Intermittent Vismodegib Therapy in Basal Cell Nevus Syndrome

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approximately 20% to 30% of patients.1,2 Characteristically, 5. Jain L, Sissung TM, Danesi R, et al. Hypertension and hand-foot skin HFSR presents as painful, hyperkeratotic, erythematous reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib. J Exp Clin Cancer Res. 2010;29:95. plaques on the palms and soles in areas subject to increased 6. Kiuru M, Schwartz M, Magro C. Cutaneous thrombogenic vasculopathy pressure. Other mucocutaneous effects described with anti- associated with bevacizumab therapy. Dermatol Online J. 2014;20(6): VEGF agents include keratoacanthoma, squamous cell carci- 13030/qt41f655g9. noma, splinter subungual hemorrhages, hair depigmenta- tion, and stomatitis.2 Both systemic and cutaneous toxic effects of axitinib are Intermittent Vismodegib Therapy consistent with other agents in the same class, with a signifi- in Basal Cell Nevus Syndrome cant incidence of HFSR.3,4 Hand-foot skin reaction has been The use of intermittent vismodegib therapy is a promising and proposed to result from blockade of VEGF receptor and platelet- sustainable medical alternative to the current mainstream sur- derived growth factor receptor in areas repeatedly subject to gical management of basal cell nevus syndrome (BCNS). We subclinical trauma, disrupting normal vascular repair pro- report our clinical experience with intermittent vismodegib cesses in fibroblasts and endothelial cells.4 While the acral le- therapy in 2 patients with BCNS. sions in the present patient were distinct from HFSR, it is pos- sible that a similar process was responsible. Inhibition of VEGF Report of Cases | Patient 1 is a white man in his 40s, and patient leads to increased vascular tone,1 and so dysregulated vaso- 2 is a white woman in her 50s. Vismodegib therapy was started constriction in the skin may disrupt normal tissue repair.4 In- in both cases because the basal cell carcinoma (BCC) lesions deed, hypertension in patients treated with concurrent in both patients were becoming more aggressive, were appear- sorafenib and bevacizumab, a monoclonal antibody against ing more frequently, and could not be managed as easily with VEGF, was found to be a risk factor for developing HFSR.5 Va- surgical and other nonsurgical treatments. sodilatory agents such as nifedipine may therefore be useful The intermittent vismodegib dosing was first adminis- for both hypertension and cutaneous lesions. One patient tered to patient 1 circumstantially; adverse effects in his case treated with bevacizumab developed hemorrhagic ulcers and resulted in patient noncompliance with the prescribed non- purpuric patches on the lower legs, termed thrombogenic intermittent regimen. However, the dramatic improvement vasculopathy,6 further supporting a direct VEGF-mediated ef- prompted us to suggest intermittent therapy to both fect. In the midst of continued characterization of toxic ef- patients. The Table contains the dosing regimen, number of fects profiles of newer oncologic agents, our case represents BCCs before and after vismodegib therapy, and adverse a distinct cutaneous vasculopathy associated with the anti- effects. Both patients agreed to a lifelong intermittent vis- VEGF agent axitinib. modegib regimen but not lifelong continuous daily therapy owing to its adverse effects. The dosing interval was indi- Veronica J. Shi, BA vidualized to adverse-effect tolerability and so differs Anjela Galan, MD between our patients. Ian D. Odell, MD, PhD Jennifer N. Choi, MD Discussion | An autosomal dominant disorder, BCNS is typi- cally due to mutation of the PTCH1 tumor suppressor gene, re- Author Affiliations: Department of Dermatology, Yale University School of sulting in uncontrolled upregulation of the sonic hedgehog Medicine, New Haven, Connecticut (Shi, Galan, Odell, Choi); Department of pathway and carcinogenesis. Although surgical excisions of- Pathology, Yale University School of Medicine, New Haven, Connecticut (Galan). fer the highest cure rate and lowest rate of recurrence, the on- Corresponding Author: Jennifer N. Choi, MD, Department of Dermatology, going repetitive traumatic procedures cause cosmetic disfig- Yale University School of Medicine, 333 Cedar St, Laboratory for Medicine and Pediatrics 5040, New Haven, CT 06510 ([email protected]). urement and lower patients’ quality of life. Vismodegib is an oral smoothened antagonist approved in Published Online: October 28, 2015. doi:10.1001/jamadermatol.2015.3209. 2012 by the US Food and Drug Administration for metastatic, Conflict of Interest Disclosures: None reported. locally advanced, or inoperable BCC. The adverse effects in- Additional Contributions: We are indebted to Edward W. Cowen, MD, MHSc, Dermatology Branch, Center for Cancer Research, National Cancer Institute, clude muscle spasms, alopecia, dysgeusia, weight loss, fa- National Institutes of Health, Bethesda, Maryland, for discussion and tigue, nausea, and constipation. In addition, vismodegib is comments on the manuscript. Dr Cowen received no compensation for his embryotoxic and teratogenic. Barrier contraception was rec- contributions. ommended to our patients during and for 7 months after treat- 1. Cohen RB, Oudard S. Antiangiogenic therapy for advanced renal cell ment, and a second method of contraception was advised for carcinoma: management of treatment-related toxicities. Invest New Drugs. 2012;30(5):2066-2079. our female patient. 1 2. Ishak RS, Aad SA, Kyei A, Farhat FS. Cutaneous manifestations of Tang et al reported a dropout rate of 54% owing to anti-angiogenic therapy in oncology: review with focus on VEGF inhibitors. Crit adverse effects in a study of vismodegib treatment for Rev Oncol Hematol. 2014;90(2):152-164. patients with BCNS. The concept of drug holiday is sup- 3. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib ported by Ally et al,2 who found that 2 of 3 patients who took versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase a 3-month break from vismodegib therapy had similar effi- 3 trial. Lancet. 2011;378(9807):1931-1939. cacy of odontogenic cyst shrinkage compared with patients 4. Fischer A, Wu S, Ho AL, Lacouture ME. The risk of hand-foot skin reaction to axitinib, a novel VEGF inhibitor: a systematic review of literature and undergoing continuous vismodegib treatment. The intermit- meta-analysis. Invest New Drugs. 2013;31(3):787-797. tent regimen was better tolerated vis-à-vis muscle cramps

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Table. Treatment Regimens, Other Treatments, and BCC Numbers Before and After IVT

Biopsy-Detected BCCs, No./y Years Before Years After IVT IVT IVT Regimen Dermatologic Follow-up Treatments Before IVT 432112 Adverse Effects Patient 1 Every 6 weeks Curettage and 12 11 15 9 2 1 Muscle cramps, 1 Month on, electrodessication, dysgeusia 2 months off Mohs surgery Patient 2 Every 3 months Imiquimod, surgical excision, 4 1 4 5 1 NA Dysgeusia, muscle cramp, 2 Months on, Mohs surgery diffuse alopecia 2 months off

Abbreviations: BCC, surgically eligible basal cell carcinoma; IVT, intermittent vismodegib therapy; NA, not applicable; VT, vismodegib therapy.

and dysgeusia than the continuous regimen. Similarly, the 1. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog muscle cramps and dysgeusia in the present patients pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366 (23):2180-2188. resolved within 1 month after interrupting the vismodegib 2. Ally MS, Tang JY, Joseph T, et al. The use of vismodegib to shrink keratocystic regimen. odontogenic tumors in patients with basal cell nevus syndrome. JAMA Dermatol. Although pharmacokinetic studies have shown subopti- 2014;150(5):542-545. mal efficacy and similar incidence and severity of adverse ef- 3. Lorusso PM, Jimeno A, Dy G, et al. Pharmacokinetic dose-scheduling study fects when vismodegib, 150 mg, was used once weekly or 3 of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with times weekly, no studies to our knowledge have investigated locally advanced or metastatic solid tumors. Clin Cancer Res. 2011;17(17): 5774-5782. the efficacy of continuous daily doses with drug breaks in 4. Chang ALS, Oro AE. Initial assessment of tumor regrowth after vismodegib in between.3 We found a mean of 1.4 new surgically eligible BCCs advanced basal cell carcinoma. Arch Dermatol. 2012;148(11):1324-1325. per year per patient undergoing intermittent therapy, which 5. Kim J, Aftab BT, Tang JY, et al. Itraconazole and arsenic trioxide inhibit is comparable to the 2.0 new surgically eligible BCCs per year Hedgehog pathway activation and tumor growth associated with acquired per patient found by Tang et al1 in patients undergoing a stan- resistance to smoothened antagonists. Cancer Cell. 2013;23(1):23-34. dard continuous daily regimen. 6. Long J, Li B, Rodriguez-Blanco J, et al. The BET bromodomain inhibitor Vismodegib resistance occurs in patients who undergo I-BET151 acts downstream of smoothened protein to abrogate the growth of hedgehog protein-driven cancers. J Biol Chem. 2014;289(51):35494-35502. continuous vismodegib dosing.4 The frequency of resistance in patients who undergo an intermittent form of treatment is largely unknown. Combination therapy with hedgehog Bullous Pemphigoid Associated With pathway inhibitors downstream of smoothened, such as itra- Linagliptin Treatment conazole and arsenic trioxide, provide opportunities to Drug-induced bullous pemphigoid (BP) has been recently re- increase efficacy and possibly reduce the incidence of ported in association with sitagliptin and vildagliptin, 2 di- resistance.5,6 peptidyl peptidase-4 (DPP-4) inhibitors used in the treatment of type 2 diabetes mellitus (T2DM). Herein, we report the Conclusions | Overall, our clinical experience suggests that in- development of BP in 2 patients with T2DM treated with lina- termittent therapy is an effective way to overcome problems gliptin, another DPP-4 inhibitor. with adverse effects and compliance with vismodegib treatment of BCNS. Photographic and histologic documentations Report of Cases | Case 1. A man in his 60s with psoriasis and of tumors and randomized clinical trials are warranted to quan- T2DM presented with pruritus and erythematous tense bul- tify the ideal duration of the intermittent regimen and com- lae on the limbs (Figure 1). The clinical diagnosis of BP was con- pare the addition of combination therapies to overcome po- firmed by histologic findings showing a subepidermal blister tential drug resistance. containing eosinophils (Figure 2) and direct immunofluores- cence analysis showing a linear deposit of IgG and C3 at the Xinyi Yang basement membrane zone. Enzyme-linked immunosorbent as- Scott M. Dinehart, MD say was performed and demonstrated reactivity with the re- combinant proteins of NC16a and C-terminal domains of BP180. Author Affiliations: Faculty of Medicine, University of New South Wales, Treatment with topical clobetasol propionate, 0.05% (50 g/d), Sydney, New South Wales, Australia (Yang); Arkansas Skin Cancer Center, improved the lesions, but the patient presented with another Little Rock (Dinehart). flare of BP 2 weeks later. Linagliptin treatment, which had be- Corresponding Author: Xinyi Yang, 101 Excelsior Parade, Carey Bay, NSW, gun 4 months previously, was stopped. One week later, un- Australia 2283 ([email protected]). der treatment with the same topical corticosteroid applica- Published Online: October 28, 2015. doi:10.1001/jamadermatol.2015.3210. tions, the lesions healed completely; there was no clinical Conflict of Interest Disclosures: Dr Dinehart serves as a consultant and speaker for Genentech. No other conflicts are reported. recurrence of BP during 3 months of follow-up. Additional Contributions: We are indebted to Mark Lebwohl, MD, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, for revision Case 2. A woman in her 70s with T2DM presented with a 2-month of the manuscript. Dr Lebwohl received no compensation for his contributions. history of pruritus and tense bullae on the trunk. The diagnosis

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