Inaugural NCCN Guidelines Designated for Uveal Melanoma

A new set of National Comprehensive Cancer Network guidelines have been created for the diagnosis and management of uveal melanoma. During the 2018 NCCN Annual Conference, a member of the NCCN Melanoma Subcommittee, Christopher A. Barker, MD, presented the inaugural guidelines as “the first pathway-based guidelines” to be developed for the disease.

Christopher A. Barker, MD

A new set of National Comprehensive Cancer Network (NCCN) guidelines have been created for the diagnosis and management of uveal melanoma. During the 2018 NCCN Annual Conference, a member of the NCCN Melanoma Subcommittee, Christopher A. Barker, MD, presented the inaugural guidelines as “the first pathway-based guidelines” to be developed for the disease.1

The unique biological characteristics of uveal melanoma necessitated a need for its own set of guidelines, separate from the guidelines for cutaneous melanoma, explained Barker, the director of clinical investigation in the Department of Radiation at Memorial Sloan Kettering Cancer Center, during an interview withTargeted Oncology. Local treatment for uveal melanoma, differing from cutaneous 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,” agreed Daniel G. Coit, MD, a surgical oncologist at Memorial Sloan Kettering Cancer Center, and the chair of the NCCN Uveal Melanoma Subcommittee, in an interview withTargeted Oncology. “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.”

Two forms of staging criteria are highlighted in the guidelines to determine therapeutic choice: the Collaborative Ocular Melanoma Study (COMS) system and the American Joint Committee on Cancer (AJCC) staging manual. Barker explained that both staging 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. While the COMS is a 3-category system, the AJCC has 4 categories, which are then 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,” noted Barker. “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.”

The 15-year COMS study consisted of 2 multicenter clinical trials to compare the efficacy and outcome of treatment options for patients with large and medium choroidal melanomas.2A third arm was added to determine the history and characteristics of small choroidal melanomas. While patients with large choroidal melanoma (n= 1,003) were randomized to receive enucleation alone or with external-bam radiation, patients with medium choroidal melanoma (n= 1,317) received either enucleation or brachytherapy using iodine-125. Patients with small choroidal melanoma (n = 204) were followed clinically upon enrollment.

For patients with large choroidal melanoma, there were no significant differences between the 2 cohorts in terms of local orbital outcome. The 5-year melanoma-related mortality rate was 27% (95% CI, 37% - 44%) and only minor complications occurred post operation between the 2 cohorts. Additionally, patients receiving preoperative radiation has no significant difference in 5-year survival.

Survival data for patients with medium choroidal melanoma were also similar across the 2 cohorts. The 5-year cumulative mortality rates were 19% (95% CI, 16% - 23%) for enucleation and 18% (95% CI, 15% - 21%) for brachytherapy. However, 39% of patients treated with brachytherapy underwent enucleation after the first 5 years and visual decline occurred for a large portion of patients.

Within the small choroidal melanoma cohort, 5-year and 8-year tumor-specific mortality rates were 1% (95% CI, 0% - 2.5%) and 3.7% (95% CI, 0.7% - 6.6%) respectively.

“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,” specified Coit. “There are obviously exceptions in the big cases, but for most people, radiotherapy has become a standard based on level 1 evidence.”

Based on the results of the COMS studies, the guidelines provide options for primary treatment according to the size of the primary tumor. For example, for patients with tumors that are <2.5 mm in thickness 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 in thickness and 2.5 to 10 mm in the largest diameter, treatment suggestions include iodine-125 brachytherapy, particle beam radiation, or enucleation for specified patients.

Particle beam radiation therapy is preferred if the tumor is >18 mm in the largest diameter with any thickness, >10 mm in thickness with any diameter, or >8 mm 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 also possible. If evidence of gross residual disease is present after enucleation however, biopsy of the extraocular tissue is recommended if tissue is available. The guidelines also consider intraoperative cryotherapy, orbital exenteration, or radiation therapy to the orbit with particle beam or photon beam radiation as viable options.

The guidelines also divide patients into 3 risk categories (low, medium, and high) for risk of distant metastasis. The risk of metastasis after first-line therapy is due to several different factors, including cell type—epithelioid or spindle cell, cytogenetics, gene expression, and genetic aberrations. There are a large number of alterations in cutaneous melanoma that are predictive of response to treatment. In uveal melanoma, on the other hand, there are fewer associated alterations, but these are prognostic of outcomes. For example, patients withBAP1orPRAMEmutations are considered high risk for metastasis. In these patients, 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 for patients 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,” said Barker. Other options include liver-directed therapies, as recurrence in uveal melanoma typically occurs in the liver, systemic therapy or radiotherapy for symptomatic disease, or palliative care.

Coit admits treatment for metastatic uveal melanoma is limited, mainly because the advancements that have been 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.

“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. When we get positive clinical trials in ocular melanoma, they will appear immediately in the guidelines,” said Coit.

The NCCN guidelines for uveal melanoma were deliberated over the course of several months by a panel of a wide range of specialists based on the best available evidence and opinion, Barker highlighted. Some of the biggest challenges that derived from the assembly of the guidelines were the “grey areas,” explained Coit. For example, many of the 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,” said Coit. “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 controversies included 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.


  1. Barker CA. new NCCN guidelines: uveal melanoma. Presented at: NCCN 23rdAnnual Conference; March 22-24, 2018; Orlando, FL.
  2. Margo CE. The collaborative ocular melanoma study: an overview.Cancer Control. 2004;11(5):304-309. doi:10.1177/107327480401100504