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Journal of Clinical Oncology, Vol 22, No 12 (June 15), 2004: pp. 2438-2444 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.194 Screening for Metastasis From Choroidal Melanoma: The Collaborative Ocular Melanoma Study Group Report 23From the The Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, MD; Midwest Eye Institute, Indianapolis, IN; Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA; Mayo Clinic, Jacksonville, FL; Retina-Vitreous Consultants; University of Pittsburgh, Pittsburgh, PA; University of Michigan, Ann Arbor; Associated Retinal Consultants; Beaumont Cancer Center, Royal Oak, MI; University of Washington, Seattle, WA; Mayo Clinic, Rochester, MN; Northwestern University, Chicago, IL; and The University of Virginia, Charlottesville, VA Address reprint requests to Marie Diener-West, PhD, COMS Coordinating Center, Wilmer Clinical Trials and Biometry, 550 N Broadway, Floor 9, Baltimore, MD 21205; e-mail: mdiener{at}jhsph.edu
PURPOSE: To describe the predictive value of liver function tests (LFTs), chest x-ray, and diagnostic imaging for detecting melanoma metastasis during routine follow-up after treatment for choroidal melanoma. MATERIALS AND METHODS: Prospective longitudinal follow-up of patients enrolled onto two randomized trials was conducted by the Collaborative Ocular Melanoma Study (COMS) Group. Baseline and annual or semiannual systemic and laboratory evaluations were performed according to a standard protocol for 2,320 patients enrolled on the COMS. RESULTS: COMS patients were screened annually for metastasis and new cancers using LFTs (alkaline phosphatase, AST, ALT, or bilirubin). Elevated findings (1.5 to 2 times upper limit of normal) on LFT prompted a diagnostic or imaging test to confirm or rule out cancer recurrence. Of 714 patients with clinical reports of metastasis, 675 patients died. Of these 675 patients, all but four had either histopathologically confirmed or clinically suspected metastatic melanoma present at the time of death. Among all patients, the 5-year cumulative diagnosis rate of metastatic melanoma was 24% (95% CI, 22% to 27%). Based on all patients with reported metastasis, the sensitivity, specificity, positive predictive value and negative predictive value associated with at least one abnormal LFT before first diagnosis of metastasis at any site was 14.7%, 92.3%, 45.7% and 71.0%, respectively. CONCLUSION: Use of LFTs results followed by diagnostic tests has high specificity and predictive values but low sensitivity. Better tests are needed to identify earlier metastatic disease associated with choroidal melanoma.
Metastasis is common following primary diagnosis of choroidal melanoma. Patterns of metastatic spread have been described. Frequently the site of metastasis is the liver, with the proportion of cases with liver metastasis ranging from 56% to 100%.1-8 Diagnosis of metastasis is often followed by rapid physical decline of the patient. Currently, there are few life-prolonging treatments for the majority of patients with liver metastasis or other distant sites of metastasis. The median time from diagnosis of liver metastasis to death is approximately 6 months.9 Early detection might identify individuals at a time when intervention may decrease the rate of metastatic spread or extend survival. Early detection also may help the patient and family in planning future medical and personal care. After diagnosis with choroidal melanoma, patients typically are screened for metastasis on a semiannual or annual basis using liver function tests (LFTs) and imaging studies. Tests that have been used include AST, ALT, alkaline phosphatase (APH), gamma-glutamyl transpeptidase, lactate dehydrogenase (LDH), or bilirubin (BIL). An abnormal or elevated LFT finding usually triggers the administration of a subsequent diagnostic test such as biopsy, magnetic resonance imaging (MRI) or computed tomography (CT) scans.10-13 More recently, routine screening by ultrasonography of the liver and a panel of LFTs have been recommended.14,15 Retrospective evaluations of screening tests for metastases in patients with choroidal melanoma have been reported. Hicks et al14 reviewed baseline LFTs of 235 patients and classified them as either normal or abnormal based on laboratory normal ranges. Sensitivity per test ranged from 1.9% for bilirubin to 25% for alkaline phosphatase; specificity ranged from 86% to 99%, respectively. Imaging tests were found to be highly specific but lacked sensitivity. For example, chest x-ray and liver ultrasound had 100% specificity but associated sensitivity of 1.8% and 14%, respectively. Eskelin et al15 had similar findings when examining the diagnostic utility of LFTs, chest x-ray and abdominal ultrasound before and at the time of diagnosis of metastasis in 46 patients with metastatic choroidal melanoma.
The Collaborative Ocular Melanoma Study (COMS) was designed to evaluate forms of radiotherapy for choroidal melanoma with respect to overall survival and metastasis-free survival.16,17 In the COMS, the linear measurements of apical height and largest basal diameter were used to classify a tumor as small (1 to 2.5 mm in apical height and > 5 mm in largest basal diameter) medium (> 2.5 to 10 mm in apical height and
The COMS design and methods have been published.16 The COMS Manual of Procedures12 and the COMS Forms Book17 are available. Before 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 onto the randomized trials18,19 and initial mortality findings by treatment arm20,21 also have been published.
The COMS procedures for initial and follow-up systemic medical evaluations were developed and approved in 1986 by the COMS Executive Committee and approved by the COMS Data and Safety Monitoring Committee; they remained in effect through the end of the study. A medical evaluation of each patient, regardless of tumor size, was performed before enrollment in the COMS to determine eligibility and rule out metastatic disease or another malignancy. A systemic evaluation was performed that included a complete cancer-oriented general physical examination and LFTs. Required laboratory tests to assess liver function were AST, ALT, APH, and BIL. A test result was considered abnormal under the following conditions: AST > 2 x the upper limit of normal for the reference laboratory; ALT > 2 x the upper limit of normal for the reference laboratory; APH > 1.5 x the upper limit of normal for the reference laboratory; BIL Abnormal LFT findings required repeat laboratory testing for verification. Subsequent to verification, biopsy of suspicious lesions, CT or MRI scan of the liver, ultrasonography, or other diagnostic procedures were required to confirm or rule out metastatic disease. In the COMS, patients in the large tumor trial were re-examined 6 months and 12 months after enrollment and annually thereafter until July 2000. Patients in the medium tumor trial were re-examined semiannually for the first 5 years after enrollment and annually thereafter; semiannual ophthalmic examinations for COMS data collection were optional after 5 years. Each patient enrolled onto 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 LFTs. A chest x-ray was performed annually. Diagnostic imaging tests or pathology examinations were performed on the basis of elevated LFTs or whenever hepatomegaly was observed. Whenever metastatic melanoma was diagnosed on the basis of any of the diagnostic tests, 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, WI) for histopathologic review. After the death of each COMS patient, clinic coordinators submitted any additional results and all medical and diagnostic reports regarding the patient's metastatic status at the time of death subsequently were reviewed by the COMS Mortality Coding Committee.22 After the COMS was initiated, serum LDH was recognized as a prognostic factor for diminished survival in patients with metastatic cutaneous melanoma23-25 and was incorporated in the revised staging of cutaneous melanoma by the American Joint Committee on Cancer.26 Although LDH, albumin, and platelet levels were not collected systematically nor recorded for COMS purposes, a retrospective substudy was performed at five COMS clinical centers. For these centers, the COMS Coordinating Center provided a listing of study identifying numbers and name codes and all follow-up visits completed and dates for patients who had at least one abnormal COMS LFT reported after enrollment. The clinic coordinators at those centers, four of whom are registered nurses and one of whom is a physician's assistant, reviewed all available laboratory evaluations and extracted dates and values of these indicators, as well as the normal reference ranges for the associated laboratories, and returned the listings to the COMS Coordinating Center, where data were entered and integrated with other data on file for each patient. Test results were considered abnormal if the LDH level was above the upper limit of the normal reference range or if the albumin or platelet levels were below their respective lower limits of the normal reference ranges.
Statistical Methods The diagnostic attributes of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for each test were estimated from cross-tabulation tables of test result (elevated v not elevated) by report of diagnosis of metastatic melanoma at any site (yes v no). Table 1 defines these attributes and provides a hypothetical example based on 300 patients. The sensitivity of the test is the number correctly identified as positive by the test (true positives) divided by the total number with disease—75 of 100 patients, or 75%. The specificity of the test is the number correctly identified as negative (true negatives) divided by the total number without disease—180 of 200 patients, or 90%. For a clinician, the measures of positive and negative predictive values, 79% and 88%, are most useful28 because they indicate the probability of disease for patients with positive results and the probability of not having the disease for those with negative results, respectively.
Diagnosis of metastasis was reported by the clinical centers and confirmed by the COMS Mortality Coding Committee (MCC) for deceased patients. It was also possible that metastasis was identified for the first time during the review by the MCC. In the present study, diagnostic attributes were calculated under three different scenarios, using (1) positive test results obtained at any follow-up evaluation before the date of diagnosis of metastasis, (2) test results associated with the most recent visit within 90 days of the the date of diagnosis of metastasis, and (3) test results obtained from the last visit before the date of diagnosis of metastasis (no restriction on time frame). For the last two scenarios, the results for patients without reported metastasis were obtained from the corresponding most recent visit with a systemic evaluation. Patients having no available tests at any time during follow-up were excluded from the calculations. All analyses were performed for all patients and separately by tumor size group (medium or large). Analyses were repeated for diagnosis of metastasis to the liver. Similar analyses were performed for the subset of patients for whom LDH, albumin and platelet levels were abstracted. SAS statistical software (SAS/STAT User's Guide version 6, 1990; SAS, Cary, NC) was used for all statistical analysis. This report is based on follow-up data of COMS patients reported and received at the COMS Coordinating Center as of December 31, 2001.
Of 2,320 patients enrolled onto the COMS randomized trials, a total of 714 patients were reported by the clinical centers as having a diagnosis of melanoma metastasis at some time during follow-up: 469 and 245 patients with large and medium choroidal melanoma at the time of enrollment, respectively. Table 2 depicts the distribution of procedures and tests used to confirm distant recurrence of melanoma. Pathologic confirmation (biopsy, cytology, autopsy) was available for 487 patients (68%). Clinical confirmation occurred frequently by scan, xray, physical examination and LFTs. Diagnosis was based on one test finding (clinical or pathologic) in only 136 patients (19%); two different test results were used in 187 patients (26%); three or more tests were available for 391 patients (55%). A total of 679 patients with melanoma metastasis reported by the clinical centers had died; the records of 675 patients were reviewed subsequently by the MCC. All but four cases were coded as either having histopathologically confirmed metastatic melanoma (79%) or clinical evidence of (suspected) metastatic melanoma (20%) at time of death. In addition, four patients of 323 who died without a prior diagnosis of metastasis were judged by the MCC to have histopathologic evidence of metastatic melanoma; for these cases, the date of diagnosis of metastasis was assumed to be the date of death. Findings were similar by tumor size group.
Overall, the 5- and 10-year cumulative metastatic melanoma rates, based on clinical diagnosis and/or mortality reviews, were 24% (95% CI, 23% to 26%) and 32% (95% CI, 30% to 34%), respectively. Rates of metastasis increased with tumor size. The 5-year cumulative rates were 38% (95% CI, 35% to 41%) and 14% (95% CI, 12% to 16%) for patients with large and medium-sized melanoma, respectively (Fig 1). Although incidence rates declined after the 2-year examination, there was no 6-month interval when no diagnosis of metastasis was made over the 12-year period. Of those diagnosed with metastasis, median survival was less than 6 months after the diagnosis. Overall, the Kaplan-Meier estimates of mortality at 1 year and 2 years after diagnosis of metastatic melanoma were 81% (95% CI, 78% to 84%) and 92% (95%CI, 90% to 94%), respectively. The sites of metastasis are shown in Table 3; the most common sites included liver (91%), lung (28%) and bone (18%) and were similar for patients enrolled with large and medium choroidal melanoma. The frequency distribution of sites was one, 52%; two, 25%; three, 13%; four, 7%; and five or more, 4%.
Table 4 displays by tumor size group the total numbers of tests of each type performed and reported during annual or semi-annual systemic evaluations. Of the combined LFTs performed, only 487 tests (< 1%) yielded abnormal findings in 221 patients. For each LFT, the median number of tests per patient was 7 (range, 0 to 28); 25% of patients had 10 or more tests.
Overall, the sensitivity, specificity, positive predictive value and negative predictive value associated with at least one abnormal LFT before first diagnosis of metastasis at any site was 14.7%, 92.3%, 45.7% and 71.0%, respectively; these values increased to 24.1%, 98.2%, 75.3% and 85.4% when restricting the time frame for test results to those obtained within 90 days before the reported diagnosis of metastasis. Restricting the analysis to test results obtained within the 90-day period before the diagnosis of metastasis resulted in increased diagnostic attributes for most tests. Results did not change appreciably for the analysis based on the last test results versus the analysis based on the test results obtained within the 90-day period. Table 5 depicts the diagnostic attributes of each liver function and diagnostic tests (CT, MRI, or other imaging scans) as well as findings of hepatomegaly and abnormal chest x-rays performed within 90 days of reported diagnosis of metastasis to any site, by tumor size group. For both tumor size groups, an individual LFT provided high specificity of 98% to 99%. However, sensitivity ranged from 0% to 19% and was higher for patients with large melanoma. PPV ranged from 67% to 92% for patients with large tumors and was lower for patients with medium-sized melanoma. Conversely, the NPV was approximately 70% versus 90% for patients with large versus medium tumors, respectively. Of the LFTs, alkaline phosphatase possessed the highest diagnostic attributes. As expected, diagnostic tests were associated with the highest sensitivity (88% to 94%), specificity (87% to 97%), PPV (94%) and NPV (87% to 93%), since these tests were mainly triggered by abnormal LFT findings. Similar results were obtained when metastasis was restricted to the site of the liver (data not shown).
For the subset of 43 patients at five COMS clinical centers where LDH, platelet and albumin levels were abstracted retrospectively, there were reports of 25 patients (58%) with LDH values above the normal reference range; six patients (14%) and 11 patients (26%) had low platelets or low albumin levels, respectively, on at least one test before diagnosis of metastasis. These patients were selected on the basis of time between first abnormal LFT to diagnosis of metastasis; time between first elevated LDH to diagnosis of metastasis revealed no systematic differences, suggesting no advantage of LDH in detecting metastasis before the routine COMS-required LFTs.
The COMS provided the opportunity to assess a large series of patients with choroidal melanoma who were followed prospectively and evaluated systematically using a standard protocol that included semi-annual LFTs and annual chest x-rays to screen for metastatic spread. The characteristics of our LFT results are similar to those reported by Hicks et al14 and Eskelin et al.15 In our series, both sensitivity and specificity improved with the use of multiple tests. Our choice of cutoff level for abnormal findings of LFTs was higher than reported in both earlier studies, which may have resulted in decreased sensitivity of COMS evaluations. Hicks et al concluded that hematologic tests were not useful for ruling out metastatic disease at presentation with uveal melanoma, due to their low positive predictive value. They recommended liver ultrasonography and chest x-ray at baseline only, given their findings of 100% specificity and low sensitivity for both tests. We recognize that LFT values are highly variable and may be influenced by other factors that elevate liver function levels, such as the use of cholesterol-lowering agents. The benefit of annual chest x-ray is questionable based on our results, in which less than 3% (297 of 11,948 x-rays performed) were abnormal. We concur with Eskelin et al15 that annual screening for metastatic uveal melanoma with LFTs is warranted and that chest x-rays should be required at baseline or whenever warranted by other test results.29,30 Our analyses suggest that alkaline phosphatase may possess the best test attributes of the LFTs we examined but that multiple tests improve sensitivity. Also, our findings of lower diagnostic attributes associated with testing of patients with medium-sized tumors suggests that different screening strategies may be warranted based on tumor size at time of diagnosis and treatment. We agree with others14,15 that periodic screening for metastatic uveal melanoma is primarily beneficial when effective treatment is available or when patients are eligible to be candidates for clinical trials of promising treatment. Such therapies are needed given the potentially high prevalence of micrometastasis at time of diagnosis of choroidal melanoma and the high incidence of metastasis detected clinically after diagnosis of the primary tumor. Among 7,541 patients screened for COMS trials, only 70 (< 1%) had metastatic melanoma detected at the time of screening. In our randomized trials, the majority of deaths were associated with histopathologically confirmed or suspected metastatic melanoma. However, because of the short time from detection of metastasis until death, early detection of metastases may be valuable to the patient and family to permit personal planning and arrangements for future medical care. Although treatments for metastatic melanoma have demonstrated equivocal results with respect to survival, development and evaluation of new combined or systemic therapies24,31-33 and adjuvant therapies34 must continue to be pursued. In the interim, we recommend continued routine surveillance of LFTs in conjunction with diagnostic imaging studies such as ultrasonography, MRI, or other scans.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received more than $2,000 a year from a company for either of the last 2 years: Wui-Jin Koh, Ortho Biotech.
Supported by the National Eye Institute and the National Cancer Institute 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, EY06899 with the National Institutes of Health, Bethesda, MD. A complete list of the COMS Group members as of September 30, 2000, is in Arch Ophthalmol 119:961–965, 2001. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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32. Alexander HR, Libutti SK, Bartlett DL, et al: A Phase I-II Study of isolated hepatic perfusion using melphalan with or without tumor necrosis factor for patients with ocular melanoma metastatic to liver. Clinical Cancer Res 6:3062-3070, 2000 33. Salmon RJ, Levy C, Plancher C, et al: Treatment of liver metastases from uveal melanoma by combined surgery-chemotherapy. Eur J Surg Oncol 24:127-130, 1998[CrossRef][Medline]
34. Alizadeh H, Howard K, Mellon J, et al: Reduction of liver metastasis of intraocular melanoma by interferon-beta gene transfer. Invest Ophthalmol Vis Sci 44:3042-3051, 2003 Submitted August 29, 2003; accepted March 30, 2004. This article has been cited by other articles:
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
16 mm in largest basal diameter), or large (
2 mm in apical height and > 16 mm in largest basal diameter or > 10 mm in apical height).
