Purpose This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk). Design Prospective, multicenter study. Participants 459 patients with posterior uveal melanoma were enrolled from 12 independent centers. Testing Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP to the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and to chromosome 3 status. Main Outcome Measures Patients were managed for their primary tumor and monitored for metastasis. Results The GEP assay successfully classified 446/459 (97.2%) cases. The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 (1.1%) class 1 cases and 44 (25.9%) class 2 cases (log rank test, P<10−14). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54/260 (20.8%) tumors were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log rank test, P=0.0001). Using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P=0.2). At three years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P=0.001) and 0.38 (P=0.004) over chromosome 3 status. Conclusions The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.

Dosimetry of eye plaques for ocular tumors presents unique challenges in brachytherapy. The challenges in accurate dosimetry are in part related to the steep dose gradient in the tumor and critical structures that are within millimeters of radioactive sources. In most clinical applications, calculations of dose distributions around eye plaques assume a homogenous water medium and full scatter conditions. Recent Monte Carlo (MC)-based eye-plaque dosimetry simulations have demonstrated that the perturbation effects of heterogeneous materials in eye plaques, including the gold-alloy backing and Silastic insert, can be calculated with reasonable accuracy. Even additional levels of complexity introduced through the use of gold foil "seed-guides" and custom-designed plaques can be calculated accurately using modern MC techniques. Simulations accounting for the aforementioned complexities indicate dose discrepancies exceeding a factor of ten to selected critical structures compared to conventional dose calculations. Task Group 129 was formed to review the literature; re-examine the current dosimetry calculation formalism; and make recommendations for eye-plaque dosimetry, including evaluation of brachytherapy source dosimetry parameters and heterogeneity correction factors. A literature review identified modern assessments of dose calculations for Collaborative Ocular Melanoma Study (COMS) design plaques, including MC analyses and an intercomparison of treatment planning systems (TPS) detailing differences between homogeneous and heterogeneous plaque calculations using the American Association of Physicists in Medicine (AAPM) TG-43U1 brachytherapy dosimetry formalism and MC techniques. This review identified that a commonly used prescription dose of 85 Gy at 5 mm depth in homogeneous medium delivers about 75 Gy and 69 Gy at the same 5 mm depth for specific (125)I and (103)Pd sources, respectively, when accounting for COMS plaque heterogeneities. Thus, the adoption of heterogeneous dose calculation methods in clinical practice would result in dose differences >10% and warrant a careful evaluation of the corresponding changes in prescription doses. Doses to normal ocular structures vary with choice of radionuclide, plaque location, and prescription depth, such that further dosimetric evaluations of the adoption of MC-based dosimetry methods are needed. The AAPM and American Brachytherapy Society (ABS) recommend that clinical medical physicists should make concurrent estimates of heterogeneity-corrected delivered dose using the information in this report's tables to prepare for brachytherapy TPS that can account for material heterogeneities and for a transition to heterogeneity-corrected prescriptive goals. It is recommended that brachytherapy TPS vendors include material heterogeneity corrections in their systems and take steps to integrate planned plaque localization and image guidance. In the interim, before the availability of commercial MC-based brachytherapy TPS, it is recommended that clinical medical physicists use...

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