Exploring non-surgical therapy for periocular skin cancer

Take-home message: Local surgical excision remains the preferred therapy for periocular and facial basal cell carcinoma. However, interest is growing in nonsurgical drug therapy for locally advanced or metastatic basal cell carcinoma.

By Nancy Groves; Reviewed by Bita Esmaeli, MD, FACS

Houston-Surgical treatment for periocular and facial basal cell carcinoma (BCC) is the preferred management approach and is associated with excellent local control and great functional and cosmetic outcome in the majority of cases.

However, there are circumstances in which surgery is not recommended, and non-surgical options, such as targeted medical therapy may be an alternative-for example, in cases of locally advanced BCC that would otherwise lead to an orbital exenteration or surgery that otherwise would lead to high morbidity.

Approved agents

Two orally administered drugs that target the hedgehog pathway-which plays a role in the pathogenesis of BCC-have received FDA approval in the last several years and are now being used to treat patients, including those who have periocular locally advanced BCC, said Bita Esmaeli, MD, FACS, professor of ophthalmology and director of ophthalmic plastic and orbital oncology Fellowship Program, Department of Plastic Surgery, Division of Surgery, the University of Texas M.D. Anderson Cancer Center, Houston.

Vismodegib (Erivedge, Genentech), a small-molecule selective hedgehog pathway inhibitor, was the first to gain FDA approval, in January 2012, and sonidegib (Odomzo, Novartis) was approved in July 2015. Both drugs are approved for locally advanced BCC; vismodegib is also approved for metastatic BCC. The recommended doses for vismodegib and sonidegib are, respectively, 150 mg/day and 200 mg/day.

Although both drugs target the hedgehog pathway through the downstream receptor smoothened, they have different mechanisms of action. Vismodegib is a competitive antagonist at the smoothened receptor, while sonidegib inhibits its expression.

Dr. Esmaeli, who has experience with vismodegib but not with sonidegib, said the drug is a “game changer.”

“Some of the eyes that we used to take out are now surviving,” she said, but added that vismodegib is not curative of the mutation involved in BBC. Rather, it can shrink tumors to a point where surgery is less morbid and the surgical procedure itself could be curative.

Which are best candidates?

While the new targeted drugs are promising, treatment with vismodegib or sonidegib is advisable as an alternative to traditional surgical or radiation therapy only in a small proportion of patients with periocular BCC, Dr. Esmaeli said.

It should be considered only when traditional treatment approaches are likely to mean loss of the eye, loss of vision, or significant facial and periorbital disfigurement.

Targeted nonsurgical therapy also could be considered for patients with basal cell nevus syndrome if the number and size of periocular lesions rules out multiple, frequent surgeries. It may be appropriate as well for patients of advanced age or with multiple comorbidities who would not be good candidates for surgery.

In the clinical trial that led to FDA approval of vismodegib, the response rate was 30% for patients with metastatic BCC and 43% in those with locally advanced BCC; 21% of the latter group had complete responses.

The literature on vismodegib therapy specifically in patients with periocular lesions is limited, but a number of small cohorts and case series have been published. These small series show that most patients achieved a partial or complete response, and in several instances an orbital exenteration could be avoided with the use of sonic hedgehog inhibitors.

To Dr. Esmaeli’s awareness, there are no published reports of sonidegib specifically used for periocular BCC.

As yet, information on the effect of discontinuation of sonic hedgehog inhibitors is limited, and the long-term prognosis of therapy is unknown.

While Dr. Esmaeli has participated in studies of vismodegib, she emphasized that the pathway inhibiting drugs would be prescribed by medical oncologists and that the role of an ophthalmic plastic surgeon is to recognize which patients might be good candidates for this type of therapy, make the referral, and assist with removal and reconstructive surgery for lesions that remain after the maximum benefit of drug therapy appears to have been reached.

Based on the experiences of Dr. Esmaeli and her colleagues at the M.D. Anderson Cancer Center, a response is often seen within a few weeks.

“We keep patients on drug treatment until such time that either the cancer is completely gone or the lesion stops responding,” Dr. Esmaeli said.

Surgery may be performed to document that that a patient has achieved a complete response, in which case the patient could be observed while discontinuing the drug, or in the case of a partial responder to remove the residual disease that is no longer responding to drug therapy. If the patient has a partial response, treatment is typically continued for about 2 years if tolerated; this seems to be the median time at which the patient may develop resistance to hedgehog inhibitors.

Ideally though, vismodegib therapy will have reduced the lesion size, allowing much less extensive surgery.

“In the periocular region that’s an attractive option because potentially you could avoid an orbital exenteration,” Dr. Esmaeli said.

Studies of hedgehog pathway inhibitors have found that the most frequent side effects are muscle spasms, weight loss, dysgeusia, alopecia, decreased appetite, and fatigue.

Dr. Esmaeli said in most studies of hedgehog inhibitors, side effects have primarily been grade I or II and required little or no additional treatment.

Bita Esmaeli, MD, FACS

E: [email protected]

This article was adapted from Dr. Esmaeli’s presentation at the 2015 meeting of the American Academy of Ophthalmology. Dr. Esmaeli served as a member of the Data Safety Monitoring Board for a vismodegib trial in Europe (Roche, Basel, Switzerland).