Melanoma Program Trial
The WHO Melanoma Program Trial 16 has evaluated the efficacy of a lower, less-toxic dosage of IFN- alpha2a, given 3 MU/d subcutaneously three times weekly for 3 years versus observation. Of 444 patients who entered this trial, a majority exhibited extracapsular extranodal involvement, a pathologic variable that made patients ineligible for the trials of the US Cooperative groups previously noted. The analysis of WHO Trial 16 has been reported preliminarily at 22 months of follow-up, and in a subset analysis an interaction between age and gender and treatment was found. This interim analysis of subsets, defined by the presence or absence of extranodal extension, has suggested an influence of this therapy upon intranodal disease, and lack of any trend to benefit among patients with extracapsular extension. Subsequent reports of interim analyses of this trial at intervals up to 39 months median follow-up have suggested the absence of a significant impact upon either relapse-free or overall survival. Canadian cialis
In summary, the analyses of E1684, NCCTG 83-7052, and WHO 16, taken together, argue that IFN- alpha2b at higher dosages, delivered intravenously, may be necessary for the benefit observed in E1684. Equivalent dosages of IFN- alpha2a administered by the IM route for shorter periods have been less effective, and lower dosages of IFN- alpha2a administered by the subcutaneous route for longer periods have been ineffective to date. The approval of IFN- alpha2b for adjuvant therapy within 2 months of surgery of high-risk node-positive and deep primary melanoma is the first adjuvant therapy approved for melanoma, and the first new agent approved for therapy of this disease in any stage or setting, since dacarbazine.
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The evaluation of newer and potentially more effective biologic agents in the adjuvant setting has been pursued in multiple trials. SWOG 86-42 is a trial of IFN- alpha administered at dosages projected to be the optimal immunomodulatory dosages (0.2 mg/d sc qod for 1 year). IFN- alpha is among the most potent immunomodulators yet tested, and one for which initial hopes for adjuvant and metastatic disease applications were elevated even beyond IFN- alpha2. As previously noted, the therapeutic activity of IFN gamma in the advanced disease setting has been negligible. The recently published SWOG 86-42 trial demonstrates the lack of therapeutic benefit for this agent at the dosage tested, in either intermediate-risk stage II or stage III resected melanoma. Of concern is that the initial report of this trial suggested a potentially adverse impact of treatment that has not yet been confirmed. In any case, the unequivocal failure of IFN- gamma to improve relapse-free or overall survival in the adjuvant setting argues that the effects of the dose, route, and schedule of IFN- gamma and the monocyte activation and NK activation associated with IFN- alpha administered as in this trial are not sufficient to alter the outcome of this disease. The pleiotropic effects of IFN- alpha2b, which account for its therapeutic benefit in melanoma, have yet to be proven. In vivo activities that may be important range from a direct antiproliferative and cytotoxic action to immunopotentiation of T- or B-cell host responses, dendritic cell antigen presentation, anti-angiogenesis factor, and tumor-restricted antigen expression. These are being evaluated prospectively in the context of the recently completed intergroup trial (ECOG 1690/SWOG 91-11, CALGB 91-90).