Nonmelanoma Skin Cancer

Practice Gap

Dermatology residents can struggle with surgical closure early in their training years. Although experienced dermatologic surgeons may intuitively be able to align edges for maximal cosmesis, doing so can prove challenging in the context of learning basic surgical techniques for early residents.

Furthermore, local anesthesia can distort cutaneous anatomy and surgical landmarks, requiring the surgeon to reexamine their closure technique. Patients may require position changes or may make involuntary movements, both of which require dynamic thinking and planning on the part of the dermatologic surgeon to achieve optimal outcomes.

The Technique

We propose the use of sutures to intraoperatively guide placement of the dermal needle. This technique can be used for various closure types; here, we demonstrate its use in a standard elliptical excision.

To begin, a standard length to width ellipse ratio of 3:1 is drawn with appropriate margins around a neoplasm.¹ After excision and appropriate undermining of the ellipse, we typically use deep sutures to close the deep space. The first pass of the needle through tissue can be performed in a place of the surgeon’s preference but typically abides by the rule of halves or the zipper method (Figure 1A). To determine optimal placement of the second needle pass through tissue, we recommend applying gentle opposing traction forces to the wound apices to approximate the linear outcome of the wound edges. The surgeon can use a skin hook to guide placement of the needle to the contralateral wound edge in an unassisted method of this technique (Figure 1B). The surgeon’s assistant also can aid in applying cutaneous traction along the length of the excision if the surgeon wishes to free their hands (Figure 1C). Because the risk of needlestick injury at this step is small, it is prudent for the surgeon to advise the assistant to avoid needlestick injury by keeping their hands away from the needle path in the surgical site.

Although traction is being applied to the wound apices, the deep suture should extend across the wound with just enough pressure to leave a serosanguineous notched mark in the contralateral tissue edge (Figure 1D). After releasing traction on the wound edges, the surgeon can effortlessly visualize the target for needle placement and make a throw through the tissue accordingly.

This process can be continued until wound closure is complete (Figure 2). Top sutures or adhesive strips can be placed afterward for completing approximation of the wound edges superficially.

Practice Implications

By using this technique to align wound edges intraoperatively, the surgeon can have a functional guide for needle placement. The technique allows improvement of function and cosmesis of surgical wounds, while also accounting for topographical variations in the patient’s surgical site. Approximation of the wound edges is particularly important at the beginning of closure, as the wound edges align and approximate more with each subsequent stitch, with decreasing tension.²

In addition, when operating on a curvilinear or challenging topographical surface of the body, this technique can provide a clear template for guiding suture placement for approximating wound edges. Furthermore, local biodynamic anatomy might become distorted after excision of the tissue specimen due to release of centripetal tangential forces that were present in the pre-excised skin.¹ Local change in biodynamic forces may be difficult to plan for preoperatively using other techniques.³

Although this technique can be utilized for all suture placements in closure, it is of greatest value when placing the first few sutures and when operating on nonplanar surfaces that might become distorted after excision. To ensure the best outcome, it is important to be certain that the area has been properly cleaned prior to surgery and a sterile technique is used.

Practice Gap

Dermatology residents can struggle with surgical closure early in their training years. Although experienced dermatologic surgeons may intuitively be able to align edges for maximal cosmesis, doing so can prove challenging in the context of learning basic surgical techniques for early residents.

Furthermore, local anesthesia can distort cutaneous anatomy and surgical landmarks, requiring the surgeon to reexamine their closure technique. Patients may require position changes or may make involuntary movements, both of which require dynamic thinking and planning on the part of the dermatologic surgeon to achieve optimal outcomes.

The Technique

We propose the use of sutures to intraoperatively guide placement of the dermal needle. This technique can be used for various closure types; here, we demonstrate its use in a standard elliptical excision.

To begin, a standard length to width ellipse ratio of 3:1 is drawn with appropriate margins around a neoplasm.¹ After excision and appropriate undermining of the ellipse, we typically use deep sutures to close the deep space. The first pass of the needle through tissue can be performed in a place of the surgeon’s preference but typically abides by the rule of halves or the zipper method (Figure 1A). To determine optimal placement of the second needle pass through tissue, we recommend applying gentle opposing traction forces to the wound apices to approximate the linear outcome of the wound edges. The surgeon can use a skin hook to guide placement of the needle to the contralateral wound edge in an unassisted method of this technique (Figure 1B). The surgeon’s assistant also can aid in applying cutaneous traction along the length of the excision if the surgeon wishes to free their hands (Figure 1C). Because the risk of needlestick injury at this step is small, it is prudent for the surgeon to advise the assistant to avoid needlestick injury by keeping their hands away from the needle path in the surgical site.

Although traction is being applied to the wound apices, the deep suture should extend across the wound with just enough pressure to leave a serosanguineous notched mark in the contralateral tissue edge (Figure 1D). After releasing traction on the wound edges, the surgeon can effortlessly visualize the target for needle placement and make a throw through the tissue accordingly.

This process can be continued until wound closure is complete (Figure 2). Top sutures or adhesive strips can be placed afterward for completing approximation of the wound edges superficially.

Practice Implications

By using this technique to align wound edges intraoperatively, the surgeon can have a functional guide for needle placement. The technique allows improvement of function and cosmesis of surgical wounds, while also accounting for topographical variations in the patient’s surgical site. Approximation of the wound edges is particularly important at the beginning of closure, as the wound edges align and approximate more with each subsequent stitch, with decreasing tension.²

In addition, when operating on a curvilinear or challenging topographical surface of the body, this technique can provide a clear template for guiding suture placement for approximating wound edges. Furthermore, local biodynamic anatomy might become distorted after excision of the tissue specimen due to release of centripetal tangential forces that were present in the pre-excised skin.¹ Local change in biodynamic forces may be difficult to plan for preoperatively using other techniques.³

Although this technique can be utilized for all suture placements in closure, it is of greatest value when placing the first few sutures and when operating on nonplanar surfaces that might become distorted after excision. To ensure the best outcome, it is important to be certain that the area has been properly cleaned prior to surgery and a sterile technique is used.

Practice Gap

Dermatology residents can struggle with surgical closure early in their training years. Although experienced dermatologic surgeons may intuitively be able to align edges for maximal cosmesis, doing so can prove challenging in the context of learning basic surgical techniques for early residents.

Furthermore, local anesthesia can distort cutaneous anatomy and surgical landmarks, requiring the surgeon to reexamine their closure technique. Patients may require position changes or may make involuntary movements, both of which require dynamic thinking and planning on the part of the dermatologic surgeon to achieve optimal outcomes.

The Technique

We propose the use of sutures to intraoperatively guide placement of the dermal needle. This technique can be used for various closure types; here, we demonstrate its use in a standard elliptical excision.

To begin, a standard length to width ellipse ratio of 3:1 is drawn with appropriate margins around a neoplasm.¹ After excision and appropriate undermining of the ellipse, we typically use deep sutures to close the deep space. The first pass of the needle through tissue can be performed in a place of the surgeon’s preference but typically abides by the rule of halves or the zipper method (Figure 1A). To determine optimal placement of the second needle pass through tissue, we recommend applying gentle opposing traction forces to the wound apices to approximate the linear outcome of the wound edges. The surgeon can use a skin hook to guide placement of the needle to the contralateral wound edge in an unassisted method of this technique (Figure 1B). The surgeon’s assistant also can aid in applying cutaneous traction along the length of the excision if the surgeon wishes to free their hands (Figure 1C). Because the risk of needlestick injury at this step is small, it is prudent for the surgeon to advise the assistant to avoid needlestick injury by keeping their hands away from the needle path in the surgical site.

Although traction is being applied to the wound apices, the deep suture should extend across the wound with just enough pressure to leave a serosanguineous notched mark in the contralateral tissue edge (Figure 1D). After releasing traction on the wound edges, the surgeon can effortlessly visualize the target for needle placement and make a throw through the tissue accordingly.

This process can be continued until wound closure is complete (Figure 2). Top sutures or adhesive strips can be placed afterward for completing approximation of the wound edges superficially.

Practice Implications

By using this technique to align wound edges intraoperatively, the surgeon can have a functional guide for needle placement. The technique allows improvement of function and cosmesis of surgical wounds, while also accounting for topographical variations in the patient’s surgical site. Approximation of the wound edges is particularly important at the beginning of closure, as the wound edges align and approximate more with each subsequent stitch, with decreasing tension.²

In addition, when operating on a curvilinear or challenging topographical surface of the body, this technique can provide a clear template for guiding suture placement for approximating wound edges. Furthermore, local biodynamic anatomy might become distorted after excision of the tissue specimen due to release of centripetal tangential forces that were present in the pre-excised skin.¹ Local change in biodynamic forces may be difficult to plan for preoperatively using other techniques.³

Although this technique can be utilized for all suture placements in closure, it is of greatest value when placing the first few sutures and when operating on nonplanar surfaces that might become distorted after excision. To ensure the best outcome, it is important to be certain that the area has been properly cleaned prior to surgery and a sterile technique is used.

Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and affects more than 3 million individuals per year in the United States.¹ Approximately 40% of patients diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis.² Most cases are successfully treated with surgical excision and occasionally topical therapy or radiotherapy. Despite the high cure rate with conventional treatments, BCC can recur and can cause substantial destruction of the surrounding tissue if left untreated.^3-5 In some instances, BCC can even metastasize and lead to death.⁶ For patients who are poor candidates for surgical or topical treatment modalities because of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic treatment may be indicated. Vismodegib, sonidegib, and cemiplimab are the only systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of laBCC and/or mBCC. Vismodegib and sonidegib target the sonic hedgehog (SHH) signaling pathway that is abnormally activated in more than 90% of BCCs.⁷ Cemiplimab is an immune checkpoint inhibitor (ICI) that targets the programmed cell death protein 1 (PD-1) receptor.⁸ Herein, we review the clinical utility of these medications and their evolving roles in the treatment of BCC.

SHH Pathway Inhibitors

The SHH pathway is a key regulator of cell proliferation and differentiation during embryogenesis.⁷ During adulthood, SHH signaling decreases but still plays an important role in stem cell activation and in regulation of the hair follicle growth cycle.^9,10 However, de novo mutations in the genes that comprise the SHH pathway can result in aberrant constitutive activation, leading to unrestricted cell proliferation. Genetic mutations resulting in activation of Smoothened (SMO), a G-protein–coupled receptor involved in the signal transduction and propagation of the SHH pathway, have been implicated in the pathogenesis of BCC. Inactivating mutations also are commonly observed in patched homolog 1, an upstream cell-surface protein that inhibits SMO.⁷ The mechanism by which vismodegib and sonidegib, 2 of the FDA-approved oral medications for the treatment of advanced BCC, block the SHH pathway is through the selective inhibition of SMO.^7,11

Vismodegib first received FDA approval in 2012 for the treatment of laBCC and mBCC after initial results from the pivotal ERIVANCE phase 2 trial demonstrated an objective response rate (ORR) of 43% (27/63) and 30% (10/33) in patients with locally advanced and metastatic disease, respectively. In this single-arm study, all enrolled patients (63 with laBCC and 33 with mBCC) received 150 mg of oral vismodegib daily.¹² Updated results at 39 months demonstrated improved ORRs of 60% (38/63) and 48% (16/33) for the laBCC and mBCC groups, respectively. A complete response (CR) and partial response (PR) were observed in 32% (n=20) and 29% (n=18) of patients with laBCC, respectively.¹³ These results have been confirmed in subsequent studies, including the large international open-label trial known as STEVIE, with ORRs of 68.5% for 1119 cases of laBCC and 37% for 96 cases of mBCC.^14-17 The CR and PR rates were 33% and 35%, respectively, for the laBCC group. The CR and PR rates for the mBCC group were 5% and 32%, respectively.¹⁴

The FDA approval of sonidegib for laBCC—but not mBCC—occurred in 2015 after the pivotal BOLT randomized phase 2 trial demonstrated an initial ORR of 43% (18/42) for laBCC and 15% (2/13) for mBCC after administration of 200 mg of sonidegib daily.¹⁸ A final follow-up analysis at 42 months resulted in ORRs of 56% (37/66) and 8% (1/13) for the laBCC and mBCC groups, respectively.¹⁹ Additionally, improved efficacy was not observed in the 151 patients who were randomized to receive treatment with the higher 800-mg dose; however, they did experience a higher incidence of adverse events.^18,19

Currently, the true clinical differences between vismodegib and sonidegib remain uncertain, as no head-to-head trials have been conducted. Moreover, direct comparison of the data from the ERIVANCE and BOLT trials is challenging owing to fundamental differences in methodologic design, including the criteria used to assess BCC severity. The ERIVANCE trial utilized the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while BOLT used the rigorous modified RECIST. However, an expert consensus study attempted to compare the 2 trials by modifying the outcomes from BOLT with the former RECIST criteria. The expert group found that the 2 SHH inhibitors had comparable efficacy and adverse event profiles.²⁰ Nevertheless, a recent meta-analysis found that although ORRs for laBCC were similar between the 2 drugs, the CR rate for vismodegib was 31% compared with 3% for sonidegib. Additionally, for mBCC, they reported the ORR of vismodegib to be 2.7 times higher than that of sonidegib (39% vs 15%).²¹

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have successfully been utilized in the treatment of cutaneous squamous cell carcinoma (cSCC); however, their use for treating BCC has been limited until recently.^22-25 In February 2021, cemiplimab became the first and only ICI approved for the treatment of laBCC and mBCC in patients who did not respond to or were intolerant to prior SHH inhibitor therapy.²⁶ Cemiplimab—a human monoclonal antibody against the PD-1 receptor expressed on T cells—blocks its interaction with programmed cell death ligand 1 and programmed cell death ligand 2 present on tumor cells. The blockade of the PD-1 pathway releases the inhibition of the antitumor immune response and enables appropriate cytotoxic T-cell activity to occur.⁸

The FDA approval of cemiplimab for the treatment of advanced BCC was based on an open-label, multicenter, single-arm phase 2 trial (NCT03132636) evaluating 84 patients with laBCC refractory or intolerant to SHH inhibitor therapy.²⁶ Patients received an intravenous infusion of cemiplimab 350 mg every 3 weeks for up to 93 weeks or until disease progression or unacceptable toxicity. An ORR of 31% (26/84) was observed with a CR and PR of 6% (5/84) and 25% (21/84), respectively. The median duration of follow-up was 15 months.²⁶ Given the clinically meaningful results of this trial, investigating the efficacy of other PD-1 inhibitors, such as pembrolizumab and nivolumab, for treatment of advanced BCC may prove worthwhile.

The 2 approved SHH inhibitors—vismodegib and sonidegib—appear to have similar side-effect profiles, with the most common adverse effects being muscle spasms, dysgeusia, alopecia, nausea, vomiting, diarrhea, weight loss, and fatigue.^20,21,27 These side effects occur at high frequencies (>40%) for both SHH inhibitors and often lead to discontinuation of the medication.²¹ Rates of treatment discontinuation range from 15% to 50% on average.^12-14,18 Fortunately, the majority of these adverse effects do not appear to increase in severity or frequency with prolonged use of these medications.^14,16,28

Various conservative and pharmacologic measures can be implemented to help manage side effects. For muscle spasms, which are the most commonly reported adverse effect, supplementation with magnesium, transcutaneous electrical nerve stimulation, acupuncture, massages, stretching, and thermal compresses can potentially be beneficial.²⁹ Calcium channel blockers also may be effective, as one small prospective cohort study reported a reduction in the frequency of muscle cramps with amlodipine 10 mg daily.³⁰ For alopecia, which typically is reversible and caused by SHH inhibition of the normal hair cycle, minoxidil theoretically can help, as it reduces telogen arrest and extends the anagen growth phase.^31,32 Although usually mild and self-limiting, management of dysgeusia, weight loss, and gastrointestinal upset often can be managed with dietary changes, such as smaller, more frequent meals.^33,34 Finally, alternative dosing strategies and drug holidays have been employed to mitigate these side effects and increase drug tolerability.^35,36 These are discussed in the Alternative Dosing section.

Given the essential role of the SHH pathway in embryologic development, SHH inhibitors carry a black box warning of embryofetal teratogenicity and are contraindicated in females who are pregnant or breastfeeding. For females of reproductive potential, verification of pregnancy status should be performed prior to initiating treatment with an SHH inhibitor. These patients should be counseled on the use of contraception during treatment and for at least 24 months and 20 months after cessation of vismodegib and sonidegib, respectively.^27,37,38 Male patients, even after a vasectomy, should use barrier contraception during treatment and for at least 3 months and 8 months after the final dose of vismodegib and sonidegib, respectively.^37,38

Laboratory abnormalities commonly associated with SHH inhibitors include elevated hepatic enzymes, particularly with vismodegib, and elevated creatine kinase levels, particularly with sonidegib.^28,39 Other laboratory abnormalities that can occur include hypercholesterolemia, hypercreatininemia, hyperglycemia, and increased serum lipase levels.^19,28 Although these laboratory abnormalities usually are asymptomatic and self-limiting, regular monitoring should be performed.

There also is concern that SHH inhibitors may induce the development of cSCC. A case-control study of 55 cases and 125 control patients found an increased risk for cSCC in those previously treated with vismodegib, with a hazard ratio of 8.12.⁴⁰ However, a subsequent retrospective cohort study of 1675 patients with BCC failed to find any association with cSCC among those treated with vismodegib compared to those who received standard surgical therapy.⁴¹ Clinical data for sonidegib are lacking, but the BOLT trial found that cSCC occurred in 3 patients receiving treatment with the SHH inhibitor.¹⁸ Thus, further studies are needed to more thoroughly assess this concern. Close monitoring for cSCC may be warranted in patients prescribed SHH inhibitors at this time.

Cemiplimab has demonstrated an acceptable safety profile and is generally well tolerated. In the phase 2 trial of cemiplimab for cSCC, approximately 5% of patients discontinued treatment because of adverse effects. The most commonly reported side effects of cemiplimab were diarrhea (27%), fatigue (24%), nausea (17%), constipation (15%), and rash (15%).²³ In the phase 2 trial for laBCC, grade 3 or 4 adverse events occurred in 48% of patients, with hypertension (5%) being the most common.²⁶ Although rare, immune-mediated adverse reactions also can occur, given the mechanism of action of ICIs. These side effects, ranging in severity from mild to fatal, include pneumonitis, colitis, hepatitis, nephritis, myocarditis, and hypophysitis. Therefore, close monitoring for these immune-mediated reactions is critical, but most can be managed with corticosteroids or treatment interruption if they occur.^42,43

No absolute contraindications exist for cemiplimab; however, extreme caution should be taken in immunosuppressed individuals, such as solid organ transplant recipients and those with chronic lymphocytic leukemia (CLL), as safety data are limited in these patients.^44,45 Although small retrospective studies have reported reasonable tolerability in solid organ transplant recipients treated with ICIs, an allograft rejection rate of 41% was found in a meta-analysis of 64 patients.^46-48 In CLL patients with keratinocyte carcinomas, ICIs have been safely used and have even demonstrated efficacy for CLL in some cases.^49-52

Alternative Dosing

The side effects of SHH inhibitors have led to alternative dosing strategies to prevent medication discontinuation and improve adherence. In patients with basal cell nevus syndrome, multimonth drug holidays have been shown to increase drug tolerability without compromising efficacy.^35,36 Weekly intermittent dosing regimens of vismodegib ranging from 1 week on followed by 1 to 3 weeks off demonstrated efficacy in a retrospective study of 7 patients with advanced BCC.⁵³ All 7 patients experienced improvement in their BCCs, with 3 patients experiencing CR. Importantly, treatment-related adverse effects were mild and well tolerated, with no patients terminating the medication.⁵³ Two other retrospective case series of patients with advanced BCC treated with vismodegib reported similar findings for those placed on an intermittent dosing schedule ranging from once every other day to once per week.^54,55

In the large phase 2 randomized trial known as MIKIE, 2 different intermittent dosing regimens of 150 mg vismodegib daily for patients with multiple BCCs were found to have good activity and tolerability.⁵⁶ The first group (n=116) received vismodegib for 12 weeks, then 3 rounds of 8 weeks of placebo, followed by 12 weeks of vismodegib; there was a 63% reduction in clinically evident BCCs after 73 weeks. The second group (n=113) received the medication for 24 weeks, then 3 rounds of 8 weeks of placebo, followed by 8 weeks of vismodegib; there was a 54% reduction at the end of 73 weeks.⁵⁶ Subsequent analyses found improvements in health-related quality-of-life outcomes that were similar for both groups.⁵⁷

Consequently, alternative dosing schedules appear to be a viable option for patients at risk of discontinuing treatment because of adverse effects, and current data support the recently approved recommendations of dose interruptions of up to 8 weeks to manage adverse effects in patients with laBCC or mBCC.⁵⁸ Nevertheless, further clinical studies are required to determine the optimal intermittent dosing regimen for patients treated with SHH inhibitors.

Neoadjuvant Administration

Recently, vismodegib has been studied as a neoadjuvant therapy for BCC with promising results. Several small retrospective studies and case reports have documented successful treatment of both operable and inoperable periocular laBCC, with preservation of the eye in all patients.^59-61 An open-label trial of 15 patients with advanced BCC who received neoadjuvant vismodegib for 3 to 6 months prior to surgical excision reported a mean reduction of 35% in the final surgical defect size, with no recurrence at 22 months.^62,63 The latest and largest study performed was a phase 2 open-label trial known as VISMONEO, where 44 of 55 laBCC patients (80%) receiving neoadjuvant vismodegib for a mean duration of 6 months (range, 4–10 months) achieved the primary end point of tumor surgical downstaging.⁶⁴ Of the 44 patients who had tumor downstaging, 27 (61%) experienced histologically proven CRs. Additionally, a 66% reduction in the average target lesion size was reported in this group compared to29% in the 11 patients who did not have tumor downstaging (P=.0002).⁶⁴ Thus, SHH inhibitors may hold an important neoadjuvant role in the treatment of BCC by decreasing surgical defect size and allowing for surgical management of previously inoperable cases.

Synergism With Radiation

Preliminary data suggest SHH inhibitors may help potentiate the effects of radiation therapy for the treatment of BCC. Currently, the evidence primarily is limited to case studies, with several reports describing complete remission in patients with advanced BCCs who were considered unsuitable candidates for surgery. In these cases, vismodegib was administered either prior to or concurrently with radiation treatment.^65-69 An in vitro study also documented the radiation-sensitizing effects of vismodegib in a BCC cell line.⁷⁰ Recently, a phase 2 trial (ClinicalTrials.gov identifier NCT01835626) evaluating the concurrent use of vismodegib and radiotherapy for patients with advanced BCC was completed, but data has yet to be published.

Synergism With and Benefit of Antifungal Therapy

The antifungal drug itraconazole is a potent inhibitor of the SHH pathway and may have an adjunctive role in the treatment of BCC. Similar to vismodegib and sonidegib, itraconazole acts as a direct antagonist of SMO. However, it is thought to bind to a distinct site on SMO.^71,72 An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.⁷³ In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).⁷⁴ One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.⁷⁵ The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.⁷⁶

Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.⁷⁷ Although clinical data are lacking, a basic science study found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).⁷⁸ Furthermore, posaconazole has demonstrated a better safety profile with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.^79,80 Thus, posaconazole may be a safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the 2 currently approved SHH inhibitors for the treatment of advanced BCC.

Treatment resistance to SHH inhibitors, though uncommon, is a growing concern. Acquired mutations in the SMO binding site or downstream mediators of the SHH pathway have been shown to confer resistance to vismodegib and sonidegib.^72,81-83 In addition, it appears that there may be shared resistance among the drugs in this class. One study assessing the efficacy of sonidegib in 9 patients with laBCC resistant to vismodegib found that these patients also did not respond to sonidegib.⁸⁴ Interestingly, 1 case report documented tumor regression of an intracranial BCC in a patient treated with sonidegib and itraconazole after failure with vismodegib.⁸⁵ An in vitro study also found that itraconazole maintained SHH inhibitory activity for all drug-resistant SMO mutations that have been reported.⁷² Therefore, itraconazole monotherapy or combination therapy with a canonical SHH inhibitor may be considered for patients with recalcitrant BCC and warrants further investigation.

Taladegib is a newly developed SMO inhibitor that may serve as another promising alternative for patients who develop resistance to vismodegib or sonidegib. A phase 1 trial of taladegib for advanced BCC found an ORR of 69% (11/16) in the SHH inhibitor–naïve group and an ORR of 36% (11/32) in the group previously treated with a SHH inhibitor.⁸⁶ Additionally, the safety profile and frequency of adverse effects appear to be similar to those associated with vismodegib and sonidegib.^86,87 Unfortunately, no clinical trials evaluating taladegib for BCC are ongoing or in development at this time.

Recurrence

There appears to be a relatively high rate of recurrence for BCC patients who achieve a CR to SHH inhibitors. In a retrospective study of 116 laBCC patients who experienced a CR after vismodegib therapy, 54 patients (47%) relapsed at 36 months. Among the 54 patients that relapsed, 27 were re-treated with vismodegib, which resulted in an ORR of 85% (23/27), a CR rate of 37% (10/27), and a PR rate of 48% (13/27).⁸⁸ Another retrospective study of 35 laBCC patients who relapsed after vismodegib treatment reported a 31% (11/35) clinical recurrence rate at 6-month follow-up.⁸⁹ An observational retrospective study also assessed the efficacy of SHH inhibitor maintenance therapy for advanced BCC patients who achieved a CR.⁹⁰ In the study, 27 (64%) patients received a maintenance dose of 150 mg vismodegib once per week for 1 year, while 15 (36%) patients decided not to take a maintenance dose following CR of their BCC. All patients who took the maintenance therapy did not experience clinical recurrence at 1-year follow-up, whereas 26% of patients not on the maintenance dose relapsed.⁹⁰ Consequently, these results indicate that BCC recurrence is frequent after SHH inhibitor therapy and highlights the importance of close surveillance after CR is attained. Nevertheless, most patients still respond to treatment with SHH inhibitors after relapsing, and intermittent maintenance doses may be an effective means to reduce risk of recurrence.

Conclusion

Vismodegib and sonidegib are SHH inhibitors approved for the treatment of laBCC and mBCC. Cemiplimab is now also approved for patients who do not respond to SHH inhibitors or for whom SHH inhibitors are not tolerable. Although these systemic targeted therapies can lead to notable tumor shrinkage and even complete regression in some patients, recurrence is common, and adverse effects may limit their use. Drug resistance is an emerging issue that requires additional examination. Further clinical studies are needed to determine which patients are likely to respond to these targeted treatments.

Various intermittent and maintenance drug regimens should be evaluated for their potential to mitigate adverse effects and reduce risk of recurrence, respectively. The synergistic effects of these medications with other therapies as well as their neoadjuvant and adjuvant roles should be further investigated. For example, administration of an SHH inhibitor prior to surgical excision of a BCC may allow for a smaller surgical defect size, thereby improving cosmetic and functional outcomes. Moreover, these systemic targeted medications may allow for previously inoperable tumors to become amenable to surgical treatment.

Although SHH inhibitors and PD-1 inhibitors represent a major advancement in the field of oncodermatology, real-world efficacy and safety data in the upcoming years will be important for elucidating their true benefit for patients with BCC.

Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and affects more than 3 million individuals per year in the United States.¹ Approximately 40% of patients diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis.² Most cases are successfully treated with surgical excision and occasionally topical therapy or radiotherapy. Despite the high cure rate with conventional treatments, BCC can recur and can cause substantial destruction of the surrounding tissue if left untreated.^3-5 In some instances, BCC can even metastasize and lead to death.⁶ For patients who are poor candidates for surgical or topical treatment modalities because of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic treatment may be indicated. Vismodegib, sonidegib, and cemiplimab are the only systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of laBCC and/or mBCC. Vismodegib and sonidegib target the sonic hedgehog (SHH) signaling pathway that is abnormally activated in more than 90% of BCCs.⁷ Cemiplimab is an immune checkpoint inhibitor (ICI) that targets the programmed cell death protein 1 (PD-1) receptor.⁸ Herein, we review the clinical utility of these medications and their evolving roles in the treatment of BCC.

SHH Pathway Inhibitors

The SHH pathway is a key regulator of cell proliferation and differentiation during embryogenesis.⁷ During adulthood, SHH signaling decreases but still plays an important role in stem cell activation and in regulation of the hair follicle growth cycle.^9,10 However, de novo mutations in the genes that comprise the SHH pathway can result in aberrant constitutive activation, leading to unrestricted cell proliferation. Genetic mutations resulting in activation of Smoothened (SMO), a G-protein–coupled receptor involved in the signal transduction and propagation of the SHH pathway, have been implicated in the pathogenesis of BCC. Inactivating mutations also are commonly observed in patched homolog 1, an upstream cell-surface protein that inhibits SMO.⁷ The mechanism by which vismodegib and sonidegib, 2 of the FDA-approved oral medications for the treatment of advanced BCC, block the SHH pathway is through the selective inhibition of SMO.^7,11

Vismodegib first received FDA approval in 2012 for the treatment of laBCC and mBCC after initial results from the pivotal ERIVANCE phase 2 trial demonstrated an objective response rate (ORR) of 43% (27/63) and 30% (10/33) in patients with locally advanced and metastatic disease, respectively. In this single-arm study, all enrolled patients (63 with laBCC and 33 with mBCC) received 150 mg of oral vismodegib daily.¹² Updated results at 39 months demonstrated improved ORRs of 60% (38/63) and 48% (16/33) for the laBCC and mBCC groups, respectively. A complete response (CR) and partial response (PR) were observed in 32% (n=20) and 29% (n=18) of patients with laBCC, respectively.¹³ These results have been confirmed in subsequent studies, including the large international open-label trial known as STEVIE, with ORRs of 68.5% for 1119 cases of laBCC and 37% for 96 cases of mBCC.^14-17 The CR and PR rates were 33% and 35%, respectively, for the laBCC group. The CR and PR rates for the mBCC group were 5% and 32%, respectively.¹⁴

The FDA approval of sonidegib for laBCC—but not mBCC—occurred in 2015 after the pivotal BOLT randomized phase 2 trial demonstrated an initial ORR of 43% (18/42) for laBCC and 15% (2/13) for mBCC after administration of 200 mg of sonidegib daily.¹⁸ A final follow-up analysis at 42 months resulted in ORRs of 56% (37/66) and 8% (1/13) for the laBCC and mBCC groups, respectively.¹⁹ Additionally, improved efficacy was not observed in the 151 patients who were randomized to receive treatment with the higher 800-mg dose; however, they did experience a higher incidence of adverse events.^18,19

Currently, the true clinical differences between vismodegib and sonidegib remain uncertain, as no head-to-head trials have been conducted. Moreover, direct comparison of the data from the ERIVANCE and BOLT trials is challenging owing to fundamental differences in methodologic design, including the criteria used to assess BCC severity. The ERIVANCE trial utilized the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while BOLT used the rigorous modified RECIST. However, an expert consensus study attempted to compare the 2 trials by modifying the outcomes from BOLT with the former RECIST criteria. The expert group found that the 2 SHH inhibitors had comparable efficacy and adverse event profiles.²⁰ Nevertheless, a recent meta-analysis found that although ORRs for laBCC were similar between the 2 drugs, the CR rate for vismodegib was 31% compared with 3% for sonidegib. Additionally, for mBCC, they reported the ORR of vismodegib to be 2.7 times higher than that of sonidegib (39% vs 15%).²¹

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have successfully been utilized in the treatment of cutaneous squamous cell carcinoma (cSCC); however, their use for treating BCC has been limited until recently.^22-25 In February 2021, cemiplimab became the first and only ICI approved for the treatment of laBCC and mBCC in patients who did not respond to or were intolerant to prior SHH inhibitor therapy.²⁶ Cemiplimab—a human monoclonal antibody against the PD-1 receptor expressed on T cells—blocks its interaction with programmed cell death ligand 1 and programmed cell death ligand 2 present on tumor cells. The blockade of the PD-1 pathway releases the inhibition of the antitumor immune response and enables appropriate cytotoxic T-cell activity to occur.⁸

The FDA approval of cemiplimab for the treatment of advanced BCC was based on an open-label, multicenter, single-arm phase 2 trial (NCT03132636) evaluating 84 patients with laBCC refractory or intolerant to SHH inhibitor therapy.²⁶ Patients received an intravenous infusion of cemiplimab 350 mg every 3 weeks for up to 93 weeks or until disease progression or unacceptable toxicity. An ORR of 31% (26/84) was observed with a CR and PR of 6% (5/84) and 25% (21/84), respectively. The median duration of follow-up was 15 months.²⁶ Given the clinically meaningful results of this trial, investigating the efficacy of other PD-1 inhibitors, such as pembrolizumab and nivolumab, for treatment of advanced BCC may prove worthwhile.

The 2 approved SHH inhibitors—vismodegib and sonidegib—appear to have similar side-effect profiles, with the most common adverse effects being muscle spasms, dysgeusia, alopecia, nausea, vomiting, diarrhea, weight loss, and fatigue.^20,21,27 These side effects occur at high frequencies (>40%) for both SHH inhibitors and often lead to discontinuation of the medication.²¹ Rates of treatment discontinuation range from 15% to 50% on average.^12-14,18 Fortunately, the majority of these adverse effects do not appear to increase in severity or frequency with prolonged use of these medications.^14,16,28

Various conservative and pharmacologic measures can be implemented to help manage side effects. For muscle spasms, which are the most commonly reported adverse effect, supplementation with magnesium, transcutaneous electrical nerve stimulation, acupuncture, massages, stretching, and thermal compresses can potentially be beneficial.²⁹ Calcium channel blockers also may be effective, as one small prospective cohort study reported a reduction in the frequency of muscle cramps with amlodipine 10 mg daily.³⁰ For alopecia, which typically is reversible and caused by SHH inhibition of the normal hair cycle, minoxidil theoretically can help, as it reduces telogen arrest and extends the anagen growth phase.^31,32 Although usually mild and self-limiting, management of dysgeusia, weight loss, and gastrointestinal upset often can be managed with dietary changes, such as smaller, more frequent meals.^33,34 Finally, alternative dosing strategies and drug holidays have been employed to mitigate these side effects and increase drug tolerability.^35,36 These are discussed in the Alternative Dosing section.

Given the essential role of the SHH pathway in embryologic development, SHH inhibitors carry a black box warning of embryofetal teratogenicity and are contraindicated in females who are pregnant or breastfeeding. For females of reproductive potential, verification of pregnancy status should be performed prior to initiating treatment with an SHH inhibitor. These patients should be counseled on the use of contraception during treatment and for at least 24 months and 20 months after cessation of vismodegib and sonidegib, respectively.^27,37,38 Male patients, even after a vasectomy, should use barrier contraception during treatment and for at least 3 months and 8 months after the final dose of vismodegib and sonidegib, respectively.^37,38

Laboratory abnormalities commonly associated with SHH inhibitors include elevated hepatic enzymes, particularly with vismodegib, and elevated creatine kinase levels, particularly with sonidegib.^28,39 Other laboratory abnormalities that can occur include hypercholesterolemia, hypercreatininemia, hyperglycemia, and increased serum lipase levels.^19,28 Although these laboratory abnormalities usually are asymptomatic and self-limiting, regular monitoring should be performed.

There also is concern that SHH inhibitors may induce the development of cSCC. A case-control study of 55 cases and 125 control patients found an increased risk for cSCC in those previously treated with vismodegib, with a hazard ratio of 8.12.⁴⁰ However, a subsequent retrospective cohort study of 1675 patients with BCC failed to find any association with cSCC among those treated with vismodegib compared to those who received standard surgical therapy.⁴¹ Clinical data for sonidegib are lacking, but the BOLT trial found that cSCC occurred in 3 patients receiving treatment with the SHH inhibitor.¹⁸ Thus, further studies are needed to more thoroughly assess this concern. Close monitoring for cSCC may be warranted in patients prescribed SHH inhibitors at this time.

Cemiplimab has demonstrated an acceptable safety profile and is generally well tolerated. In the phase 2 trial of cemiplimab for cSCC, approximately 5% of patients discontinued treatment because of adverse effects. The most commonly reported side effects of cemiplimab were diarrhea (27%), fatigue (24%), nausea (17%), constipation (15%), and rash (15%).²³ In the phase 2 trial for laBCC, grade 3 or 4 adverse events occurred in 48% of patients, with hypertension (5%) being the most common.²⁶ Although rare, immune-mediated adverse reactions also can occur, given the mechanism of action of ICIs. These side effects, ranging in severity from mild to fatal, include pneumonitis, colitis, hepatitis, nephritis, myocarditis, and hypophysitis. Therefore, close monitoring for these immune-mediated reactions is critical, but most can be managed with corticosteroids or treatment interruption if they occur.^42,43

No absolute contraindications exist for cemiplimab; however, extreme caution should be taken in immunosuppressed individuals, such as solid organ transplant recipients and those with chronic lymphocytic leukemia (CLL), as safety data are limited in these patients.^44,45 Although small retrospective studies have reported reasonable tolerability in solid organ transplant recipients treated with ICIs, an allograft rejection rate of 41% was found in a meta-analysis of 64 patients.^46-48 In CLL patients with keratinocyte carcinomas, ICIs have been safely used and have even demonstrated efficacy for CLL in some cases.^49-52

Alternative Dosing

The side effects of SHH inhibitors have led to alternative dosing strategies to prevent medication discontinuation and improve adherence. In patients with basal cell nevus syndrome, multimonth drug holidays have been shown to increase drug tolerability without compromising efficacy.^35,36 Weekly intermittent dosing regimens of vismodegib ranging from 1 week on followed by 1 to 3 weeks off demonstrated efficacy in a retrospective study of 7 patients with advanced BCC.⁵³ All 7 patients experienced improvement in their BCCs, with 3 patients experiencing CR. Importantly, treatment-related adverse effects were mild and well tolerated, with no patients terminating the medication.⁵³ Two other retrospective case series of patients with advanced BCC treated with vismodegib reported similar findings for those placed on an intermittent dosing schedule ranging from once every other day to once per week.^54,55

In the large phase 2 randomized trial known as MIKIE, 2 different intermittent dosing regimens of 150 mg vismodegib daily for patients with multiple BCCs were found to have good activity and tolerability.⁵⁶ The first group (n=116) received vismodegib for 12 weeks, then 3 rounds of 8 weeks of placebo, followed by 12 weeks of vismodegib; there was a 63% reduction in clinically evident BCCs after 73 weeks. The second group (n=113) received the medication for 24 weeks, then 3 rounds of 8 weeks of placebo, followed by 8 weeks of vismodegib; there was a 54% reduction at the end of 73 weeks.⁵⁶ Subsequent analyses found improvements in health-related quality-of-life outcomes that were similar for both groups.⁵⁷

Consequently, alternative dosing schedules appear to be a viable option for patients at risk of discontinuing treatment because of adverse effects, and current data support the recently approved recommendations of dose interruptions of up to 8 weeks to manage adverse effects in patients with laBCC or mBCC.⁵⁸ Nevertheless, further clinical studies are required to determine the optimal intermittent dosing regimen for patients treated with SHH inhibitors.

Neoadjuvant Administration

Recently, vismodegib has been studied as a neoadjuvant therapy for BCC with promising results. Several small retrospective studies and case reports have documented successful treatment of both operable and inoperable periocular laBCC, with preservation of the eye in all patients.^59-61 An open-label trial of 15 patients with advanced BCC who received neoadjuvant vismodegib for 3 to 6 months prior to surgical excision reported a mean reduction of 35% in the final surgical defect size, with no recurrence at 22 months.^62,63 The latest and largest study performed was a phase 2 open-label trial known as VISMONEO, where 44 of 55 laBCC patients (80%) receiving neoadjuvant vismodegib for a mean duration of 6 months (range, 4–10 months) achieved the primary end point of tumor surgical downstaging.⁶⁴ Of the 44 patients who had tumor downstaging, 27 (61%) experienced histologically proven CRs. Additionally, a 66% reduction in the average target lesion size was reported in this group compared to29% in the 11 patients who did not have tumor downstaging (P=.0002).⁶⁴ Thus, SHH inhibitors may hold an important neoadjuvant role in the treatment of BCC by decreasing surgical defect size and allowing for surgical management of previously inoperable cases.

Synergism With Radiation

Preliminary data suggest SHH inhibitors may help potentiate the effects of radiation therapy for the treatment of BCC. Currently, the evidence primarily is limited to case studies, with several reports describing complete remission in patients with advanced BCCs who were considered unsuitable candidates for surgery. In these cases, vismodegib was administered either prior to or concurrently with radiation treatment.^65-69 An in vitro study also documented the radiation-sensitizing effects of vismodegib in a BCC cell line.⁷⁰ Recently, a phase 2 trial (ClinicalTrials.gov identifier NCT01835626) evaluating the concurrent use of vismodegib and radiotherapy for patients with advanced BCC was completed, but data has yet to be published.

Synergism With and Benefit of Antifungal Therapy

The antifungal drug itraconazole is a potent inhibitor of the SHH pathway and may have an adjunctive role in the treatment of BCC. Similar to vismodegib and sonidegib, itraconazole acts as a direct antagonist of SMO. However, it is thought to bind to a distinct site on SMO.^71,72 An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.⁷³ In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).⁷⁴ One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.⁷⁵ The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.⁷⁶

Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.⁷⁷ Although clinical data are lacking, a basic science study found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).⁷⁸ Furthermore, posaconazole has demonstrated a better safety profile with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.^79,80 Thus, posaconazole may be a safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the 2 currently approved SHH inhibitors for the treatment of advanced BCC.

Treatment resistance to SHH inhibitors, though uncommon, is a growing concern. Acquired mutations in the SMO binding site or downstream mediators of the SHH pathway have been shown to confer resistance to vismodegib and sonidegib.^72,81-83 In addition, it appears that there may be shared resistance among the drugs in this class. One study assessing the efficacy of sonidegib in 9 patients with laBCC resistant to vismodegib found that these patients also did not respond to sonidegib.⁸⁴ Interestingly, 1 case report documented tumor regression of an intracranial BCC in a patient treated with sonidegib and itraconazole after failure with vismodegib.⁸⁵ An in vitro study also found that itraconazole maintained SHH inhibitory activity for all drug-resistant SMO mutations that have been reported.⁷² Therefore, itraconazole monotherapy or combination therapy with a canonical SHH inhibitor may be considered for patients with recalcitrant BCC and warrants further investigation.

Taladegib is a newly developed SMO inhibitor that may serve as another promising alternative for patients who develop resistance to vismodegib or sonidegib. A phase 1 trial of taladegib for advanced BCC found an ORR of 69% (11/16) in the SHH inhibitor–naïve group and an ORR of 36% (11/32) in the group previously treated with a SHH inhibitor.⁸⁶ Additionally, the safety profile and frequency of adverse effects appear to be similar to those associated with vismodegib and sonidegib.^86,87 Unfortunately, no clinical trials evaluating taladegib for BCC are ongoing or in development at this time.

Recurrence

There appears to be a relatively high rate of recurrence for BCC patients who achieve a CR to SHH inhibitors. In a retrospective study of 116 laBCC patients who experienced a CR after vismodegib therapy, 54 patients (47%) relapsed at 36 months. Among the 54 patients that relapsed, 27 were re-treated with vismodegib, which resulted in an ORR of 85% (23/27), a CR rate of 37% (10/27), and a PR rate of 48% (13/27).⁸⁸ Another retrospective study of 35 laBCC patients who relapsed after vismodegib treatment reported a 31% (11/35) clinical recurrence rate at 6-month follow-up.⁸⁹ An observational retrospective study also assessed the efficacy of SHH inhibitor maintenance therapy for advanced BCC patients who achieved a CR.⁹⁰ In the study, 27 (64%) patients received a maintenance dose of 150 mg vismodegib once per week for 1 year, while 15 (36%) patients decided not to take a maintenance dose following CR of their BCC. All patients who took the maintenance therapy did not experience clinical recurrence at 1-year follow-up, whereas 26% of patients not on the maintenance dose relapsed.⁹⁰ Consequently, these results indicate that BCC recurrence is frequent after SHH inhibitor therapy and highlights the importance of close surveillance after CR is attained. Nevertheless, most patients still respond to treatment with SHH inhibitors after relapsing, and intermittent maintenance doses may be an effective means to reduce risk of recurrence.

Conclusion

Vismodegib and sonidegib are SHH inhibitors approved for the treatment of laBCC and mBCC. Cemiplimab is now also approved for patients who do not respond to SHH inhibitors or for whom SHH inhibitors are not tolerable. Although these systemic targeted therapies can lead to notable tumor shrinkage and even complete regression in some patients, recurrence is common, and adverse effects may limit their use. Drug resistance is an emerging issue that requires additional examination. Further clinical studies are needed to determine which patients are likely to respond to these targeted treatments.

Various intermittent and maintenance drug regimens should be evaluated for their potential to mitigate adverse effects and reduce risk of recurrence, respectively. The synergistic effects of these medications with other therapies as well as their neoadjuvant and adjuvant roles should be further investigated. For example, administration of an SHH inhibitor prior to surgical excision of a BCC may allow for a smaller surgical defect size, thereby improving cosmetic and functional outcomes. Moreover, these systemic targeted medications may allow for previously inoperable tumors to become amenable to surgical treatment.

Although SHH inhibitors and PD-1 inhibitors represent a major advancement in the field of oncodermatology, real-world efficacy and safety data in the upcoming years will be important for elucidating their true benefit for patients with BCC.

Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and affects more than 3 million individuals per year in the United States.¹ Approximately 40% of patients diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis.² Most cases are successfully treated with surgical excision and occasionally topical therapy or radiotherapy. Despite the high cure rate with conventional treatments, BCC can recur and can cause substantial destruction of the surrounding tissue if left untreated.^3-5 In some instances, BCC can even metastasize and lead to death.⁶ For patients who are poor candidates for surgical or topical treatment modalities because of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic treatment may be indicated. Vismodegib, sonidegib, and cemiplimab are the only systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of laBCC and/or mBCC. Vismodegib and sonidegib target the sonic hedgehog (SHH) signaling pathway that is abnormally activated in more than 90% of BCCs.⁷ Cemiplimab is an immune checkpoint inhibitor (ICI) that targets the programmed cell death protein 1 (PD-1) receptor.⁸ Herein, we review the clinical utility of these medications and their evolving roles in the treatment of BCC.

SHH Pathway Inhibitors

The SHH pathway is a key regulator of cell proliferation and differentiation during embryogenesis.⁷ During adulthood, SHH signaling decreases but still plays an important role in stem cell activation and in regulation of the hair follicle growth cycle.^9,10 However, de novo mutations in the genes that comprise the SHH pathway can result in aberrant constitutive activation, leading to unrestricted cell proliferation. Genetic mutations resulting in activation of Smoothened (SMO), a G-protein–coupled receptor involved in the signal transduction and propagation of the SHH pathway, have been implicated in the pathogenesis of BCC. Inactivating mutations also are commonly observed in patched homolog 1, an upstream cell-surface protein that inhibits SMO.⁷ The mechanism by which vismodegib and sonidegib, 2 of the FDA-approved oral medications for the treatment of advanced BCC, block the SHH pathway is through the selective inhibition of SMO.^7,11

Vismodegib first received FDA approval in 2012 for the treatment of laBCC and mBCC after initial results from the pivotal ERIVANCE phase 2 trial demonstrated an objective response rate (ORR) of 43% (27/63) and 30% (10/33) in patients with locally advanced and metastatic disease, respectively. In this single-arm study, all enrolled patients (63 with laBCC and 33 with mBCC) received 150 mg of oral vismodegib daily.¹² Updated results at 39 months demonstrated improved ORRs of 60% (38/63) and 48% (16/33) for the laBCC and mBCC groups, respectively. A complete response (CR) and partial response (PR) were observed in 32% (n=20) and 29% (n=18) of patients with laBCC, respectively.¹³ These results have been confirmed in subsequent studies, including the large international open-label trial known as STEVIE, with ORRs of 68.5% for 1119 cases of laBCC and 37% for 96 cases of mBCC.^14-17 The CR and PR rates were 33% and 35%, respectively, for the laBCC group. The CR and PR rates for the mBCC group were 5% and 32%, respectively.¹⁴

The FDA approval of sonidegib for laBCC—but not mBCC—occurred in 2015 after the pivotal BOLT randomized phase 2 trial demonstrated an initial ORR of 43% (18/42) for laBCC and 15% (2/13) for mBCC after administration of 200 mg of sonidegib daily.¹⁸ A final follow-up analysis at 42 months resulted in ORRs of 56% (37/66) and 8% (1/13) for the laBCC and mBCC groups, respectively.¹⁹ Additionally, improved efficacy was not observed in the 151 patients who were randomized to receive treatment with the higher 800-mg dose; however, they did experience a higher incidence of adverse events.^18,19

Currently, the true clinical differences between vismodegib and sonidegib remain uncertain, as no head-to-head trials have been conducted. Moreover, direct comparison of the data from the ERIVANCE and BOLT trials is challenging owing to fundamental differences in methodologic design, including the criteria used to assess BCC severity. The ERIVANCE trial utilized the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while BOLT used the rigorous modified RECIST. However, an expert consensus study attempted to compare the 2 trials by modifying the outcomes from BOLT with the former RECIST criteria. The expert group found that the 2 SHH inhibitors had comparable efficacy and adverse event profiles.²⁰ Nevertheless, a recent meta-analysis found that although ORRs for laBCC were similar between the 2 drugs, the CR rate for vismodegib was 31% compared with 3% for sonidegib. Additionally, for mBCC, they reported the ORR of vismodegib to be 2.7 times higher than that of sonidegib (39% vs 15%).²¹

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have successfully been utilized in the treatment of cutaneous squamous cell carcinoma (cSCC); however, their use for treating BCC has been limited until recently.^22-25 In February 2021, cemiplimab became the first and only ICI approved for the treatment of laBCC and mBCC in patients who did not respond to or were intolerant to prior SHH inhibitor therapy.²⁶ Cemiplimab—a human monoclonal antibody against the PD-1 receptor expressed on T cells—blocks its interaction with programmed cell death ligand 1 and programmed cell death ligand 2 present on tumor cells. The blockade of the PD-1 pathway releases the inhibition of the antitumor immune response and enables appropriate cytotoxic T-cell activity to occur.⁸

The FDA approval of cemiplimab for the treatment of advanced BCC was based on an open-label, multicenter, single-arm phase 2 trial (NCT03132636) evaluating 84 patients with laBCC refractory or intolerant to SHH inhibitor therapy.²⁶ Patients received an intravenous infusion of cemiplimab 350 mg every 3 weeks for up to 93 weeks or until disease progression or unacceptable toxicity. An ORR of 31% (26/84) was observed with a CR and PR of 6% (5/84) and 25% (21/84), respectively. The median duration of follow-up was 15 months.²⁶ Given the clinically meaningful results of this trial, investigating the efficacy of other PD-1 inhibitors, such as pembrolizumab and nivolumab, for treatment of advanced BCC may prove worthwhile.

The 2 approved SHH inhibitors—vismodegib and sonidegib—appear to have similar side-effect profiles, with the most common adverse effects being muscle spasms, dysgeusia, alopecia, nausea, vomiting, diarrhea, weight loss, and fatigue.^20,21,27 These side effects occur at high frequencies (>40%) for both SHH inhibitors and often lead to discontinuation of the medication.²¹ Rates of treatment discontinuation range from 15% to 50% on average.^12-14,18 Fortunately, the majority of these adverse effects do not appear to increase in severity or frequency with prolonged use of these medications.^14,16,28

Various conservative and pharmacologic measures can be implemented to help manage side effects. For muscle spasms, which are the most commonly reported adverse effect, supplementation with magnesium, transcutaneous electrical nerve stimulation, acupuncture, massages, stretching, and thermal compresses can potentially be beneficial.²⁹ Calcium channel blockers also may be effective, as one small prospective cohort study reported a reduction in the frequency of muscle cramps with amlodipine 10 mg daily.³⁰ For alopecia, which typically is reversible and caused by SHH inhibition of the normal hair cycle, minoxidil theoretically can help, as it reduces telogen arrest and extends the anagen growth phase.^31,32 Although usually mild and self-limiting, management of dysgeusia, weight loss, and gastrointestinal upset often can be managed with dietary changes, such as smaller, more frequent meals.^33,34 Finally, alternative dosing strategies and drug holidays have been employed to mitigate these side effects and increase drug tolerability.^35,36 These are discussed in the Alternative Dosing section.

Given the essential role of the SHH pathway in embryologic development, SHH inhibitors carry a black box warning of embryofetal teratogenicity and are contraindicated in females who are pregnant or breastfeeding. For females of reproductive potential, verification of pregnancy status should be performed prior to initiating treatment with an SHH inhibitor. These patients should be counseled on the use of contraception during treatment and for at least 24 months and 20 months after cessation of vismodegib and sonidegib, respectively.^27,37,38 Male patients, even after a vasectomy, should use barrier contraception during treatment and for at least 3 months and 8 months after the final dose of vismodegib and sonidegib, respectively.^37,38

Laboratory abnormalities commonly associated with SHH inhibitors include elevated hepatic enzymes, particularly with vismodegib, and elevated creatine kinase levels, particularly with sonidegib.^28,39 Other laboratory abnormalities that can occur include hypercholesterolemia, hypercreatininemia, hyperglycemia, and increased serum lipase levels.^19,28 Although these laboratory abnormalities usually are asymptomatic and self-limiting, regular monitoring should be performed.

There also is concern that SHH inhibitors may induce the development of cSCC. A case-control study of 55 cases and 125 control patients found an increased risk for cSCC in those previously treated with vismodegib, with a hazard ratio of 8.12.⁴⁰ However, a subsequent retrospective cohort study of 1675 patients with BCC failed to find any association with cSCC among those treated with vismodegib compared to those who received standard surgical therapy.⁴¹ Clinical data for sonidegib are lacking, but the BOLT trial found that cSCC occurred in 3 patients receiving treatment with the SHH inhibitor.¹⁸ Thus, further studies are needed to more thoroughly assess this concern. Close monitoring for cSCC may be warranted in patients prescribed SHH inhibitors at this time.

Cemiplimab has demonstrated an acceptable safety profile and is generally well tolerated. In the phase 2 trial of cemiplimab for cSCC, approximately 5% of patients discontinued treatment because of adverse effects. The most commonly reported side effects of cemiplimab were diarrhea (27%), fatigue (24%), nausea (17%), constipation (15%), and rash (15%).²³ In the phase 2 trial for laBCC, grade 3 or 4 adverse events occurred in 48% of patients, with hypertension (5%) being the most common.²⁶ Although rare, immune-mediated adverse reactions also can occur, given the mechanism of action of ICIs. These side effects, ranging in severity from mild to fatal, include pneumonitis, colitis, hepatitis, nephritis, myocarditis, and hypophysitis. Therefore, close monitoring for these immune-mediated reactions is critical, but most can be managed with corticosteroids or treatment interruption if they occur.^42,43

No absolute contraindications exist for cemiplimab; however, extreme caution should be taken in immunosuppressed individuals, such as solid organ transplant recipients and those with chronic lymphocytic leukemia (CLL), as safety data are limited in these patients.^44,45 Although small retrospective studies have reported reasonable tolerability in solid organ transplant recipients treated with ICIs, an allograft rejection rate of 41% was found in a meta-analysis of 64 patients.^46-48 In CLL patients with keratinocyte carcinomas, ICIs have been safely used and have even demonstrated efficacy for CLL in some cases.^49-52

Alternative Dosing

The side effects of SHH inhibitors have led to alternative dosing strategies to prevent medication discontinuation and improve adherence. In patients with basal cell nevus syndrome, multimonth drug holidays have been shown to increase drug tolerability without compromising efficacy.^35,36 Weekly intermittent dosing regimens of vismodegib ranging from 1 week on followed by 1 to 3 weeks off demonstrated efficacy in a retrospective study of 7 patients with advanced BCC.⁵³ All 7 patients experienced improvement in their BCCs, with 3 patients experiencing CR. Importantly, treatment-related adverse effects were mild and well tolerated, with no patients terminating the medication.⁵³ Two other retrospective case series of patients with advanced BCC treated with vismodegib reported similar findings for those placed on an intermittent dosing schedule ranging from once every other day to once per week.^54,55

In the large phase 2 randomized trial known as MIKIE, 2 different intermittent dosing regimens of 150 mg vismodegib daily for patients with multiple BCCs were found to have good activity and tolerability.⁵⁶ The first group (n=116) received vismodegib for 12 weeks, then 3 rounds of 8 weeks of placebo, followed by 12 weeks of vismodegib; there was a 63% reduction in clinically evident BCCs after 73 weeks. The second group (n=113) received the medication for 24 weeks, then 3 rounds of 8 weeks of placebo, followed by 8 weeks of vismodegib; there was a 54% reduction at the end of 73 weeks.⁵⁶ Subsequent analyses found improvements in health-related quality-of-life outcomes that were similar for both groups.⁵⁷

Consequently, alternative dosing schedules appear to be a viable option for patients at risk of discontinuing treatment because of adverse effects, and current data support the recently approved recommendations of dose interruptions of up to 8 weeks to manage adverse effects in patients with laBCC or mBCC.⁵⁸ Nevertheless, further clinical studies are required to determine the optimal intermittent dosing regimen for patients treated with SHH inhibitors.

Neoadjuvant Administration

Recently, vismodegib has been studied as a neoadjuvant therapy for BCC with promising results. Several small retrospective studies and case reports have documented successful treatment of both operable and inoperable periocular laBCC, with preservation of the eye in all patients.^59-61 An open-label trial of 15 patients with advanced BCC who received neoadjuvant vismodegib for 3 to 6 months prior to surgical excision reported a mean reduction of 35% in the final surgical defect size, with no recurrence at 22 months.^62,63 The latest and largest study performed was a phase 2 open-label trial known as VISMONEO, where 44 of 55 laBCC patients (80%) receiving neoadjuvant vismodegib for a mean duration of 6 months (range, 4–10 months) achieved the primary end point of tumor surgical downstaging.⁶⁴ Of the 44 patients who had tumor downstaging, 27 (61%) experienced histologically proven CRs. Additionally, a 66% reduction in the average target lesion size was reported in this group compared to29% in the 11 patients who did not have tumor downstaging (P=.0002).⁶⁴ Thus, SHH inhibitors may hold an important neoadjuvant role in the treatment of BCC by decreasing surgical defect size and allowing for surgical management of previously inoperable cases.

Synergism With Radiation

Preliminary data suggest SHH inhibitors may help potentiate the effects of radiation therapy for the treatment of BCC. Currently, the evidence primarily is limited to case studies, with several reports describing complete remission in patients with advanced BCCs who were considered unsuitable candidates for surgery. In these cases, vismodegib was administered either prior to or concurrently with radiation treatment.^65-69 An in vitro study also documented the radiation-sensitizing effects of vismodegib in a BCC cell line.⁷⁰ Recently, a phase 2 trial (ClinicalTrials.gov identifier NCT01835626) evaluating the concurrent use of vismodegib and radiotherapy for patients with advanced BCC was completed, but data has yet to be published.

Synergism With and Benefit of Antifungal Therapy

The antifungal drug itraconazole is a potent inhibitor of the SHH pathway and may have an adjunctive role in the treatment of BCC. Similar to vismodegib and sonidegib, itraconazole acts as a direct antagonist of SMO. However, it is thought to bind to a distinct site on SMO.^71,72 An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.⁷³ In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).⁷⁴ One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.⁷⁵ The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.⁷⁶

Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.⁷⁷ Although clinical data are lacking, a basic science study found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).⁷⁸ Furthermore, posaconazole has demonstrated a better safety profile with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.^79,80 Thus, posaconazole may be a safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the 2 currently approved SHH inhibitors for the treatment of advanced BCC.

Treatment resistance to SHH inhibitors, though uncommon, is a growing concern. Acquired mutations in the SMO binding site or downstream mediators of the SHH pathway have been shown to confer resistance to vismodegib and sonidegib.^72,81-83 In addition, it appears that there may be shared resistance among the drugs in this class. One study assessing the efficacy of sonidegib in 9 patients with laBCC resistant to vismodegib found that these patients also did not respond to sonidegib.⁸⁴ Interestingly, 1 case report documented tumor regression of an intracranial BCC in a patient treated with sonidegib and itraconazole after failure with vismodegib.⁸⁵ An in vitro study also found that itraconazole maintained SHH inhibitory activity for all drug-resistant SMO mutations that have been reported.⁷² Therefore, itraconazole monotherapy or combination therapy with a canonical SHH inhibitor may be considered for patients with recalcitrant BCC and warrants further investigation.

Taladegib is a newly developed SMO inhibitor that may serve as another promising alternative for patients who develop resistance to vismodegib or sonidegib. A phase 1 trial of taladegib for advanced BCC found an ORR of 69% (11/16) in the SHH inhibitor–naïve group and an ORR of 36% (11/32) in the group previously treated with a SHH inhibitor.⁸⁶ Additionally, the safety profile and frequency of adverse effects appear to be similar to those associated with vismodegib and sonidegib.^86,87 Unfortunately, no clinical trials evaluating taladegib for BCC are ongoing or in development at this time.

Recurrence

There appears to be a relatively high rate of recurrence for BCC patients who achieve a CR to SHH inhibitors. In a retrospective study of 116 laBCC patients who experienced a CR after vismodegib therapy, 54 patients (47%) relapsed at 36 months. Among the 54 patients that relapsed, 27 were re-treated with vismodegib, which resulted in an ORR of 85% (23/27), a CR rate of 37% (10/27), and a PR rate of 48% (13/27).⁸⁸ Another retrospective study of 35 laBCC patients who relapsed after vismodegib treatment reported a 31% (11/35) clinical recurrence rate at 6-month follow-up.⁸⁹ An observational retrospective study also assessed the efficacy of SHH inhibitor maintenance therapy for advanced BCC patients who achieved a CR.⁹⁰ In the study, 27 (64%) patients received a maintenance dose of 150 mg vismodegib once per week for 1 year, while 15 (36%) patients decided not to take a maintenance dose following CR of their BCC. All patients who took the maintenance therapy did not experience clinical recurrence at 1-year follow-up, whereas 26% of patients not on the maintenance dose relapsed.⁹⁰ Consequently, these results indicate that BCC recurrence is frequent after SHH inhibitor therapy and highlights the importance of close surveillance after CR is attained. Nevertheless, most patients still respond to treatment with SHH inhibitors after relapsing, and intermittent maintenance doses may be an effective means to reduce risk of recurrence.

Conclusion

Vismodegib and sonidegib are SHH inhibitors approved for the treatment of laBCC and mBCC. Cemiplimab is now also approved for patients who do not respond to SHH inhibitors or for whom SHH inhibitors are not tolerable. Although these systemic targeted therapies can lead to notable tumor shrinkage and even complete regression in some patients, recurrence is common, and adverse effects may limit their use. Drug resistance is an emerging issue that requires additional examination. Further clinical studies are needed to determine which patients are likely to respond to these targeted treatments.

Various intermittent and maintenance drug regimens should be evaluated for their potential to mitigate adverse effects and reduce risk of recurrence, respectively. The synergistic effects of these medications with other therapies as well as their neoadjuvant and adjuvant roles should be further investigated. For example, administration of an SHH inhibitor prior to surgical excision of a BCC may allow for a smaller surgical defect size, thereby improving cosmetic and functional outcomes. Moreover, these systemic targeted medications may allow for previously inoperable tumors to become amenable to surgical treatment.

Although SHH inhibitors and PD-1 inhibitors represent a major advancement in the field of oncodermatology, real-world efficacy and safety data in the upcoming years will be important for elucidating their true benefit for patients with BCC.

A large study showing an increased risk of keratinocyte carcinoma (KC) in children who receive a solid-organ transplant highlights the need for early education about risk reduction and more research to determine optimal timing for screening, say an investigator and two dermatologists with expertise in transplant-related skin issues.

The increased incidence of KC in pediatric transplant recipients is “really high, so we definitely know there’s risk there,” just as there is for adult recipients of solid-organ transplants, said Cathryn Sibbald, MD, MSc, a dermatologist at the Hospital for Sick Children in Toronto and coauthor of a research letter published in June in JAMA Dermatology.

For their study, Dr. Sibbald and her coinvestigators turned to the Ontario Health Insurance plan database, which covers health care for Canadian citizens and qualified residents in the province. They identified 951 patients younger than the age of 18 who received a solid-organ transplant between 1991 and 2004 at an Ontario hospital

They then used a validated health insurance claims–based algorithm to identify diagnoses of KC for the transplant recipients and for more than 5 million age-matched controls. KC, including squamous and basal cell carcinoma, is the most prevalent skin cancer for people who have had a solid-organ transplant.

Fifteen posttransplant KCs (10 patients, 1.1%) were reported a mean of 13.1 years after transplant, with none reported in the first 4 years. The mean age at transplant was 7.8 years, and the mean age at KC diagnosis was 25.2 years. Kidney transplants were the most common (42.1% of transplantations). Most of the transplants recipients (eight patients) who developed KC had kidney transplantation, and most of them had functional graft at the time of KC diagnosis.

Researchers found an increased incidence of KC compared with that of the general population (standardized incidence ratio, 9.09; 95% confidence interval, 5.48-15.08). And the risk for KC increased with time since transplant, with adjusted hazard ratios for KC of 3.63 (95% CI, 0.51-25.77) for 1-5 years, 5.14 (95% CI, 1.28-20.55) for 5-10 years, and 4.80 (95% CI, 2.29-10.08) for 10 years or more, compared with the control population.

Several years ago, another research team performed a similar population-based cohort study of adult transplant recipients in Ontario and found a 6.6-times increased risk of KC in transplant recipients compared with the general population.

Sun protection and skin cancer screening

In commenting on the study, Sarah Arron, MD, PhD, a San Francisco Bay area dermatologist and immediate past president of the International Immunosuppression and Transplant Skin Cancer Collaborative (www.itscc.org), said she feels “reassured” that young transplant patients tend not to develop the skin cancer until young adulthood.

A ”large study like this is important because the overall rate of KC is low in this age group,” she noted.

The findings “suggest that we can focus our efforts on prevention during childhood, with sun protection and skin cancer education,” she said. “Then, as these children move into adulthood, we can begin screening with skin examinations. Of course, [any child] with a skin lesion or mole that concerns their parents or transplant team should be referred to dermatology for evaluation.”

Pediatric transplant recipients and their parents are most interested in learning about skin cancer prevention either before or immediately after transplantation, according to a survey by other researchers.

Intervention studies needed

The increased risk of KC probably stems largely from immunosuppression, said Dr. Sibbald in an interview. “We know [this is the case] in the older population, and it’s likely true in the younger population as well that it’s one of the primary drivers,” she said.

More research to extensively analyze risk factors should come next, she said. This includes “the granularity of what [immunosuppressants and other] medications are received, and at what dose and for what periods of time, so we can calculate cumulative exposure and its relation to risk,” she said.

Kristin Bibee, MD, PhD, assistant professor of dermatology at Johns Hopkins University in Baltimore, said she’d like to see further studies “evaluate appropriate interventions, like sun-protective behavior in childhood and adolescence or immunosuppression modulation, to prevent malignancy development.”

The optimal time and intensity of screening for young transplant recipients must still be determined, both Dr. Bibee and Dr. Arron said. Patients deemed through further research to be at higher risk may need earlier and/or more intensive surveillance.

The role of race in skin cancer risk in this population is “one question the study leaves open,” said Dr. Arron. U.S. studies have shown that among adult transplant recipients White patients are “at highest risk for the ultraviolet-associated melanoma and squamous cell carcinoma, followed by Asian and Latino patients. African Americans have had the lowest risk, but some still developed skin cancer after transplant,” she said.

Prior studies of cancer in pediatric transplant recipients have reported primarily on internal malignant neoplasms, with limited data on KC, Dr. Sibbald and coauthors wrote. It is possible the incidence of KS is underestimated in the new study because of “undiagnosed or unreported KCs,” they noted.

The new study was funded by a grant from the Pediatric Dermatology Research Alliance and a Hospital for Sick Children grant. In disclosures, Dr. Sibbald reported to JAMA Dermatology receiving grants from the alliance and from Paediatric Consultants Partnership during the conduct of the study. Dr. Arron and Dr. Bibee both said they have no disclosures relevant to the study and its content.

A large study showing an increased risk of keratinocyte carcinoma (KC) in children who receive a solid-organ transplant highlights the need for early education about risk reduction and more research to determine optimal timing for screening, say an investigator and two dermatologists with expertise in transplant-related skin issues.

The increased incidence of KC in pediatric transplant recipients is “really high, so we definitely know there’s risk there,” just as there is for adult recipients of solid-organ transplants, said Cathryn Sibbald, MD, MSc, a dermatologist at the Hospital for Sick Children in Toronto and coauthor of a research letter published in June in JAMA Dermatology.

For their study, Dr. Sibbald and her coinvestigators turned to the Ontario Health Insurance plan database, which covers health care for Canadian citizens and qualified residents in the province. They identified 951 patients younger than the age of 18 who received a solid-organ transplant between 1991 and 2004 at an Ontario hospital

They then used a validated health insurance claims–based algorithm to identify diagnoses of KC for the transplant recipients and for more than 5 million age-matched controls. KC, including squamous and basal cell carcinoma, is the most prevalent skin cancer for people who have had a solid-organ transplant.

Fifteen posttransplant KCs (10 patients, 1.1%) were reported a mean of 13.1 years after transplant, with none reported in the first 4 years. The mean age at transplant was 7.8 years, and the mean age at KC diagnosis was 25.2 years. Kidney transplants were the most common (42.1% of transplantations). Most of the transplants recipients (eight patients) who developed KC had kidney transplantation, and most of them had functional graft at the time of KC diagnosis.

Researchers found an increased incidence of KC compared with that of the general population (standardized incidence ratio, 9.09; 95% confidence interval, 5.48-15.08). And the risk for KC increased with time since transplant, with adjusted hazard ratios for KC of 3.63 (95% CI, 0.51-25.77) for 1-5 years, 5.14 (95% CI, 1.28-20.55) for 5-10 years, and 4.80 (95% CI, 2.29-10.08) for 10 years or more, compared with the control population.

Several years ago, another research team performed a similar population-based cohort study of adult transplant recipients in Ontario and found a 6.6-times increased risk of KC in transplant recipients compared with the general population.

Sun protection and skin cancer screening

In commenting on the study, Sarah Arron, MD, PhD, a San Francisco Bay area dermatologist and immediate past president of the International Immunosuppression and Transplant Skin Cancer Collaborative (www.itscc.org), said she feels “reassured” that young transplant patients tend not to develop the skin cancer until young adulthood.

A ”large study like this is important because the overall rate of KC is low in this age group,” she noted.

The findings “suggest that we can focus our efforts on prevention during childhood, with sun protection and skin cancer education,” she said. “Then, as these children move into adulthood, we can begin screening with skin examinations. Of course, [any child] with a skin lesion or mole that concerns their parents or transplant team should be referred to dermatology for evaluation.”

Pediatric transplant recipients and their parents are most interested in learning about skin cancer prevention either before or immediately after transplantation, according to a survey by other researchers.

Intervention studies needed

The increased risk of KC probably stems largely from immunosuppression, said Dr. Sibbald in an interview. “We know [this is the case] in the older population, and it’s likely true in the younger population as well that it’s one of the primary drivers,” she said.

More research to extensively analyze risk factors should come next, she said. This includes “the granularity of what [immunosuppressants and other] medications are received, and at what dose and for what periods of time, so we can calculate cumulative exposure and its relation to risk,” she said.

Kristin Bibee, MD, PhD, assistant professor of dermatology at Johns Hopkins University in Baltimore, said she’d like to see further studies “evaluate appropriate interventions, like sun-protective behavior in childhood and adolescence or immunosuppression modulation, to prevent malignancy development.”

The optimal time and intensity of screening for young transplant recipients must still be determined, both Dr. Bibee and Dr. Arron said. Patients deemed through further research to be at higher risk may need earlier and/or more intensive surveillance.

The role of race in skin cancer risk in this population is “one question the study leaves open,” said Dr. Arron. U.S. studies have shown that among adult transplant recipients White patients are “at highest risk for the ultraviolet-associated melanoma and squamous cell carcinoma, followed by Asian and Latino patients. African Americans have had the lowest risk, but some still developed skin cancer after transplant,” she said.

Prior studies of cancer in pediatric transplant recipients have reported primarily on internal malignant neoplasms, with limited data on KC, Dr. Sibbald and coauthors wrote. It is possible the incidence of KS is underestimated in the new study because of “undiagnosed or unreported KCs,” they noted.

The new study was funded by a grant from the Pediatric Dermatology Research Alliance and a Hospital for Sick Children grant. In disclosures, Dr. Sibbald reported to JAMA Dermatology receiving grants from the alliance and from Paediatric Consultants Partnership during the conduct of the study. Dr. Arron and Dr. Bibee both said they have no disclosures relevant to the study and its content.

A large study showing an increased risk of keratinocyte carcinoma (KC) in children who receive a solid-organ transplant highlights the need for early education about risk reduction and more research to determine optimal timing for screening, say an investigator and two dermatologists with expertise in transplant-related skin issues.

The increased incidence of KC in pediatric transplant recipients is “really high, so we definitely know there’s risk there,” just as there is for adult recipients of solid-organ transplants, said Cathryn Sibbald, MD, MSc, a dermatologist at the Hospital for Sick Children in Toronto and coauthor of a research letter published in June in JAMA Dermatology.

For their study, Dr. Sibbald and her coinvestigators turned to the Ontario Health Insurance plan database, which covers health care for Canadian citizens and qualified residents in the province. They identified 951 patients younger than the age of 18 who received a solid-organ transplant between 1991 and 2004 at an Ontario hospital

They then used a validated health insurance claims–based algorithm to identify diagnoses of KC for the transplant recipients and for more than 5 million age-matched controls. KC, including squamous and basal cell carcinoma, is the most prevalent skin cancer for people who have had a solid-organ transplant.

Fifteen posttransplant KCs (10 patients, 1.1%) were reported a mean of 13.1 years after transplant, with none reported in the first 4 years. The mean age at transplant was 7.8 years, and the mean age at KC diagnosis was 25.2 years. Kidney transplants were the most common (42.1% of transplantations). Most of the transplants recipients (eight patients) who developed KC had kidney transplantation, and most of them had functional graft at the time of KC diagnosis.

Researchers found an increased incidence of KC compared with that of the general population (standardized incidence ratio, 9.09; 95% confidence interval, 5.48-15.08). And the risk for KC increased with time since transplant, with adjusted hazard ratios for KC of 3.63 (95% CI, 0.51-25.77) for 1-5 years, 5.14 (95% CI, 1.28-20.55) for 5-10 years, and 4.80 (95% CI, 2.29-10.08) for 10 years or more, compared with the control population.

Several years ago, another research team performed a similar population-based cohort study of adult transplant recipients in Ontario and found a 6.6-times increased risk of KC in transplant recipients compared with the general population.

Sun protection and skin cancer screening

In commenting on the study, Sarah Arron, MD, PhD, a San Francisco Bay area dermatologist and immediate past president of the International Immunosuppression and Transplant Skin Cancer Collaborative (www.itscc.org), said she feels “reassured” that young transplant patients tend not to develop the skin cancer until young adulthood.

A ”large study like this is important because the overall rate of KC is low in this age group,” she noted.

The findings “suggest that we can focus our efforts on prevention during childhood, with sun protection and skin cancer education,” she said. “Then, as these children move into adulthood, we can begin screening with skin examinations. Of course, [any child] with a skin lesion or mole that concerns their parents or transplant team should be referred to dermatology for evaluation.”

Pediatric transplant recipients and their parents are most interested in learning about skin cancer prevention either before or immediately after transplantation, according to a survey by other researchers.

Intervention studies needed

The increased risk of KC probably stems largely from immunosuppression, said Dr. Sibbald in an interview. “We know [this is the case] in the older population, and it’s likely true in the younger population as well that it’s one of the primary drivers,” she said.

More research to extensively analyze risk factors should come next, she said. This includes “the granularity of what [immunosuppressants and other] medications are received, and at what dose and for what periods of time, so we can calculate cumulative exposure and its relation to risk,” she said.

Kristin Bibee, MD, PhD, assistant professor of dermatology at Johns Hopkins University in Baltimore, said she’d like to see further studies “evaluate appropriate interventions, like sun-protective behavior in childhood and adolescence or immunosuppression modulation, to prevent malignancy development.”

The optimal time and intensity of screening for young transplant recipients must still be determined, both Dr. Bibee and Dr. Arron said. Patients deemed through further research to be at higher risk may need earlier and/or more intensive surveillance.

The role of race in skin cancer risk in this population is “one question the study leaves open,” said Dr. Arron. U.S. studies have shown that among adult transplant recipients White patients are “at highest risk for the ultraviolet-associated melanoma and squamous cell carcinoma, followed by Asian and Latino patients. African Americans have had the lowest risk, but some still developed skin cancer after transplant,” she said.

Prior studies of cancer in pediatric transplant recipients have reported primarily on internal malignant neoplasms, with limited data on KC, Dr. Sibbald and coauthors wrote. It is possible the incidence of KS is underestimated in the new study because of “undiagnosed or unreported KCs,” they noted.

The new study was funded by a grant from the Pediatric Dermatology Research Alliance and a Hospital for Sick Children grant. In disclosures, Dr. Sibbald reported to JAMA Dermatology receiving grants from the alliance and from Paediatric Consultants Partnership during the conduct of the study. Dr. Arron and Dr. Bibee both said they have no disclosures relevant to the study and its content.

Patients who are immunocompromised showed no increased risk of surgical site infection when undergoing Mohs micrographic surgery, regardless of whether or not they received antibiotics, suggesting that antibiotic prophylaxis, which is often used for these patients, may not be necessary, according to new research.

The retrospective cohort study found that “immunosuppressed patients had similar infection rates as immunocompetent patients following Mohs micrographic surgery,” first author Tuyet A. Nguyen, MD, of the department of dermatology, Cedars-Sinai Medical Center, Los Angeles, told this news organization.

“Therefore, antibiotic prescribing patterns should not change simply due to immunosuppression. Furthermore, immunosuppressed patients appear to respond well to antibiotics and recover similarly to immunocompetent patients,” she said.

Dr. Nguyen

Overall, postprocedural infections occurred in 1.6% (95) of patients, a rate that mirrors that of the general population, Dr. Nguyen noted. No significant differences in surgical site infection rates were observed between immunocompromised patients (2.1%, n = 15) and those who were immunocompetent (1.6%, n = 80; P = .30).

Importantly, among those who were immunocompromised, the rates of infection were not significantly different between those who did receive antibiotics (3.0%, n = 8) and those who did not receive antibiotics (1.5%, n = 7; P = .19).

The lack of a difference in surgical site infection rates among those who did and those who did not receive antibiotics extended to the entire study population (2.0% vs. 1.4%; P = .12).

The study cohort mainly comprised immunosuppressed transplant patients, notably, heart, lung, and kidney transplant patients. However, “even in this population, we did not see a higher rate of infection,” senior author Nima M. Gharavi, MD, PhD, director of dermatologic surgery and Mohs micrographic surgery and associate professor of medicine and pathology and laboratory medicine at Cedars-Sinai Medical Center, said in an interview.

Dr. Nima M. Gharavi

A version of this article first appeared on Medscape.com.

Patients who are immunocompromised showed no increased risk of surgical site infection when undergoing Mohs micrographic surgery, regardless of whether or not they received antibiotics, suggesting that antibiotic prophylaxis, which is often used for these patients, may not be necessary, according to new research.

The retrospective cohort study found that “immunosuppressed patients had similar infection rates as immunocompetent patients following Mohs micrographic surgery,” first author Tuyet A. Nguyen, MD, of the department of dermatology, Cedars-Sinai Medical Center, Los Angeles, told this news organization.

“Therefore, antibiotic prescribing patterns should not change simply due to immunosuppression. Furthermore, immunosuppressed patients appear to respond well to antibiotics and recover similarly to immunocompetent patients,” she said.

Dr. Nguyen

Overall, postprocedural infections occurred in 1.6% (95) of patients, a rate that mirrors that of the general population, Dr. Nguyen noted. No significant differences in surgical site infection rates were observed between immunocompromised patients (2.1%, n = 15) and those who were immunocompetent (1.6%, n = 80; P = .30).

Importantly, among those who were immunocompromised, the rates of infection were not significantly different between those who did receive antibiotics (3.0%, n = 8) and those who did not receive antibiotics (1.5%, n = 7; P = .19).

The lack of a difference in surgical site infection rates among those who did and those who did not receive antibiotics extended to the entire study population (2.0% vs. 1.4%; P = .12).

The study cohort mainly comprised immunosuppressed transplant patients, notably, heart, lung, and kidney transplant patients. However, “even in this population, we did not see a higher rate of infection,” senior author Nima M. Gharavi, MD, PhD, director of dermatologic surgery and Mohs micrographic surgery and associate professor of medicine and pathology and laboratory medicine at Cedars-Sinai Medical Center, said in an interview.

Dr. Nima M. Gharavi

A version of this article first appeared on Medscape.com.

Patients who are immunocompromised showed no increased risk of surgical site infection when undergoing Mohs micrographic surgery, regardless of whether or not they received antibiotics, suggesting that antibiotic prophylaxis, which is often used for these patients, may not be necessary, according to new research.

The retrospective cohort study found that “immunosuppressed patients had similar infection rates as immunocompetent patients following Mohs micrographic surgery,” first author Tuyet A. Nguyen, MD, of the department of dermatology, Cedars-Sinai Medical Center, Los Angeles, told this news organization.

“Therefore, antibiotic prescribing patterns should not change simply due to immunosuppression. Furthermore, immunosuppressed patients appear to respond well to antibiotics and recover similarly to immunocompetent patients,” she said.

Dr. Nguyen

Overall, postprocedural infections occurred in 1.6% (95) of patients, a rate that mirrors that of the general population, Dr. Nguyen noted. No significant differences in surgical site infection rates were observed between immunocompromised patients (2.1%, n = 15) and those who were immunocompetent (1.6%, n = 80; P = .30).

Importantly, among those who were immunocompromised, the rates of infection were not significantly different between those who did receive antibiotics (3.0%, n = 8) and those who did not receive antibiotics (1.5%, n = 7; P = .19).

The lack of a difference in surgical site infection rates among those who did and those who did not receive antibiotics extended to the entire study population (2.0% vs. 1.4%; P = .12).

The study cohort mainly comprised immunosuppressed transplant patients, notably, heart, lung, and kidney transplant patients. However, “even in this population, we did not see a higher rate of infection,” senior author Nima M. Gharavi, MD, PhD, director of dermatologic surgery and Mohs micrographic surgery and associate professor of medicine and pathology and laboratory medicine at Cedars-Sinai Medical Center, said in an interview.

Dr. Nima M. Gharavi

A version of this article first appeared on Medscape.com.

As increasing numbers of patients in their 80s, 90s, and even 100s present for possible Mohs micrographic surgery, surgeons are confronted with deciding when the risks of treatment may outweigh the benefits.

In one of two presentations at the annual meeting of the American College of Mohs Surgery that addressed this topic, Howard W. Rogers, MD, of Advanced Dermatology in Norwich, Conn., said that the crux of the issue is the concern not to undertreat. He noted that reduced access to dermatologic care during the pandemic has provided a stark lesson in the risks of delaying treatment in all age groups. “Mohs surgeons have all seen the consequences of delayed treatment due to the pandemic with enormous, destructive, and sometimes fatal cancers coming to the office in the last year,” he told this news organization.

“Pandemic-related treatment delay has caused increased suffering and morbidity for countless skin cancer patients across the U.S.,” he said. “In general, not treating skin cancer and hoping it’s not going to grow or having significant delays in treatment are a recipe for disastrous outcomes.”

That said, active monitoring may be appropriate “for select small cancers that tend to grow slowly in the very elderly,” added Dr. Rogers, the incoming ACMS president. Among the key situations where the benefits of active monitoring may outweigh the risks of surgery are small, slowly growing cancers, when frailty is an issue.

Frailty has been equated to compromised functionality, which can increase the risk of an array of complications, including prolonged wound healing and secondary complications stemming from immobility. The toll those issues can take on patients’ quality of life can be considerable, Dr. Rogers said.

When weighing treatment options with elderly patients, he emphasized that careful consideration should be given to whether the “time needed to benefit from a Mohs procedure is longer than the patient’s life expectancy.” Furthermore, a decision not to treat does not have to be the last word. “We need to have an honest dialogue on the consequences of nontreatment, but part of that should be that just because we don’t treat today, doesn’t mean we can’t treat it tomorrow, if necessary.”

Of note, he added, “more than 100,00 patients have surgery for basal cell carcinoma [BCC] in their last year of life.” And that figure will likely rise exponentially if population projections come to fruition, considering that the population of people over the age of 85 is predicted to increase to nearly 18 million in 2050, from 5.8 million in 2012, Dr. Rogers said.

Until more research emerges on how to best treat this age group, Dr. Rogers noted that experts recommend that for elderly patients, “treatment should be individualized with consideration of active monitoring of primary BCC that is not in the H-zone, asymptomatic, smaller than 1 cm, with treatment initiated if there is substantial growth or symptoms.” Ultimately, he urged surgeons to “be sensitive and treat our patients like ourselves or our family members.”
 

When appropriate – Mohs is safe in the very elderly

Taking on the issue in a separate presentation, Deborah MacFarlane, MD, professor of dermatology and head and neck surgery at MD Anderson Cancer Center, Houston, said that for skin cancer cases that warrant treatment, clinicians should not let age alone stand in the way of Mohs surgery.

The evidence of its safety in the elderly dates back to a paper published in 1997 that Dr. MacFarlane coauthored, describing Mohs surgery of BCCs, squamous cell cancers (SCCs), and melanomas among 115 patients aged 90 and older (average, 92.4 years) who had an average of 1.9 comorbid medical conditions, and were taking an average of 2.3 medications. “Overall, we had just one complication among the patients,” she said.

In a subsequent paper, Dr. MacFarlane and her colleagues found that age at the time of Mohs surgery, even in older patients, was unrelated to survival, stage of cancer, or the type of repair. “We have concluded that this rapidly growing segment of the population can undergo Mohs surgery and should not be relegated to less effective treatment out of fear of its affecting their survival,” Dr. MacFarlane said.

She agreed with the concern about frailty and hence functionality, which may need to be factored in when making a decision to perform Mohs surgery. “I think this is something we do intuitively anyway,” she added. “We’re going to offer Mohs to someone who we think will survive and who is in relatively good health,” Dr. MacFarlane noted.

The point is illustrated in a new multicenter study of 1,181 patients at 22 U.S. sites, aged 85 years and older with nonmelanoma skin cancer referred for Mohs surgery. In the study, published in JAMA Dermatology after the ACMS meeting, patients who had Mohs surgery were almost four times more likely to have high functional status (P < .001) and were more likely to have facial tumors (P < .001), compared with those who had an alternate surgery.

The main reasons provided by the surgeons for opting to treat with Mohs included a patient’s desire for treatment with a high cure rate (66%), good/excellent patient functional status for age (57%), and a high risk associated with the tumor based on histology (40%), noted Dr. MacFarlane, one of the authors.

She reiterated the point raised by Dr. Rogers that “this is something we’re going to increasingly face,” noting that people over 85 represent the fastest growing segment of the population. “I have more patients over the age of 100 than I’ve ever had before,” she said.

Nevertheless, her own experience with elderly patients speaks to the safety of Mohs surgery in this population: Dr. MacFarlane reported a review of her practice’s records of 171 patients aged 85 years and older between May 2016 and May 2022, who received 414 separate procedures, without a single complication.

Sharing many of Dr. Rogers’ concerns about using caution in at-risk patients, Dr. MacFarlane offered recommendations for the optimal treatment of elderly patients receiving Mohs, including handling tissue delicately, and “keep undermining to a minimum.” She noted that intermediate closures and full thickness skin grafts are ideal closures for the elderly, while flaps may be performed in selected robust skin. It is also important to involve caretakers from the onset, talk and listen to patients – and play their choice of music during treatment, she said.

Commenting on the debate, comoderator Nahid Y. Vidal, MD, of the department of dermatology, Mayo Clinic, Rochester, Minn., noted that the expanding older population is accompanied by increases in skin cancer, in addition to more immunosenescence that is related to development of infections, autoimmune disease, and malignant tumors.

“In our academic practice, as with both the reference speakers, we do frequently see elderly, and not uncommonly the super-elderly,” she told this news organization. “The take-home point for me is to treat your whole patient, not just the tumor,” considering social factors, frailty/spry factor, and preferences, “and to do the humanistic thing, while also remaining evidence based,” she said.

“Don’t assume that increased age translates to morbidity, worse outcomes, or futility of treatment,” she added. “Chances are, if [a patient] made it to 90 years old with only a few medications and few medical problems, they may make it to 100, so why put the patient at risk for metastasis and death from a treatable/curable skin cancer,” in the case of SCC, she said.

“By the same token, why not perform more conservative treatments such as ED&C [electrodesiccation and curettage] for very low-risk skin cancers in low-risk locations, such as a superficial basal cell carcinoma on the trunk?” Overall, instead of trying to determine how long a super-elderly individual will live, Dr. Vidal said that “it’s better to educate the patient, engage in a discussion about goals of care, and to make few assumptions.”

Dr. Rogers, Dr. MacFarlane, and Dr. Vidal report no disclosures.

A version of this article first appeared on Medscape.com.

As increasing numbers of patients in their 80s, 90s, and even 100s present for possible Mohs micrographic surgery, surgeons are confronted with deciding when the risks of treatment may outweigh the benefits.

In one of two presentations at the annual meeting of the American College of Mohs Surgery that addressed this topic, Howard W. Rogers, MD, of Advanced Dermatology in Norwich, Conn., said that the crux of the issue is the concern not to undertreat. He noted that reduced access to dermatologic care during the pandemic has provided a stark lesson in the risks of delaying treatment in all age groups. “Mohs surgeons have all seen the consequences of delayed treatment due to the pandemic with enormous, destructive, and sometimes fatal cancers coming to the office in the last year,” he told this news organization.

“Pandemic-related treatment delay has caused increased suffering and morbidity for countless skin cancer patients across the U.S.,” he said. “In general, not treating skin cancer and hoping it’s not going to grow or having significant delays in treatment are a recipe for disastrous outcomes.”

That said, active monitoring may be appropriate “for select small cancers that tend to grow slowly in the very elderly,” added Dr. Rogers, the incoming ACMS president. Among the key situations where the benefits of active monitoring may outweigh the risks of surgery are small, slowly growing cancers, when frailty is an issue.

Frailty has been equated to compromised functionality, which can increase the risk of an array of complications, including prolonged wound healing and secondary complications stemming from immobility. The toll those issues can take on patients’ quality of life can be considerable, Dr. Rogers said.

When weighing treatment options with elderly patients, he emphasized that careful consideration should be given to whether the “time needed to benefit from a Mohs procedure is longer than the patient’s life expectancy.” Furthermore, a decision not to treat does not have to be the last word. “We need to have an honest dialogue on the consequences of nontreatment, but part of that should be that just because we don’t treat today, doesn’t mean we can’t treat it tomorrow, if necessary.”

Of note, he added, “more than 100,00 patients have surgery for basal cell carcinoma [BCC] in their last year of life.” And that figure will likely rise exponentially if population projections come to fruition, considering that the population of people over the age of 85 is predicted to increase to nearly 18 million in 2050, from 5.8 million in 2012, Dr. Rogers said.

Until more research emerges on how to best treat this age group, Dr. Rogers noted that experts recommend that for elderly patients, “treatment should be individualized with consideration of active monitoring of primary BCC that is not in the H-zone, asymptomatic, smaller than 1 cm, with treatment initiated if there is substantial growth or symptoms.” Ultimately, he urged surgeons to “be sensitive and treat our patients like ourselves or our family members.”
 

When appropriate – Mohs is safe in the very elderly

Taking on the issue in a separate presentation, Deborah MacFarlane, MD, professor of dermatology and head and neck surgery at MD Anderson Cancer Center, Houston, said that for skin cancer cases that warrant treatment, clinicians should not let age alone stand in the way of Mohs surgery.

The evidence of its safety in the elderly dates back to a paper published in 1997 that Dr. MacFarlane coauthored, describing Mohs surgery of BCCs, squamous cell cancers (SCCs), and melanomas among 115 patients aged 90 and older (average, 92.4 years) who had an average of 1.9 comorbid medical conditions, and were taking an average of 2.3 medications. “Overall, we had just one complication among the patients,” she said.

In a subsequent paper, Dr. MacFarlane and her colleagues found that age at the time of Mohs surgery, even in older patients, was unrelated to survival, stage of cancer, or the type of repair. “We have concluded that this rapidly growing segment of the population can undergo Mohs surgery and should not be relegated to less effective treatment out of fear of its affecting their survival,” Dr. MacFarlane said.

She agreed with the concern about frailty and hence functionality, which may need to be factored in when making a decision to perform Mohs surgery. “I think this is something we do intuitively anyway,” she added. “We’re going to offer Mohs to someone who we think will survive and who is in relatively good health,” Dr. MacFarlane noted.

The point is illustrated in a new multicenter study of 1,181 patients at 22 U.S. sites, aged 85 years and older with nonmelanoma skin cancer referred for Mohs surgery. In the study, published in JAMA Dermatology after the ACMS meeting, patients who had Mohs surgery were almost four times more likely to have high functional status (P < .001) and were more likely to have facial tumors (P < .001), compared with those who had an alternate surgery.

The main reasons provided by the surgeons for opting to treat with Mohs included a patient’s desire for treatment with a high cure rate (66%), good/excellent patient functional status for age (57%), and a high risk associated with the tumor based on histology (40%), noted Dr. MacFarlane, one of the authors.

She reiterated the point raised by Dr. Rogers that “this is something we’re going to increasingly face,” noting that people over 85 represent the fastest growing segment of the population. “I have more patients over the age of 100 than I’ve ever had before,” she said.

Nevertheless, her own experience with elderly patients speaks to the safety of Mohs surgery in this population: Dr. MacFarlane reported a review of her practice’s records of 171 patients aged 85 years and older between May 2016 and May 2022, who received 414 separate procedures, without a single complication.

Sharing many of Dr. Rogers’ concerns about using caution in at-risk patients, Dr. MacFarlane offered recommendations for the optimal treatment of elderly patients receiving Mohs, including handling tissue delicately, and “keep undermining to a minimum.” She noted that intermediate closures and full thickness skin grafts are ideal closures for the elderly, while flaps may be performed in selected robust skin. It is also important to involve caretakers from the onset, talk and listen to patients – and play their choice of music during treatment, she said.

Commenting on the debate, comoderator Nahid Y. Vidal, MD, of the department of dermatology, Mayo Clinic, Rochester, Minn., noted that the expanding older population is accompanied by increases in skin cancer, in addition to more immunosenescence that is related to development of infections, autoimmune disease, and malignant tumors.

“In our academic practice, as with both the reference speakers, we do frequently see elderly, and not uncommonly the super-elderly,” she told this news organization. “The take-home point for me is to treat your whole patient, not just the tumor,” considering social factors, frailty/spry factor, and preferences, “and to do the humanistic thing, while also remaining evidence based,” she said.

“Don’t assume that increased age translates to morbidity, worse outcomes, or futility of treatment,” she added. “Chances are, if [a patient] made it to 90 years old with only a few medications and few medical problems, they may make it to 100, so why put the patient at risk for metastasis and death from a treatable/curable skin cancer,” in the case of SCC, she said.

“By the same token, why not perform more conservative treatments such as ED&C [electrodesiccation and curettage] for very low-risk skin cancers in low-risk locations, such as a superficial basal cell carcinoma on the trunk?” Overall, instead of trying to determine how long a super-elderly individual will live, Dr. Vidal said that “it’s better to educate the patient, engage in a discussion about goals of care, and to make few assumptions.”

Dr. Rogers, Dr. MacFarlane, and Dr. Vidal report no disclosures.

A version of this article first appeared on Medscape.com.

As increasing numbers of patients in their 80s, 90s, and even 100s present for possible Mohs micrographic surgery, surgeons are confronted with deciding when the risks of treatment may outweigh the benefits.

In one of two presentations at the annual meeting of the American College of Mohs Surgery that addressed this topic, Howard W. Rogers, MD, of Advanced Dermatology in Norwich, Conn., said that the crux of the issue is the concern not to undertreat. He noted that reduced access to dermatologic care during the pandemic has provided a stark lesson in the risks of delaying treatment in all age groups. “Mohs surgeons have all seen the consequences of delayed treatment due to the pandemic with enormous, destructive, and sometimes fatal cancers coming to the office in the last year,” he told this news organization.

“Pandemic-related treatment delay has caused increased suffering and morbidity for countless skin cancer patients across the U.S.,” he said. “In general, not treating skin cancer and hoping it’s not going to grow or having significant delays in treatment are a recipe for disastrous outcomes.”

That said, active monitoring may be appropriate “for select small cancers that tend to grow slowly in the very elderly,” added Dr. Rogers, the incoming ACMS president. Among the key situations where the benefits of active monitoring may outweigh the risks of surgery are small, slowly growing cancers, when frailty is an issue.

Frailty has been equated to compromised functionality, which can increase the risk of an array of complications, including prolonged wound healing and secondary complications stemming from immobility. The toll those issues can take on patients’ quality of life can be considerable, Dr. Rogers said.

When weighing treatment options with elderly patients, he emphasized that careful consideration should be given to whether the “time needed to benefit from a Mohs procedure is longer than the patient’s life expectancy.” Furthermore, a decision not to treat does not have to be the last word. “We need to have an honest dialogue on the consequences of nontreatment, but part of that should be that just because we don’t treat today, doesn’t mean we can’t treat it tomorrow, if necessary.”

Of note, he added, “more than 100,00 patients have surgery for basal cell carcinoma [BCC] in their last year of life.” And that figure will likely rise exponentially if population projections come to fruition, considering that the population of people over the age of 85 is predicted to increase to nearly 18 million in 2050, from 5.8 million in 2012, Dr. Rogers said.

Until more research emerges on how to best treat this age group, Dr. Rogers noted that experts recommend that for elderly patients, “treatment should be individualized with consideration of active monitoring of primary BCC that is not in the H-zone, asymptomatic, smaller than 1 cm, with treatment initiated if there is substantial growth or symptoms.” Ultimately, he urged surgeons to “be sensitive and treat our patients like ourselves or our family members.”
 

When appropriate – Mohs is safe in the very elderly

Taking on the issue in a separate presentation, Deborah MacFarlane, MD, professor of dermatology and head and neck surgery at MD Anderson Cancer Center, Houston, said that for skin cancer cases that warrant treatment, clinicians should not let age alone stand in the way of Mohs surgery.

The evidence of its safety in the elderly dates back to a paper published in 1997 that Dr. MacFarlane coauthored, describing Mohs surgery of BCCs, squamous cell cancers (SCCs), and melanomas among 115 patients aged 90 and older (average, 92.4 years) who had an average of 1.9 comorbid medical conditions, and were taking an average of 2.3 medications. “Overall, we had just one complication among the patients,” she said.

In a subsequent paper, Dr. MacFarlane and her colleagues found that age at the time of Mohs surgery, even in older patients, was unrelated to survival, stage of cancer, or the type of repair. “We have concluded that this rapidly growing segment of the population can undergo Mohs surgery and should not be relegated to less effective treatment out of fear of its affecting their survival,” Dr. MacFarlane said.

She agreed with the concern about frailty and hence functionality, which may need to be factored in when making a decision to perform Mohs surgery. “I think this is something we do intuitively anyway,” she added. “We’re going to offer Mohs to someone who we think will survive and who is in relatively good health,” Dr. MacFarlane noted.

The point is illustrated in a new multicenter study of 1,181 patients at 22 U.S. sites, aged 85 years and older with nonmelanoma skin cancer referred for Mohs surgery. In the study, published in JAMA Dermatology after the ACMS meeting, patients who had Mohs surgery were almost four times more likely to have high functional status (P < .001) and were more likely to have facial tumors (P < .001), compared with those who had an alternate surgery.

The main reasons provided by the surgeons for opting to treat with Mohs included a patient’s desire for treatment with a high cure rate (66%), good/excellent patient functional status for age (57%), and a high risk associated with the tumor based on histology (40%), noted Dr. MacFarlane, one of the authors.

She reiterated the point raised by Dr. Rogers that “this is something we’re going to increasingly face,” noting that people over 85 represent the fastest growing segment of the population. “I have more patients over the age of 100 than I’ve ever had before,” she said.

Nevertheless, her own experience with elderly patients speaks to the safety of Mohs surgery in this population: Dr. MacFarlane reported a review of her practice’s records of 171 patients aged 85 years and older between May 2016 and May 2022, who received 414 separate procedures, without a single complication.

Sharing many of Dr. Rogers’ concerns about using caution in at-risk patients, Dr. MacFarlane offered recommendations for the optimal treatment of elderly patients receiving Mohs, including handling tissue delicately, and “keep undermining to a minimum.” She noted that intermediate closures and full thickness skin grafts are ideal closures for the elderly, while flaps may be performed in selected robust skin. It is also important to involve caretakers from the onset, talk and listen to patients – and play their choice of music during treatment, she said.

Commenting on the debate, comoderator Nahid Y. Vidal, MD, of the department of dermatology, Mayo Clinic, Rochester, Minn., noted that the expanding older population is accompanied by increases in skin cancer, in addition to more immunosenescence that is related to development of infections, autoimmune disease, and malignant tumors.

“In our academic practice, as with both the reference speakers, we do frequently see elderly, and not uncommonly the super-elderly,” she told this news organization. “The take-home point for me is to treat your whole patient, not just the tumor,” considering social factors, frailty/spry factor, and preferences, “and to do the humanistic thing, while also remaining evidence based,” she said.

“Don’t assume that increased age translates to morbidity, worse outcomes, or futility of treatment,” she added. “Chances are, if [a patient] made it to 90 years old with only a few medications and few medical problems, they may make it to 100, so why put the patient at risk for metastasis and death from a treatable/curable skin cancer,” in the case of SCC, she said.

“By the same token, why not perform more conservative treatments such as ED&C [electrodesiccation and curettage] for very low-risk skin cancers in low-risk locations, such as a superficial basal cell carcinoma on the trunk?” Overall, instead of trying to determine how long a super-elderly individual will live, Dr. Vidal said that “it’s better to educate the patient, engage in a discussion about goals of care, and to make few assumptions.”

Dr. Rogers, Dr. MacFarlane, and Dr. Vidal report no disclosures.

A version of this article first appeared on Medscape.com.

SAN DIEGO – Twelve years ago, Merete Haedersdal, MD, PhD, and colleagues published data from a swine study, which showed for the first time that the ablative fractional laser can be used to boost the uptake of drugs into the skin.

That discovery paved the way for what are now well-established clinical applications of laser-assisted drug delivery for treating actinic keratoses and scars. According to Dr. Haedersdal, professor of dermatology at the University of Copenhagen, evolving clinical indications for laser-assisted drug delivery include rejuvenation, local anesthesia, melasma, onychomycosis, hyperhidrosis, alopecia, and vitiligo, while emerging indications include treatment of skin cancer with PD-1 inhibitors and combination chemotherapy regimens, and vaccinations.

During a presentation at the annual conference of the American Society for Laser Medicine and Surgery, she said that researchers have much to learn about laser-assisted drug delivery, including biodistribution of the drug being delivered. Pointing out that so far, “what we have been dealing with is primarily looking at the skin as a black box,” she asked, “what happens when we drill the holes and drugs are applied on top of the skin and swim through the tiny channels?”

By using high-performance liquid chromatography (HPLC) and HPLC mass spectrometry to measure drug concentration in the skin, she and her colleagues have observed enhanced uptake of drugs – 4-fold to 40-fold greater – primarily in ex vivo pig skin. “We do know from ex vivo models that it’s much easier to boost the uptake in the skin” when compared with in vivo human use, where much lower drug concentrations are detected, said Dr. Haedersdal, who, along with Emily Wenande, MD, PhD, and R. Rox Anderson, MD, at the Wellman Center for Photomedicine, at Massachusetts General Hospital, Boston, authored a clinical review, published in 2020, on the basics of laser-assisted drug delivery.

“What we are working on now is visualizing what’s taking place when we apply the holes and the drugs in the skin. This is the key to tailoring laser-assisted uptake to specific dermatologic diseases being treated,” she said. To date, she and her colleagues have examined the interaction with tissue using different devices, including ex vivo confocal microscopy, to view the thermal response to ablative fractional laser and radiofrequency. “We want to take that to the next level and look at the drug biodistribution.”

Efforts are underway to compare the pattern of drug distribution with different modes of delivery, such as comparing ablative fractional laser to intradermal needle injection. “We are also working on pneumatic jet injection, which creates a focal drug distribution,” said Dr. Haedersdal, who is a visiting scientist at the Wellman Center. “In the future, we may take advantage of device-tailored biodistribution, depending on which clinical indication we are treating.”

Another important aspect to consider is drug retention in the skin. In a study presented as an abstract at the meeting, led by Dr. Wenande, she, Dr. Haedersdal, and colleagues used a pig model to evaluate the effect of three vasoregulative interventions on ablative fractional laser-assisted 5-fluororacil concentrations in in vivo skin. The three interventions were brimonidine 0.33% solution, epinephrine 10 mcg/mL gel, and a 595-nm pulsed dye laser (PDL) in designated treatment areas.

“What we learned from that was in the short term – 1-4 hours – the ablative fractional laser enhanced the uptake of 5-FU, but it was very transient,” with a twofold increased concentration of 5-FU, Dr. Haedersdal said. Over 48-72 hours, after PDL, there was “sustained enhancement of drug in the skin by three to four times,” she noted.

The synergy of systemic drugs with ablative fractional laser therapy is also being evaluated. In a mouse study led by Dr. Haedersdal’s colleague, senior researcher Uffe H. Olesen, PhD, the treatment of advanced squamous cell carcinoma tumors with a combination of ablative fractional laser and systemic treatment with PD-1 inhibitors resulted in the clearance of more tumors than with either treatment as monotherapy. “What we want to explore is the laser-induced tumor immune response in keratinocyte cancers,” she added.

“When you shine the laser on the skin, there is a robust increase of neutrophilic granulocytes.” Combining this topical immune-boosting response with systemic delivery of PD-1 inhibitors in a mouse model with basal cell carcinoma, she said, “we learned that, when we compare systemic PD-1 inhibitors alone to the laser alone and then with combination therapy, there was an increased tumor clearance of basal cell carcinomas and also enhanced survival of the mice” with the combination, she said. There were also “enhanced neutrophilic counts and both CD4- and CD8-positive cells were increased,” she added.

Dr. Haedersdal disclosed that she has received grants or research funding from Lutronic, Venus Concept, Leo Pharma, and Mirai Medical.

SAN DIEGO – Twelve years ago, Merete Haedersdal, MD, PhD, and colleagues published data from a swine study, which showed for the first time that the ablative fractional laser can be used to boost the uptake of drugs into the skin.

That discovery paved the way for what are now well-established clinical applications of laser-assisted drug delivery for treating actinic keratoses and scars. According to Dr. Haedersdal, professor of dermatology at the University of Copenhagen, evolving clinical indications for laser-assisted drug delivery include rejuvenation, local anesthesia, melasma, onychomycosis, hyperhidrosis, alopecia, and vitiligo, while emerging indications include treatment of skin cancer with PD-1 inhibitors and combination chemotherapy regimens, and vaccinations.

During a presentation at the annual conference of the American Society for Laser Medicine and Surgery, she said that researchers have much to learn about laser-assisted drug delivery, including biodistribution of the drug being delivered. Pointing out that so far, “what we have been dealing with is primarily looking at the skin as a black box,” she asked, “what happens when we drill the holes and drugs are applied on top of the skin and swim through the tiny channels?”

By using high-performance liquid chromatography (HPLC) and HPLC mass spectrometry to measure drug concentration in the skin, she and her colleagues have observed enhanced uptake of drugs – 4-fold to 40-fold greater – primarily in ex vivo pig skin. “We do know from ex vivo models that it’s much easier to boost the uptake in the skin” when compared with in vivo human use, where much lower drug concentrations are detected, said Dr. Haedersdal, who, along with Emily Wenande, MD, PhD, and R. Rox Anderson, MD, at the Wellman Center for Photomedicine, at Massachusetts General Hospital, Boston, authored a clinical review, published in 2020, on the basics of laser-assisted drug delivery.

“What we are working on now is visualizing what’s taking place when we apply the holes and the drugs in the skin. This is the key to tailoring laser-assisted uptake to specific dermatologic diseases being treated,” she said. To date, she and her colleagues have examined the interaction with tissue using different devices, including ex vivo confocal microscopy, to view the thermal response to ablative fractional laser and radiofrequency. “We want to take that to the next level and look at the drug biodistribution.”

Efforts are underway to compare the pattern of drug distribution with different modes of delivery, such as comparing ablative fractional laser to intradermal needle injection. “We are also working on pneumatic jet injection, which creates a focal drug distribution,” said Dr. Haedersdal, who is a visiting scientist at the Wellman Center. “In the future, we may take advantage of device-tailored biodistribution, depending on which clinical indication we are treating.”

Another important aspect to consider is drug retention in the skin. In a study presented as an abstract at the meeting, led by Dr. Wenande, she, Dr. Haedersdal, and colleagues used a pig model to evaluate the effect of three vasoregulative interventions on ablative fractional laser-assisted 5-fluororacil concentrations in in vivo skin. The three interventions were brimonidine 0.33% solution, epinephrine 10 mcg/mL gel, and a 595-nm pulsed dye laser (PDL) in designated treatment areas.

“What we learned from that was in the short term – 1-4 hours – the ablative fractional laser enhanced the uptake of 5-FU, but it was very transient,” with a twofold increased concentration of 5-FU, Dr. Haedersdal said. Over 48-72 hours, after PDL, there was “sustained enhancement of drug in the skin by three to four times,” she noted.

The synergy of systemic drugs with ablative fractional laser therapy is also being evaluated. In a mouse study led by Dr. Haedersdal’s colleague, senior researcher Uffe H. Olesen, PhD, the treatment of advanced squamous cell carcinoma tumors with a combination of ablative fractional laser and systemic treatment with PD-1 inhibitors resulted in the clearance of more tumors than with either treatment as monotherapy. “What we want to explore is the laser-induced tumor immune response in keratinocyte cancers,” she added.

“When you shine the laser on the skin, there is a robust increase of neutrophilic granulocytes.” Combining this topical immune-boosting response with systemic delivery of PD-1 inhibitors in a mouse model with basal cell carcinoma, she said, “we learned that, when we compare systemic PD-1 inhibitors alone to the laser alone and then with combination therapy, there was an increased tumor clearance of basal cell carcinomas and also enhanced survival of the mice” with the combination, she said. There were also “enhanced neutrophilic counts and both CD4- and CD8-positive cells were increased,” she added.

Dr. Haedersdal disclosed that she has received grants or research funding from Lutronic, Venus Concept, Leo Pharma, and Mirai Medical.

SAN DIEGO – Twelve years ago, Merete Haedersdal, MD, PhD, and colleagues published data from a swine study, which showed for the first time that the ablative fractional laser can be used to boost the uptake of drugs into the skin.

That discovery paved the way for what are now well-established clinical applications of laser-assisted drug delivery for treating actinic keratoses and scars. According to Dr. Haedersdal, professor of dermatology at the University of Copenhagen, evolving clinical indications for laser-assisted drug delivery include rejuvenation, local anesthesia, melasma, onychomycosis, hyperhidrosis, alopecia, and vitiligo, while emerging indications include treatment of skin cancer with PD-1 inhibitors and combination chemotherapy regimens, and vaccinations.

During a presentation at the annual conference of the American Society for Laser Medicine and Surgery, she said that researchers have much to learn about laser-assisted drug delivery, including biodistribution of the drug being delivered. Pointing out that so far, “what we have been dealing with is primarily looking at the skin as a black box,” she asked, “what happens when we drill the holes and drugs are applied on top of the skin and swim through the tiny channels?”

By using high-performance liquid chromatography (HPLC) and HPLC mass spectrometry to measure drug concentration in the skin, she and her colleagues have observed enhanced uptake of drugs – 4-fold to 40-fold greater – primarily in ex vivo pig skin. “We do know from ex vivo models that it’s much easier to boost the uptake in the skin” when compared with in vivo human use, where much lower drug concentrations are detected, said Dr. Haedersdal, who, along with Emily Wenande, MD, PhD, and R. Rox Anderson, MD, at the Wellman Center for Photomedicine, at Massachusetts General Hospital, Boston, authored a clinical review, published in 2020, on the basics of laser-assisted drug delivery.

“What we are working on now is visualizing what’s taking place when we apply the holes and the drugs in the skin. This is the key to tailoring laser-assisted uptake to specific dermatologic diseases being treated,” she said. To date, she and her colleagues have examined the interaction with tissue using different devices, including ex vivo confocal microscopy, to view the thermal response to ablative fractional laser and radiofrequency. “We want to take that to the next level and look at the drug biodistribution.”

Efforts are underway to compare the pattern of drug distribution with different modes of delivery, such as comparing ablative fractional laser to intradermal needle injection. “We are also working on pneumatic jet injection, which creates a focal drug distribution,” said Dr. Haedersdal, who is a visiting scientist at the Wellman Center. “In the future, we may take advantage of device-tailored biodistribution, depending on which clinical indication we are treating.”

Another important aspect to consider is drug retention in the skin. In a study presented as an abstract at the meeting, led by Dr. Wenande, she, Dr. Haedersdal, and colleagues used a pig model to evaluate the effect of three vasoregulative interventions on ablative fractional laser-assisted 5-fluororacil concentrations in in vivo skin. The three interventions were brimonidine 0.33% solution, epinephrine 10 mcg/mL gel, and a 595-nm pulsed dye laser (PDL) in designated treatment areas.

“What we learned from that was in the short term – 1-4 hours – the ablative fractional laser enhanced the uptake of 5-FU, but it was very transient,” with a twofold increased concentration of 5-FU, Dr. Haedersdal said. Over 48-72 hours, after PDL, there was “sustained enhancement of drug in the skin by three to four times,” she noted.

The synergy of systemic drugs with ablative fractional laser therapy is also being evaluated. In a mouse study led by Dr. Haedersdal’s colleague, senior researcher Uffe H. Olesen, PhD, the treatment of advanced squamous cell carcinoma tumors with a combination of ablative fractional laser and systemic treatment with PD-1 inhibitors resulted in the clearance of more tumors than with either treatment as monotherapy. “What we want to explore is the laser-induced tumor immune response in keratinocyte cancers,” she added.

“When you shine the laser on the skin, there is a robust increase of neutrophilic granulocytes.” Combining this topical immune-boosting response with systemic delivery of PD-1 inhibitors in a mouse model with basal cell carcinoma, she said, “we learned that, when we compare systemic PD-1 inhibitors alone to the laser alone and then with combination therapy, there was an increased tumor clearance of basal cell carcinomas and also enhanced survival of the mice” with the combination, she said. There were also “enhanced neutrophilic counts and both CD4- and CD8-positive cells were increased,” she added.

Dr. Haedersdal disclosed that she has received grants or research funding from Lutronic, Venus Concept, Leo Pharma, and Mirai Medical.

Using adjunctive reflectance confocal microscopy (RCM) for examining suspect skin lesions reduced the number of unnecessary skin excisions by 43%, results from a large randomized clinical trial showed.

“Skin cancer management exerts a sizable burden on health systems,” researchers led by Giovanni Pellacani, MD, wrote in an article published in JAMA Dermatology. “The systematic application of RCM in the triage of high-risk patients should improve diagnostic accuracy and reduce unnecessary excisions for histopathological diagnostic confirmation, thereby reducing costs, surgical waiting lists, and delayed diagnoses.”

However, they added, “the clinical application of RCM has mainly been limited to retrospective and prospective observational studies producing hypothetical estimates of clinical applicability without intention to affect clinical and therapeutic patient pathways.”

For the current study, Dr. Pellacani, who chairs the department of dermatology at Sapienza University, Rome, and colleagues hypothesized that RCM would reduce unnecessary excisions by more than 30% and would identify all melanoma lesions 0.5 mm or thinner at baseline. They enrolled 3,165 patients with suspect lesions from three dermatology referral centers between January 2017 and December 2019, with a mean follow-up of 9.6 months in the study. Participants were randomly assigned 1:1 to standard therapeutic care, which consisted of clinical and dermoscopy evaluation with or without adjunctive RCM, a novel noninvasive technology that provides in vivo imaging of the skin, with a high diagnostic accuracy.

Histopathologic examination of all excised lesions was performed at the pathology department of the referral center. Resulting information guided prospective clinical decision-making (excision or follow-up). The mean age of patients was 49 years, 49% were women, 21% had a personal history of melanoma, and 51% had Fitzpatrick phototype 2 skin.

When compared with standard therapeutic care only, adjunctive RCM was associated with a higher positive predictive value (18.9 vs. 33.3, respectively), lower benign to malignant ratio (3.7:1.0 vs. 1.8:1.0), and a reduction in the number needed to excise of 43.4% (5.3 vs. 3.0). In addition, all 15 lesions with delayed melanoma diagnoses were thinner than 0.5 mm. Of these, eight were diagnosed as melanoma in situ.

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study, said that a strength of the analysis was its follow-up and histopathologic evaluation, “which are both essentially forms of feedback. Good, relevant feedback is necessary for all of us to improve.”

She pointed out that, while RCM does appear to reduce the number of benign lesions unnecessarily removed and increase the number of skin cancers appropriately excised, the authors acknowledged that they had at least 4 years of experience with RCM. “The study also does not address the time factor (the procedure takes about 7 minutes per lesion) and the financial cost of reflectance confocal microscopy, as compared to the cost of standard follow-up alone with an increased number of excisions.”

She added that the findings “are not yet applicable to general dermatology across the world, as the authors comment, given that reflectance confocal microscopy is not yet widely available.”

The Italian Ministry of Health supported the study. Neither the researchers nor Dr. Ko reported having relevant financial conflicts.

Using adjunctive reflectance confocal microscopy (RCM) for examining suspect skin lesions reduced the number of unnecessary skin excisions by 43%, results from a large randomized clinical trial showed.

“Skin cancer management exerts a sizable burden on health systems,” researchers led by Giovanni Pellacani, MD, wrote in an article published in JAMA Dermatology. “The systematic application of RCM in the triage of high-risk patients should improve diagnostic accuracy and reduce unnecessary excisions for histopathological diagnostic confirmation, thereby reducing costs, surgical waiting lists, and delayed diagnoses.”

However, they added, “the clinical application of RCM has mainly been limited to retrospective and prospective observational studies producing hypothetical estimates of clinical applicability without intention to affect clinical and therapeutic patient pathways.”

For the current study, Dr. Pellacani, who chairs the department of dermatology at Sapienza University, Rome, and colleagues hypothesized that RCM would reduce unnecessary excisions by more than 30% and would identify all melanoma lesions 0.5 mm or thinner at baseline. They enrolled 3,165 patients with suspect lesions from three dermatology referral centers between January 2017 and December 2019, with a mean follow-up of 9.6 months in the study. Participants were randomly assigned 1:1 to standard therapeutic care, which consisted of clinical and dermoscopy evaluation with or without adjunctive RCM, a novel noninvasive technology that provides in vivo imaging of the skin, with a high diagnostic accuracy.

Histopathologic examination of all excised lesions was performed at the pathology department of the referral center. Resulting information guided prospective clinical decision-making (excision or follow-up). The mean age of patients was 49 years, 49% were women, 21% had a personal history of melanoma, and 51% had Fitzpatrick phototype 2 skin.

When compared with standard therapeutic care only, adjunctive RCM was associated with a higher positive predictive value (18.9 vs. 33.3, respectively), lower benign to malignant ratio (3.7:1.0 vs. 1.8:1.0), and a reduction in the number needed to excise of 43.4% (5.3 vs. 3.0). In addition, all 15 lesions with delayed melanoma diagnoses were thinner than 0.5 mm. Of these, eight were diagnosed as melanoma in situ.

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study, said that a strength of the analysis was its follow-up and histopathologic evaluation, “which are both essentially forms of feedback. Good, relevant feedback is necessary for all of us to improve.”

She pointed out that, while RCM does appear to reduce the number of benign lesions unnecessarily removed and increase the number of skin cancers appropriately excised, the authors acknowledged that they had at least 4 years of experience with RCM. “The study also does not address the time factor (the procedure takes about 7 minutes per lesion) and the financial cost of reflectance confocal microscopy, as compared to the cost of standard follow-up alone with an increased number of excisions.”

She added that the findings “are not yet applicable to general dermatology across the world, as the authors comment, given that reflectance confocal microscopy is not yet widely available.”

The Italian Ministry of Health supported the study. Neither the researchers nor Dr. Ko reported having relevant financial conflicts.

Using adjunctive reflectance confocal microscopy (RCM) for examining suspect skin lesions reduced the number of unnecessary skin excisions by 43%, results from a large randomized clinical trial showed.

“Skin cancer management exerts a sizable burden on health systems,” researchers led by Giovanni Pellacani, MD, wrote in an article published in JAMA Dermatology. “The systematic application of RCM in the triage of high-risk patients should improve diagnostic accuracy and reduce unnecessary excisions for histopathological diagnostic confirmation, thereby reducing costs, surgical waiting lists, and delayed diagnoses.”

However, they added, “the clinical application of RCM has mainly been limited to retrospective and prospective observational studies producing hypothetical estimates of clinical applicability without intention to affect clinical and therapeutic patient pathways.”

For the current study, Dr. Pellacani, who chairs the department of dermatology at Sapienza University, Rome, and colleagues hypothesized that RCM would reduce unnecessary excisions by more than 30% and would identify all melanoma lesions 0.5 mm or thinner at baseline. They enrolled 3,165 patients with suspect lesions from three dermatology referral centers between January 2017 and December 2019, with a mean follow-up of 9.6 months in the study. Participants were randomly assigned 1:1 to standard therapeutic care, which consisted of clinical and dermoscopy evaluation with or without adjunctive RCM, a novel noninvasive technology that provides in vivo imaging of the skin, with a high diagnostic accuracy.

Histopathologic examination of all excised lesions was performed at the pathology department of the referral center. Resulting information guided prospective clinical decision-making (excision or follow-up). The mean age of patients was 49 years, 49% were women, 21% had a personal history of melanoma, and 51% had Fitzpatrick phototype 2 skin.

When compared with standard therapeutic care only, adjunctive RCM was associated with a higher positive predictive value (18.9 vs. 33.3, respectively), lower benign to malignant ratio (3.7:1.0 vs. 1.8:1.0), and a reduction in the number needed to excise of 43.4% (5.3 vs. 3.0). In addition, all 15 lesions with delayed melanoma diagnoses were thinner than 0.5 mm. Of these, eight were diagnosed as melanoma in situ.

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study, said that a strength of the analysis was its follow-up and histopathologic evaluation, “which are both essentially forms of feedback. Good, relevant feedback is necessary for all of us to improve.”

She pointed out that, while RCM does appear to reduce the number of benign lesions unnecessarily removed and increase the number of skin cancers appropriately excised, the authors acknowledged that they had at least 4 years of experience with RCM. “The study also does not address the time factor (the procedure takes about 7 minutes per lesion) and the financial cost of reflectance confocal microscopy, as compared to the cost of standard follow-up alone with an increased number of excisions.”

She added that the findings “are not yet applicable to general dermatology across the world, as the authors comment, given that reflectance confocal microscopy is not yet widely available.”

The Italian Ministry of Health supported the study. Neither the researchers nor Dr. Ko reported having relevant financial conflicts.

Patients receiving treatment with ibrutinib for chronic lymphocytic leukemia (CLL) show significant increases in the risk for bleeding when undergoing Mohs micrographic surgery for skin cancer, indicating the need for temporary treatment interruptions, new research shows.

“Our cohort of CLL patients on ibrutinib had a two-times greater risk of bleeding complications relative to those on anticoagulants and a nearly 40-times greater risk of bleeding complications relative to those patients on no anticoagulants or CLL therapy,” Kelsey E. Hirotsu, MD, first author of one of two studies on the issue presented at the American College of Mohs Surgery annual meeting, told this news organization.

“It was definitely surprising to see this doubled risk with ibrutinib relative to anticoagulants, and certainly highlights the clinically relevant increased bleeding risk in patients on ibrutinib,” said Dr. Hirotsu, a Mohs micrographic surgery fellow in the department of dermatology, University of California, San Diego (UCSD).

With CLL associated with an increased risk for aggressive skin cancers, particularly squamous cell carcinoma, Mohs surgeons may commonly find themselves treating patients with these unique considerations. Surgical treatment of those cancers can be complicated not only because of potential underlying thrombocytopenia, which occurs in about 5% of untreated CLL patients, but also because of the increased risk for bleeding that is associated with the use of the Bruton tyrosine kinase inhibitor ibrutinib, commonly used for CLL.

While the nature of the increased bleeding-related complications among patients with CLL undergoing Mohs surgery has been documented in some case reports, evidence from larger studies has been lacking.

In one of the studies presented at the ACMS meeting, Dr. Hirotsu and her colleagues evaluated data on patients with CLL who underwent at least one Mohs surgery procedure at UCSD Dermatologic Surgery over 10 years. Of the 362 Mohs cases among 98 patients with CLL, 32 cases had at least one complication. Patients on anticoagulants, including antiplatelet agents, Coumadin, and direct oral anticoagulants (DOACs), not surprisingly, had higher rates of complications, particularly bleeding.

However, those treated with ibrutinib had the highest rates of complications among all of the patients (40.6%), with all of their complications involving bleeding-related events. In comparison, the complication rates, for instance, of patients treated with antiplatelets were 21.9%; Coumadin, 6.2%; and DOACs, 15.6%.

The incidence of bleeding-related complications among the cases in the ibrutinib-treated patients was 30.2% compared with 13.2% among those on blood thinners and no CLL therapy (relative risk [RR], 2.08; 95% confidence interval [CI], 0.85-5.11; P = .11). “Although not statistically significant, these results could trend toward significance with larger sample sizes,” Dr. Hirotsu said.

The risk for bleeding among patients on ibrutinib compared with patients on no medications, however, was significant, with a relative risk of 39.0 (95% CI, 2.35-646; P = .011).

Of note, among 12 patients on ibrutinib who experienced bleeding complications, 7 had previously undergone Mohs surgeries when they were not taking ibrutinib and no bleeding complications had occurred in those procedures. “This may further implicate ibrutinib as a cause of the bleeding-related complications,” Dr. Hirotsu said.

In investigating the role of thrombocytopenia at the time of Mohs surgery, the authors found that, among ibrutinib-treated patients who had no complications, 30% had thrombocytopenia, compared with 70% of those who did have bleeding while on ibrutinib at the time of surgery.

“It was interesting that thrombocytopenia is more common in ibrutinib patients with bleeding-related complications, but further research needs to be done to determine the clinical relevance and possible management implications,” Dr. Hirotsu said.

In a separate study presented at the meeting, 37 patients treated with ibrutinib for CLL while undergoing cutaneous surgery that included Mohs surgery and excisions had a significantly increased bleeding complication rate compared with a control group of 64 age- and sex-matched patients with CLL undergoing cutaneous surgery: 6 of 75 procedures (8%) versus 1 of 115 procedures (0.9%; P = .02).

Those with bleeding complications while on ibrutinib were all male, older (mean age, 82.7 vs. 73.0; P = .01), and had lower mean platelet counts (104 K/mcL vs. 150.5 K/mcL; P = .03).

There were no significant differences between the case and control groups in terms of anatomic site, type of procedure (Mohs versus excision), tumor diagnosis, lesion size, or type of reconstruction, while the control group was more likely to be on aspirin or other anticoagulants (P < .0001).

In an interview, senior author Nahid Y. Vidal, MD, a Mohs surgeon and dermatologic oncologist at the Mayo Clinic, Rochester, Minn., said that “the take-home message is that patients on ibrutinib should be considered higher risk for bleeding events, regardless of whether they are having a simpler surgery [excision] or more involved skin surgery procedure [Mohs with flap].”

Holding treatment

To offset the bleeding risk, Dr. Vidal notes that holding the treatment is considered safe and that the manufacturer recommends holding ibrutinib for at least 3-7 days pre- and post surgery, “depending on type of surgery and risk of bleeding.”

“In our institution, with the hematologist/oncologist’s input, we hold ibrutinib for 5 days preop and 3 days post op, and have not had bleed complications in these patients,” she said, noting that there were no bleeding events in the patients in the study when ibrutinib was held.

Likewise, Dr. Hirotsu noted that at her center at UCSD, patients on ibrutinib are asked during the preop call to hold treatment for 3 days before and after Mohs surgery – but are advised to discuss the decision with their hematologist/oncologist for approval.

The measure isn’t always successful in preventing bleeding, however, as seen in a case study describing two patients who experienced bleeding complications following Mohs surgery despite being taken off ibrutinib 3 days prior to the procedure.

The senior author of that study, Kira Minkis, MD, PhD, department of dermatology, Weill Cornell/New York Presbyterian, New York, told this news organization that her team concluded that in those cases ibrutinib perhaps should have been held longer than 3 days.

“In some cases, especially if the Mohs surgery is a large procedure with a more advanced reconstruction, such as a large flap, it might be more prudent to continue it longer than 3 days,” Dr. Minkis said. She noted that the high bleeding risk observed in the studies at ACMS was notable – but not unexpected.

“I’m not that surprised because if you look at the hematologic literature, the risk is indeed pretty significant, so it makes sense that it would also occur with Mohs surgeries,” she said.

She underscored that a 3-day hold of ibrutinib should be considered the minimum, “and in some cases, it should be held up to 7 days prior to surgery, depending on the specific surgery,” with the important caveat of consulting with the patient’s hematology team.

“Multidisciplinary decision-making is necessary for these cases, and the interruption of therapy should always be discussed with their hematology team,” she added. That said, Dr. Minkis noted that “I’ve never had a hematologist who had any concerns for withholding ibrutinib even for a week around the time of a surgery.”

Dr. Hirotsu, Dr. Vidal, and Dr. Minkis reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients receiving treatment with ibrutinib for chronic lymphocytic leukemia (CLL) show significant increases in the risk for bleeding when undergoing Mohs micrographic surgery for skin cancer, indicating the need for temporary treatment interruptions, new research shows.

“Our cohort of CLL patients on ibrutinib had a two-times greater risk of bleeding complications relative to those on anticoagulants and a nearly 40-times greater risk of bleeding complications relative to those patients on no anticoagulants or CLL therapy,” Kelsey E. Hirotsu, MD, first author of one of two studies on the issue presented at the American College of Mohs Surgery annual meeting, told this news organization.

“It was definitely surprising to see this doubled risk with ibrutinib relative to anticoagulants, and certainly highlights the clinically relevant increased bleeding risk in patients on ibrutinib,” said Dr. Hirotsu, a Mohs micrographic surgery fellow in the department of dermatology, University of California, San Diego (UCSD).

With CLL associated with an increased risk for aggressive skin cancers, particularly squamous cell carcinoma, Mohs surgeons may commonly find themselves treating patients with these unique considerations. Surgical treatment of those cancers can be complicated not only because of potential underlying thrombocytopenia, which occurs in about 5% of untreated CLL patients, but also because of the increased risk for bleeding that is associated with the use of the Bruton tyrosine kinase inhibitor ibrutinib, commonly used for CLL.

While the nature of the increased bleeding-related complications among patients with CLL undergoing Mohs surgery has been documented in some case reports, evidence from larger studies has been lacking.

In one of the studies presented at the ACMS meeting, Dr. Hirotsu and her colleagues evaluated data on patients with CLL who underwent at least one Mohs surgery procedure at UCSD Dermatologic Surgery over 10 years. Of the 362 Mohs cases among 98 patients with CLL, 32 cases had at least one complication. Patients on anticoagulants, including antiplatelet agents, Coumadin, and direct oral anticoagulants (DOACs), not surprisingly, had higher rates of complications, particularly bleeding.

However, those treated with ibrutinib had the highest rates of complications among all of the patients (40.6%), with all of their complications involving bleeding-related events. In comparison, the complication rates, for instance, of patients treated with antiplatelets were 21.9%; Coumadin, 6.2%; and DOACs, 15.6%.

The incidence of bleeding-related complications among the cases in the ibrutinib-treated patients was 30.2% compared with 13.2% among those on blood thinners and no CLL therapy (relative risk [RR], 2.08; 95% confidence interval [CI], 0.85-5.11; P = .11). “Although not statistically significant, these results could trend toward significance with larger sample sizes,” Dr. Hirotsu said.

The risk for bleeding among patients on ibrutinib compared with patients on no medications, however, was significant, with a relative risk of 39.0 (95% CI, 2.35-646; P = .011).

Of note, among 12 patients on ibrutinib who experienced bleeding complications, 7 had previously undergone Mohs surgeries when they were not taking ibrutinib and no bleeding complications had occurred in those procedures. “This may further implicate ibrutinib as a cause of the bleeding-related complications,” Dr. Hirotsu said.

In investigating the role of thrombocytopenia at the time of Mohs surgery, the authors found that, among ibrutinib-treated patients who had no complications, 30% had thrombocytopenia, compared with 70% of those who did have bleeding while on ibrutinib at the time of surgery.

“It was interesting that thrombocytopenia is more common in ibrutinib patients with bleeding-related complications, but further research needs to be done to determine the clinical relevance and possible management implications,” Dr. Hirotsu said.

In a separate study presented at the meeting, 37 patients treated with ibrutinib for CLL while undergoing cutaneous surgery that included Mohs surgery and excisions had a significantly increased bleeding complication rate compared with a control group of 64 age- and sex-matched patients with CLL undergoing cutaneous surgery: 6 of 75 procedures (8%) versus 1 of 115 procedures (0.9%; P = .02).

Those with bleeding complications while on ibrutinib were all male, older (mean age, 82.7 vs. 73.0; P = .01), and had lower mean platelet counts (104 K/mcL vs. 150.5 K/mcL; P = .03).

There were no significant differences between the case and control groups in terms of anatomic site, type of procedure (Mohs versus excision), tumor diagnosis, lesion size, or type of reconstruction, while the control group was more likely to be on aspirin or other anticoagulants (P < .0001).

In an interview, senior author Nahid Y. Vidal, MD, a Mohs surgeon and dermatologic oncologist at the Mayo Clinic, Rochester, Minn., said that “the take-home message is that patients on ibrutinib should be considered higher risk for bleeding events, regardless of whether they are having a simpler surgery [excision] or more involved skin surgery procedure [Mohs with flap].”

Holding treatment

To offset the bleeding risk, Dr. Vidal notes that holding the treatment is considered safe and that the manufacturer recommends holding ibrutinib for at least 3-7 days pre- and post surgery, “depending on type of surgery and risk of bleeding.”

“In our institution, with the hematologist/oncologist’s input, we hold ibrutinib for 5 days preop and 3 days post op, and have not had bleed complications in these patients,” she said, noting that there were no bleeding events in the patients in the study when ibrutinib was held.

Likewise, Dr. Hirotsu noted that at her center at UCSD, patients on ibrutinib are asked during the preop call to hold treatment for 3 days before and after Mohs surgery – but are advised to discuss the decision with their hematologist/oncologist for approval.

The measure isn’t always successful in preventing bleeding, however, as seen in a case study describing two patients who experienced bleeding complications following Mohs surgery despite being taken off ibrutinib 3 days prior to the procedure.

The senior author of that study, Kira Minkis, MD, PhD, department of dermatology, Weill Cornell/New York Presbyterian, New York, told this news organization that her team concluded that in those cases ibrutinib perhaps should have been held longer than 3 days.

“In some cases, especially if the Mohs surgery is a large procedure with a more advanced reconstruction, such as a large flap, it might be more prudent to continue it longer than 3 days,” Dr. Minkis said. She noted that the high bleeding risk observed in the studies at ACMS was notable – but not unexpected.

“I’m not that surprised because if you look at the hematologic literature, the risk is indeed pretty significant, so it makes sense that it would also occur with Mohs surgeries,” she said.

She underscored that a 3-day hold of ibrutinib should be considered the minimum, “and in some cases, it should be held up to 7 days prior to surgery, depending on the specific surgery,” with the important caveat of consulting with the patient’s hematology team.

“Multidisciplinary decision-making is necessary for these cases, and the interruption of therapy should always be discussed with their hematology team,” she added. That said, Dr. Minkis noted that “I’ve never had a hematologist who had any concerns for withholding ibrutinib even for a week around the time of a surgery.”

Dr. Hirotsu, Dr. Vidal, and Dr. Minkis reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients receiving treatment with ibrutinib for chronic lymphocytic leukemia (CLL) show significant increases in the risk for bleeding when undergoing Mohs micrographic surgery for skin cancer, indicating the need for temporary treatment interruptions, new research shows.

“Our cohort of CLL patients on ibrutinib had a two-times greater risk of bleeding complications relative to those on anticoagulants and a nearly 40-times greater risk of bleeding complications relative to those patients on no anticoagulants or CLL therapy,” Kelsey E. Hirotsu, MD, first author of one of two studies on the issue presented at the American College of Mohs Surgery annual meeting, told this news organization.

“It was definitely surprising to see this doubled risk with ibrutinib relative to anticoagulants, and certainly highlights the clinically relevant increased bleeding risk in patients on ibrutinib,” said Dr. Hirotsu, a Mohs micrographic surgery fellow in the department of dermatology, University of California, San Diego (UCSD).

With CLL associated with an increased risk for aggressive skin cancers, particularly squamous cell carcinoma, Mohs surgeons may commonly find themselves treating patients with these unique considerations. Surgical treatment of those cancers can be complicated not only because of potential underlying thrombocytopenia, which occurs in about 5% of untreated CLL patients, but also because of the increased risk for bleeding that is associated with the use of the Bruton tyrosine kinase inhibitor ibrutinib, commonly used for CLL.

While the nature of the increased bleeding-related complications among patients with CLL undergoing Mohs surgery has been documented in some case reports, evidence from larger studies has been lacking.

In one of the studies presented at the ACMS meeting, Dr. Hirotsu and her colleagues evaluated data on patients with CLL who underwent at least one Mohs surgery procedure at UCSD Dermatologic Surgery over 10 years. Of the 362 Mohs cases among 98 patients with CLL, 32 cases had at least one complication. Patients on anticoagulants, including antiplatelet agents, Coumadin, and direct oral anticoagulants (DOACs), not surprisingly, had higher rates of complications, particularly bleeding.

However, those treated with ibrutinib had the highest rates of complications among all of the patients (40.6%), with all of their complications involving bleeding-related events. In comparison, the complication rates, for instance, of patients treated with antiplatelets were 21.9%; Coumadin, 6.2%; and DOACs, 15.6%.

The incidence of bleeding-related complications among the cases in the ibrutinib-treated patients was 30.2% compared with 13.2% among those on blood thinners and no CLL therapy (relative risk [RR], 2.08; 95% confidence interval [CI], 0.85-5.11; P = .11). “Although not statistically significant, these results could trend toward significance with larger sample sizes,” Dr. Hirotsu said.

The risk for bleeding among patients on ibrutinib compared with patients on no medications, however, was significant, with a relative risk of 39.0 (95% CI, 2.35-646; P = .011).

Of note, among 12 patients on ibrutinib who experienced bleeding complications, 7 had previously undergone Mohs surgeries when they were not taking ibrutinib and no bleeding complications had occurred in those procedures. “This may further implicate ibrutinib as a cause of the bleeding-related complications,” Dr. Hirotsu said.

In investigating the role of thrombocytopenia at the time of Mohs surgery, the authors found that, among ibrutinib-treated patients who had no complications, 30% had thrombocytopenia, compared with 70% of those who did have bleeding while on ibrutinib at the time of surgery.

“It was interesting that thrombocytopenia is more common in ibrutinib patients with bleeding-related complications, but further research needs to be done to determine the clinical relevance and possible management implications,” Dr. Hirotsu said.

In a separate study presented at the meeting, 37 patients treated with ibrutinib for CLL while undergoing cutaneous surgery that included Mohs surgery and excisions had a significantly increased bleeding complication rate compared with a control group of 64 age- and sex-matched patients with CLL undergoing cutaneous surgery: 6 of 75 procedures (8%) versus 1 of 115 procedures (0.9%; P = .02).

Those with bleeding complications while on ibrutinib were all male, older (mean age, 82.7 vs. 73.0; P = .01), and had lower mean platelet counts (104 K/mcL vs. 150.5 K/mcL; P = .03).

There were no significant differences between the case and control groups in terms of anatomic site, type of procedure (Mohs versus excision), tumor diagnosis, lesion size, or type of reconstruction, while the control group was more likely to be on aspirin or other anticoagulants (P < .0001).

In an interview, senior author Nahid Y. Vidal, MD, a Mohs surgeon and dermatologic oncologist at the Mayo Clinic, Rochester, Minn., said that “the take-home message is that patients on ibrutinib should be considered higher risk for bleeding events, regardless of whether they are having a simpler surgery [excision] or more involved skin surgery procedure [Mohs with flap].”

Holding treatment

To offset the bleeding risk, Dr. Vidal notes that holding the treatment is considered safe and that the manufacturer recommends holding ibrutinib for at least 3-7 days pre- and post surgery, “depending on type of surgery and risk of bleeding.”

“In our institution, with the hematologist/oncologist’s input, we hold ibrutinib for 5 days preop and 3 days post op, and have not had bleed complications in these patients,” she said, noting that there were no bleeding events in the patients in the study when ibrutinib was held.

Likewise, Dr. Hirotsu noted that at her center at UCSD, patients on ibrutinib are asked during the preop call to hold treatment for 3 days before and after Mohs surgery – but are advised to discuss the decision with their hematologist/oncologist for approval.

The measure isn’t always successful in preventing bleeding, however, as seen in a case study describing two patients who experienced bleeding complications following Mohs surgery despite being taken off ibrutinib 3 days prior to the procedure.

The senior author of that study, Kira Minkis, MD, PhD, department of dermatology, Weill Cornell/New York Presbyterian, New York, told this news organization that her team concluded that in those cases ibrutinib perhaps should have been held longer than 3 days.

“In some cases, especially if the Mohs surgery is a large procedure with a more advanced reconstruction, such as a large flap, it might be more prudent to continue it longer than 3 days,” Dr. Minkis said. She noted that the high bleeding risk observed in the studies at ACMS was notable – but not unexpected.

“I’m not that surprised because if you look at the hematologic literature, the risk is indeed pretty significant, so it makes sense that it would also occur with Mohs surgeries,” she said.

She underscored that a 3-day hold of ibrutinib should be considered the minimum, “and in some cases, it should be held up to 7 days prior to surgery, depending on the specific surgery,” with the important caveat of consulting with the patient’s hematology team.

“Multidisciplinary decision-making is necessary for these cases, and the interruption of therapy should always be discussed with their hematology team,” she added. That said, Dr. Minkis noted that “I’ve never had a hematologist who had any concerns for withholding ibrutinib even for a week around the time of a surgery.”

Dr. Hirotsu, Dr. Vidal, and Dr. Minkis reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

SAN DIEGO – Using the ablative fractional laser and other wounding therapies to destroy actinic keratoses (AKs) as a way to prevent skin cancer appears to spark other beneficial effects on skin biology, according to Molly Wanner, MD, MBA.

As a case in point, Dr. Wanner discussed the results of a trial of 48 people over aged 60 years with actinic damage, who received ablative fractional laser treatment on one arm and no treatment on the other arm, which served as the control. At 24 months, only two nonmelanoma skin cancers (NMSCs) developed on the treated arms, compared with 26 on the treated arms.

“What I find interesting is that the treated arm did not develop basal cell carcinoma, only squamous cell carcinoma,” she said at the annual meeting of the American Society for Laser Medicine and Surgery. “It appears that this is working through more than just treatment of the AK precursor lesions, for which fractional lasers are cleared for use. It appears to impact both types of NMSCs.”

The ablative fractional laser and other wounding therapies can modulate a response to UV light – a process that naturally diminishes with age, according to Dr. Wanner, a dermatologist at Massachusetts General Hospital’s Dermatology Laser and Cosmetic Center in Boston. “This ability to repair DNA is actually modulated by insulin-like growth factor 1,” she said. “IGF-1 is produced by papillary dermal fibroblasts and communicates with keratinocytes. If keratinocytes are exposed to UV light and there is no IGF-1 around, you get a mutated cell, and that keeps spreading, and you could potentially get a skin cancer.”

On the other hand, she continued, if IGF-1 is injected around the keratinocytes, they are able to respond. “Keratinocytes, which are the most superficial layer of the skin, are really active,” noted Dr. Wanner, who is also an assistant professor of dermatology at Harvard Medical School, Boston. “They’re dividing and replicating, whereas fibroblasts are more non-proliferative and more long-lived. They stick around for a long time. I think of them as the adults in the room, giving these new keratinocytes direction.”

In a review of wounding therapies for the prevention of photocarcinogenesis, she and her coauthors noted that IGF-1 increases nucleotide excision repair of damaged DNA, promotes checkpoint signaling and suppression of DNA synthesis, favors specialized polymerases that are better able to repair DNA damage, and enhances p53-dependent transcriptional responses to DNA damage.

“Older fibroblasts produce less IGF-1 and lead to a situation where keratinocytes can grow unchecked,” she said. “We can use fractional laser to help with this. Fractional laser increases fibroblast production and decreases senescent fibroblasts.”

In a 2017 review on the impact of age and IGF-1 on DNA damage responses in UV-irradiated skin, the authors noted the high levels of IGF-1 in the skin of younger individuals and lower levels in the skin of their older counterparts.

“But once older skin has been treated with either dermabrasion or fractional laser, the levels of IGF-1 are restored to that of a young adult,” Dr. Wanner said. “The restoration of IGF-1 then restores that level of appropriate response to UV light. So, what’s interesting is that fractional lasers treat more than a fraction [of skin]. Fractional lasers were developed to have an easier way to improve wound healing by leaving the skin intact around these columns [of treated skin]. It turns out that treatment of these columns of skin does not just impact the cells in that area. There is a true global effect that’s allowing us to almost normalize skin.”

Dr. Wanner now thinks of fractional lasers as stimulating a laser-cell biology interaction, not just a laser-tissue interaction. “It’s incredible that we can use these photons to not only impact the tissue itself but how the cells actually respond,” she said. “What’s going to be interesting for us in the next few years is to look at how lasers impact our cellular biology. How can we harness it to help our patients?”

She and her colleagues are conducting a trial of different wounding modalities to assess their impact on IGF-1. “Does depth matter? Does density matter? Does the wavelength matter?” she asked. “The bottom line is, it turns out that when the skin looks healthier, it is healthier. Cosmetic treatments can impact medical outcomes.”

Dr. Wanner disclosed that she is a consultant and advisor to Nu Skin. She has also received research funding and equipment from Solta.

SAN DIEGO – Using the ablative fractional laser and other wounding therapies to destroy actinic keratoses (AKs) as a way to prevent skin cancer appears to spark other beneficial effects on skin biology, according to Molly Wanner, MD, MBA.

As a case in point, Dr. Wanner discussed the results of a trial of 48 people over aged 60 years with actinic damage, who received ablative fractional laser treatment on one arm and no treatment on the other arm, which served as the control. At 24 months, only two nonmelanoma skin cancers (NMSCs) developed on the treated arms, compared with 26 on the treated arms.

“What I find interesting is that the treated arm did not develop basal cell carcinoma, only squamous cell carcinoma,” she said at the annual meeting of the American Society for Laser Medicine and Surgery. “It appears that this is working through more than just treatment of the AK precursor lesions, for which fractional lasers are cleared for use. It appears to impact both types of NMSCs.”

The ablative fractional laser and other wounding therapies can modulate a response to UV light – a process that naturally diminishes with age, according to Dr. Wanner, a dermatologist at Massachusetts General Hospital’s Dermatology Laser and Cosmetic Center in Boston. “This ability to repair DNA is actually modulated by insulin-like growth factor 1,” she said. “IGF-1 is produced by papillary dermal fibroblasts and communicates with keratinocytes. If keratinocytes are exposed to UV light and there is no IGF-1 around, you get a mutated cell, and that keeps spreading, and you could potentially get a skin cancer.”

On the other hand, she continued, if IGF-1 is injected around the keratinocytes, they are able to respond. “Keratinocytes, which are the most superficial layer of the skin, are really active,” noted Dr. Wanner, who is also an assistant professor of dermatology at Harvard Medical School, Boston. “They’re dividing and replicating, whereas fibroblasts are more non-proliferative and more long-lived. They stick around for a long time. I think of them as the adults in the room, giving these new keratinocytes direction.”

In a review of wounding therapies for the prevention of photocarcinogenesis, she and her coauthors noted that IGF-1 increases nucleotide excision repair of damaged DNA, promotes checkpoint signaling and suppression of DNA synthesis, favors specialized polymerases that are better able to repair DNA damage, and enhances p53-dependent transcriptional responses to DNA damage.

“Older fibroblasts produce less IGF-1 and lead to a situation where keratinocytes can grow unchecked,” she said. “We can use fractional laser to help with this. Fractional laser increases fibroblast production and decreases senescent fibroblasts.”

In a 2017 review on the impact of age and IGF-1 on DNA damage responses in UV-irradiated skin, the authors noted the high levels of IGF-1 in the skin of younger individuals and lower levels in the skin of their older counterparts.

“But once older skin has been treated with either dermabrasion or fractional laser, the levels of IGF-1 are restored to that of a young adult,” Dr. Wanner said. “The restoration of IGF-1 then restores that level of appropriate response to UV light. So, what’s interesting is that fractional lasers treat more than a fraction [of skin]. Fractional lasers were developed to have an easier way to improve wound healing by leaving the skin intact around these columns [of treated skin]. It turns out that treatment of these columns of skin does not just impact the cells in that area. There is a true global effect that’s allowing us to almost normalize skin.”

Dr. Wanner now thinks of fractional lasers as stimulating a laser-cell biology interaction, not just a laser-tissue interaction. “It’s incredible that we can use these photons to not only impact the tissue itself but how the cells actually respond,” she said. “What’s going to be interesting for us in the next few years is to look at how lasers impact our cellular biology. How can we harness it to help our patients?”

She and her colleagues are conducting a trial of different wounding modalities to assess their impact on IGF-1. “Does depth matter? Does density matter? Does the wavelength matter?” she asked. “The bottom line is, it turns out that when the skin looks healthier, it is healthier. Cosmetic treatments can impact medical outcomes.”

Dr. Wanner disclosed that she is a consultant and advisor to Nu Skin. She has also received research funding and equipment from Solta.

SAN DIEGO – Using the ablative fractional laser and other wounding therapies to destroy actinic keratoses (AKs) as a way to prevent skin cancer appears to spark other beneficial effects on skin biology, according to Molly Wanner, MD, MBA.

As a case in point, Dr. Wanner discussed the results of a trial of 48 people over aged 60 years with actinic damage, who received ablative fractional laser treatment on one arm and no treatment on the other arm, which served as the control. At 24 months, only two nonmelanoma skin cancers (NMSCs) developed on the treated arms, compared with 26 on the treated arms.

“What I find interesting is that the treated arm did not develop basal cell carcinoma, only squamous cell carcinoma,” she said at the annual meeting of the American Society for Laser Medicine and Surgery. “It appears that this is working through more than just treatment of the AK precursor lesions, for which fractional lasers are cleared for use. It appears to impact both types of NMSCs.”

The ablative fractional laser and other wounding therapies can modulate a response to UV light – a process that naturally diminishes with age, according to Dr. Wanner, a dermatologist at Massachusetts General Hospital’s Dermatology Laser and Cosmetic Center in Boston. “This ability to repair DNA is actually modulated by insulin-like growth factor 1,” she said. “IGF-1 is produced by papillary dermal fibroblasts and communicates with keratinocytes. If keratinocytes are exposed to UV light and there is no IGF-1 around, you get a mutated cell, and that keeps spreading, and you could potentially get a skin cancer.”

On the other hand, she continued, if IGF-1 is injected around the keratinocytes, they are able to respond. “Keratinocytes, which are the most superficial layer of the skin, are really active,” noted Dr. Wanner, who is also an assistant professor of dermatology at Harvard Medical School, Boston. “They’re dividing and replicating, whereas fibroblasts are more non-proliferative and more long-lived. They stick around for a long time. I think of them as the adults in the room, giving these new keratinocytes direction.”

In a review of wounding therapies for the prevention of photocarcinogenesis, she and her coauthors noted that IGF-1 increases nucleotide excision repair of damaged DNA, promotes checkpoint signaling and suppression of DNA synthesis, favors specialized polymerases that are better able to repair DNA damage, and enhances p53-dependent transcriptional responses to DNA damage.

“Older fibroblasts produce less IGF-1 and lead to a situation where keratinocytes can grow unchecked,” she said. “We can use fractional laser to help with this. Fractional laser increases fibroblast production and decreases senescent fibroblasts.”

In a 2017 review on the impact of age and IGF-1 on DNA damage responses in UV-irradiated skin, the authors noted the high levels of IGF-1 in the skin of younger individuals and lower levels in the skin of their older counterparts.

“But once older skin has been treated with either dermabrasion or fractional laser, the levels of IGF-1 are restored to that of a young adult,” Dr. Wanner said. “The restoration of IGF-1 then restores that level of appropriate response to UV light. So, what’s interesting is that fractional lasers treat more than a fraction [of skin]. Fractional lasers were developed to have an easier way to improve wound healing by leaving the skin intact around these columns [of treated skin]. It turns out that treatment of these columns of skin does not just impact the cells in that area. There is a true global effect that’s allowing us to almost normalize skin.”

Dr. Wanner now thinks of fractional lasers as stimulating a laser-cell biology interaction, not just a laser-tissue interaction. “It’s incredible that we can use these photons to not only impact the tissue itself but how the cells actually respond,” she said. “What’s going to be interesting for us in the next few years is to look at how lasers impact our cellular biology. How can we harness it to help our patients?”

She and her colleagues are conducting a trial of different wounding modalities to assess their impact on IGF-1. “Does depth matter? Does density matter? Does the wavelength matter?” she asked. “The bottom line is, it turns out that when the skin looks healthier, it is healthier. Cosmetic treatments can impact medical outcomes.”

Dr. Wanner disclosed that she is a consultant and advisor to Nu Skin. She has also received research funding and equipment from Solta.

The use of adjunctive topical tranexamic acid (TXA) showed benefits in significantly reducing postoperative bleeding with second intention healing, or allowing wounds to heal naturally without sutures, following Mohs micrographic surgery, in a double-blind, randomized, controlled trial.

The findings suggest that “topical TXA application is an inexpensive and easy topical preventative measure to consider adding to the wound care of granulating defects in the setting of Mohs micrographic surgery,” first author Brianna Castillo, MD, chief dermatology resident at the University of Missouri, Columbia, told this news organization.

The study results were presented at the annual meeting of the American College of Mohs Surgery.

In wound healing by second intent after Mohs micrographic surgery, postoperative bleeding is common and can lead to patient distress, as well as return visits or emergency care, resulting in additional health care costs, Dr. Castillo said.

Topical TXA, an antifibrinolytic, synthetic lysine analogue that prevents blood clots from breaking down, is commonly used in surgical settings including cardiothoracic, orthopedic, gynecologic, oral, and trauma surgery, showing no increased risk of thrombotic events. However, its use is relatively new in dermatology.

TXA is approved by the Food and Drug Administration only as an oral formulation for menorrhagia in women and as a short-term preventative measure for hemophilia; however, other formulations are available for topical and subcutaneous uses, Dr. Castillo noted.

To evaluate the potential benefits of the treatment in postsurgical Mohs microsurgery bleeding, Dr. Castillo and colleagues enrolled 124 patients undergoing the surgery between October 2020 and December 2021 who had surgical defects deemed appropriate for second intention healing.

The patients were randomized to groups of 62 patients each to receive normal saline-soaked Telfa pads applied to the wound bed upon completion of surgery or TXA 25 mg/mL at a volume of 1 mL/cm²-soaked Telfa pads to the wound bed upon completion of the surgery.

In both groups, a standard pressure dressing was placed on top of the Telfa pads.

Most participants were men (90 vs. 34 patients), 45 were taking antiplatelet therapy, and 20 were taking anticoagulants, and in all cases, patients were similarly randomized in the two groups. Most of the surgical defects were on the head and neck or an extremity, and most (74) were under 2 cm.

All patients were provided with instructions to apply pressure to their wounds and to report bleeding complications. They were interviewed by phone 3 days following their surgeries regarding postoperative bleeding and any potential issues relating to the TXA treatment.

In follow-up interviews, six patients in the placebo group (9.7%) reported active bleeding from their wounds within 48 hours of surgery, with one patient requiring an intervention, while there were no reports of bleeding in the TXA group (P = .028). No side effects were reported in either group.

In the setting of Mohs micrographic surgery, subcutaneous TXA has previously been studied as an intraoperative hemostatic agent, with bleeding measured prior to the second layer or closure, Dr. Castillo explained. However, “no studies have evaluated topical TXA with the aim to reduce postoperative bleeding in the setting of Mohs micrographic surgery,” she said. 

Dr. Castillo noted that topical TXA is relatively inexpensive and typically available in hospital pharmacies. “It’s only about $7 per vial of 10 ccs and we do dilute it,” she noted during the session. “It has a pretty good shelf-life and does not have to be refrigerated.”

“We have implemented this into our practice at the University of Missouri,” she added.

Commenting on the study, M. Laurin Council, MD, associate professor of dermatology in the division of dermatology, department of internal medicine, Washington University, St. Louis, noted that second intention healing is “an excellent option for certain patients after skin cancer removal.

“One problem with this method, however, is that postsurgical wounds may bleed in the hours after a procedure, [and] this can be incredibly distressing to patients and their families,” she told this news organization.

“The study presented here shows great promise for the drug TXA for preventing postsurgical bleeding in this subset of patients,” said Dr. Council, director of dermatologic surgery and director of micrographic surgery and the dermatologic oncology fellowship at Washington University.

Commenting that “the results are impressive,” she noted the study had some limitations. “This is a small pilot study, and we don’t know about confounding factors in each group, such as the proportion of patients who are on blood thinners or who have low platelets, and therefore trouble clotting, for example.”

The authors have reported no relevant financial relationships. Dr. Council has consulted for AbbVie, Castle Biosciences, and Sanofi-Genzyme/Regeneron; however, the consulting was not relevant to the current study.

A version of this article first appeared on Medscape.com.

The use of adjunctive topical tranexamic acid (TXA) showed benefits in significantly reducing postoperative bleeding with second intention healing, or allowing wounds to heal naturally without sutures, following Mohs micrographic surgery, in a double-blind, randomized, controlled trial.

The findings suggest that “topical TXA application is an inexpensive and easy topical preventative measure to consider adding to the wound care of granulating defects in the setting of Mohs micrographic surgery,” first author Brianna Castillo, MD, chief dermatology resident at the University of Missouri, Columbia, told this news organization.

The study results were presented at the annual meeting of the American College of Mohs Surgery.

In wound healing by second intent after Mohs micrographic surgery, postoperative bleeding is common and can lead to patient distress, as well as return visits or emergency care, resulting in additional health care costs, Dr. Castillo said.

Topical TXA, an antifibrinolytic, synthetic lysine analogue that prevents blood clots from breaking down, is commonly used in surgical settings including cardiothoracic, orthopedic, gynecologic, oral, and trauma surgery, showing no increased risk of thrombotic events. However, its use is relatively new in dermatology.

TXA is approved by the Food and Drug Administration only as an oral formulation for menorrhagia in women and as a short-term preventative measure for hemophilia; however, other formulations are available for topical and subcutaneous uses, Dr. Castillo noted.

To evaluate the potential benefits of the treatment in postsurgical Mohs microsurgery bleeding, Dr. Castillo and colleagues enrolled 124 patients undergoing the surgery between October 2020 and December 2021 who had surgical defects deemed appropriate for second intention healing.

The patients were randomized to groups of 62 patients each to receive normal saline-soaked Telfa pads applied to the wound bed upon completion of surgery or TXA 25 mg/mL at a volume of 1 mL/cm²-soaked Telfa pads to the wound bed upon completion of the surgery.

In both groups, a standard pressure dressing was placed on top of the Telfa pads.

Most participants were men (90 vs. 34 patients), 45 were taking antiplatelet therapy, and 20 were taking anticoagulants, and in all cases, patients were similarly randomized in the two groups. Most of the surgical defects were on the head and neck or an extremity, and most (74) were under 2 cm.

All patients were provided with instructions to apply pressure to their wounds and to report bleeding complications. They were interviewed by phone 3 days following their surgeries regarding postoperative bleeding and any potential issues relating to the TXA treatment.

In follow-up interviews, six patients in the placebo group (9.7%) reported active bleeding from their wounds within 48 hours of surgery, with one patient requiring an intervention, while there were no reports of bleeding in the TXA group (P = .028). No side effects were reported in either group.

In the setting of Mohs micrographic surgery, subcutaneous TXA has previously been studied as an intraoperative hemostatic agent, with bleeding measured prior to the second layer or closure, Dr. Castillo explained. However, “no studies have evaluated topical TXA with the aim to reduce postoperative bleeding in the setting of Mohs micrographic surgery,” she said. 

Dr. Castillo noted that topical TXA is relatively inexpensive and typically available in hospital pharmacies. “It’s only about $7 per vial of 10 ccs and we do dilute it,” she noted during the session. “It has a pretty good shelf-life and does not have to be refrigerated.”

“We have implemented this into our practice at the University of Missouri,” she added.

Commenting on the study, M. Laurin Council, MD, associate professor of dermatology in the division of dermatology, department of internal medicine, Washington University, St. Louis, noted that second intention healing is “an excellent option for certain patients after skin cancer removal.

“One problem with this method, however, is that postsurgical wounds may bleed in the hours after a procedure, [and] this can be incredibly distressing to patients and their families,” she told this news organization.

“The study presented here shows great promise for the drug TXA for preventing postsurgical bleeding in this subset of patients,” said Dr. Council, director of dermatologic surgery and director of micrographic surgery and the dermatologic oncology fellowship at Washington University.

Commenting that “the results are impressive,” she noted the study had some limitations. “This is a small pilot study, and we don’t know about confounding factors in each group, such as the proportion of patients who are on blood thinners or who have low platelets, and therefore trouble clotting, for example.”

The authors have reported no relevant financial relationships. Dr. Council has consulted for AbbVie, Castle Biosciences, and Sanofi-Genzyme/Regeneron; however, the consulting was not relevant to the current study.

A version of this article first appeared on Medscape.com.

The use of adjunctive topical tranexamic acid (TXA) showed benefits in significantly reducing postoperative bleeding with second intention healing, or allowing wounds to heal naturally without sutures, following Mohs micrographic surgery, in a double-blind, randomized, controlled trial.

The findings suggest that “topical TXA application is an inexpensive and easy topical preventative measure to consider adding to the wound care of granulating defects in the setting of Mohs micrographic surgery,” first author Brianna Castillo, MD, chief dermatology resident at the University of Missouri, Columbia, told this news organization.

The study results were presented at the annual meeting of the American College of Mohs Surgery.

In wound healing by second intent after Mohs micrographic surgery, postoperative bleeding is common and can lead to patient distress, as well as return visits or emergency care, resulting in additional health care costs, Dr. Castillo said.

Topical TXA, an antifibrinolytic, synthetic lysine analogue that prevents blood clots from breaking down, is commonly used in surgical settings including cardiothoracic, orthopedic, gynecologic, oral, and trauma surgery, showing no increased risk of thrombotic events. However, its use is relatively new in dermatology.

TXA is approved by the Food and Drug Administration only as an oral formulation for menorrhagia in women and as a short-term preventative measure for hemophilia; however, other formulations are available for topical and subcutaneous uses, Dr. Castillo noted.

To evaluate the potential benefits of the treatment in postsurgical Mohs microsurgery bleeding, Dr. Castillo and colleagues enrolled 124 patients undergoing the surgery between October 2020 and December 2021 who had surgical defects deemed appropriate for second intention healing.

The patients were randomized to groups of 62 patients each to receive normal saline-soaked Telfa pads applied to the wound bed upon completion of surgery or TXA 25 mg/mL at a volume of 1 mL/cm²-soaked Telfa pads to the wound bed upon completion of the surgery.

In both groups, a standard pressure dressing was placed on top of the Telfa pads.

Most participants were men (90 vs. 34 patients), 45 were taking antiplatelet therapy, and 20 were taking anticoagulants, and in all cases, patients were similarly randomized in the two groups. Most of the surgical defects were on the head and neck or an extremity, and most (74) were under 2 cm.

All patients were provided with instructions to apply pressure to their wounds and to report bleeding complications. They were interviewed by phone 3 days following their surgeries regarding postoperative bleeding and any potential issues relating to the TXA treatment.

In follow-up interviews, six patients in the placebo group (9.7%) reported active bleeding from their wounds within 48 hours of surgery, with one patient requiring an intervention, while there were no reports of bleeding in the TXA group (P = .028). No side effects were reported in either group.

In the setting of Mohs micrographic surgery, subcutaneous TXA has previously been studied as an intraoperative hemostatic agent, with bleeding measured prior to the second layer or closure, Dr. Castillo explained. However, “no studies have evaluated topical TXA with the aim to reduce postoperative bleeding in the setting of Mohs micrographic surgery,” she said. 

Dr. Castillo noted that topical TXA is relatively inexpensive and typically available in hospital pharmacies. “It’s only about $7 per vial of 10 ccs and we do dilute it,” she noted during the session. “It has a pretty good shelf-life and does not have to be refrigerated.”

“We have implemented this into our practice at the University of Missouri,” she added.

Commenting on the study, M. Laurin Council, MD, associate professor of dermatology in the division of dermatology, department of internal medicine, Washington University, St. Louis, noted that second intention healing is “an excellent option for certain patients after skin cancer removal.

“One problem with this method, however, is that postsurgical wounds may bleed in the hours after a procedure, [and] this can be incredibly distressing to patients and their families,” she told this news organization.

“The study presented here shows great promise for the drug TXA for preventing postsurgical bleeding in this subset of patients,” said Dr. Council, director of dermatologic surgery and director of micrographic surgery and the dermatologic oncology fellowship at Washington University.

Commenting that “the results are impressive,” she noted the study had some limitations. “This is a small pilot study, and we don’t know about confounding factors in each group, such as the proportion of patients who are on blood thinners or who have low platelets, and therefore trouble clotting, for example.”

The authors have reported no relevant financial relationships. Dr. Council has consulted for AbbVie, Castle Biosciences, and Sanofi-Genzyme/Regeneron; however, the consulting was not relevant to the current study.

A version of this article first appeared on Medscape.com.