New therapies for uveal melanoma target radiation toxicity, metastatic risk

August 7, 2017

Ongoing research for the treatment of uveal melanoma is providing hope that the future may bring new approaches for improving the safety of local therapy–along with modalities that will increase survival by reducing metastatic risk.

Reviewed by Arun D. Singh, MD

Dr. SinghOngoing research for the treatment of uveal melanoma is providing hope that the future may bring new approaches for improving the safety of local therapy–along with modalities that will increase survival by reducing metastatic risk.

“One of the problems with treatment of uveal melanoma is that while radiation therapy is associated with excellent local control, untreatable vision loss from radiation retinopathy still occurs in more than 50% of cases,” explained Arun D. Singh, MD. “Although our local treatment is very successful for saving eyes and preserving vision, the survival rate for patients with uveal melanoma has not improved over the past 40 years because the risk for metastatic disease and death from liver metastases remains high.”

Dr. Singh is professor of ophthalmology, director of ophthalmic oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH.

Mitigating radiation toxicity

Avoidance is the best management for radiation retinopathy, and there are several preventive strategies that show promise. One approach is a lower dose, aiming for <85 Gy. Support for this technique comes from a systematic review conducted by Dr. Singh and colleagues.

The review included data from 15 studies encompassing 2,662 patients. It found no statistically significant difference in the recurrence rate for patients treated with a radiation dose ranging from 65 Gy to 100 Gy.

“The number of cases treated with the 65 Gy dose was low, and we cannot make any definite conclusions from this analysis,” Dr. Singh said. “The findings suggest there may be room to reduce the radiation dose to improve the risk:benefit ratio.”

Reducing the scatter using a new plaque design is another potential approach for minimizing radiation retinopathy.

“The Collaborative Ocular Melanoma Study plaques that are being used in radiation therapy for uveal melanoma were designed in 1985,” he added. “We have to move on to better designs.”

One option is the EP917 plaque (Eye Physics) that would reduce radiation exposure of the optic disc and macula by a level clinically significant for preserving vision, according to theoretic dosimetry calculations performed by Dr. Singh and colleagues.

Adjuvant treatment with corticosteroids or other agents is another possibility for the reduction of radiation toxicity. Dr. Singh suggested this approach would be offered to patients at risk for vision loss. Selection of appropriate candidates could be guided by a risk calculator, which is undergoing validation.

There also is excitement about alternatives to radiation for local treatment of uveal melanoma. AU-011 (Aura Biosciences) is a first-in-class, targeted therapy under clinical investigation.

Delivered by intravitreal injection, it consists of viral nanoparticle conjugates that bind selectively to the cancer cells. The drug is activated by laser irradiation.

“This is an exciting idea, especially for treating small size uveal melanomas,” Dr. Singh said.

Mitigating metastasis

Systemic adjuvant therapy for uveal melanoma would treat patients at risk for metastasis, and with genetic analysis of a tumor sample retrieved by fine needle aspiration biopsy, there is now a safe and reliable way to identify such individuals.

“Fine needle aspiration biopsy has a high yield, >95%, and is associated with a low rate of complications,” said Dr. Singh. “We have two commercially available tests for molecular analysis that are equally robust for reliably predicting metastatic risk.”

Dr. Singh noted that adjuvant therapies for patients with uveal melanoma have been investigated in the past, but overall, they failed to show any survival benefit, possibly because the studies treated all-comers without risk stratification.

“If we can identify patients at risk, studies of adjuvant therapies might have the power to give us more meaningful information,” Dr. Singh said. “Knowing the molecular basis of metastasis and tumor progression would allow us to develop and select drugs that target the underlying pathways.”

Several clinical trials are underway to assess adjuvant systemic therapy.

 

Arun D. Singh, MD

E: singha@ccf.org

This article is based on a presentation given by Dr. Singh at the 2017 Retina World Congress. Dr. Singh is a member of the advisory board for Castle Biosciences, Aura Biosciences, Iconic Therapeutics, and Isoaid Inc. He has a pending-patent application for a risk calculator of vision loss following brachytherapy.