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

Background: A phase III, randomized, double-blind, multicenter trial o f active specific immunotherapy (ASI) using vaccinia melanoma oncolysa te (VMO) was performed in patients with stage III (American Joint Comm ission on Cancer) melanoma to determine the efficacy of VMO to increas e the disease-free interval (DFI) or overall survival (OS) in these pa tients. Two interim analyses of data from this trial were performed in May 1994 and June 1995. Although the results from these analyses show ed no statistically significant improvement in DFI or OS in all patien ts using VMO, two subsets-men aged 44-57 years with one to five positi ve nodes and all patients with clinical stage I and pathologic stage I I disease-showed an overall survival advantage with VMO therapy. A fin al analysis of data from this trial was performed in May 1996 and is r eported here. The design of future melanoma vaccine trials is discusse d based on information learned from this first randomized, multicenter trial of ASI therapy. Study Design: A polyvalent VMO was prepared usi ng melanoma cells derived from four melanoma cell lines and vaccinia v accine virus (V). Patients were accrued from 11 United States institut ions and were randomized by the Statistical Center at the University o f Alabama, Birmingham. Two hundred fifty patients were randomized to t reatment with either VMO (1 U containing 2 mg of total protein derived from 5 x 10(6) melanoma cells and 10(5.6) 50% tissue culture infectio us dose of vaccinia virus) or control VMO (1 U containing 105.4 50% ti ssue culture infectious dose of vaccinia virus) once a week for 1.3 we eks and then once every 2 weeks for a total of 12 months, or until rec urrence. Patient data were collected by the Statistical Center and ana lyzed as of May 1996 for DFI and OS using Wilcoxon test and log-rank a nalysis. Results: Two hundred seventeen patients were found to be elig ible according to the inclusion criteria. Data from these patients wer e analyzed for DFI and OS after a median followup of 46.3 months (50.2 months for VMO and 41.3 months for V). This final analysis showed no statistically significant increase in either DFI (p = 0.61) or OS (p = 0.79) of patients treated with VMO (n = 104) compared with V (n = 113 ). At 2-, 3-, and 5-year intervals, 47.8%, 43.8%, and 41.7% of patient s treated with VMO were disease-free, respectively, compared with 51.2 %, 44.8%, and 40.4% of patients treated with V. At the same intervals, 70.0%, 60.0%, and 48.6% of patients treated with VMO survived, compar ed with 65.4%, 55.6%, and 48.2% of patients treated with V. In a retro spective subset analysis, male patients aged 44-57 years (n = 20) with one to five positive nodes showed 18.9%, 26.82%, and 21.3% improvemen t in survival at 2-, 3-, and 5-year intervals, respectively after trea tment with VMO when compared with V (n = 18) (p = 0.046). Conclusions: This study was a randomized, multicenter, placebo-controlled evaluati on of an active specific immunotherapeutic agent to increase the DFI o r OS of patients with stage III melanoma in a surgical adjuvant settin g. In this trial, ASI with VMO when compared with V showed no differen ce in either DFI or OS. In a retrospective subset analysis, however, a subset of men with one to five positive nodes, between the ages of 44 and 57 years, showed a survival advantage with VR VMO. This result su ggests that one must include a detailed subset analysis in the design of future trials of ASI for patients with American Joint Commission on Gander stage III melanoma. An appropriate control arm also must be in cluded in ASI trials. (J Am Coil Surg 1998;187:69-79. (C) 1998 by the American College of Surgeons).