Clinical Trials in Ocular Oncology

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COMS (Collaborative Ocular Melanoma Study) 1985

Servodidio C, Abramson D. The Collaborative Ocular Melanoma Study. In: Kertes PJ, Conway MD, eds. Clinical Trials in Ophthalmology: A Summary and Practice Guide. Baltimore,Md: Williams & Wilkins; 1998.
Collaborative Ocular Melanoma Study Group. Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study
(COMS): COMS report No. 15. Arch Ophthalmol. 2001;119:670-676.
The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma, II: initial mortality findings. COMS report No. 10. Am J Ophthalmol. 1998;125:779-796.
The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma III: local complication and observation following enucleation COMS report No. 11. Am J Ophthalmol. 1998;126:362-371.
Diener-West M, Earle JD, Fine SL, et al. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: Initial mortality findings. COMS report No. 18. Arch Ophthalmol. 2001; 119:969-982.
The Collaborative Ocular Melanoma Study Group. Accuracy of diagnosis of choroidal melanomas in the Collaborative Ocular Melanoma Study. COMS report No. 1. Arch Ophthalmol. 1990; 108:1268-1273.

Objectives

The goal of the Collaborative Ocular Melanoma Study was to determine the best management for melanomas, depending on the size and comparing the treatment of radiation and enucleation.

Design

3-arm study included two multicenter randomized clinical trials designed to compare the effectiveness of brachytherapy to enucleation for treatment of medium-size choroidal melanomas, and the effectiveness of enucleation with and without preoperative external-beam radiotherapy for large choroidal melanomas. The third arm is an observational study of small choroidal melanomas, natural history.

Patients with large choroidal melanomas were randomized to enucleation alone or enucleation preceded by external-beam radiation (20 Gy). Patients with medium choroidal melanomas were randomized to enucleation or brachytherapy using iodine-125.

The classification was: 1) large choroidal melanoma: more than 8 mm in thickness and/or greater than 16 mm in longest base diameter. 2) Medium choroidal tumors 3.1 to 8 mm in thickness and no more than 16 mm in longest base diameter. 3) Small choroidal melanomas were 1 to 3 mm in apical thickness and at least 5 mm in diameter.

Main outcome measures

Primary endpoint: time to death from all-cause mortality. Secondary endpoint: metastasis-free survival, cancer-free survival, and years of functional vision.

Results

In the large choroidal melanoma clinical trial, 1003 patients were randomized to either enucleation or enucleation preceded by external-beam radiation. The 5-year melanoma-related mortality rate was 27%. Patients receiving preoperative radiation had no statistically significant difference in 5-year survival. Postoperative complications were infrequent and minor and did not differ between the two groups.

In the medium-sized choroidal melanoma clinical trial, 1317 patients were enrolled, with 660 assigned to enucleation and 657 to iodine-125 brachytherapy. The 5-year cumulative mortality rates were 19% for enucleation and 18% for brachytherapy, with nearly identical mortality rates in the two groups. 101 patients from each group (57% from the enucleation group; 60% from the brachytherapy group) had metastatic melanoma confirmed or suspected at death.

After the first 5 years following brachytherapy, 69 patients underwent enucleation and 57 of these were for treatment failure. The risk of treatment failure was 10.3%. Risk factors for treatment failure were greater tumor thickness, older age, and proximity of the tumor to the foveal avascular zone.

Visual acuity declined in a substantial proportion of eyes treated with brachytherapy. There was a quadrupling loss of 6 or more lines of visual acuity from baseline in 18% of patients by 1 year, 34% by 2 years, and 49% by 3 years.25 Visual acuity was 20/200 or worse in 43% of eyes. The risk of vision loss was associated with a history of diabetes, thick tumors, tumors close to or beneath the macula, tumors with secondary retinal detachments, and tumors that were not dome-shaped.

42 patients in the COMS clinical trial for medium-size melanoma had no treatment for choroidal melanoma and enrolled in a natural history study. The estimated 5-year melanoma mortality rate was 30%. While these results are not statistically different from the 5-year melanoma risk of death in the clinical trial, the trend for a higher death rate suggests that a real survival benefit of therapy may be found with greater long-term follow-up.

In the small choroidal melanoma clinical trial, 204 patients were enrolled in a natural history study with a median length of follow-up of 92 months. The 5-year and 8-year tumor-specific mortality rates were 1% and 3.7%, respectively. 6 deaths were due to metastatic melanoma, and 4 of them occurred more than 5 years after enrollment.

Limitations

There is no analysis of other therapies other than enucleation for large melanomas.

The clinical importance of localized treatment failure with brachytherapy is not clear at the moment; it could be associated with an increased risk of metastasis even after enucleation. COMS demonstrated a trend toward reduced survival after adjustment for other risk factors, but long-term follow-up will determine if this trend becomes clinically important.

Ciliary body melanomas are not included; the results should not be extrapolated to melanomas of the peripapillary choroid or ciliary body.

Conclusions

There is no difference in 5-year all-cause mortality for large- and medium-sized choroidal melanomas in enucleation or brachytherapy. Preoperative radiation for large choroidal melanomas does not improve survival.

Pearls for clinical practice

In large choroidal melanoma, enucleation or enucleation preceded by radiation have similar results.

In medium-sized choroidal melanoma, enucleation and brachytherapy have similar results.

Small choroidal melanoma can be observed safely.