Vismodegib Plus Radiotherapy Promising in Recurrent Advanced BCC

Megan Brooks

September 17, 2015

A case report of two patients suggests potential synergy between concurrent vismodegib (Erivedge, Genentech) and radiotherapy for recurrent advanced basal cell carcinoma (BCC).

Combining vismodegib with radiotherapy "appeared to be well tolerated and efficacious, with both patients having no evidence of progressive disease at last follow-up, despite discontinuing vismodegib treatment because of adverse effects and not using any subsequent therapy," the authors report.

Vismodegib is an oral drug that selectively inhibits abnormal signaling in the Hedgehog pathway, a molecular driver of BCC. Vismodegib binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction.

The US Food and Drug Administration approved vismodegib in 2012 for BCC that has metastasized or relapsed after surgery and for patients who are not candidates for surgery or radiation.

"There has been great interest in expanding the use of vismodegib, and using it not just as monotherapy but as an adjunct to existing treatments," Wendy Y. Hara, MD, from the Department of Radiation Oncology at the Stanford University School of Medicine in California, and colleagues note in their report published in the September issue of JAMA Dermatology.

Although the interaction between radiotherapy and Hedgehog pathway inhibition has not been well studied, these two cases, coupled with available preclinical data, "support combining vismodegib with radiotherapy," they say.

The first case they present is that of a man in his 60s with a BCC on the tip of his nose that was initially treated with Mohs surgery. Ten months later, he developed pain and numbness in the left cranial nerve, which was thought to be trigeminal neuralgia. The patient's pain progressed over the next 3.5 years, and he was ultimately found to have left cranial palsies. MRI raised concern about perineural spread of the tumor. BCC with perineural invasion was confirmed on biopsy. He was prescribed vismodegib 150 mg/d with concurrent radiotherapy (66 Gy in 33 fractions).

The patient developed grade 1 dermatitis and grade 1 mucositis during radiotherapy but successfully completed radiotherapy uninterrupted; his pain had improved by the halfway point. He continued on vismodegib for 3 months after radiotherapy, but stopped the drug because of taste changes, loss of appetite, muscle cramps, and fatigue. At 9-month follow-up, the patient had stable disease, less facial weakness, and no pain, the authors report.

The second case they present is that of a man in his 70s with a left lower eyelid and lateral canthal BCC initially treated with Mohs surgery. Three years later, he developed diplopia and a new mass over the left lateral canthus at the site of the original lower lid reconstruction. He was prescribed vismodegib 150 mg/d to try to shrink the lesion before resection. After 2 months on vismodegib, MRI of the orbit revealed a left lateral orbital lesion. After the lesion was resected (sparing the globe) with positive margins, he was treated with radiotherapy (51 Gy in 17 fractions) and continued vismodegib. This radiotherapy schedule was chosen because of the patient's social and transportation issues. The patient developed grade 1 dermatitis in the radiation field during radiotherapy. He stopped vismodegib 2 weeks after completing radiotherapy because of increased fatigue, weight loss, and shortness of breath. But at 12-month follow-up, the patient was disease-free.

Combination Therapy a Real Possibility

These two cases demonstrate the "possibility of true combination therapy" for advanced BCC, John M. Strasswimmer, MD, PhD, from the Lynn Cancer Institute, Moffitt Oncology Network, Boca Raton, Florida, writes in an accompanying editorial.

He notes that the two patients could not tolerate more than 6 months of therapy, "a problem noted by other researchers." Therefore, it is "particularly significant" that both patients appear to have maintained improvement for more than a year after cessation of dual treatment.

"It is promising to see the control achieved by [the authors], which should help guide other teams caring for these challenging tumors," Dr Strasswimmer concludes.

Dr Hara and colleagues note that there is "scarce clinical experience" to lend guidance on concurrent vismodegib and radiotherapy in advanced BCC.

Last year, William W. Huang, MD, MPH, FAAD, and colleagues from the Wake Forest School of Medicine in Winston-Salem, North Carolina, reported on a patient who was taking vismodegib for BCC who developed squamous cell carcinomas of the skin. These were successfully treated with radiotherapy while the patient continued vismodegib treatment (J Am Acad Dermatol. 2014;70:e88-e89).

"I see vismodegib as a complementary therapy for patients who are not candidates for surgery and where radiation therapy alone is not enough," Dr Huang told Medscape Medical News.

More generally, he noted, most skin cancers are BCCs and most are treated with traditional approaches, such as excisional surgery, Mohs surgery, and electrodessication and curettage, depending on the size, location, and, of course, the health of the patient.

"Metastatic BCC is more a rare exception, rather than the rule. In general, BCCs are slow growing and locally invasive tumors with a metastatic rate of less than 0.5%. Recurrent BCCs can occur. In these cases, Mohs surgery is a terrific option. Radiation therapy for BCCs is an option for those cases where surgery is not an option," Dr Huang noted.

Dr Hara, Dr Strasswimmer, and Dr Huang have disclosed no relevant financial relationships.

JAMA Dermatol. 2015;151:925-926, 998-1001. Editorial, Abstract

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