The use of intermittent vismodegib therapy is a promising and sustainable medical alternative to the current mainstream surgical management of basal cell nevus syndrome (BCNS). We report our clinical experience with intermittent vismodegib therapy in 2 patients with BCNS.
Patient 1 is a white man in his 40s, and patient 2 is a white woman in her 50s. Vismodegib therapy was started in both cases because the basal cell carcinoma (BCC) lesions in both patients were becoming more aggressive, were appearing more frequently, and could not be managed as easily with surgical and other nonsurgical treatments.
The intermittent vismodegib dosing was first administered to patient 1 circumstantially; adverse effects in his case resulted in patient noncompliance with the prescribed nonintermittent regimen. However, the dramatic improvement prompted us to suggest intermittent therapy to both patients. The Table contains the dosing regimen, number of BCCs before and after vismodegib therapy, and adverse effects. Both patients agreed to a lifelong intermittent vismodegib regimen but not lifelong continuous daily therapy owing to its adverse effects. The dosing interval was individualized to adverse-effect tolerability and so differs between our patients.
An autosomal dominant disorder, BCNS is typically due to mutation of the PTCH1 tumor suppressor gene, resulting in uncontrolled upregulation of the sonic hedgehog pathway and carcinogenesis. Although surgical excisions offer the highest cure rate and lowest rate of recurrence, the ongoing repetitive traumatic procedures cause cosmetic disfigurement and lower patients’ quality of life.
Vismodegib is an oral smoothened antagonist approved in 2012 by the US Food and Drug Administration for metastatic, locally advanced, or inoperable BCC. The adverse effects include muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, and constipation. In addition, vismodegib is embryotoxic and teratogenic. Barrier contraception was recommended to our patients during and for 7 months after treatment, and a second method of contraception was advised for our female patient.
Tang et al1 reported a dropout rate of 54% owing to adverse effects in a study of vismodegib treatment for patients with BCNS. The concept of drug holiday is supported by Ally et al,2 who found that 2 of 3 patients who took a 3-month break from vismodegib therapy had similar efficacy of odontogenic cyst shrinkage compared with patients undergoing continuous vismodegib treatment. The intermittent regimen was better tolerated vis-à-vis muscle cramps and dysgeusia than the continuous regimen. Similarly, the muscle cramps and dysgeusia in the present patients resolved within 1 month after interrupting the vismodegib regimen.
Although pharmacokinetic studies have shown suboptimal efficacy and similar incidence and severity of adverse effects when vismodegib, 150 mg, was used once weekly or 3 times weekly, no studies to our knowledge have investigated the efficacy of continuous daily doses with drug breaks in between.3 We found a mean of 1.4 new surgically eligible BCCs per year per patient undergoing intermittent therapy, which is comparable to the 2.0 new surgically eligible BCCs per year per patient found by Tang et al1 in patients undergoing a standard continuous daily regimen.
Vismodegib resistance occurs in patients who undergo continuous vismodegib dosing.4 The frequency of resistance in patients who undergo an intermittent form of treatment is largely unknown. Combination therapy with hedgehog pathway inhibitors downstream of smoothened, such as itraconazole and arsenic trioxide, provide opportunities to increase efficacy and possibly reduce the incidence of resistance.5,6
Overall, our clinical experience suggests that intermittent therapy is an effective way to overcome problems with adverse effects and compliance with vismodegib treatment of BCNS. Photographic and histologic documentations of tumors and randomized clinical trials are warranted to quantify the ideal duration of the intermittent regimen and compare the addition of combination therapies to overcome potential drug resistance.
Corresponding Author: Xinyi Yang, 101 Excelsior Parade, Carey Bay, NSW, Australia 2283 (email@example.com).
Published Online: October 28, 2015. doi:10.1001/jamadermatol.2015.3210.
Conflict of Interest Disclosures: Dr Dinehart serves as a consultant and speaker for Genentech. No other conflicts are reported.
Additional Contributions: We are indebted to Mark Lebwohl, MD, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, for revision of the manuscript. Dr Lebwohl received no compensation for his contributions.
Yang X, Dinehart SM. Intermittent Vismodegib Therapy in Basal Cell Nevus Syndrome. JAMA Dermatol. 2016;152(2):223-224. doi:10.1001/jamadermatol.2015.3210