Novel Hedgehog Inhibitor Strategies Improve BCC Outcomes

Debulking large exophytic basal cell carcinomas prior to hedgehog inhibitor therapy might improve outcomes, according to Allison Vidimos, MD, a Mohs surgeon and chair of the department of dermatology at the Cleveland Clinic.

She and her colleagues have noticed an accelerated and durable response to hedgehog inhibitors after debulking and are studying cell signaling before and after debulking to better understand the issue.

Vidimos shared a remarkable case to illustrate the point during a clinical pearls talk at the annual meeting of the American College of Mohs Surgery.

An 82-year-old woman presented with a crusted, hemorrhagic, nodular basal cell carcinoma (BCC) that had overgrown over nearly her entire nose and left lower eyelid. A recurrence of a previous BCC, the tumor had been growing for a decade and had invaded her nasal bones but not the periorbital tissue.

An outside surgeon suggested a full rhinectomy and removal of the lower eyelid, but the woman refused.

Vidimos decided to treat her with vismodegib, but prior to doing so, she debulked the tumor to help with the pain and bleeding. She did not curette the portion of tumor extending through the ala into the nasal vestibule. “I let the vismodegib take care of that,” she said.

After 9 months, the tumor was virtually gone, with no recurrence after 3 years. Surgical debulking prior to hedgehog inhibition “reduces the tumor burden and may increase the efficacy and shorten the course of therapy,” Vidimos said.

The hedgehog inhibitors vismodegib (Erivedge) and sonidegib (Odomzo) are both approved for treating locally advanced BCC, with a complete response of 31% of locally advanced disease with vismodegib, according to one report.

But monotherapy is limited by intolerable side effects, most commonly muscle spasms, alopecia, and dysgeusia. To minimize the impact, Vidimos generally puts patients on treatment with Monday through Friday dosing and gives them the weekends off, a schedule she and her colleagues have reported works as well as daily dosing.

Still, many patients discontinue the drugs because of the side effects. Hedgehog inhibitors are also expensive and responses aren’t always durable. To increase efficacy and shorten the course of therapy, “we need alternative treatment strategies,” Vidimos said.

Up-front tumor debulking is one such strategy. Altered cell signaling pathways associated with tissue remodeling might improve response, and debulking may reduce the genetic heterogeneity of tumor cells, rendering remaining cells less resistant to hedgehog inhibition, she explained.

“It is exciting to see how tumor debulking may reduce tumor burden and heterogeneity, and thus lead to a durable response in extensive tumors,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who heard the presentation. “More investigation is needed to reproduce these results, but this approach may lead to improved outcomes with targeted therapies,” he said in an interview.

Combination therapy with other agents is another option, and there also seems to be a synergistic effect with radiation, with hedgehog inhibitors increasing cellular response to radiation therapy, Vidimos said.

Hedgehog inhibitors can also be used to shrink tumors before surgery. One small series found a 27% decrease in the area of the tumor after 3 to 6 months of preoperative vismodegib.

Vidimos shared another case to illustrate the point.

A 64-year-old woman fainted and presented to the ED with a hemoglobin of 3.2 mg/dL because of chronic blood loss from an ulcerated BCC on her upper back. The lesion measured 25 cm by 9 cm, and was 3.5 cm deep with no bone involvement. The woman was addicted to opioids by the time she presented.

She was started on vismodegib; the ulcer shrunk considerably after 6 months, and the woman underwent a resection. Only one small focus of BCC was found across 78 specimens submitted to Vidimos for Mohs reading.

Resection was followed by a muscle flap repair and radiation. At 5 and a half years, there is no evidence of disease; the only sign that the lesion had been there was a scar running along the woman’s upper spine.

The approach “was very successful for a very aggressive and worrisome tumor,” Vidimos said.

Vidimos did not have any relevant disclosures. Patel had no relevant disclosures.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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