The unique biological characteristics of uveal melanoma have prompted the National Comprehensive Cancer Network to develop the first set of guidelines for the diagnosis and management of the rare cancer.
Chris Barker, MD, PhD
The unique biological characteristics of uveal melanoma have prompted the National Comprehensive Cancer Network (NCCN) to develop the first set of guidelines for the diagnosis and management of the rare but deadly cancer, according to Christopher A. Barker, MD.
The recommendations represent “the first pathway-based guidelines” for the malignancy, Barker said in presenting the highlights of the paradigm during the 2018 NCCN Annual Conference.1 He is the director of clinical investigation in the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center and a member of the NCCN Melanoma Subcommittee.
The goals of treating uveal melanoma differ from those for cutaneous melanoma, Barker explained during an interview with OncologyLive®. Local treatment for uveal melanoma consists of globe-preserving therapies or enucleation.
“Ocular or uveal melanoma is genetically and biologically a very distinct form of melanoma that has very little overlap with cutaneous melanoma,” Daniel G. Coit, MD, a surgical oncologist at Memorial Sloan Kettering and chair of the NCCN Uveal Melanoma Subcommittee, said in an interview. “What we have wanted to do for years is to codify the treatment [of patients with uveal melanoma] so that practitioners would have a consistent management algorithm.”
The guidelines highlight 2 forms of staging criteria to determine therapeutic choice: the Collaborative Ocular Melanoma Study (COMS) system and the American Joint Committee on Cancer (AJCC) staging manual. Both systems are based on the size of the primary tumor, including thickness and diameter, which has consistently been associated with outcome for patients with uveal melanoma, Barker said. The COMS system has 3 categories and AJCC’s has 4, which are further subdivided based on the anatomical extent of the tumor according to ciliary body and extrascleral involvement.
“The COMS was developed as part of the COMS trials. These landmark trials helped to establish the current standards of care and therefore are of considerable relevance to contemporary practice,” Barker said. “The AJCC system was developed more recently in an attempt to refine clinical predictions based on tumor features. Both systems are of value to clinicians, and for this reason, both were used in the development of the guidelines.”
A total of 1003 patients with choroidal melanoma were enrolled in the COMS large-tumor trial and randomized to receive standard enucleation or external radiation of the orbit and globe prior to enucleation. Patients were followed for 10 years to analyze potential predictors of treatment effectiveness and mortality. No significant difference was found between the 2 arms in terms of survival.2
“The COMS trials showed 4 ocular melanomas that can be adequately treated with radiation therapy. That is the best level 1 evidence we have, that the prior practice of removing the eye is simply not necessary for many people with ocular melanoma,” Coit said. “There are obviously exceptions in the big cases, but for most people, radiotherapy has become a standard based on level 1 evidence.”
The guidelines, based on the results of the COMS studies, provide options for primary treatment according to the size of the primary tumor. For example, for patients with tumors that are <2.5 mm thick and 5 to 16 mm in the largest diameter, the guidelines recommend brachytherapy plaque, particle beam radiation, or laser ablation for patients who are not good candidates for radiation or surgery.
If the tumor is <18 mm thick and 2.5 to 10 mm in the largest diameter, suggested treatments include iodine-125 brachytherapy, particle beam radiation, and enucleation for specified patients.
Particle beam radiation therapy is preferred if a tumor of any thickness is >18 mm in the largest diameter, >10 mm thick with any diameter, or >8 mm thick with optic nerve involvement and any diameter. The guidelines recommend stereotactic radiosurgery as an acceptable alternative, or enucleation for certain patients.
If there is no evidence of gross residual disease in the eye orbit, observation is the first suggestion, but particle beam or photon beam radiation is a possibility. If evidence of gross residual disease is present after enucleation, however, the guidelines recommend biopsy of the extraocular tissue, if sufficient tissue is available. Intraoperative cryotherapy, orbital exenteration, and radiation therapy to the orbit with particle beam or photon beam radiation are viable options.
The guidelines divide patients into 3 categories of risk (low, medium, and high) of distant metastasis. The risk of metastasis after first-line therapy is due to several factors, including cell type—epithelioid or spindle cell, cytogenetics, gene expression, and genetic aberrations. A large number of alterations in cutaneous melanoma are predictive of response to treatment. Although there are fewer associated alterations in uveal melanoma, these are prognostic of outcomes. For example, patients with BAP1 or PRAME mutations are considered at high risk of metastasis. In these cases, frequent surveillance imaging— every 3 to 6 months for 5 years, then every 6 to 12 months for up to 10 years—is suggested.
Once a patient develops distant metastatic disease, the guidelines’ foremost suggestion is to enroll in clinical trials. “As in many cancers, metastasis is one of the biggest issues for patients with uveal melanoma. There is a complete void of treatments available to prevent metastasis or to effectively treat metastasis when it occurs,” Barker said. Other options include liver-directed therapies— because recurrence in uveal melanoma typically occurs in the live—systemic therapy or radiotherapy for symptomatic disease, or palliative care.
Treatment for metastatic uveal melanoma is limited, mainly because the advancements made in cutaneous melanoma, such as targeted therapy and immunotherapy, do not easily translate, and randomized clinical trials are limited for such a rare disease, according to Coit. “Community oncologists should recognize that because conventional systemic treatments do not work very well for metastatic ocular melanoma, this is a disease where clinical trials are imperative,” he said. “When we get positive clinical trials in ocular melanoma, they will appear immediately in the guidelines.”
The NCCN guidelines for uveal melanoma were deliberated for several months by a wide-ranging panel of specialists, based on the best available evidence and opinion, Barker said.
Certain “gray areas” created some of the biggest challenges while assembling the guidelines, Coit said. For example, many panel members were divided on how best to manage lesions of the eye that are not obvious uveal melanomas and the risks associated with initiating treatment. “This is one of the rare tumors that is often treated without biopsy and just based on clinical appearance,” he said. “When to make the diagnosis of melanoma and when the patient crosses from an indeterminate lesion in the eye to melanoma—that is a huge controversy.”
Other debates centered on the role of biopsy in material genomic analysis, follow-up treatment for patients for recurrence, and the best way to guide community oncologists with a lack of available data.