Introduction

A large number of excellent clinical studies concerning treatment of ocular melanoma have been cited elsewhere in this text. The Collaborative Ocular Melanoma Study (COMS) was the first set of randomized clinical trials designed and conducted with sufficient power to compare survival outcomes between two or more treatments for this primary ocular cancer with a high degree of confidence.

Background

The choice of management of choroidal melanoma was controversial at the time the COMS was designed and initiated, and it remains controversial for tumors of small size. No data comparing enucleation or any other treatment with natural history were available; however, most ophthalmologists and oncologists were unwilling to undertake a randomized trial in which observation was one of the treatment arms. Large choroidal melanoma in the absence of metastasis traditionally has been treated with enucleation of the affected eye. Pre-enucleation irradiation of the eye had been proposed with the goal of minimizing the possibility of dissemination of viable tumor cells at time of enucleation.^1–8 Other adjunctive treatments also had been proposed, including post-enucleation irradiation of the socket, cryotherapy before enucleation, and chemotherapy.

A consensus had been reached that growing choroidal melanoma of intermediate size (“medium”) should be treated. However, the choice of treatment, enucleation or some type of radiotherapy to avoid loss of the eye and preserve some vision, was unclear. At the time the COMS was designed, radiotherapy was available at relatively few centers within the USA and Canada, where patients who elected radiotherapy were referred. Concerns regarding diagnostic accuracy, particularly for small choroidal melanoma, persuaded most ophthalmologists to observe smaller tumors for growth before treating.

The length of survival after a diagnosis of choroidal melanoma is quite variable. A meta-analysis of data published from 1966 through 1988 regarding survival following enucleation, yielded 5-year survival rates of 50% for large choroidal melanoma, 70% for medium choroidal melanoma, and 85% for small choroidal melanoma.⁹ However, few studies reported survival or mortality rates according to tumor size. It is accepted that the most important predictor of survival is tumor cell type. However, because of concerns regarding complications and inadequate sampling during fine-needle aspiration biopsy, choroidal melanoma typically is not biopsied. Thus, cell type is not known until the eye is removed or the patient dies. Also, the cell type(s) might change over time.

Design of the collaborative ocular melanoma study (coms)

The COMS was designed as a set of clinical trials of treatment for choroidal melanoma to be conducted by a group of investigators in the USA and Canada. Initially, three separate studies were undertaken, two randomized clinical trials and one observational study.¹⁰ Initial funding was provided in 1985 by the National Eye Institute, National Institutes of Health, US Department of Health and Human Services; beginning in 1991, both the National Eye Institute and the National Cancer Institute provided funding to conduct the study.

Methods

The COMS design and many of the methods have been published; the COMS Manual of Procedures¹¹ is available. Patients were evaluated for eligibility, enrolled, and treated at 43 different clinical centers, 41 in the USA and two in Canada. A standard schedule of clinical examinations was followed for data collection purposes. An unusual feature of the COMS design was that the participating ophthalmologists reported de-identified basic demographic information (age, gender, race, or ethnicity) and tumor dimensions for all cases of choroidal melanoma examined during the period of patient accrual, regardless of tumor size, eligibility for the COMS, or willingness of eligible patients to enroll in the COMS.

Random assignment to treatment, oversight of data collection, data management, and data analysis were assigned to the COMS Coordinating Center in Baltimore, Maryland. This center also had major responsibility for monitoring the quality of data provided by the participating centers. Other centers with major quality assurance and monitoring responsibilities included an Echography Center (in Mars Hill, North Carolina; initially in Miami, Florida), where tumor height was measured independently from photoechograms, a Photograph Reading Center (in Iowa City), where tumor characteristics at baseline and postirradiation changes in the posterior retina during follow-up were assessed and recorded, a Pathology Center (in Madison, Wisconsin; initially in Boston, Massachusetts), where tumor size and diagnosis were confirmed from all eyes enucleated, and the Radiological Physics Center in Houston, Texas, where adherence to the radiotherapy protocols was monitored. Overall leadership responsibility for the COMS Group was vested in the COMS Chairman’s Office (in Philadelphia, Pennsylvania; initially in Baltimore, Maryland).

An independent Data and Safety Monitoring Committee, appointed by the Director of the National Eye Institute, was the only group with access to survival data from the randomized clinical trials by treatment arm until this committee judged that the objectives of each individual trial had been met. This group had responsibility for ensuring that COMS trials were conducted in a scientifically valid and ethically sound manner. Scientific leadership of the COMS was provided by the Executive Committee, whose members included representatives of both the resource centers and the participating clinical centers. Three ophthalmic pathologists comprised the Pathology Review Committee who reviewed every enucleated eye from COMS patients to determine whether the clinical diagnosis of choroidal melanoma was correct. Mechanisms for quality assurance and monitoring were developed by the Quality Assurance Committee, which oversaw all aspects of data collection and protocol adherence. Classification of causes of death was the responsibility of the Mortality Coding Committee, whose members did not have responsibility for medical care of COMS patients. The COMS Archives Committee has responsibility for reviewing and approving applications for access to original COMS data by researchers.

Chronology of the COMS

Accrual of patients to the randomized trial of pre-enucleation radiation (PERT) of large choroidal melanoma began in November 1986 and ended in December 1994, with 1003 patients enrolled. Scheduled clinical follow-up of all surviving patients for vital status, incidence of metastasis and second cancers, and complications continued until July 31, 2000. Interim mortality findings and related information that emphasized 5-year outcomes were published in 1998^12,16,17; mortality findings through 10 years and prognostic factors were published in 2004.¹⁸

Accrual of patients to the randomized trial of I-125 brachytherapy for medium choroidal melanoma began in January 1987 and ended in July 1998, with 1317 patients enrolled, at the recommendation of the Data and Safety Monitoring Committee. Scheduled clinical follow-up of all surviving patients, for clinical and vital status and for quality of life, continued until July 31, 2003, and October 31, 2003, respectively. Interim mortality findings were published in 2001¹³; mortality findings through 12 years after enrollment and subgroup findings were published in 2006.¹⁹ Information about complications^20–22 and related information²³ also have been published.

Patient accrual to the nonrandomized study for small choroidal melanoma began in 1987 and ended in 1989, with 204 patients enrolled. Annual follow-up examinations were halted in 1991 as a result of funding constraints. Vital status and treatment status were reassessed in 1993 through 1994, and again in 1995 through 1996, for all patients who had not been lost to follow-up. Findings from this study have been published.^24,25

The COMS database, copies of all publications from the COMS Group, and the “COMS Manual of Procedures” were deposited in the Alan Mason Chesney Medical Archives at the Johns Hopkins University in August 2008. An anonymized public use dataset, containing baseline characteristics and survival outcomes, the COMS Manual, and copies of all COMS publications are available by application to the Medical Archives (http://www.medicalarchives.jhmi.edu). Access to more extensive data, including images of original data forms received at the COMS Coordinating Center, is available to qualified researchers whose application to the COMS Archives Committee (via: schacha@ccf.org or bhawkins@jhmi.edu) is approved by the COMS Archives Committee and by the Medical Archives institutional review board.

Findings from the COMS trial of I-125 brachytherapy for medium choroidal melanoma