Second Primary Cancers After Enrollment in the COMS Trials for Treatment of Choroidal Melanoma: Title and subTitle BreakCOMS Report No. 25 FREE

There has been growing interest in the occurrence of second malignancies (second primary cancers) after treatment for primary cancer. Of particular concern is the development of treatment-induced, particularly radiation-induced, second primary cancers and their relationship with dose as well as mode of delivery.¹ Increased risk of developing a second primary cancer has been reported with a number of cancers, including retinoblastoma,² Hodgkin disease, and breast and lung cancer.

In a recent study, Inskip³ investigated the relationship between cancer of the brain and central nervous system with other types of cancers using data from the Surveillance Epidemiology and End Results Program for cancers diagnosed in the United States from 1973 through 1998. Excess risk of solid cancers was discovered in patients receiving initial radiotherapy and those diagnosed before 17 years of age. Shared genetic susceptibility as well as close medical screening of such patients were hypothesized to explain some of the association.³

The risk of second primary tumors also has been investigated in breast cancer and patients with non-small-cell lung cancer.⁴ Analyses from the National Surgical Adjuvant Breast and Bowel Project suggest increased incidence of second primary lung tumors in patients with breast carcinoma receiving extensive postmastectomy chest-wall radiotherapy as part of their treatment. Such an association was not observed with postlumpectomy irradiation with lower radiation doses.⁵ Similarly, an analysis of the Surveillance Epidemiology and End Results Program data revealed an increased risk of ipsilateral lung cancer following postmastectomy radiotherapy but not after postlumpectomy radiotherapy.⁶ Increased risk postmastectomy was not observed until 10 years after treatment. The incidence of second primary tumors also has been studied in both stage I and stages II and IIA non-small-cell lung cancer. Findings have been comparable, with approximately 5% to 6% of patients developing nonskin second tumors.⁷ Recently, breast cancer risk was observed to increase with increasing radiation dose in female survivors of Hodgkin disease.⁸ Previous reports have suggested an association between development of second primary cancers and history of tobacco use.⁴ The effect modification of smoking and radiotherapy on mortality has been described.^{9 - 10}

Wong et al¹¹ described the occurrence of second primary tumors in patients treated for retinoblastoma. Little has been published regarding the development of new primary tumors in patients treated for choroidal melanoma. The Collaborative Ocular Melanoma Study (COMS) was designed as 2 randomized trials to evaluate forms of radiotherapy for choroidal melanoma with respect to overall survival and metastasis-free survival.¹² The COMS provides the largest series to date of patients with choroidal melanoma without detectable other cancers present at the time of treatment who were evaluated prospectively, enrolled, treated, and followed up in a standardized fashion. Our aim was to describe the sites and time to diagnosis of second primary tumors during follow-up among patients participating in these 2 randomized trials.

The COMS design and methods have been published.¹² The COMS Manual of Procedures¹³ and the COMS Study Forms Book¹⁴ are available. Prior to patient enrollment, the institutional review boards of all participating institutions reviewed and approved the COMS protocol and patient consent forms. All patients gave written consent before enrollment and random assignment to treatment. Descriptions of patients who enrolled in the randomized trials^{15 - 16} and initial mortality findings by treatment arm^{17 - 18} also have been published.

A COMS medical evaluation of each patient, regardless of tumor size, was performed prior to enrollment in the COMS to determine eligibility and rule out metastatic disease or another malignancy. The systemic evaluation was performed by an appropriate specialist, preferably a medical oncologist or radiation oncologist. The evaluation included a complete cancer-oriented general physical examination, chest x-ray, and liver function tests. In each trial, patients were assigned randomly to enucleation or to radiotherapy.

Each patient enrolled in one of the COMS trials was required to have an annual medical evaluation. Additional medical visits were scheduled to evaluate symptoms as required for good patient care. The follow-up evaluation was similar to that performed at the baseline visit and included a physical examination and liver function tests. A chest x-ray was performed annually. Whenever a new primary cancer or metastatic melanoma was diagnosed on the basis of any diagnostic study, a report was submitted by the clinical center coordinator to the COMS Coordinating Center (Baltimore, Md) along with copies of reports of all procedures that were performed to support the diagnosis. Biopsy or cytology slides or blocks of embedded tissue were sent to the COMS Pathology Center (Madison, Wis) for histopathologic review. Diagnosis of the new second primary cancer as reported by the clinical centers was confirmed by the COMS Mortality Coding Committee when the results of the histopathologic review were available for deceased patients. A new second primary cancer also may have been identified for the first time during the review by the Mortality Coding Committee.^{19 - 20}

Kaplan-Meier estimates of time to diagnosis of new second primary cancer were calculated along with 95% confidence intervals.²¹ SAS statistical software (SAS Institute Inc, Cary, NC) was used for all statistical analysis. Scheduled clinical follow-up ended on July 31, 2000, and July 31, 2003, for patients in the large- and medium-tumor trials, respectively. This report is based on follow-up data reported and received at the COMS Coordinating Center as of February 9, 2004.

Owing to the COMS eligibility criteria, eligible patients were required to have no previous diagnosis of another primary cancer or metastasis. History of 1 or more primary cancers was the sole reason for exclusion in 28% and 20% of patients who were otherwise eligible for the large and medium trials, respectively.^{15 - 16} Patients with nonocular tumors represented approximately 10% of all patients with choroidal melanoma of all sizes who were evaluated for the COMS.²²

For the 2320 patients enrolled in the COMS randomized trials, potential follow-up ranged from 5 to 16 years; the median follow-up was approximately 10 years. A total of 222 (9.6%) patients were reported by the clinical centers as having a diagnosis of 1 or more new second primary cancers, other than basal cell or squamous cell skin cancer, at some time during follow-up. Seventy-eight additional patients had a diagnosis of basal cell or squamous cell skin carcinoma only. The Table provides the distribution of sites of these second primary cancers associated with the time of first diagnosis. The most common sites were prostate (23%), breast (17%), and genitourinary, gastrointestinal, and leukemia/lymphoma (each, 9%-10%). Of sites coded as “other,” no single category exceeded 2 cases. The frequency distribution of number of reported sites at time of first diagnosis was 210 (95%), 9 (4%), and 3 (1%) for 1, 2, and 3 sites, respectively.

Pathologic confirmation (biopsy, cytology, autopsy) was available for 55 cases. Clinical confirmation occurred frequently by scan, x-ray, and physical examination. A total of 113 patients with a second primary cancer reported by the clinical centers had died; the records of all of these patients were reviewed subsequently by the COMS Mortality Coding Committee. Of these reviews, 37 (33%) cases were coded as death with melanoma metastasis, 33 (29%) as death with a malignant tumor (not metastatic melanoma), 13 (11%) as death with a malignant tumor of unknown origin, and 30 (27%) with insufficient or no available clinical information.

Overall, the 5-year cumulative second primary cancer rate (excluding basal cell skin carcinoma), based on clinical diagnosis and/or mortality reviews, was 7.7% (95% confidence interval, 6.6%-9.0%) and the 10-year rate was 14.9% (95% confidence interval, 12.9%-17.1%) (Figure 1). There was no statistically significant difference in these rates by treatment (radiotherapy or enucleation) nor tumor size (data not shown). Time to development of second primary cancer did not differ significantly by smoking history at baseline (Figure 2). However, the overall proportion developing a second primary cancer was slightly higher among former smokers.

The COMS provided a unique opportunity to assess a large series of patients with choroidal melanoma, but no other known cancers, who were followed up prospectively and evaluated systematically using a standard protocol that included an annual medical evaluation for detection of new cancers and metastatic spread. In addition, the randomized design permitted assessment of the effects of local radiation on development of second primary tumors within the next 5 to 10 years.

Our estimated 5- and 10-year second primary cancer rates are similar to the calculated 8% and 9% probabilities of developing invasive cancer during the 10-year interval between ages 40 to 59 years for men and women, respectively, in the United States based on data from 1998 to 2000.²³ Also, our findings suggest that the occurrence of second primary cancers following treatment for choroidal melanoma is similar to that observed with other primary cancers, with prostate and breast cancers as the most commonly diagnosed cancers. Our data do not suggest increased incidence of second primary cancer in patients treated for choroidal melanoma. However, our findings support routine posttreatment surveillance since some second primary cancers may be treated effectively if detected early. There was no statistically significant increase in second primary cancers in patients receiving radiotherapy as compared with those not receiving radiotherapy. We agree with Rice et al¹⁰ that it may be especially important to monitor patients with a history of smoking for new primary cancers. Even if mortality is not decreased with improved detection of second primary cancers, it is possible that routine surveillance for second primary cancers will result in less patient morbidity and improved quality of life.

Correspondence: Marie Diener-West, PhD, COMS Coordinating Center, Wilmer Clinical Trials and Biometry, 550 N Broadway, Ninth Floor, Baltimore, MD 21205 (mdiener@jhsph.edu).

Submitted for Publication: June 17, 2004; final revision received November 18, 2004; accepted December 28, 2004.

Financial Disclosure: None.

Funding/Support: The COMS Group has received support from the National Eye Institute and the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Md, through cooperative agreements EY06253, EY06257, EY06258, EY06259, EY06020, EY06264, EY06265, EY06266, EY06268, EY06269, EY06270, EY06274, EY06275, EY06276, EY06279, EY06280, EY06282, EY06283, EY06284, EY06287, EY06288, EY06289, EY06291, EY06839, EY06843, EY06844, EY06848, EY06858, and EY06899.

Group Information: A complete list of the members of the COMS Group can be found at Arch Ophthalmol. 2001;119:961-965.