a 50% chance of being colonized in the current pregnancy, and their newborns are therefore at higher risk for early-onset GBS disease.  

Managing patients with penicillin allergy 

Intravenous penicillin (or ampicillin) remains the antibiotic of choice for intrapartum prophylaxis against GBS due to its efficacy and specific, narrow coverage of gram-positive organisms. The updated recommendations emphasize that it is important to carefully evaluate patients with reported penicillin allergies for several reasons: determining risk of anaphylaxis and clindamycin susceptibility testing in GBS evaluations are often overlooked by obstetric providers, the need for antibiotic stewardship to reduce the development of antibiotic resistance, and clarification of allergy status for future health care needs. 

Three recommendations are made: 

• Laboratory requisitions for cultures should specifically note a penicillin allergy so that clindamycin susceptibility testing can be performed. 
• Penicillin allergy skin testing should be considered for patients at unknown or low risk for anaphylaxis, as it is considered safe in pregnancy and most patients (80%-90%) who report a penicillin allergy are actually penicillin tolerant. 
• For patients at high risk for anaphylaxis to penicillin, the recommended vancomycin dosing has been changed from 1 g IV every 12 hours to 20 mg/kg IV every 8 hours (maximum single dose, 2 g). Renal function should be assessed prior to dosing. This weight- and renal function-based dosing increased neonatal therapeutic levels in several studies of different doses.

Continue to: Managing hypertension in pregnancy: New recommendations...

Managing hypertension in pregnancy: New recommendations  

American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 202. Gestational hypertension and preeclampsia. Obstet Gynecol. 2019;133:e1-e25. 

In 2013, ACOG released "Hypertension in pregnancy," a 99-page comprehensive document developed by their Task Force on Hypertension in Pregnancy, to summarize knowledge on the subject, provide guidelines for management, and identify needed areas of research.⁹ I summarized key points from that document in the 2014 "Update on Obstetrics" (OBG Manag. 2013;26[1]:28-36). Now, ACOG has released 2 Practice Bulletins—"Gestational hypertension and preeclampsia" and "Chronic hypertension in pregnancy"—that replace the 2013 document.^10,11 These Practice Bulletins are quite comprehensive and warrant a thorough read. Several noteworthy changes relevant to the practicing obstetrician are summarized below. 

Highlights of revised guidance 

Expectant management vs early delivery in preeclampsia with fetal growth restriction. Fetal growth restriction, which was removed from the definition of preeclampsia with severe features in 2013, is no longer an indication for delivery in preeclampsia with severe features (previously, if the estimated fetal weight was < 5th percentile for gestational age, delivery after steroid administration was recommended). Rather, expectant management is reasonable if fetal antenatal testing, amniotic fluid, and Doppler ultrasound studies are reassuring. Abnormal umbilical artery Doppler studies continue to be an indication for earlier delivery. 

Postpartum NSAID use in hypertension. The 2013 document cautioned against nonsteroidal anti-inflammatory drug (NSAID) use postpartum in women with hypertensive disorders of pregnancy because of concern for exacerbating hypertension. The updated Practice Bulletins recommend NSAIDs as the preferred choice over opioid analgesics as data have not shown these drugs to increase blood pressure, antihypertensive requirements, or other adverse events in postpartum patients with blood pressure issues. 

More women will be diagnosed with chronic hypertension. Recently, the American College of Cardiology and the American Heart Association changed the definition of hypertension. Stage 1 hypertension is now defined as a systolic blood pressure of 130-139 mm Hg or a diastolic blood pressure of 80-89 mm Hg. Treatment of stage 1 hypertension is recommended for nonpregnant adults with risk factors for current or future cardiovascular disease. The potential impact is that more women will enter pregnancy with a diagnosis of chronic hypertension, and more may be on prepregnancy antihypertensive therapy that will need to be addressed during the pregnancy.  

Blood pressure goals. The target blood pressure range for pregnant women with chronic hypertension is recommended to be ≥ 120/80 mm Hg and < 160/110 mm Hg (this represents a slight change, as previously diastolic blood pressure was to be < 105 mm Hg). Postpartum blood pressure goals of < 150/100 mm Hg remain the same.