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© 2002 American Society for Clinical Oncology Adjuvant Immunotherapy of Resected, Intermediate-Thickness, Node-Negative Melanoma With an Allogeneic Tumor Vaccine: Overall Results of a Randomized Trial of the Southwest Oncology GroupByFrom the University of Michigan Comprehensive Cancer Center, Ann Arbor, and the Karmanos Cancer Institute of the Wayne State University, Detroit, MI; the Statistical Center of the Southwest Oncology Group and the University of Washington, Seattle, WA; the Cleveland Clinic Foundation, Cleveland, OH; the University of Southern California, Los Angeles, and the University of California at Irvine, Orange, CA; Vanderbilt University, Nashville, TN; the University of Texas at San Antonio, San Antonio, TX; and the University of Utah, Salt Lake City, UT. Address reprint requests to Publications Specialist, Southwest Oncology Group (SWOG-9035), 14980 Omicron Dr, San Antonio, TX 78245-3217.
PURPOSE: Patients with clinically negative nodes constitute over 85% of new melanoma cases. There is no adjuvant therapy for intermediate-thickness, node-negative melanoma patients. PATIENTS AND METHODS: The Southwest Oncology Group conducted a randomized phase III trial of an allogeneic melanoma vaccine for 2 years versus observation in patients with intermediate-thickness (1.5 to 4.0 mm or Clark’s level IV if thickness unknown), clinically or pathologically node-negative melanoma (T3N0M0).
RESULTS: Six hundred eighty-nine patients were accrued over 4.5 years; 89 patients (13%) were ineligible. Surgical node staging was performed in 24%, the remainder were clinical N0. Thirteen eligible patients refused assigned treatment: seven on the observation arm and six on the vaccine arm. Most vaccine patients experienced mild to moderate local toxicity, but 26 (9%) experienced grade 3 toxicity. After a median follow-up of 5.6 years, there were 107 events (tumor recurrences or deaths) among the 300 eligible patients randomized to vaccine compared with 114 among the 300 eligible patients randomized to observation (hazard ratio, 0.92; Cox-adjusted P2 = 0.51). There was no difference in vaccine efficacy among patients with tumors CONCLUSION: This represents one of the largest randomized, controlled trials of adjuvant vaccine therapy in human cancer reported to date. Compliance with randomization was excellent, with only 2% refusing assigned therapy. There is no evidence of improved disease-free survival among patients randomized to receive vaccine, although the power to detect a small but clinically significant difference was low. Future investigations of adjuvant vaccine approaches for patients with intermediate-thickness melanoma should involve larger numbers of patients and ideally should include sentinel node biopsy staging.
BECAUSE OF THE poor outcome associated with metastatic melanoma and the existence of defined prognosticators for failure after surgical therapy of localized disease, the search for effective adjuvant therapy of melanoma has generated intense interest. The limited efficacy of available cytotoxic chemotherapeutic agents against advanced disease, combined with the perception that melanoma was occasionally susceptible to attack by the immune system, focused attention on vaccines composed of autologous or allogeneic melanoma cells or cell lysates. To date, melanoma vaccines have been used in two settings: for treatment of patients with documented metastatic disease, and in the adjuvant setting in patients considered to be at risk of harboring microscopic residual tumor after apparently curative resection. In patients with stage IV melanoma, both autologous and allogeneic melanoma vaccines have been associated with low levels of antitumor response; no series has reported higher than a 10% objective response rate.1 Even in the absence of objective tumor regression, however, it has been postulated that vaccines could prove to be efficacious in prolonging survival and/or improving quality of life in patients with advanced disease. One phase III clinical trial has been conducted comparing an allogeneic melanoma cell lysate (Melacine; Corixa Corporation [formerly RIBI Immunochem], Seattle, WA) to multiagent chemotherapy (the so-called Dartmouth regimen) in advanced melanoma.2 The response rates and survival of patients receiving the vaccine was slightly but not significantly less than for those receiving chemotherapy, but toxicity was also less and hence overall quality of life was considered to be improved. Without an untreated control group, it is not possible to determine whether either therapy was associated with a significant improvement of survival. It stands to reason that melanoma vaccines might be most effective when the tumor burden is least. Two theoretical reasons have been advanced: less antigenic heterogeneity in earlier tumors and less tumor-induced immunosuppression from lower total tumor burden.3 Recognizing this, most clinical trials have focused on the use of vaccines in the adjuvant setting, after resection of all known disease. To date, however, almost all of these have been phase II studies using comparisons with historical controls.1 Although such trials cannot prove efficacy, they have established that vaccines are candidates for phase III testing. Autologous vaccines have theoretical advantages, but practical disadvantages: for melanoma, there is rarely enough autologous tumor available to allow a phase III trial, especially in localized disease. Defined antigen vaccines are still in the earliest stages of development, and are applicable only to patients whose tumors express the target antigen. For most localized melanoma patients, allogeneic vaccines from whole-cell or cell lysate preparations have constituted the only practical option for broad-based phase III trials. In 1990, the Southwest Oncology Group (SWOG) initiated development of a phase III clinical trial of an allogeneic melanoma cell lysate for patients with localized melanoma after complete resection of all known disease. The vaccine chosen had shown evidence of antitumor activity, with an objective response rate of 7% in 81 patients in multicenter phase I and II clinical trials in advanced melanoma, and was recognized to contain melanoma-associated antigens potentially relevant to generating an effective antitumor immune response (Table 1).4,5 It must be noted, however, that it has not been proven that any of these antigens as administered in this vaccine actually generate a tumor-specific immune response in melanoma patients. The vaccine was compared to observation in patients with resected intermediate-thickness, clinically node-negative melanoma. This patient population has a substantial risk of recurrence, as evidenced by the results of a preceding SWOG trial (SWOG-8642, initiated in 1986) which documented that 33% of patients in this category had relapsed within 2.5 years.6 Initial results of this trial have previously been presented in abstract form with shorter follow-up.7 This report details the results of an updated analysis of this trial evaluating the impact of 2 years of vaccine therapy on disease-free survival, with a minimum follow-up of 4 years and a median follow-up of 5.6 years for living patients.
Eligibility Criteria To be eligible to participate in this trial, patients had to be age 18 years or older, treated at a participating SWOG institution, and diagnosed with a completely resected primary cutaneous melanoma 1.5 to 4.0 mm thick as assessed by the Breslow technique or Clark’s level IV if Breslow’s thickness was indeterminate for technical reasons (shave biopsy or tangential excision), with no gross evidence of satellitosis. This group corresponds to T3N0M0 in the current American Joint Committee on Cancer staging system for melanoma. Patients had to have clinically negative regional nodes, and pathologically negative regional nodes if surgical staging of the nodes was performed. Patients must have had no evidence of metastatic disease by physical examination and chest x-ray; computed tomographic scans or other staging work-up was not required but had to be negative for metastases if performed. Registration was required within 56 days of definitive surgery, defined as the last operation performed specifically for the treatment of the patient’s melanoma. For example, for a patient who underwent biopsy of the primary tumor followed by wide excision, registration had to be performed within 56 days of the wide excision. If, however, the patient subsequently underwent a regional lymph node dissection after the wide excision, randomization was required within 56 days of the lymphadenectomy.
Patients were also required to be in good health, with a Zubrod Performance Status of 0 (fully active without restriction) or 1 (ambulatory and able to carry out work of a light or sedentary nature), and satisfactory organ function as defined by WBC count
Review of Pathologic Specimens and Surgical Techniques
Treatment Assignment
Vaccine Treatment Each vaccine treatment consisted of two intramuscular injections of the vaccine/adjuvant combination (1.0 mL of Melacine cell lysate plus 0.25 mL DETOX split between two injection sites) given into extremities that were not involved with melanoma. The vaccinations were delivered as four 6-month cycles, each cycle consisting of 10 treatments (20 injections) given weekly for 4 weeks, then biweekly for 4 weeks, then monthly for 4 months, followed by a 3-week rest period. To minimize the potential for bias against the vaccine arm by virtue of patients being seen more frequently by a physician and hence presenting sooner with recurrence, all patients, whether randomized to observation or vaccine arms, were to be seen by the treating physician and evaluated for disease recurrence at specified intervals (weeks 12, 24, 39, 51, 66, 78, 93, and 105). After the first 2 years, patients were to be seen and evaluated by a physician every 4 months for 3 years and annually thereafter.
Assessment of Toxicity/Dose Reduction
Criteria for Removal From Protocol Treatment
Statistical Considerations Data and Safety Monitoring Committee. This study was monitored by the Southwest Oncology Group Data and Safety Monitoring Committee, established on the basis of existing regulations governing cooperative group phase III clinical trials. This committee met every 6 months, and consisted of National Cancer Institute–appointed representatives and selected members of the Southwest Oncology Group. The study coordinators and individual treating physicians were not members of the committee and were not privy to the outcome data and other information evaluated by the committee. Interim and planned analyses. Interim analyses were conducted when one fourth, one half, and three fourths of the expected events (disease recurrence or death) had occurred. Evidence suggesting early termination would be if either the null hypothesis of no difference in disease-free survival, or the alternative hypothesis that the disease-free survival of the treatment arm is 50% better than the observation arm was rejected at the 0.005 level of significance. The last interim analysis took place in September 1998, and concluded that the study should continue to planned analysis and reporting. Planned analyses were to be conducted on two populations: a primary analysis consisting of the population of eligible patients, and a secondary analysis consisting of all randomized patients regardless of eligibility status. This secondary analysis is sometimes referred to as the intent-to-treat analysis, but in fact both the primary and secondary analyses are conducted using the intent-to-treat principle of reporting results on the basis of the randomly assigned study arm regardless of actual treatment received. It is SWOG practice that detailed results of the secondary analysis are not presented unless they differ substantively from the results of the primary analysis. Two formal analyses of the data were planned, on the basis of the estimated time to reaching the requisite number of events: analysis for disease-free survival approximately 2 years after the end of the accrual period, and analysis for overall survival approximately 2 years after the disease-free survival analysis. In actuality, because the actual event rate was substantially less than estimated on the basis of data from SWOG-8642, the first analysis for disease-free survival was conducted at 39 months after the completion of accrual and published in abstract form.7 This report describes the results of an updated analysis of the disease-free survival results of SWOG-9035, analyzed 55 months after the completion of accrual.
Patient Characteristics and Eligibility A total of 689 patients were accrued over 4.5 years (from April 15, 1992, through November 15, 1996); 89 patients (13%) were found to be ineligible (43 from the observation and 46 from the vaccine groups). The main reason for ineligibility (76 patients) was that central pathology review indicated the primary lesion did not represent intermediate-thickness cutaneous melanoma as defined for this study. Reasons for ineligibility on the basis of pathology review included the following: the lesion was too thin (42 patients), too thick (23 patients), or had satellitosis or lymph node metastases (five patients) or other ineligible pathology (six patients). Nonpathology reasons for ineligibility were inadequate surgery in 10 patients and serum alkaline phosphatase above the institutional level of normal in three patients. Eligible patients had a median age of 51 years (range, 18 to 85 years); 59% were male and 41% female; and tumor thickness was 1.5 to 3.0 mm in 79%, 3.1 to 4.0 mm in 18%, and Clark level IV, thickness unknown in 3%. Surgical lymph node staging was performed in 24% of patients (about one fourth of which were sentinel node biopsies); the remainder were clinical N0 patients. There was good balance between the treatment arms in all three stratification factors (sex, tumor thickness, and lymph node staging), but there was a slight imbalance in favor of the vaccine arm in terms of two other prognostic factors, anatomic location of the primary tumor and ulceration (Table 2).
Compliance With Assigned Treatment Six eligible patients on the vaccine arm (2%) refused assigned treatment. Seven eligible patients on the observation arm (2%) refused assigned treatment: four received alternative vaccine therapy off protocol, two received interferon, and one received other investigational therapy. Among the 300 eligible patients on the vaccine arm, 170 (57%) completed 2 years of vaccine treatment as planned, 59 (20%) progressed while on treatment, 33 (11%) discontinued vaccine therapy because of persistent toxicity (see below), and 38 (13%) discontinued vaccine therapy because of patient refusal to continue or other reasons.
Vaccine Toxicity
Outcome After a median follow-up among patients still living of 5.6 years and a minimum follow-up of 4 years since registration, there were 107 recurrences or deaths without recurrence among the 300 eligible patients randomized to the vaccine arm compared with 114 recurrences or deaths among the 300 eligible patients randomized to the observation arm (hazard ratio, 0.92; 95% confidence interval [CI], 0.70 to 1.19) (Fig 1). Five-year estimated disease-free survival rates were 65% for patients randomized to the vaccine arm versus 63% for patients randomized to the observation arm. There was evidence of significant prognostic influence of two of the three stratification factors (thickness and sex), with the third (lymph node staging) being of borderline significance (Table 4). The level of significance for the treatment effect as assessed using a Cox model adjusted for the three stratification factors was P2 = .51. Because of an imbalance of other recognized prognostic factors (anatomic site of the primary tumor and ulceration, which were not incorporated as stratification factors), further analysis was performed including these factors into the Cox model. The hazard ratio changes accordingly to 0.97 (95% CI, 0.74 to 1.27, P2 = .83). In contrast to results presented at the time of initial analysis,7 with further follow-up there is no evidence of a difference in the results for the entire group of 689 randomized patients. There were 120 recurrences or deaths among the 346 patients randomized to the vaccine arm compared with 133 recurrences or deaths among the 343 patients randomized to the observation arm (hazard ratio, 0.84; 95% CI, 0.66 to 1.08; P2 = .17) (Fig 2). The 5-year estimated disease-free survival rate was 66% for vaccine patients versus 62% for observation patients. Further analysis including primary site and ulceration into the Cox model revealed that the hazard ratio changes to 0.89 (95% CI, 0.69 to 1.14; P2 = .34).
An exploratory Cox model analysis was conducted to determine whether there was evidence for an interaction between treatment effect and tumor thickness. This analysis was performed accounting for all stratification and recognized prognostic factors. Tumor thickness was analyzed as a dichotomous variable,  3.0 mm versus > 3.0 mm. In contrast to the initial analysis, the results revealed no evidence that the efficacy of the vaccine differed in eligible patients with melanomas 3.0 mm (P2 = .64) (Fig 3A) from those with tumors > 3 mm (P2 = .67, Fig 3B). The results were identical for all randomized patients, when analyzed by tumor thickness (data not shown).
Overall survival for the eligible patient population is presented in Fig 4. The study has not reached the predetermined level of maturity to analyze overall survival and hence statistical analysis of the impact of vaccine treatment on survival has not been conducted.
SWOG-9035 is the largest randomized controlled trial of vaccine therapy for human cancer reported to date. Patients with completely resected intermediate-thickness, node-negative cutaneous melanoma (T3N0M0) randomized to receive intramuscular injections of an allogeneic melanoma cell lysate plus an immunologic adjuvant for 2 years had a relapse-free survival that was not significantly different from patients randomized to observation without further therapy. The observed hazard ratio, when adjusted for all recognized stratification and prognostic variables, was 0.97 with a 95% CI of 0.74 to 1.27 (P2 = .83). It is worth pointing out that the results of the primary analysis of all eligible patients have remained constant between this analysis and the initial analysis of this trial,7 whereas the initially observed statistically significant improvement in disease-free survival for the entire randomized cohort of 689 patients has disappeared with further follow-up. Similarly, an initial suggestion that patients with tumors 3 mm in thickness had improved outcome with vaccine treatment has also disappeared with further follow-up. These findings serve both to clarify the results of this trial and as a reminder that secondary or subset analyses are inherently less reliable than the primary analysis of eligible patients. In evaluating the results of this study, it is important to recognize that this trial was inadequately powered to detect a small but clinically meaningful difference. This trial was designed to detect a 50% increase in median relapse-free survival. Clearly, even though the vaccine used was associated with some toxicity (most of which was attributable to the immunologic adjuvant rather than the allogeneic melanoma lysate), most melanoma patients would readily accept this degree of toxicity for a smaller incremental improvement in relapse-free survival.15 It is also important to note that three quarters of the patients in this trial had only clinical staging of the regional lymph nodes, and hence this study included patients with both pathologically negative and pathologically positive lymph nodes. Staging of the regional nodes by the modern technique of sentinel node biopsy with immunochemical analysis was performed in only about 5% of the patients. No data are presently available regarding sites of disease relapse in study patients (regional v distant) or regarding the relative efficacy of the vaccine in surgically staged versus clinically staged patients. A number of questions remain regarding this trial. Was the optimal vaccination strategy chosen and did patients achieve immunologic responses relevant to their own tumors? This trial was not designed to address this issue, and so these questions cannot be answered without further studies. Previous clinical trials with this vaccine have indicated that between 42% and 67% of patients with stage IV melanoma experienced an increase in the frequency of melanoma-specific cytotoxic T lymphocytes, and that these lymphocytes could lyse allogeneic melanoma cells in an HLA-restricted fashion.4,5,16,17 Antibody titers to melanoma antigens were increased in the majority of stage IV melanoma patients treated with the vaccine, and delayed-type hypersensitivity reactivity to the allogeneic melanoma lysate developed in about 15%. Of the observed immune reactions, only an increase in cytotoxic T lymphocytes appeared to correlate with objective regression of metastatic disease and survival (Melacine Investigators Brochure, Corixa Corp, July 1999). Since these immunologic responses were observed in patients with stage IV melanoma, it is reasonable to postulate that the responses of patients with stage II melanoma, with lower tumor burdens, better performance status, and less tumor-induced and treatment-induced immunosuppression, would be at least as good. The question remains as to whether vaccine treatment will improve overall survival. The trial data will undergo a planned analysis for overall survival in approximately 2 years. However, a number of factors could confound the interpretation of survival data in this trial, the most significant of which may be postrelapse therapy. The most common site of relapse in patients with clinically negative nodes is in the regional nodes, and some of those patients are cured by radical lymphadenectomy. Moreover, many patients who undergo resection of stage III and even stage IV melanoma are treated with adjuvant interferon alfa-2b, and it has been suggested that stage IV melanoma patients treated with interferon alfa-2b after allogeneic melanoma vaccine therapy fared better than expected.18 The results of SWOG-9035 have major implications for future adjuvant therapy trials in clinically node-negative patients. Data analysis occurred later than expected because the relapse rate was less than estimated from prior clinical trials. In the future, as more patients are staged by sentinel node biopsy, the relapse rate of N0 melanoma patients will likely be even lower. Hence, future adjuvant trials will need much larger sample sizes than the 689 patients entered onto SWOG-9035. Intergroup and perhaps even international participation will be necessary to make such trials possible. Furthermore, identification of appropriate biologic and immunologic intermediate end points should be a priority, as they will be necessary for selecting among various promising vaccine strategies for future phase III trials in appropriate patient populations. The need for phase III trials cannot be overemphasized; the results of this trial highlight once again the pitfalls of relying on historical controls, as the control group fared far better than comparable patients in a prior study by the same cooperative group conducted just 4 years earlier (SWOG-8642).6 Further investigation of adjuvant vaccine approaches for patients with intermediate-thickness melanoma and clinically negative nodes, taking advantage of improvements in our understanding of the human immune system in the decade since this study was conceived, is clearly warranted. For the specific allogeneic melanoma vaccine used in this clinical trial, the observation was made in stage IV melanoma that patients expressing particular HLA antigens were more likely to derive clinical benefit than others.19 The overall results of our trial do not exclude the possibility that a subset of patients derived more benefit than others. This possibility was prospectively evaluated in SWOG-9035 and is presented separately in a companion publication.20 The unfulfilled promise of vaccines21 in preventing recurrence in prospective, controlled trials underscores the fact that we still do not know which patients may stand to benefit most from individual vaccines or vaccine therapy in general.
Supported in part by the following Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA20319, CA27057, CA58723, CA22433, CA58861, CA04920, CA46113, CA46441, CA37981, CA7648, CA04919, CA35281, CA58686, CA35176, CA35090, CA16385, CA35119, CA35262, CA12644, CA46136, CA14028, CA45450, CA42777, CA45377, CA35178, CA46282, CA35192, CA58416, CA96429, CA35431, CA13612, CA45807, CA74647, CA58415, CA58348, CA12213, CA45560, CA58882, CA76447, CA46368, CA35261, CA52386, CA76462, CA67663, CA52654, and CA63845. We thank Malcolm S. Mitchell, MD, PhD, developer of Melacine, for his contributions to the initial design of this study. We thank Suzan Myers, Dana Sparks, Claire Chapdu, Camille White, Diana Lowry, and Laura Kingsbury for protocol coordination, data entry, and analysis. We especially thank the 689 patients who volunteered to participate.
1. Haigh PI, Difronzo LA, Gammon G, et al: Vaccine therapy for patients with melanoma. Oncology 13: 1561-1574, 1999[Medline] 2. Mitchell MS, von Eschen KB: Phase III trial of Melacine melanoma theraccine versus combination chemotherapy in the treatment of stage IV melanoma. Proc Am Soc Clin Oncol 16: 494a, 1997 (abstr) 3. Hain JM, Sondak VK: Tumor-induced suppression of T cells, in Chang AE, Shu S (eds): Immunotherapy of Cancer With Sensitized T Lymphocytes. Georgetown, TX, RG Landes, 1994, pp 111-121
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Mitchell MS, Kan-Mitchell J, Kempf RA, et al: Active specific immunotherapy for melanoma: Phase I trial of allogeneic lysates and a novel adjuvant. Cancer Res 48: 5883-5893, 1988 5. Mitchell MS, Harel W, Kemph RA, et al: Active specific immunotherapy for melanoma. J Clin Oncol 8: 856-869, 1990[Abstract]
6.
Meyskens FL Jr, Kopecky KJ, Taylor CW, et al: A randomized trial of adjuvant human interferon- 7. Sondak VK, Liu P-Y, Tuthill RJ, et al: SWOG-9035: Adjuvant therapy of intermediate-thickness node-negative melanoma with an allogeneic tumor vaccine. J Immunother 23: 600, 2000 (abstr) 8. Pocock SJ, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 31: 103-115, 1975[CrossRef][Medline] 9. Astiz ME, Rackow EC, Yim YB, et al: Hemodynamic effects of monophosphoryl lipid A compared to endotoxin. Circ Shock 27: 193-198, 1989[Medline] 10. Johnson AG, Tomai MA: A study of the cellular and molecular mediators of the adjuvant action of a nontoxic monophosphoryl lipid A. Adv Exp Med Biol 256: 567-579, 1990[Medline] 11. Gray GR, Ribi E, Granger D, et al: Immunotherapy of cancer: Tumor suppression and regression by cell walls of Mycobacterium phlei attached to oil droplets. J Natl Cancer Inst 55: 727-730, 1975 12. Schultz N, Oratz R, Chen D, et al: Effect of DETOX as an adjuvant for melanoma vaccine. Vaccine 13: 503-508, 1995[CrossRef][Medline]
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Helling F, Zhang S, Shang A, et al: GM2-KLH conjugate vaccine: Increased immunogenicity in melanoma patients after administration with immunological adjuvant QS-21. Cancer Res 55: 2783-2788, 1995 14. Green S, Weiss GR: Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 10: 239-253, 1992[CrossRef][Medline]
15.
Kilbridge KL, Weeks JC, Sober AJ, et al: Patient preferences for adjuvant interferon alfa-2b treatment. J Clin Oncol 19: 812-823, 2001 16. Elliott GT, Mcleod RA, Perez J, et al: Interim results of a phase II multicenter clinical trial evaluating the activity of a therapeutic allogeneic melanoma vaccine (theraccine) in the treatment of disseminated malignant melanoma. Semin Surg Oncol 2: 41-53, 1993 17. Harel W, Goedegebuure PS, LeMay LG, et al: Melanoma-specific lysis by cloned CD4+ and CD8+ T cells from actively immunized melanoma patients. Vaccine Res 2: 41-53, 1993 18. Mitchell MS, Jakowatz J, Harel W, et al: Increased effectiveness of interferon alfa-2b following active specific immunotherapy for melanoma. J Clin Oncol 12: 402-411, 1994[Abstract] 19. Mitchell MS, Harel W, Groshen S: Association of HLA phenotype with response to active specific immunotherapy of melanoma. J Clin Oncol 10: 1158-1164, 1992[Abstract]
20.
Sosman JA, Unger JM, Liu P-Y, et al: Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: II. Impact of HLA class I antigen expression on outcome. J Clin Oncol 20: 2067-2075, 2002
21.
Livingston P: The unfulfilled promise of melanoma vaccines. Clin Cancer Res 7: 1837-1838, 2001 Submitted April 16, 2001; accepted January 9, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3,000/µL, platelet count 
versus observation in high-risk cutaneous melanoma: A Southwest Oncology Group study. J Natl Cancer Inst 87: 1710-1713, 1995
