High- and Low-Dose Interferon Alfa-2b in High-Risk Melanoma: First Analysis of Intergroup Trial E1690/S9111/C9190

Kirkwood, John M.; Ibrahim, Joseph G.; Sondak, Vernon K.; Richards, Jon M.; Flaherty, Lawrence E.; Ernstoff, Marc S.; Smith, Thomas J.; Rao, Uma; Steele, Mary; Blum, Ronald H.

doi:10.1200/jco.2000.18.12.2444

Cited by 836 publications

(475 citation statements)

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“…The authors reported a clear disease-free survival advantage for the patients given interferon, but there were insufficient deaths observed during the relatively short follow-up period to evaluate any effect on survival. The next ECOG study, E1690, compared the high-dose Kirkwood regimen with 2 years of 3 MU interferon given subcutaneously 3 times a week, and an observation only group (Kirkwood et al, 2000a). In contrast to the earlier E1684 study, E1690 has not demonstrated a survival advantage for either treatment arm as compared to the control observation arm, but has reported a statistically significant disease-free survival advantage for the high-dose regimen as compared with the observation arm (hazard ratio 1.28, P = 0.05).…”

Section: Discussionmentioning

confidence: 99%

Adjuvant interferon alpha 2b in high risk melanoma – the Scottish study

et al. 2001

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In 1989, the Scottish melanoma group initiated a randomized trial, comparing observation alone with 6 months' therapy with low dose interferon α (given subcutaneously 3 MU day –1 , thrice weekly), for patients with primary melanomas of at least 3 mm Breslow thickness, or with evidence of regional node involvement. The trial was closed in 1993 with only 95 eligible patients randomized. There were no toxic deaths, and no patient failed to complete the treatment for reasons of toxicity. 6 months' treatment with low-dose interferon-α resulted in a statistically significant improved disease-free survival for up to 24 months after randomization ( P < 0.05). However, at a median follow-up of over 6 years, although there was an apparent improvement in disease-free survival (from 9 to 22 months), and overall survival (from 27 to 39 months), consistent with larger studies powered to detect such differences, these differences were not statistically significant. The data therefore suggest that 6 months of low-dose interferon is active, and confirm the importance of the large randomized studies, such as the UKCCCR AIM-High and EORTC trials, that seek to confirm a possible survival advantage for low or intermediate dose interferon. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Section: Discussionmentioning

confidence: 99%

Adjuvant interferon alpha 2b in high risk melanoma – the Scottish study

et al. 2001

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“…4 The E2690 Intergroup laboratory corollary study included 148 of 642 patients who entered Trial E1690. Immunologic data for at least one of the four time points prior to the end of the study period were obtained for 143 of these patients, who comprised the current study population for phenotypic and functional assays.…”

Section: Methodsmentioning

confidence: 99%

“…2 The Eastern Cooperative Oncology Group (ECOG) and the United States Intergroup, which is comprised of the ECOG, the Southwest Oncology Group, and Cancer and Leukemia Group B (CALGB) along with the M. D. Anderson Cancer Center, have established the benefit of chemotherapy with interferon ␣2b (IFN␣2b) at high doses (HDI) in four prospective clinical trials. [3][4][5][6] Those trials enrolled more than 1900 patients with deep primary melanoma (AJCC Stage IIB), regionally metastatic melanoma (AJCC Stage III), or recurrent melanoma involving regional lymph nodes, and a consistent reduction was demonstrated in the recurrence of melanoma at all sites, with a significant prolongation of survival for the participants in two of those trials. The toxicity of HDI therapy has been an obstacle to its application, and features of the disease or patient characteristics that may predict response to this therapy have been sought to improve its therapeutic index.…”

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confidence: 99%

Immunomodulatory effects of high‐dose and low‐dose interferon α2b in patients with high‐risk resected melanoma

Kirkwood

Richards

Zarour

et al. 2002

Cancer

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BACKGROUNDThe clinical antitumor activity of recombinant interferon α2b (IFNα2b) has been well documented in patients with advanced and high‐risk melanoma; however, its mechanism of action remains conjectural. Trial E2690 evaluated the immunomodulatory effects of IFNα2b in vivo during treatment at high doses (the HDI arm; n = 51 patients) and at low doses (the LDI arm; n = 54 patients) in relation to standard observation (OBS; n = 43 patients).METHODSThis study evaluated peripheral blood lymphocytes (PBLs) for phenotypic markers and cytotoxic functions at 1 month, 3 months, and 12 months in the HDI arm, the LDI arm, and the OBS arm and examined correlations between changes observed in PBLs or in tumors with regard to treatment dosage and disease outcome. Tumor biopsy samples were studied for response to IFNα2b at a range of concentrations in vitro.RESULTSBaseline blood phenotypic and functional assays did not predict disease outcome; however, modulation of these immunologic assays by IFNα2b treatment was observed and was associated with IFNα2b dosage. Tumor cell class II major histocompatibility antigen expression (human leukocyte/lymphocyte antigen DR) and adhesion molecule expression (ICAM‐1) were modulated by exposure to IFNα2b in a dose dependent manner. Blood natural killer (NK) cell function, T‐cell function, and subset distribution were modulated early by patients in the HDI arm and later by patients in the LDI arm. None of the variables tested in these studies predicted recurrence free survival. The numbers of patients studied were smaller than may be needed to detect potentially clinically significant changes.CONCLUSIONSThese data demonstrate changes in immunologic parameters associated with IFNα2b treatment and dosage that may account for some of the differences in the clinical efficacy of this modality. The current results also suggest the need for further study of newer molecular intermediates of IFNα2b and T‐cell response to specific antigens of melanoma. Cancer 2002;95:1101–12. © 2002 American Cancer Society.DOI 10.1002/cncr.10775

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“…The consensus panel identified two immunotherapy agents with potential clinical benefit in the adjuvant therapy of patients with stage III melanoma: interferon-α2b and pegylated-interferon-α2b. 4,[24][25][26][27] Consensus management of microscopic nodal disease The panel recognized that patients with microscopically involved lymph nodes (N1a disease) might represent a different population than those with macroscopic nodal disease (N1b and N2-N3 disease). A majority (52.2%) of the panel recommends a standard 1-year course of interferon-α2b for the adjuvant therapy of microscopic nodal disease.…”

Section: Initial Assessmentmentioning

confidence: 99%

“…26 Subsequent randomized studies confirmed a benefit in relapse-free survival, but results indicating an overall survival benefit were inconsistent. 25,33 Several metaanalyses evaluated the clinical benefits of interferon-α2b and indicate a benefit in relapse-free survival and a trend toward improved overall survival. [29][30][31] The panel generally considered the data to provide level A evidence for a benefit in relapse-free survival with level B support for an improvement in overall survival from treatment with interferon-α2b.…”

Section: Literature Review and Analysismentioning

confidence: 99%

The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma

et al. 2013

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| Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts-including physicians, nurses, and patient advocates-to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.

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High- and Low-Dose Interferon Alfa-2b in High-Risk Melanoma: First Analysis of Intergroup Trial E1690/S9111/C9190

Abstract: The results of the intergroup E1690 trial demonstrate an RFS benefit of IFNalpha2b that is dose-dependent and significant for HDI by Cox multivariable analysis.

Cited by 836 publications

References 12 publications

Adjuvant interferon alpha 2b in high risk melanoma – the Scottish study

Adjuvant interferon alpha 2b in high risk melanoma – the Scottish study

Immunomodulatory effects of high‐dose and low‐dose interferon α2b in patients with high‐risk resected melanoma

The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma

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