Collaborative Ocular Melanoma Study

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Chapter 150 Collaborative Ocular Melanoma Study

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.18 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.

Randomized trials of radiotherapy

For COMS purposes, choroidal melanoma was categorized broadly by size. Size criteria are summarized in Table 150.1; other eligibility criteria are provided elsewhere11 and have been published.12,13

The COMS randomized clinical trial of primary interest was designed to compare enucleation alone with I-125 brachytherapy for treatment of “medium” choroidal melanoma, which was believed to comprise the majority of newly diagnosed cases. Brachytherapy was chosen as the most feasible method of radiation delivery to the melanoma with respect to standardization of dosimetry and ability to monitor adherence to the radiotherapy protocol. I-125 was selected as the isotope because of the ability to protect the surgeon and other tissues in the orbit from radiation damage by using a gold shield and because of the half-life of the isotope.14 Patients were assigned randomly with equal probability between enucleation and I-125 brachytherapy. All patients were to be followed for a minimum of 5 years or until death. The minimum sample size targeted a priori was 1250 patients for comparison of overall survival between treatment arms based on conventional Type I and Type II errors of 0.05 and 0.20, respectively. A desired sample size of 2400 patients also was established a priori to provide more precise estimates of survival overall and within patient subgroups and for evaluation of secondary outcomes.10,11 The desired sample size was based on Type I and Type II errors of 0.01 and 0.10, respectively.

The clinical trial for “large” (high-risk of metastasis and death) choroidal melanoma was designed to compare enucleation alone with pre-enucleation radiation treatment (PERT). Pre-enucleation radiation was chosen for comparison with enucleation alone because a similar approach had been shown to be effective in other types and sites of cancer in which surgery was employed. In addition, external radiation was widely available throughout the USA and Canada. Patients were assigned randomly, with equal probability, between the two treatment arms and were to be followed for a minimum of 5 years or until death. The sample size was estimated on the basis of overall survival. Taking account of possible losses to follow-up, treatment crossovers, and treatment refusals, a target sample size of 1000 patients was established a priori based on Type I and Type II errors of 0.01 and 0.10, respectively.1012

A parallel study of quality of life of patients enrolled in the randomized trial of I-125 brachytherapy for medium choroidal melanoma was initiated in 1994.15 The purpose of the parallel study was to compare treatment arms over time with respect to general health, visual function, and anxiety and depression using scores from several standard interview instruments. The study had two components: (1) a prospective randomized component consisting of 209 patients who enrolled in the trial of I-125 brachytherapy and were interviewed prior to random treatment assignment, at 6 months following treatment, and on annual anniversaries of enrollment for up to 8 years; and (2) a cross-sectional component consisting of 645 additional patients who had enrolled in the randomized trial before the quality of life study was initiated and who were interviewed at least once during scheduled follow-up. These 854 patients represent 90% of patients who were eligible for the quality of life study and 65% of all patients who enrolled in the trial of I-125 brachytherapy.

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 199812,16,17; 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 complications2022 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 (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

Participants

By July 1998, a total of 8712 patients with choroidal melanoma had been reported by COMS investigators; 5046 were classified to be of medium size by COMS criteria (Table 150.1). Among 2882 patients eligible for the randomized trial of I-125 brachytherapy versus standard enucleation, 1317 patients gave signed consent, enrolled, and were assigned randomly to treatment arm: 660 to standard enucleation and 657 to I-125 brachytherapy. Treatment arms were well balanced; adherence to the COMS protocol was excellent.13

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