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© 2002 American Society for Clinical Oncology Adjuvant Immunotherapy of Patients With High-Risk Melanoma Using Vaccinia Viral Lysates of Melanoma: Results of a Randomized TrialByFrom the Sydney Melanoma Unit, University of Sydney and Royal Prince Alfred Hospital, and the Cancer Council Australia, Sydney; Oncology and Immunology Unit and Newcastle Melanoma Unit, Newcastle Mater Hospital, Newcastle, and National Health and Medical Research Council Trials Centre, Camperdown, New South Wales; Melanoma Project, Princess Alexandra Hospital, Brisbane, Queensland; and Adelaide Melanoma Unit, Adelaide University and Royal Adelaide Hospital, Adelaide, South Australia, Australia. Address reprint requests to Peter Hersey, MD, Oncology and Immunology Unit, Rm 443, David Maddison Clinical Sciences Bldg, Cnr King and Watt Sts, Newcastle, NSW 2300, Australia; email: peter.hersey{at}newcastle.edu.au
PURPOSE: Patients with high-risk melanoma treated by immunotherapy with vaccinia viral lysates were found in phase II studies to have improved survival compared with historical controls. We therefore elected to test this therapy in a phase III study. PATIENTS AND METHODS: A prospective, randomized, multicenter trial to determine whether immunotherapy with a vaccine prepared from vaccinia melanoma cell lysates (VMCL) over a 2-year period after definitive surgery would improve relapse-free survival (RFS) and overall survival (OS) in patients with American Joint Committee on Cancer stage IIB and III melanoma compared with a control group treated only with surgery. RESULTS: A total of 700 patients were randomized: 353 to VMCL and 347 to no immunotherapy. Seventy-seven percent had lymph node (LN) metastases and 66% had clinically detected LN metastases. Analysis on the basis of all eligible, randomized patients (n = 675) found, after a median follow-up period of 8 years, a median OS of 88 months in the control versus 151 months in the treated group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.64 to 1.02; P = .068 by stratified univariate Cox analysis). At 5 and 10 years, survival rates for control and treated patients were 54.8% v 60.6% and 41% v 53.4%, respectively. Median RFS was 43 months in the control group compared with 83 months in the treated group (HR, 0.86; 95% CI, 0.7 to 1.07; P = .17). RFS at 5 years was 50.9% for the treated group and 46.8% for the control group. There were no selective benefits from the vaccine for particular subsets of patients. CONCLUSION: Immunotherapy with VMCL was not associated with a statistically significant improvement in OS or RFS, with CIs not ruling out important gains from such treatment.
PATIENTS WITH THICK primary melanoma or regional lymph node (LN) metastases are known to be at high risk of disease recurrence. Previously published estimates of the risk over a 5-year period approximates 60% in patients with primary melanoma 4 mm or greater in thickness (American Joint Committee on Cancer [AJCC] stage IIB) and 70% in those with regional LN metastases (AJCC stage III disease).1-3 Median survivals for patients with stage IIb and III disease in three recent trials were 34,4 41.3,5 and 72 months.6 A number of different adjuvant therapies given after surgery have not been shown to reduce the risk of recurrence or death in such patients. These include chemotherapy with DTIC with or without immunotherapy with bacillus Calmette-Guérin7 and recombinant interferon alpha 2a (IFN  -2a) given at relatively low doses (3 megaunits/d subcutaneously three times a week) for 3 years.8,9 Trials of IFN-2b at higher doses conducted by the Eastern Cooperative Oncology Group (ECOG) in the United States have given inconclusive results, with one trial (ECOG 1684) showing clear benefit of relapse-free (RFS) and overall survival (OS),4 whereas a subsequent trial (ECOG 1690) showed improved RFS but no improvement in OS.6 The most recent trial (ECOG 1694) showed benefit in terms of RFS and OS in comparison with immunotherapy with a GM-2/KLH vaccine. An untreated control group was not included in the latter study.10 The present study was designed to determine whether immunotherapy with a melanoma vaccine prepared from vaccinia melanoma cell lysates (VMCL) may reduce the risk of recurrence and improve OS in these groups of melanoma patients. The basis for this approach was, first, evidence that melanoma frequently induces an immune response as evidenced by signs of regression of primary melanoma11 associated with lymphocytic infiltration into the tumor12,13 and many in vitro studies showing antibody and T-cell responses to melanoma.14,15 Second, prior studies in animal models had shown that viral infection of tumors could induce long-lasting immunity to the tumor.16,17 Furthermore, studies in humans with lysates induced by Newcastle disease virus18 and vaccinia virus in melanoma19 and influenza virus in gynecologic malignancies20 supported a possible therapeutic role for this form of therapy. On the basis of these reports, we initiated a series of phase II studies in patients with AJCC stage IIB and III melanoma to determine whether immunization with VMCL over a 2-year period may have therapeutic efficacy. The first of these trials indicated a highly significant difference in survival for 80 patients treated with VMCL compared with the survival of 151 historical and 56 concurrent nonrandomized controls.21 The second phase II study examined whether pretreatment of patients with cyclophosphamide improved results any further. This was prompted by previous reports that pretreatment with cyclophosphamide increased cell-mediated immunity to an autologous melanoma vaccine.22 Again, the survival of 102 patients treated with VMCL plus cyclophosphamide was significantly above that of the historical controls but was no better than the group of patients treated with VMCL alone.23 The vaccine appeared highly immunogenic in terms of antibody production in the patients24,25 and electron microscopy confirmed the particulate nature of the vaccine24 and the presence of viral material in the membrane fragments used. In view of these results from the phase II studies, a randomized, controlled trial was initiated in 1988 within Australia to test the efficacy of the vaccine against a control group treated only by surgery. An interim analysis of this trial26 after accrual of 569 patients in 1996 indicated a difference in favor of the VMCL-treated group that was not significant. This article describes the updated results of the trial that was closed to accrual in April 1998 with a total of 700 patients. The median follow-up at this analysis was 8 years.
Patient Selection Between 1988 and 1998, randomization onto the trial was offered to Caucasian patients aged between 16 and 72 years with histologically proven AJCC (1988) stage IIB primary (T4 or Clark’s level V) or stage III regional nodal involvement from cutaneous melanoma without evidence of systemic metastatic disease, as assessed by chest x-ray, liver function, and routine hematologic examination. ECOG performance status was 0 or 1. Patients who had extracapsular extension of LN metastases were excluded. Patients were required to have definitive surgery with pathologic confirmation of adequate surgical margins (ie, 1- to 2-cm minimum except in cosmetically compromised areas) and full clearance of regional LNs in those with involved nodes. They were required to be randomized within 42 days of definitive surgery, and treatment was commenced by 8 weeks from surgery. The definition of nodal involvement required the identification of tumor cells by routine hematoxylin and eosin stains. Patients with micrometastases in LNs identified by the sentinel lymph node (SLN) technique, who were participants in the Multicenter Selective Lymphadenopathy Trial, were not entered onto this study. Patients with T4 (Breslow depth greater than 4 mm or Clark’s level V) primary lesions and no clinical evidence of LN metastasis (T4N0) were not required to undergo lymphadenectomy, but elective LN dissection was a routine procedure in the Sydney Melanoma Unit until 1992, and 106 of the 161 patients in this stratum had resection of their LNs (ie, in at least 66% of the patients with T4 disease, the LNs were shown pathologically not to be involved). Centers involved in the trial were the Sydney Melanoma Unit, Newcastle Melanoma Unit, Princess Alexandra Hospital, and Royal Adelaide Hospital, and patients were also enrolled from Darwin, Melbourne, and Perth.
Vaccine Preparation The vaccinia virus was the strain referred to as strain O, which was derived in 1921 from two strains imported from the Lister Institute in 1912 and a strain from Japan imported in 1913. After 24 hours of incubation, the lysed cells were further homogenized with a sterile Dounce (type B pestle) homogenizer and centrifuged at 400 x g for 7 minutes. The supernatant (1) was kept and the pellet frozen and thawed in 1 to 3 mL of distilled sterile water. The latter was then made up to 20 mL, centrifuged at 400 x g for 7 minutes and the supernatant (2) added to supernatant (1). The pooled supernatant was centrifuged at 38,000 x g for 60 minutes and the sediment resuspended in saline to give an equivalent of 5 x 106 MM200 cells/0.5 mL saline. The vaccine was tested for pathogenic viral, bacterial, or fungal contamination and kept at -80°C until use. The protein content (100 to 200 µg/mL) viral titer (105 to 4.5 x 105 pock-forming units) and initial studies on antigenic content are described elsewhere.24
Study Design
Statistical Analysis All data of patients in the trial were collected by the National Health and Medical Research Council Clinical Trails Centre in Sydney. The trial was designed to recruit 400 patients and to have 80% power to detect a 30% difference in overall survival using a two-sided 5% level test. However, on the basis of a lower event rate than expected with better overall survival for the control patients in the trial than originally anticipated, a decision was made after accrual had reached the original goal to increase the accrual to 700 patients in order to be able to detect smaller absolute survival differences between the groups. Three interim analyses were performed. The first interim analysis was performed as planned in the protocol in September 1991 after 53 deaths had occurred among the 287 patients then accrued. The second analysis was unplanned in 1993 after accrual of the initial target of 400 patients (and included 117 deaths among 429 patients). The motivation for this analysis was consideration then being given to converting the trial to a 2 x 2 factorial design to examine the value of IFN -2a, a design that was not in fact pursued. Because it was evident that the survival of the control group was better than expected (by comparison with a historical control group), a decision was made to increase the accrual to 700 patients to allow more power to detect differences between the groups. A third interim analysis was performed in 1996 after accrual of 569 patients, in preparation for presentation of interim results at an international meeting.26 The defined primary efficacy comparison between the treatment and control arms was a stratified univariate analysis. In view of the initially unplanned alteration of trial size and additional interim analyses, the impact of expenditure of the type I error would be difficult to quantitate. Because the trial results did not achieve conventional statistical significance, no such allowance was made in the present analysis, which is simply reported as not showing a significant difference in outcome by treatment. Supplementary exploratory analyses included nonstratified two-sided log-rank test statistics based both on eligible patients and on the intent-to-treat (ITT) population. The probability of RFS and OS was estimated by the Kaplan-Meier method.31 The hazard ratio (HR) for relapse or death was calculated by Cox proportional hazards regression. The comparison between treatment arms on the basis of HRs was performed as indicated. HR was defined as the ratio of the hazard of the treatment arm relative to that of the control arm. A HR less than 1 indicates that the risk of relapse or death was less on the treatment arm than on the control arm. The analyses were carried out using the SPIDA statistical program (Version 6.04, Macquarie University, New South Wales, Australia).32
Patient Accrual and Characteristics Statistical analysis was performed on data collected up to July 31, 2000. Median follow-up at this time was 8 years. Patients were accrued from the Sydney Melanoma Unit (57%); Newcastle Melanoma Unit (21%), Princess Alexandra Hospital, Brisbane (10%); and Royal Adelaide Hospital (8%); with the remainder (4%) from hospitals in Melbourne, Perth, and Darwin. There were no major differences in patient details or outcomes between the centers. The overall accrual onto each stratum is shown in Fig 2. There were 319 patients (45.6%) with one involved LN and 220 patients (31.4%) with two or more involved LNs. Table 1 indicates that the treatment and control groups were well matched for age, sex, primary tumor thickness, and ulceration of the primary tumor. Median tumor thickness for strata 1 to 5 was 5.15, 3.40, 4.00, 1.38, and 1.5 mm, respectively. Eleven (29%) of 38 patients had clinically palpable nodes in stratum 2, and 12 (46%) of 26 had clinically palpable nodes in stratum 3.
There were 19 deaths unrelated to melanoma, 10 in the VMCL-treated group and nine in the control group. These were included in the survival analyses. Protocol violations included less than six injections of vaccine (n = 6) and treatment with vaccine in the control group (n = 1). These were also included in the analyses in the groups to which they were randomized. Twenty-five patients were considered ineligible on review after accrual was complete. They included three with an incorrect diagnosis, nine with recurrent cutaneous metastases near the site of the previous primary tumor, six with distant metastases at the time of randomization, three with gross extracapsular extension of melanoma from LNs, three with multiple primary tumors before LN metastases, and one with a thin primary melanoma without LN metastases. An additional two patients did not commence randomized treatment. The primary analysis was by ITT including all patients. No substantial difference was noted from a secondary analysis limited to eligible patients (and also excluding the two who did not commence treatment), which is the analysis presented here.
Effect of Treatment With VMCL on RFS and OS
The Kaplan-Meier estimate of OS for each stratification group is shown in Fig 4. Stratum 1 (T4N0) and stratum 4 (one involved delayed LN) were similar in survival and superior to stratum 2, which included patients with one LN removed at the time of removal of the primary tumor. OS in stratum 5 with two or more delayed involved LNs also appeared superior to that in stratum 3, which was similar to stratum 5, but involvement of LNs was detected at the time of surgery. The effect of treatment with VMCL on OS of patients in each stratum is summarized in Table 3. This highlights the good prognosis for patients with T4N0 disease and those in stratum 4 with one involved LN. For most strata, the estimated survival rates slightly favored the VMCL-treated group, but treatment effects on survival did not differ significantly across the strata.
Other variables identified by multivariate stratified Cox regression analysis to affect prognosis were sex, tumor thickness, and presence of tumor ulceration. The median OS of males was 6.8 years and was not reached for females (P < .001). Patients with ulcerated tumors had a median OS of 4.6 years, and median survival was not reached in those with nonulcerated tumors (P = .001). The median OS of patients with tumors smaller than 2.7 mm (the median thickness of tumors in all patients) was not reached and was 7.8 years in those with tumors larger than 2.7 mm (P = .078).
Side Effects
This is the fourth trial of adjuvant immunotherapy in patients at high risk of relapse to be reported over the past few years. Wallack et al5 reported that immunotherapy with a vaccine produced from vaccinia melanoma cell lysates had no effect on OS. Median survivals were 41.3 months for the control group and 50.2 months for the treated groups (P = .79). In the ECOG 1694 trial, high-dose IFN -2a was compared to immunotherapy with a GM-2 ganglioside vaccine (GM-2/KLH in the adjuvant QS-21). At the first interim analysis, a highly significant difference in RFS (P = .0015) and OS (P = .009) was found in favor of the IFN-2b–treated group. The median survivals had not been reached because of the short median follow-up of 1 year.10 The Southwest Oncology Group reported the results of an immunotherapy trial (Southwest Oncology Group 9035) in 689 melanoma patients with intermediate-risk stage IIA (1.5 to 4.00 mm) melanoma with a melanoma cell vaccine referred to as Melacine. On an ITT basis there was a significant effect on RFS (P = .04) but not OS. Most of the treatment effect was in patients with melanoma 1.5 to 3 mm in thickness.33 The present results indicate that immunotherapy with VMCL was associated with a nonsignificant trend to improvement in OS that amounted to a 20% reduction in the risk of dying when assessed by HRs. The confidence limits for the HRs, however, included 1.0, indicating this may have been a chance finding. The lack of any significant effect on RFS makes this a plausible explanation of the results. Nevertheless, the size of the estimated effects on survival (as illustrated by an increase in estimated median survival from 88 months to 151 months or a 10% increase in absolute survival at 5 years) would, if true, be important. Similarly, the treated group had a 14% reduction in the HR for development of recurrences which, if carried through to a similar reduction in the risk of death, would represent worthwhile clinical benefit. When viewed in these terms and given the negligible toxicity of the vaccine, a useful clinical benefit from the vaccine remains a possibility. Even though the present trial included approximately 700 patients and had a median follow-up of 8 years, the number of deaths (n = 294) was still relatively low. It will be of interest to review the results after longer follow-up. Subset analysis did not reveal benefit from treatment in any particular stratum, but did show that detection of LN metastases at the time of surgical removal of the primary tumor defined patients with an adverse prognosis, presumably because they had a more aggressive form of melanoma. These findings differ from those in an earlier trial30 that indicated that the latter patient group survived for longer periods than patients with LN metastases detected at some time after removal of the primary tumor. The therapeutic effect of the vaccine was much less than was expected on the basis of the phase II studies, where the median survival of the historical and nonrandomized control group was 32 months and the median survival of the treated group had not been reached with a minimum follow-up period of 5 years.21 As noted by previous authors,34 it is common for the control group in phase III studies to have much better survivals than the control groups in phase II studies, and highlights the need for randomized studies in assessment of new therapeutic agents.
Although cross-study comparisons are hazardous, the improved survival of the control patients on this study appears remarkable, given that at the commencement of this study the published 5-year survival rates for patients with AJCC stage IIB and III disease ranged from 23 to 42 months and median survivals ranged from 32 to 36 months.35-38 In more recent studies, listed in Table 4, the median survivals of patients in the ECOG 16844 IFN
Another well-known cause of increased survival in control groups is so-called stage migration caused by better diagnostic methods that result in the detection of distant metastases in patients who would otherwise be included in the trial as stage IIB or III melanoma. This is difficult to exclude, although in the present study the evaluation of patients had not changed significantly over the period of the study. Improved quality of imaging may be subtle as technology evolves. Improved surgical techniques may play some role but would not appear to be a major factor in the present study, as each participating center had a stable surgical team that did not change significantly over the course of the study. The present trial was one of the first randomized trials of a melanoma vaccine to be initiated and was based on the results of phase II studies commenced in 1984. The underlying vaccine strategy was based on information accumulated in the 1970s that T- and B-cell responses could be enhanced by helper T-cell responses to strong antigens.39 Vaccinia virus was used as the helper antigen in the present study, having been shown to be effective in induction of antibodies to autologous melanoma.24,25 Over the course of the trial, however, many of the specific antigens recognized by T cells have been described.40,41 The melanoma cell line used in the present study contains the differentiation antigens tyrosinase, gp100, and MART-1, and the tumor-specific antigens MAGE-A3 and MAGE-A10, and BAGE, GAGE, and XAGE. It does not contain MAGE-1, CT7, NA17-1 or NY-ESO-1 (unpublished data). The availability of well-defined melanoma antigens has allowed the development of a number of new vaccine strategies that can be assessed by measurement of T-cell responses. These developments have largely overtaken studies on vaccines prepared from whole melanoma cells and this, together with the results of the present study, suggests that further evaluation of vaccinia viral lysates in treatment of melanoma is not warranted.
APPENDIX The appendix listing data managers at participating centers is available online at www.jco.org.
Supported by a grant from the Cancer Council, New South Wales, by grants in aid by the Sydney Melanoma Foundation, University of Sydney. The data management was supplied without charge by the National Health and Medical Research Council Clinical Trials Centre. We thank Val Gebski, PhD, and Martin Stockler, MD. Elaine Beller, PhD, Lisa Tyndall, Marianne Schreuder, Adam Ray, and Davina Gherse also provided much helpful assistance.
1. Kirkwood JM: Adjuvant IFN 2 therapy of melanoma. Lancet 351: 1901-1903, 1998[CrossRef][Medline]2. Sondak VK, Wolfe JA: Adjuvant therapy for melanoma. Curr Opin Oncol 9: 189-204, 1997[Medline] 3. Dickler MN, Coit DG, Meyers ML: Adjuvant therapy of malignant melanoma. Surg Oncol Clin North Am 6: 793-812, 1997[Medline] 4. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon-alpha-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14: 7-17, 1996[Abstract] 5. Wallack MK, Sivanandham M, Balch CM, et al: Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: The final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial. J Am Coll Surg 187: 69-77, 1998[CrossRef][Medline]
6. Kirkwood JM, Ibrahim JG, Sondak VK, et al: High- and low-dose interferon alpha-2b in high-risk melanoma: First analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18: 2444-2458, 2000 7. Veronesi U, Adamus J, Aubert C, et al: A randomized trial of adjuvant chemotherapy and immunotherapy in cutaneous melanoma. N Engl J Med 307: 913-916, 1982[Abstract]
8. Cascinelli N: Evaluation of efficacy of adjuvant rIFN 9. Cascinelli N, Bufalino R, Morabito A, et al: Results of adjuvant interferon study in WHO melanoma programme. Lancet 343: 913-914, 1994[CrossRef][Medline]
10. Kirkwood JM, Ibrahim JG, Sosman JA, et al: High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: Results of intergroup trial E1694/S9512/C509801. J Clin Oncol 19: 2370-2380, 2001 11. McGovern VJ: Spontaneous regression of malignant melanoma, in Blaustein A (ed): Melanoma: Histological Diagnosis and Prognosis. New York, Raven Press, 1982, pp 138-147 12. Hersey P, Murray E, Grace J, et al: Current research on immunopathology of melanoma: Analysis of lymphocyte populations in relation to antigen expression and histological features of melanoma. Pathology 17: 385-391, 1985[Medline] 13. Brocker EB, Zwadlo G, Holzmann B, et al: Inflammatory cell infiltrates in human melanoma at different stages of tumor progression. Int J Cancer 41: 562-567, 1988[Medline] 14. Hersey P, Edwards A, Murray E, et al: Prognostic significance of leukocyte-dependent antibody activity in melanoma patients. J Natl Cancer Inst 71: 45-53, 1983[Medline] 15. Platsoucas CD: Human autologous tumor-specific T cells in malignant melanoma. Cancer Metastasis Rev 10: 151-176, 1991[CrossRef][Medline] 16. Austin FC, Boone CW: Virus augmentation of the antigenicity of tumor cell extracts. Adv Cancer Res 30: 301-345, 1979[Medline] 17. Heicappell R, Schirrmacher V, Von Hoegen P, et al: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells: I. Parameters for optimal therapeutic effects. Int J Cancer 37: 569-577, 1986[Medline] 18. Cassel WA, Murray DR, Phillips HS: A phase II study on the postsurgical management of stage II malignant melanoma with a Newcastle disease virus oncolysate. Cancer 52: 856-860, 1983[CrossRef][Medline] 19. Wallack MK, McNally KR, Leftheriotis E, et al: A Southeastern Cancer Study Group phase I/II trial with vaccinia melanoma oncolysates. Cancer 57: 649-655, 1986[CrossRef][Medline] 20. Freedman RS, Bowen JM, Herson J, et al: Virus modified homologous tumor cell extract in the treatment of vulvar carcinoma. Cancer Immunol Immunother 8: 33-39, 1980[CrossRef] 21. Hersey P, Edwards A, Coates A, et al: Evidence that treatment with vaccinia melanoma cell lysates (VMCL) may improve survival of patients with stage II melanoma. Cancer Immunol Immunother 25: 257-265, 1987[Medline]
22. Berd D, Maquire HC, Mastrangelo MJ: Induction of cell-mediated immunity to autologous melanoma cells and regression of metastases after treatment with a melanoma cell vaccine preceded by cyclophosphamide. Cancer Res 46: 2572-2577, 1986 23. Hersey P: Active immunotherapy with viral lysates of micrometastases following surgical removal of high risk melanoma. World J Surg 16: 251-260, 1992[CrossRef][Medline] 24. Hersey P, Edwards A, D’Alessandro G, et al: Phase II study of vaccinia melanoma cell lysates (VMCL) as adjuvant to surgical treatment of stage II melanoma: II. Effects on cell mediated cytotoxicity and leucocyte dependent antibody activity—Immunological effects of VMCL in melanoma patients. Cancer Immunol Immunother 22: 221-231, 1986[Medline] 25. Hersey P, Werkman H, Edwards AE: Western blot analysis of serological responses following immunization with vaccinia viral lysates of melanoma cells. Int J Cancer 46: 612-617, 1990[Medline] 26. Hersey P, Coates A, McCarthy WH: Interim analysis of a randomized trial of immunotherapy with vaccinia melanoma cell lysates (VMCL) following surgical removal of high risk melanoma. Proc Am Assoc Cancer Res 37: 489, 1996 (abstr) 27. Pope JH, Morrison L, Moss DJ, et al: Human malignant melanoma cell lines. Pathology 11: 191-195, 1979[Medline] 28. Muir PD, Gunz FW: A cytogenetic study of eight human melanoma cell lines. Pathology 11: 597-606, 1979[Medline] 29. Hersey P, Edwards AE, Murray E, et al: Sequential studies of melanoma leukocyte-dependent antibody activity in melanoma patients. Eur J Cancer 14: 629-637, 1978 30. Cascinelli N, Morabito A, Santinami M, et al: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: A randomised trial. Lancet 351: 793-796, 1998[CrossRef][Medline] 31. Ewell M, Ibrahim JG: The large sample distribution of the weighted log rank statistic under general local alternatives. Lifetime Data Anal 3: 5-12, 1997[CrossRef][Medline] 32. Gebski V, Leung O, McNeil DR, et al: SPIDA User’s Manual. Sydney, Statistical Computing Laboratory, 1992
33. 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 Clin Oncol 20: 2067-2075, 2002 34. Sacks H, Chalmers TC, Smith H: Randomized versus historical controls for clinical trials. Am J Med 72: 233-240, 1982[CrossRef][Medline] 35. Balch CM, Soong SJ, Murad TM, Ingalls AL, Maddox WA: A multifactorial analysis of melanoma: III. Prognostic factors in melanoma patients with lymph node metastases (stage II). Ann Surg 193: 377-388, 1981[Medline] 36. Balch CM, Soong SJ, Shaw HM, Milton GW: An analysis of prognostic factors in 4000 patients with cutaneous melanoma, in Cutaneous Melanoma. Philadelphia PA, Lippincott, 1985 p 338 37. Cascinelli N, Vaglini M, Nava M, et al: Prognosis of skin melanoma with regional node metastases. J Surg Oncol 25: 240-247, 1984[Medline] 38. Veronesi U, Adamua J, Albert C, et al: WHO study group trial no 6: A randomized trial of adjuvant chemotherapy and immunotherapy in cutaneous melanoma. N Engl J Med 307: 913-916, 1982[Abstract] 39. Mitchison NA: Immunologic approach to cancer. Transplant Proc 2: 92-103, 1970[Medline] 40. Street NE, Mosmann TR: Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J 5: 171-177, 1991[Abstract] 41. Renkvist N, Castelli C, Robbins PF, et al: A listing of human tumor antigens recognized by T cells. Cancer Immunol Immunother 50: 3-15, 2001[CrossRef][Medline] Submitted December 19, 2001; accepted July 2, 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
