- Email: [email protected]
Practical management of the adverse effects of Hedgehog pathway inhibitor therapy for basal cell carcinoma
J AM ACAD DERMATOL VOLUME 76, NUMBER 4
Well-controlled population-based cohort studies are needed to investigate potential associations between GA and comorbidities, particularly thyroid disease. Dermatologists should consider antimalarials as first-line treatment for generalized GA. Sungat K. Grewal, BS, Courtney Rubin, MD, and Misha Rosenbach, MD Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania Dr Rosenbach has received support from the Dermatology Foundation’s Medical Dermatology Career Development Award. Conflicts of interest: None declared. Reprints not available from the authors. Correspondence to: Misha Rosenbach, MD, Department of Dermatology, University of Pennsylvania, 2 Maloney Bldg, 3600 Spruce St, Philadelphia, PA 19104-4208 E-mail: [email protected] REFERENCES 1. Piette EW, Rosenbach M. Granuloma annulare: pathogenesis, disease associations and triggers, and therapeutic options. J Am Acad Dermatol. 2016;75:467-479. 2. Piette EW, Rosenbach M. Granuloma annulare: clinical and histologic variants, epidemiology, and genetics. J Am Acad Dermatol. 2016;75:457-465. 3. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA. 2015;314:1021-1029. 4. Goff DC Jr, Bertoni AG, Kramer H, et al. Dyslipidemia prevalence, treatment, and control in the Multi-Ethnic Study of Atherosclerosis (MESA): gender, ethnicity, and coronary artery calcium. Circulation. 2006;113:647-656. 5. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87:489-499. http://dx.doi.org/10.1016/j.jaad.2016.11.044
Practical management of the adverse effects of Hedgehog pathway inhibitor therapy for basal cell carcinoma To the Editor: The Hedgehog pathway inhibitors (HPIs), sonidegib and vismodegib, are indicated for locally advanced BCC or metastatic BCC but have a high incidence of adverse effects (AE) resulting in therapy interruption or discontinuation. We conducted a literature review according to the Preferred Items for Systematic Review and Meta-Analysis (PRISMA) guidelines on the management of AEs to
Research Letters 767
improve knowledge gaps in therapy. Combined with our own 5-year experience,1 we identified the major AEs leading to management challenges: alopecia, dysgeusia, weight loss, elevated creatine phosphokinase (CPK), muscle spasms, ovarian dysfunction, and new onset squamous cell carcinoma. Myopathies and elevations of CPK are the most common AEs. Ally et al,2 in a small clinical trial (n ¼ 17), noted that patients experienced a modest improvement in symptoms within 2 weeks of amlodipine treatment. A study is in progress to evaluate levocarnitine in alleviating HPI-associated muscle spasms (NCT01893892). Elevated CPK has been described for both sonidegib and vismodegib, with monitoring for required for sonidegib but not vismodegib. Significantly, CPK levels were not monitored during vismodegib trials. HPI patients at risk for CPK abnormalities or myopathies, such as those concurrently using a statin, may benefit from periodic monitoring. Alopecia is the second most common AE. Unlike with chemotherapy, alopecia usually involves less than 50% of the scalp.3 MacDonald et al3 recommend concealment measures and minoxidil 2-5% continued for 6 months after therapy. Dysgeusia is the third most common AE. Le Moigne et al4 demonstrated a benefit of early nutritional screening for those taking vismodegib, with less weight loss in the intervention group that received nutritional counseling. Significantly, a greater than 5% weight loss can occur without dysgeusia, possibly due to diarrhea, nausea, xerostomia, oral thrush, or abdominal pain.4 Addressing oral hygiene, reflux disease, low-grade oral infection, and postnasal drip are reported to improve taste sensation in non-HPI patients.3 While patients who undergo HPI therapy are generally older adults, premenopausal women of childbearing age may experience amenorrhea likely due to reversible follicle-stimulating hormone receptor inhibition.1 It is essential to counsel primary care physicians on both the teratogenicity and sequelae of ovarian failure because nondermatologists are largely unfamiliar with the side effects of HPIs. As use of HPIs for basal cell nevus syndrome expands to a younger population, a larger number of patients may experience amenorrhea. Recently, new onset squamous cell carcinomas have been reported during HPI therapy. Zhu et al5 recommend that a new or persistent ulceration, nodule or erythema in the BCC tumor site should be biopsied if present after 3 months of HPI therapy. We recommend that total body skin exams be conducted during therapy and non-BCC lesions
768 Research Letters
comprehensively treated, because we have identified synchronous occult amelanotic melanoma in 3 of 12 patients considered for HPI therapy.1 We have successfully maintained 2 patients on continuous daily therapy for more 5 years by judicious attention to management of AEs.1 Alternate dosage regimens to mitigate AEs are promising and a clinical trial is underway (NCT01815840). Audrey A. Jacobsen, BA,a Andre R. Kydd, MD, PhD,b and John Strasswimmer, MD, PhDa,b University of Miami Miller School of Medicinea and Internal Medicine Residency Program, Florida Atlantic University, Boca Raton,b Florida Funding sources: None. Conflicts of interest: Dr Strasswimmer has served as a paid consultant to Novartis, the manufacturer of sonidegib, and to Genentech-Roche, the manufacturer of vismodegib. Dr Kydd and Ms Jacobsen have no conflicts of interest to report.
J AM ACAD DERMATOL
APRIL 2017
Correspondence to: John Strasswimmer, MD, PhD, 2605 W Atlantic Ave #204, Delray Beach, FL 33445 E-mail: [email protected] REFERENCES 1. Simone PD, Schwarz JM, Strasswimmer JM. Four-year experience with vismodegib hedgehog inhibitor therapy. J Am Acad Dermatol. 2016;74:1264-1265. 2. Ally MS, Tang JY, Lindgren J, et al. Effect of calcium channel blockade on vismodegib-induced muscle cramps. JAMA Dermatol. 2015;151:1132-1134. 3. Macdonald JB, Macdonald B, Golitz LE, LoRusso P, Sekulic A. Cutaneous adverse effects of targeted therapies: Part II: Inhibitors of intracellular molecular signaling pathways. J Am Acad Dermatol. 2015;72:221-228. 4. Le Moigne M, Saint-Jean M, Jirka A, et al. Dysgeusia and weight loss under treatment with vismodegib: benefit of nutritional management. Support Care Cancer. 2016;24:1689-1695. 5. Zhu GA, Sundram U, Chang AL. Two different scenarios of squamous cell carcinoma within advanced basal cell carcinomas: cases illustrating the importance of serial biopsy during vismodegib usage. JAMA Dermatol. 2014;150:970-973. http://dx.doi.org/10.1016/j.jaad.2016.04.063
Well-controlled population-based cohort studies are needed to investigate potential associations between GA and comorbidities, particularly thyroid disease. Dermatologists should consider antimalarials as first-line treatment for generalized GA. Sungat K. Grewal, BS, Courtney Rubin, MD, and Misha Rosenbach, MD Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania Dr Rosenbach has received support from the Dermatology Foundation’s Medical Dermatology Career Development Award. Conflicts of interest: None declared. Reprints not available from the authors. Correspondence to: Misha Rosenbach, MD, Department of Dermatology, University of Pennsylvania, 2 Maloney Bldg, 3600 Spruce St, Philadelphia, PA 19104-4208 E-mail: [email protected] REFERENCES 1. Piette EW, Rosenbach M. Granuloma annulare: pathogenesis, disease associations and triggers, and therapeutic options. J Am Acad Dermatol. 2016;75:467-479. 2. Piette EW, Rosenbach M. Granuloma annulare: clinical and histologic variants, epidemiology, and genetics. J Am Acad Dermatol. 2016;75:457-465. 3. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA. 2015;314:1021-1029. 4. Goff DC Jr, Bertoni AG, Kramer H, et al. Dyslipidemia prevalence, treatment, and control in the Multi-Ethnic Study of Atherosclerosis (MESA): gender, ethnicity, and coronary artery calcium. Circulation. 2006;113:647-656. 5. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87:489-499. http://dx.doi.org/10.1016/j.jaad.2016.11.044
Practical management of the adverse effects of Hedgehog pathway inhibitor therapy for basal cell carcinoma To the Editor: The Hedgehog pathway inhibitors (HPIs), sonidegib and vismodegib, are indicated for locally advanced BCC or metastatic BCC but have a high incidence of adverse effects (AE) resulting in therapy interruption or discontinuation. We conducted a literature review according to the Preferred Items for Systematic Review and Meta-Analysis (PRISMA) guidelines on the management of AEs to
Research Letters 767
improve knowledge gaps in therapy. Combined with our own 5-year experience,1 we identified the major AEs leading to management challenges: alopecia, dysgeusia, weight loss, elevated creatine phosphokinase (CPK), muscle spasms, ovarian dysfunction, and new onset squamous cell carcinoma. Myopathies and elevations of CPK are the most common AEs. Ally et al,2 in a small clinical trial (n ¼ 17), noted that patients experienced a modest improvement in symptoms within 2 weeks of amlodipine treatment. A study is in progress to evaluate levocarnitine in alleviating HPI-associated muscle spasms (NCT01893892). Elevated CPK has been described for both sonidegib and vismodegib, with monitoring for required for sonidegib but not vismodegib. Significantly, CPK levels were not monitored during vismodegib trials. HPI patients at risk for CPK abnormalities or myopathies, such as those concurrently using a statin, may benefit from periodic monitoring. Alopecia is the second most common AE. Unlike with chemotherapy, alopecia usually involves less than 50% of the scalp.3 MacDonald et al3 recommend concealment measures and minoxidil 2-5% continued for 6 months after therapy. Dysgeusia is the third most common AE. Le Moigne et al4 demonstrated a benefit of early nutritional screening for those taking vismodegib, with less weight loss in the intervention group that received nutritional counseling. Significantly, a greater than 5% weight loss can occur without dysgeusia, possibly due to diarrhea, nausea, xerostomia, oral thrush, or abdominal pain.4 Addressing oral hygiene, reflux disease, low-grade oral infection, and postnasal drip are reported to improve taste sensation in non-HPI patients.3 While patients who undergo HPI therapy are generally older adults, premenopausal women of childbearing age may experience amenorrhea likely due to reversible follicle-stimulating hormone receptor inhibition.1 It is essential to counsel primary care physicians on both the teratogenicity and sequelae of ovarian failure because nondermatologists are largely unfamiliar with the side effects of HPIs. As use of HPIs for basal cell nevus syndrome expands to a younger population, a larger number of patients may experience amenorrhea. Recently, new onset squamous cell carcinomas have been reported during HPI therapy. Zhu et al5 recommend that a new or persistent ulceration, nodule or erythema in the BCC tumor site should be biopsied if present after 3 months of HPI therapy. We recommend that total body skin exams be conducted during therapy and non-BCC lesions
768 Research Letters
comprehensively treated, because we have identified synchronous occult amelanotic melanoma in 3 of 12 patients considered for HPI therapy.1 We have successfully maintained 2 patients on continuous daily therapy for more 5 years by judicious attention to management of AEs.1 Alternate dosage regimens to mitigate AEs are promising and a clinical trial is underway (NCT01815840). Audrey A. Jacobsen, BA,a Andre R. Kydd, MD, PhD,b and John Strasswimmer, MD, PhDa,b University of Miami Miller School of Medicinea and Internal Medicine Residency Program, Florida Atlantic University, Boca Raton,b Florida Funding sources: None. Conflicts of interest: Dr Strasswimmer has served as a paid consultant to Novartis, the manufacturer of sonidegib, and to Genentech-Roche, the manufacturer of vismodegib. Dr Kydd and Ms Jacobsen have no conflicts of interest to report.
J AM ACAD DERMATOL
APRIL 2017
Correspondence to: John Strasswimmer, MD, PhD, 2605 W Atlantic Ave #204, Delray Beach, FL 33445 E-mail: [email protected] REFERENCES 1. Simone PD, Schwarz JM, Strasswimmer JM. Four-year experience with vismodegib hedgehog inhibitor therapy. J Am Acad Dermatol. 2016;74:1264-1265. 2. Ally MS, Tang JY, Lindgren J, et al. Effect of calcium channel blockade on vismodegib-induced muscle cramps. JAMA Dermatol. 2015;151:1132-1134. 3. Macdonald JB, Macdonald B, Golitz LE, LoRusso P, Sekulic A. Cutaneous adverse effects of targeted therapies: Part II: Inhibitors of intracellular molecular signaling pathways. J Am Acad Dermatol. 2015;72:221-228. 4. Le Moigne M, Saint-Jean M, Jirka A, et al. Dysgeusia and weight loss under treatment with vismodegib: benefit of nutritional management. Support Care Cancer. 2016;24:1689-1695. 5. Zhu GA, Sundram U, Chang AL. Two different scenarios of squamous cell carcinoma within advanced basal cell carcinomas: cases illustrating the importance of serial biopsy during vismodegib usage. JAMA Dermatol. 2014;150:970-973. http://dx.doi.org/10.1016/j.jaad.2016.04.063