Interferon ALFA-2B in High-Risk Melanoma
ABSTRACT & COMMENTARY
Synopsis: The efficacy of high-dose interferon alfa-2b (HDI) for one year and low-dose interferon alfa-2b (LDI) for two years vs. observation (OBS) in high-risk (stage IIB and III) melanoma was evaluated in a prospective, randomized clinical trial (intergroup E1690 trial). A significant effect of HDI on relapse-free survival (RFS) was demonstrated. No overall survival (OS) benefit was demonstrated with HDI or LDI compared with observation. An analysis of treatments administered at recurrence was presented.
Source: Kirkwood JM, et al. J Clin Oncol 2000;18:2444-2458.
Patients with resected thick primary melanoma (T4) and patients with resected regional nodal metastases (N1) have a high risk of disease recurrence following surgery.1 The recurrence risk following resection of stage IIB disease is approximately 60%, and approximately 75% of patients will have a recurrence following resection of stage III disease.1 High-dose interferon alfa-2b was shown in ECOG study E1684 to be a beneficial adjuvant treatment for patients with resected high-risk melanoma. The treatment included an induction treatment of interferon alfa-2b at a dose of 20 MIU/m2 IV five days per week for four weeks followed by a maintenance treatment with 10 MIU/m2 SC three times weekly for 48 weeks. The five-year overall survival rate of patients randomized to observation was 37%, and the five-year overall survival rate of patients randomized to receive interferon alfa-2b was 46%. This difference was statistically significant.2 This resulted in FDA approval of high-dose adjuvant interferon for melanoma patients following resection of high-risk (stage IIB and III) melanoma.
The intergroup trial E1690 was performed to confirm results from E1684 as well as concurrently compare HDI and LDI with observation following resection of high-risk melanoma. A total of 642 patients were enrolled in this prospective, randomized three-arm study. The treatments included HDI for one year (20 MIU/m2 IV five days per week for four weeks followed by maintenance with 10 MIU/m2 SC three times weekly for 48 weeks), LDI for two years (3 MIU/d SC 3 times weekly for 2 years), and observation. Known prognostic factors such as Breslow depth and nodal status were well balanced between treatment groups. Approximately 75% of patients had received resection of regional lymph node involvement, and 25% of patients entered the study with T4N0 disease. Regional lymph node evaluation was not required for patients with T4N0 disease.
A significant improvement in RFS was seen for patients receiving HDI vs. OBS. The five-year RFS rate for HDI was 44%, the RFS rate for LDI was 40%, and the RFS rate for OBS was 35%. In contrast, no significant improvement in overall survival was achieved by either HDI or LDI in comparison with OBS.
Comparison of the OBS groups from the E1684 study and the current E1690 study revealed a marked (64%) improvement for overall survival for OBS patients in the E1690 study compared with patients in the E1684 study. Various possibilities, including patient demographics, surgical interventions, and salvage medical therapies were evaluated. Differences in salvage therapy with interferon and/or other agents were considered a plausible explanation for this finding. The median overall survival of patients in the E1690 study was six years, compared with a median OS of 2.8 years for patients on E1684. While analysis of treatment upon relapse was not part of the original treatment plan, it was performed to evaluate the striking median OS following relapse in patients randomized to OBS. This analysis of salvage medical therapies revealed that significantly more of the OBS patients in E1690 received an interferon alfa-containing salvage regimen following relapse than did patients initially randomized to HDI. The effect of interferon alfa-2b-containing salvage therapy was greatest for patients with regional recurrences.
Kirkwood and colleagues conclude that a treatment advantage exists for HDI for one year compared with OBS for melanoma patients following resection of stage IIB and III disease. This treatment benefit was manifest in terms of an improvement in RFS but not overall survival. A similar benefit was not present for LDI in comparison with OBS. The disproportionate use of interferon alfa-containing salvage therapy for patients with relapse following OBS was considered a potential influence regarding overall survival end points on this study. It was suggested that RFS might be an appropriate primary end point for subsequent adjuvant clinical studies.
COMMENT by Mark R. Albertini, MD
This large prospective, randomized study by Kirkwood et al clearly demonstrates RFS benefit of interferon alfa-2b therapy for patients following resection of high-risk melanoma. This RFS benefit confirms results previously seen in the E1684 study. However, this study failed to demonstrate an overall survival benefit as was demonstrated in the prior E1684 study. The detailed analysis of post relapse therapy, while not in the original experimental plan, helps evaluate the results from this study. The large number of patients randomized to OBS who subsequently received adjuvant interferon alfa therapy following regional relapse and resection of disease represent an important subset from this study. This post relapse salvage therapy could explain the impressive six- year median OS of patients in E1690, compared with the median OS of 2.8 years in the E1684 OBS patients.
A subsequent study E1694—a Phase III Study of Adjuvant Ganglioside Vaccination GM2-KLH/QS-21 Therapy vs. High Dose Interferon Alfa-2b for High Risk Melanoma (T4 > 4 mm Primary or Regional Lymph Node Metastasis)—was recently completed. The E1694 study opened in June 1996 and completed accrual in October 1999. An independent data-monitoring committee recently evaluated results from this study following 16 months of median follow-up. Results from this independent data-monitoring committee were communicated to ECOG investigators in May of this year. Results from this analysis demonstrated that treatment results had crossed the stopping boundaries specified by the study. The estimated one-and two-year relapse-free survival rates for the interferon-treated patients were 71% and 62%; and the GM2-KLH/QS21-treated group had one-and two-year relapse-free survival rates of 62% and 49%. These results resulted in the recommendation for discontinuation of GM2-KLH/QS21 for patients still receiving it, as it was determined to be inferior to interferon.3
High-dose interferon alfa-2b remains the standard adjuvant therapy for melanoma patients following resection of stage IIB and III disease. Further improvements are still needed in our adjuvant treatment of patients with resected high-risk melanoma. An upcoming ECOG study will evaluate a combination biochemotherapy regimen vs. high-dose interferon alfa-2b for patients with resected high-risk melanoma. Additional studies are evaluating vaccine treatments in combination with interferon alfa-2b. Outside of the protocol setting, high-dose interferon alfa-2b remains the standard of care for patients with resected stage IIB and III high-risk melanoma.
1. Stadelmann WK, et al. In: Balch, Houghton, Sober, Soong, eds. Prognostic Clinical and Pathologic Features, Cutaneous Melanomas. 3rd ed. 1998:11-35.
2. Kirkwood JM, et al. J Clin Oncol 1996;14:7-17.
3. ECOG correspondence regarding E1694 Adjuvant Melanoma Trial recommending discontinuation of vaccine treatment for patients on E1694. Additional information may be found on the ECOG web page at http://ecog.dfci.harvard.edu/