Survival
It is not known whether ocular treatment for uveal melanoma prolongs life and if so in whom.[62] The COMS comparing plaque radiotherapy with enucleation and comparing enucleation alone with enucleation plus neoadjuvant radiotherapy were highly influential because they suggested that all treatments evaluated were equally effective (or ineffective) at prolonging life.[59,64] In patients with small tumors, the Kaplan-Meier estimate of all-cause mortality was 6% (95% CI, 3–9) and of melanoma-related mortality was 1% (95% CI, 0–3) at 5 years.[63] In the medium-sized tumor group, the Kaplan-Meier estimates for cumulative all-cause mortality rates were comparable in both enucleation and plaque brachytherapy arms (P=0.70, log-rank test) with a pooled 5-year rate of 19% (95% CI, 17–21) and pooled 10-year rate of 35% (95% CI, 32%-38%).[59] In the large tumor group, the Kaplan-Meier estimates of 5-year all-cause mortality were similar in both enucleation and preenucleation radiation arms: 57% (95% CI, 52–62) and 62% (95% CI, 57–66), respectively.[64] However, the argument can be made that these studies were statistically inconclusive because many patients died in the first few postoperative years, which indicated that micrometastases were already present at the time of ocular treatment. If these patients had been excluded from analysis, on the grounds that it is not possible to prevent what has already happened, then the patient numbers would have been too small for statistical power to be achieved.[65]
The finding that metastatic disease develops only from monosomy-3/class 2 melanomas has raised questions as to whether these tumors are lethal or nonlethal from their inception. This gave rise to the hypothesis that ocular treatment does not influence survival, because monosomy-3/class 2 tumors have already metastasized by the time the patient presents and because disomy-3/class 1 tumors never will, even if left untreated.[66,67] One of the authors (B.E.D.) has obtained circumstantial evidence that uveal melanomas accumulate mutations over time, along different routes, with some developing metastatic potential and disseminating at an early stage, others at a late stage and a significant minority never doing so at all.[62] This would suggest that ocular treatment does prevent the development of lethal mutations and metastatic spread in some patients, especially those with a small tumor. Unfortunately, nonrandomized trials are subject to several different forms of bias (eg, lead-time bias, bias from competing risks, etc.). Whereas clinical trials have focused on survival time after treatment, it may be better to analyze cause of death, but this would require very long follow-up until all patients in the cohort have died.[5] Thus, there is a need to preserve survival data indefinitely.
Until adequate evidence becomes available, there will continue to be debate regarding the safety of delaying treatment of small melanomas and the risks of procedures such as biopsy, eccentric plaque placement, endoresection, and eyewall resection.
Randomized trials of immediate versus delayed treatment and comparisons between rival therapies would be ideal but are difficult to undertake because of the rarity of uveal melanoma, the limited choice of therapeutic modalities at most centers, and the lack of sufficient equipoise in the large majority of patients.
Int Ophthalmol Clin. 2015;55(1):23-43. © 2015 Lippincott Williams & Wilkins
