Abstract
The effect of interferon alpha (IFNα2) given alone or in combination has been widely explored in clinical trials over the past 30 years. Despite the number of adjuvant studies that have been conducted, controversy remains in the oncology community regarding the role of this treatment.Recently an individual patient data (IPD) meta-analysis at longer follow-up was reported, showing a statistically significant benefit for IFN in relation to relapse-free survival, without any difference according to dosage (p = 0.2) or duration of IFN therapy (p = 0.5). Most interestingly, there was a statistically significant benefit of IFN upon overall survival (OS) that translates into an absolute benefit of at least 3% (CI 1–5%) at 5 years. Thus, both the individual trials and this meta-analysis provide evidence that adjuvant IFNα2 significantly reduces the risk of relapse and mortality of high-risk melanoma, albeit with a relatively small absolute improvement in survival in the overall population.We have surveyed the international literature from the meta-analysis (2006) to summarize and assimilate current biological evidence that indicates a potent impact of this molecule upon the tumor microenvironment and STAT signaling, as well as the immunological polarization of the tumor tissue in vivo. In conclusion, we argue that there is a compelling rationale for new research upon IFN, especially in the adjuvant setting where the most pronounced effects of this agent have been discovered. These efforts have already shed light upon the immunological and proinflammatory predictors of therapeutic benefit from this agent – that may allow practitioners to determine which patients may benefit from IFN therapy, and approaches that may enable us to overcome resistance or enhance the efficacy of IFN. Future efforts may well build toward patient-oriented therapy based upon the knowledge of the unique molecular features of this disease and the immune system of each melanoma patient.
Highlights
Future efforts may well build toward patientoriented therapy based upon the knowledge of the unique molecular features of this disease and the immune system of each melanoma patient. It has been more than 10 years since the pivotal trial E1684 first showed improvement in overall survival (OS) for melanoma patients treated with adjuvant high-dose interferon (HDI) [1], but controversies continue regarding the use of interferon (IFN) as adjuvant therapy in melanoma patients
Since LDI has been relatively welltolerated in comparison to HDI, prolonged LDI for more than 2 years was suggested as a reasonable option for melanoma patients, considering its cost-effectiveness
After the most recent meta-analysis and the reports of the latest results of ongoing clinical trials testing new variations on adjuvant treatment for high-risk patients, what more do we know and what can we conclude? Recent announcements regarding the negative results for the EORTC 18961 trial that compared GMK vaccination with observation [OS worse with GMK (p < 0.02)], indicate that there may be less certainty in regard to the results of E1694 than previously
Summary
It has been more than 10 years since the pivotal trial E1684 first showed improvement in overall survival (OS) for melanoma patients treated with adjuvant high-dose interferon (HDI) [1], but controversies continue regarding the use of interferon (IFN) as adjuvant therapy in melanoma patients. For the first group, whose number of adherents has grown in recent years, HDI represents the standard therapy based on the initial ECOG and subsequent US Intergroup studies that confirmed RFS impact and in two trials, OS impact1, [25-27]. After more than 20 years of research and clinical experience with IFN, it is time to make some definitive conclusions in order to avoid eternal discussions regarding the issues of sample size, dosage, route and duration of therapy, in order to move forward in our field For this purpose we surveyed the international literature starting with the meta-analysis published in 2006 [28] and dealing with the adjuvant treatment of high-risk melanoma, to incorporate current biological evidence regarding this molecule and its impact in vivo, so as to arrive at conclu-
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