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Letter to the Editor |
2b"
University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
Key Words. High-risk melanoma • Adjuvant therapy • High-dose interferon-
2b
Correspondence: John M. Kirkwood, M.D., Department of Medicine, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Research Pavilion, Suite 132, 5117 Centre Avenue, Pittsburgh, Pennsylvania 15213-2584, USA. Telephone: 412–623–7707; Fax: 412–623–7704; e-mail: kirkwoodjm{at}upmc.edu
Received January 4, 2006; accepted for publication March 29, 2006.
We read with concern the article by Hurley and Chapman entitled "Helping Melanoma Patients Decide Whether to Choose Adjuvant High-Dose Interferon-2b" [1]. We believe the article misses key information that is required for both patients and physicians to appropriately decide whether adjuvant high-dose interferon-2b (HDI) therapy is indicated for the treatment of high-risk melanoma. These key data have been published in the Eastern Cooperative Oncology Group and cooperative group studies testing HDI and in a report upon the aggregate information from a pooled analysis updated through last spring.
Since 1984, three national cooperative group studies have evaluated the benefit of HDI as adjuvant therapy for resectable high-risk cutaneous melanoma. The first and third of these studies demonstrated significantly longer survival compared with observation (E1684) and compared with a vaccine (GM2 conjugated to keyhole limpet hemocyanin and administered with QS-21 [GMK]) that was selected as the optimal vaccine candidate at the time (E1694). E1684 showed a median relapse-free survival (RFS) time of 1.72 years in the HDI arm versus 0.98 years in the observation arm (stratified log-rank one-sided p- value [p1] = .0023], and a median overall survival (OS) time of 3.82 versus 2.78 years (p1 = .0237), respectively [2]. At a median follow-up of 12.6 years, the significant clinical benefit of HDI versus observation with respect to RFS was still evident (hazard ration [HR], 1.38; p2 = .02). It bears note that because all patients entering E1684 were required to undergo regional lymphadenectomy, this outcome also represents "distant disease-free survival," which has been adopted as a surrogate for OS by some cooperative groups. With additional follow-up, the longer OS associated with HDI versus observation has diminished somewhat (HR, 1.22; p2 = .18), which may be a result of deaths from competing causes in an aging study population that is now well into the seventh decade of life (median age is now >60 years) [3].
E1694 was closed early based on an interim analysis in April 2000 indicating that GMK was significantly inferior to HDI for both relapse and mortality end points. The results of this trial were reported in 2001 based on a final analysis in June 2000, with a median follow-up interval of 16 months. Among eligible patients in the trial, HDI provided a statistically significant RFS benefit (HR, 1.47; p1 = .0015) and OS benefit (HR, 1.52; p1 = .009) compared with GMK. A similar benefit was observed in the intent-to-treat analysis of RFS (HR, 1.49) and OS (HR, 1.38) [4].
The second trial, E1690, conducted in part before and in part after the approval of HDI, was associated with systematic crossover of patients from the observation-assigned arm to treatment at nodal relapse with HDI. That trial showed differences in terms of RFS but not OS. In the intent-to-treat analysis of RFS, treatment with HDI was associated with a statistically significant benefit compared with observation (HR, 1.28; p1 = .025). Moreover, this benefit was maintained after adjusting for significant prognostic factors, including stage of disease and number of positive lymph nodes (p1 = .015). In contrast, low-dose interferon (LDI) was not associated with a significant RFS benefit compared with observation. Neither the HDI nor LDI regimen had an apparent impact on OS compared with observation in the trial. However, a retrospective analysis of salvage therapy suggested a disproportionate crossover of patients from the observation arm to HDI therapy off protocol at the time of regional recurrence (stage IIB patients in the trial were not required to undergo lymphadenectomy), which may have confounded the survival analysis. Therefore, this result was attributed in part to post protocol therapy with HDI that was administered to most patients who had been assigned to observation and then had resectable regional nodal relapse [5].
The analysis of each of the foregoing studies was formally conducted at the closure of each study [2, 4, 5], and was updated in a pooled analysis of survival and relapse-free outcomes to April 2001 [3]. The pooled analysis and separately conducted meta-analyses of the published outcomes of these and other trials of interferon (IFN) that have been published over the past 20 years have firmly demonstrated the prevention of melanoma relapse by IFN at a range of dosages tested in the U.S. and across the world, and yet these analyses have not yielded compelling evidence of an impact upon survival despite the two separate randomized U.S. Cooperative Group and Intergroup studies (E1684 and E1694) that have individually shown an impact of HDI on OS. This may not be surprising, given that the larger of the two trials included in the pooled analysis (E1690) did not show an OS benefit for HDI versus observation in the primary analysis of that trial. The OS analysis of E1690 was confounded by the unusually prolonged post relapse survival of patients in the observation arm, which is likely also a factor in the OS analysis reported here. This, as noted previously, is potentially attributable to crossover use of IFN in patients originally assigned to observation. Patients treated with HDI in E1694 were not included in the pooled analysis because the comparator in that trial was the GMK vaccine and not placebo, which is the comparator in E1684 and E1690.
Thus, the published literature contains two reports of RFS and OS benefit of HDI that have yet to be equaled by any other therapy available for high-risk melanoma—and patients who are candidates for high-dose IFN stand to lose RFS benefits that are universally agreed upon with IFN therapy, amounting to relapse frequency reductions of 24%–38% and mortality reductions of 22%–32% based on the HRs for patients treated with IFN or observation, or the GMK vaccine. In relation to either observation or this previously promising vaccine, HDI stands as a consistently beneficial intervention—and one that the authors of the article, as well as patients with melanoma, ought to be familiar with.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST |
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REFERENCES |
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2b. The Oncologist 2005;10:739–742.This article has been cited by other articles:
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  K. E. Hurley and P. B. Chapman In reply. Oncologist, May 1, 2006; 11(5): 539 - 540. [Full Text] [PDF]
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