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

Marc K. Wallack, Muthukumaran Sivanandham, Charles M. Balch, Marshall M. Urist, Kirby I. Bland, Douglas Murray, William A. Robinson, Lawrence Flaherty, Jon M. Richards, Alfred A. Bartolucci, Les Rosen

Research output: Contribution to journalArticle

Abstract

Background: A phase III, randomized, double-blind, multicenter trial of active specific immunotherapy (ASI) using vaccinia melanoma oncolysate (VMO) was performed in patients with stage III (American Joint Commission on Cancer) melanoma to determine the efficacy of VMO to increase the disease- bee interval (DFI) or overall survival (OS) in these patients. Two interim analyses of data from this trial were performed in May 1994 and June 1995. Although the results from these analyses showed no statistically significant improvement in DFI or OS in all patients using VMO, two subsets - men aged 44-57 years with one to five positive nodes and all patients with clinical stage I and pathologic stage II disease - showed an overall survival advantage with VMO therapy. A final analysis of data from this trial was performed in May 1996 and is reported here. The design of future melanoma vaccine trials is discussed based on information learned from this first randomized, multicenter trial of ASI therapy. Study Design: A polyvalent VMO was prepared using melanoma cells derived from four melanoma cell lines and vaccinia vaccine virus (V). Patients were accrued from 11 United States institutions and were randomized by the Statistical Center at the University of Alabama, Birmingham. Two hundred fifty patients were randomized to treatment with either VMO (1 U containing 2 mg of total protein derived from 5 X 106 melanoma cells and 105.6 50% tissue culture infectious dose of vaccinia virus) or control V (1 U containing 105.4 50% tissue culture infectious dose of vaccinia virus) once a week for 13 weeks and then once every 2 weeks for a total of 12 months, or until recurrence. Patient data were collected by the Statistical Center and analyzed as of May 1996 for DFI and OS using Wilcoxon test and log-rank analysis. Results: Two hundred seventeen patients were found to be eligible according to the inclusion criteria. Data from these patients were 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 patients 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, compared with 65.4%, 55.6%, and 48.2% of patients treated with V. In a retrospective subset analysis, male patients aged 44-57 years (n = 20) with one to five positive nodes showed 18.9%, 26.82%, and 21.3% improvement in survival at 2-, 3-, and 5-year intervals, respectively, after treatment with VMO when compared with V (n = 18) (p = 0.046). Conclusions: This study was a randomized, multicenter, placebo-controlled evaluation of an active specific immunotherapeutic agent to increase the DFI or OS of patients with stage III melanoma in a surgical adjuvant setting. In this trial, ASI with VMO when compared with V showed no difference 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 VMO. This result suggests that one must include a detailed subset analysis in the design of future trials of ASI for patients with American Joint Commission on Cancer stage III melanoma. An appropriate control arm also must be included in ASI trials.

Original languageEnglish (US)
Pages (from-to)69-79
Number of pages11
JournalJournal of the American College of Surgeons
Volume187
Issue number1
DOIs
StatePublished - 1998
Externally publishedYes

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Active Immunotherapy
Vaccinia
Melanoma
Survival
Vaccinia virus
Multicenter Studies
Vaccines
Joints

ASJC Scopus subject areas

  • Surgery

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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. / Wallack, Marc K.; Sivanandham, Muthukumaran; Balch, Charles M.; Urist, Marshall M.; Bland, Kirby I.; Murray, Douglas; Robinson, William A.; Flaherty, Lawrence; Richards, Jon M.; Bartolucci, Alfred A.; Rosen, Les.

In: Journal of the American College of Surgeons, Vol. 187, No. 1, 1998, p. 69-79.

Research output: Contribution to journalArticle

Wallack, Marc K. ; Sivanandham, Muthukumaran ; Balch, Charles M. ; Urist, Marshall M. ; Bland, Kirby I. ; Murray, Douglas ; Robinson, William A. ; Flaherty, Lawrence ; Richards, Jon M. ; Bartolucci, Alfred A. ; Rosen, Les. / 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. In: Journal of the American College of Surgeons. 1998 ; Vol. 187, No. 1. pp. 69-79.
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title = "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",
abstract = "Background: A phase III, randomized, double-blind, multicenter trial of active specific immunotherapy (ASI) using vaccinia melanoma oncolysate (VMO) was performed in patients with stage III (American Joint Commission on Cancer) melanoma to determine the efficacy of VMO to increase the disease- bee interval (DFI) or overall survival (OS) in these patients. Two interim analyses of data from this trial were performed in May 1994 and June 1995. Although the results from these analyses showed no statistically significant improvement in DFI or OS in all patients using VMO, two subsets - men aged 44-57 years with one to five positive nodes and all patients with clinical stage I and pathologic stage II disease - showed an overall survival advantage with VMO therapy. A final analysis of data from this trial was performed in May 1996 and is reported here. The design of future melanoma vaccine trials is discussed based on information learned from this first randomized, multicenter trial of ASI therapy. Study Design: A polyvalent VMO was prepared using melanoma cells derived from four melanoma cell lines and vaccinia vaccine virus (V). Patients were accrued from 11 United States institutions and were randomized by the Statistical Center at the University of Alabama, Birmingham. Two hundred fifty patients were randomized to treatment with either VMO (1 U containing 2 mg of total protein derived from 5 X 106 melanoma cells and 105.6 50{\%} tissue culture infectious dose of vaccinia virus) or control V (1 U containing 105.4 50{\%} tissue culture infectious dose of vaccinia virus) once a week for 13 weeks and then once every 2 weeks for a total of 12 months, or until recurrence. Patient data were collected by the Statistical Center and analyzed as of May 1996 for DFI and OS using Wilcoxon test and log-rank analysis. Results: Two hundred seventeen patients were found to be eligible according to the inclusion criteria. Data from these patients were 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 patients 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, compared with 65.4{\%}, 55.6{\%}, and 48.2{\%} of patients treated with V. In a retrospective subset analysis, male patients aged 44-57 years (n = 20) with one to five positive nodes showed 18.9{\%}, 26.82{\%}, and 21.3{\%} improvement in survival at 2-, 3-, and 5-year intervals, respectively, after treatment with VMO when compared with V (n = 18) (p = 0.046). Conclusions: This study was a randomized, multicenter, placebo-controlled evaluation of an active specific immunotherapeutic agent to increase the DFI or OS of patients with stage III melanoma in a surgical adjuvant setting. In this trial, ASI with VMO when compared with V showed no difference 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 VMO. This result suggests that one must include a detailed subset analysis in the design of future trials of ASI for patients with American Joint Commission on Cancer stage III melanoma. An appropriate control arm also must be included in ASI trials.",
author = "Wallack, {Marc K.} and Muthukumaran Sivanandham and Balch, {Charles M.} and Urist, {Marshall M.} and Bland, {Kirby I.} and Douglas Murray and Robinson, {William A.} and Lawrence Flaherty and Richards, {Jon M.} and Bartolucci, {Alfred A.} and Les Rosen",
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TY - JOUR

T1 - Surgical adjuvant active specific immunotherapy for patients with stage III melanoma

T2 - The final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial

AU - Wallack, Marc K.

AU - Sivanandham, Muthukumaran

AU - Balch, Charles M.

AU - Urist, Marshall M.

AU - Bland, Kirby I.

AU - Murray, Douglas

AU - Robinson, William A.

AU - Flaherty, Lawrence

AU - Richards, Jon M.

AU - Bartolucci, Alfred A.

AU - Rosen, Les

PY - 1998

Y1 - 1998

N2 - Background: A phase III, randomized, double-blind, multicenter trial of active specific immunotherapy (ASI) using vaccinia melanoma oncolysate (VMO) was performed in patients with stage III (American Joint Commission on Cancer) melanoma to determine the efficacy of VMO to increase the disease- bee interval (DFI) or overall survival (OS) in these patients. Two interim analyses of data from this trial were performed in May 1994 and June 1995. Although the results from these analyses showed no statistically significant improvement in DFI or OS in all patients using VMO, two subsets - men aged 44-57 years with one to five positive nodes and all patients with clinical stage I and pathologic stage II disease - showed an overall survival advantage with VMO therapy. A final analysis of data from this trial was performed in May 1996 and is reported here. The design of future melanoma vaccine trials is discussed based on information learned from this first randomized, multicenter trial of ASI therapy. Study Design: A polyvalent VMO was prepared using melanoma cells derived from four melanoma cell lines and vaccinia vaccine virus (V). Patients were accrued from 11 United States institutions and were randomized by the Statistical Center at the University of Alabama, Birmingham. Two hundred fifty patients were randomized to treatment with either VMO (1 U containing 2 mg of total protein derived from 5 X 106 melanoma cells and 105.6 50% tissue culture infectious dose of vaccinia virus) or control V (1 U containing 105.4 50% tissue culture infectious dose of vaccinia virus) once a week for 13 weeks and then once every 2 weeks for a total of 12 months, or until recurrence. Patient data were collected by the Statistical Center and analyzed as of May 1996 for DFI and OS using Wilcoxon test and log-rank analysis. Results: Two hundred seventeen patients were found to be eligible according to the inclusion criteria. Data from these patients were 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 patients 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, compared with 65.4%, 55.6%, and 48.2% of patients treated with V. In a retrospective subset analysis, male patients aged 44-57 years (n = 20) with one to five positive nodes showed 18.9%, 26.82%, and 21.3% improvement in survival at 2-, 3-, and 5-year intervals, respectively, after treatment with VMO when compared with V (n = 18) (p = 0.046). Conclusions: This study was a randomized, multicenter, placebo-controlled evaluation of an active specific immunotherapeutic agent to increase the DFI or OS of patients with stage III melanoma in a surgical adjuvant setting. In this trial, ASI with VMO when compared with V showed no difference 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 VMO. This result suggests that one must include a detailed subset analysis in the design of future trials of ASI for patients with American Joint Commission on Cancer stage III melanoma. An appropriate control arm also must be included in ASI trials.

AB - Background: A phase III, randomized, double-blind, multicenter trial of active specific immunotherapy (ASI) using vaccinia melanoma oncolysate (VMO) was performed in patients with stage III (American Joint Commission on Cancer) melanoma to determine the efficacy of VMO to increase the disease- bee interval (DFI) or overall survival (OS) in these patients. Two interim analyses of data from this trial were performed in May 1994 and June 1995. Although the results from these analyses showed no statistically significant improvement in DFI or OS in all patients using VMO, two subsets - men aged 44-57 years with one to five positive nodes and all patients with clinical stage I and pathologic stage II disease - showed an overall survival advantage with VMO therapy. A final analysis of data from this trial was performed in May 1996 and is reported here. The design of future melanoma vaccine trials is discussed based on information learned from this first randomized, multicenter trial of ASI therapy. Study Design: A polyvalent VMO was prepared using melanoma cells derived from four melanoma cell lines and vaccinia vaccine virus (V). Patients were accrued from 11 United States institutions and were randomized by the Statistical Center at the University of Alabama, Birmingham. Two hundred fifty patients were randomized to treatment with either VMO (1 U containing 2 mg of total protein derived from 5 X 106 melanoma cells and 105.6 50% tissue culture infectious dose of vaccinia virus) or control V (1 U containing 105.4 50% tissue culture infectious dose of vaccinia virus) once a week for 13 weeks and then once every 2 weeks for a total of 12 months, or until recurrence. Patient data were collected by the Statistical Center and analyzed as of May 1996 for DFI and OS using Wilcoxon test and log-rank analysis. Results: Two hundred seventeen patients were found to be eligible according to the inclusion criteria. Data from these patients were 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 patients 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, compared with 65.4%, 55.6%, and 48.2% of patients treated with V. In a retrospective subset analysis, male patients aged 44-57 years (n = 20) with one to five positive nodes showed 18.9%, 26.82%, and 21.3% improvement in survival at 2-, 3-, and 5-year intervals, respectively, after treatment with VMO when compared with V (n = 18) (p = 0.046). Conclusions: This study was a randomized, multicenter, placebo-controlled evaluation of an active specific immunotherapeutic agent to increase the DFI or OS of patients with stage III melanoma in a surgical adjuvant setting. In this trial, ASI with VMO when compared with V showed no difference 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 VMO. This result suggests that one must include a detailed subset analysis in the design of future trials of ASI for patients with American Joint Commission on Cancer stage III melanoma. An appropriate control arm also must be included in ASI trials.

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