Journal of Clinical Oncology, Vol 18, Issue 12
(June), 2000: 2444-2458
© 2000 American Society for Clinical Oncology
High- and Low-Dose Interferon Alfa-2b in High-Risk Melanoma: First Analysis of Intergroup Trial E1690/S9111/C9190
By John M. Kirkwood,
Joseph G. Ibrahim,
Vernon K. Sondak,
Jon Richards,
Lawrence E. Flaherty,
Marc S. Ernstoff,
Thomas J. Smith,
Uma Rao,
Mary Steele,
Ronald H. Blum
From the Department of Pathology, University of Pittsburgh Medical Center, and Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Cancer Institute Melanoma Center, Pittsburgh, PA; Dana-Farber Cancer Institute and Department of Biostatistics, Harvard School of Public Health, Boston; Department of Data Management, Eastern Cooperative Oncology Group Coordinating Center, Brookline, MA; Department of Surgery, Division of Surgical Oncology, University of Michigan, Ann Arbor; Department of Medicine, Division of Hematology/Oncology, Karmanos Cancer Center/Wayne State University, Detroit, MI; Department of Medicine, Division of Hematology-Oncology, Lutheran General Hospital, Chicago, IL; Department of Medicine, Division of Hematology-Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, NH; Department of Surgery, Division of Surgical Oncology, Morristown Memorial Hospital, Morristown, NJ; and Department of Medicine, Section of Oncology, St Vincent’s Hospital and Medical Center, New York, NY.
Address reprint requests to John M. Kirkwood, MD, University of Pittsburgh Cancer Institute, 200 Lothrop St, Pittsburgh, PA 15213-2582; email jmk{at}jimmy.harvard.edu © 2000 by American Society of Clinical Oncology. 0732-183X/0-2000/00-1
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ABSTRACT
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PURPOSE: Pivotal trial E1684 of adjuvant high-dose interferon alfa-2b (IFN 2b) therapy in high-risk melanoma patients demonstrated a significant relapse-free and overall survival (RFS and OS) benefit compared with observation (Obs).
PATIENTS AND METHODS: A prospective, randomized, three-arm, intergroup trial evaluated the efficacy of high-dose IFN2b (HDI) for 1 year and low-dose IFN2b (LDI) for 2 years versus Obs in high-risk (stage IIB and III) melanoma with RFS and OS end points.
RESULTS: A total of 642 patients were enrolled (608 patients eligible), of whom a majority (75%) had nodal metastasis (50% had nodal recurrence). Unlike E1684, E1690 allowed entry of patients with T4 (> 4 mm) deep primary tumors, regardless of nodal dissection, and 25% of the patients entered onto this trial had deep primary tumors (compared with 11% in E1684). At 52 months’ median follow-up, HDI demonstrated an RFS benefit exceeding that of LDI compared with Obs. The 5-year estimated RFS rates for the HDI, LDI, and Obs arms were 44%, 40%, and 35%, respectively. The hazards ratio for the intent-to-treat analysis of HDI versus Obs was 1.28 (P2 = .05); for LDI versus Obs, it was 1.19 (P2 = .17). By Cox analysis, the impact of HDI on RFS achieved significance (P2 = .03). The RFS benefit was equivalent for node-negative and node-positive patients. Neither HDI nor LDI has demonstrated an OS benefit compared with Obs at this time. A major improvement in the median OS of patients in the E1690 Obs arm was noted in comparison with E1684 (6 years v 2.8 years). An analysis of salvage therapy for patients who relapsed on E1690 demonstrated that a significantly larger proportion of patients in the Obs arm received IFN-containing salvage therapy compared with the HDI arm; this therapy was unavailable to patients during E1684, and patients with undissected regional nodes were not included in E1684. This study did not specify therapy at recurrence. Analysis of treatments received at recurrence demonstrated significantly more frequent use of IFN2b at relapse from Obs than from HDI, which may have confounded interpretation of the survival benefit of assigned treatments in E1690.
CONCLUSION: The results of the intergroup E1690 trial demonstrate an RFS benefit of IFN2b that is dose-dependent and significant for HDI by Cox multivariable analysis.
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INTRODUCTION
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THE PROGNOSIS OF patients with cutaneous melanoma is dependent on the number of involved regional lymph nodes and the thickness of the primary tumor (Breslow’s microstage of invasion). Patients with pathologic or clinical evidence of regional nodal metastasis (N1) as well as those with thick primary lesions (T4) have been demonstrated to be at high risk of disease recurrence after definitive surgery.1-5 The risk of disease recurrence is approximately 60% in patients with T4N0M0 disease (American Joint Committee on Cancer [AJCC] stage IIB) and approximately 75% in patients with T1-4N1M0 (AJCC stage III) disease. These patients, as well as patients with regional nodal recurrences, have been the focus of a series of Eastern Cooperative Oncology Group (ECOG) and United States (US) intergroup adjuvant studies.
The pivotal ECOG trial E1684 demonstrated that adjuvant therapy with high-dose interferon alfa-2b (IFN2b; Schering-Plough, Kenilworth, NJ), administered intravenously (IV) and subcutaneously (SC) for 1 year, significantly prolongs relapse-free and overall survival (RFS and OS) compared with observation (Obs) in high-risk melanoma patients (stage IIB and III).6,7 The 5-year RFS rate was 37% in the IFN2b arm versus 26% in the Obs arm, a 42% relative increase in the number of patients who remained continuously disease-free at 5 years (Cox model estimated improvement, 50%; P2 = .001). The 5-year OS rate was similarly improved from 37% to 46% with IFN2b therapy, a 25% improvement in relative survival for treated patients. On the basis of these data, high-dose IFN2b (HDI) (20 megaunits/m2/d IV for 5 days a week for 4 weeks and 10 megaunits/m2 SC three times per week [TIW] for 11 months) was approved as adjuvant therapy for high-risk melanoma by the US Food and Drug Administration in 1995.8
However, given the substantial toxicities associated with high-dose IV IFN2b, alternative regimens have also been widely investigated. A trial of high-dose intramuscular (IM) IFN2a (20 megaunits/m2/d TIW) administered for 3 months to intermediate- and high-risk patients was conducted by the North Central Cancer Treatment Group (NCCTG). This study demonstrated a benefit that rivaled that of E1684 for RFS of node-positive patients, but it did not show a significant RFS or OS benefit for the entire study population.9 World Health Organization (WHO) trial 16 evaluated the efficacy of low-dose IFN2a (3 megaunits/d SC TIW) for 3 years versus Obs in node-positive patients but did not demonstrate an impact of low-dose IFN2a on either RFS or OS at a median follow-up of 39 months.10 These trials suggested that the HDI regimen used in trial E1684 had superior efficacy to both high-dose IM IFN2a for a shorter duration and low-dose SC IFN2a for a longer duration.
We conducted intergroup trial E1690 to confirm the results of E1684 and to prospectively evaluate HDI and low-dose IFN2b (LDI) regimens in a direct concurrent comparison versus Obs.
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PATIENTS AND METHODS
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Patient Selection
As in trial E1684, patients eligible for E1690 had histologically proven AJCC stage IIB or stage III primary or recurrent regional nodal involvement from cutaneous melanoma without evidence of systemic metastatic disease (T4cN0, T1-4pN1cN0, T1-4cN1, and T1-4N+ recurrent). Eligible patients also had normal organ function, no significant medical or psychiatric comorbidity, and an ECOG performance status of 0 or 1. Patients who had received prior adjuvant radiotherapy, chemotherapy, or immunotherapy, or for whom IFN2b therapy was medically contraindicated, were ineligible.
Patients were stratified before randomization into eight strata based upon the current AJCC tumor-node-metastasis staging system and by number of involved lymph nodes, as shown in Fig 1. All patients were initially staged by history and physical examination, as well as by computed tomography scan of the head and chest, complete blood hematologic and biochemical panel, electrocardiography, and thyroid functions. Patients were required to have definitive surgery with pathologic confirmation of adequate surgical margins (ie, 2 cm minimum except in cosmetically compromised areas) within 56 days of initial biopsy, and patients with recurrent regional lymph node disease were required to be randomized within 42 days of lymphadenectomy. The definition of nodal involvement required the identification of tumor cells by routine stains, and neither positive immunohistochemical stains nor positive reverse transcriptase polymerase chain reactions alone were considered sufficient evidence of tumor involvement for study entry. Patients with T4 (Breslow depth > 4 mm) primary lesions and no clinical evidence of lymph node metastasis (T4cN0) were not required to undergo lymphadenectomy, in contrast to E1684, on the grounds that high risk was established by the presence of invasion to more than 4 mm Breslow depth and the absence of any survival benefit of elective node dissection in four randomized studies. This trial accrued 642 patients from February 1991 to June 1, 1995, and the presently analyzed database was current to September 1998. We report here the initial analysis of this trial at a median follow-up of 52 months.
Treatment
Patients were randomized by permuted blocks within each stratum to treatment with HDI for 1 year (20 megaunits/m2/d IV 5 days/week for 4 weeks; 10 megaunits/m2 SC TIW for 48 weeks), LDI for 2 years (3 megaunits/d TIW), or Obs. Dose modification was performed in accordance with the common toxicity criteria established by the National Cancer Institute Cancer Treatment Evaluation Program.11 If criteria dictating dose modification were met, treatment was withheld until the patient recovered from toxicity. Treatment was resumed with a 33% dose reduction after the first treatment interruption for toxicity; a 66% dose reduction was required after a second treatment interruption for toxicity. Dose re-escalation was not attempted. Any patient who required a third treatment interruption for toxicity was removed from the study.
Study Design
Patients were monitored for toxicity weekly during the first month on study and for toxicity and disease status at 1- to 3-month intervals during the first year. Patients were monitored every 4 months in year 2 and every 6 months in subsequent years. Criteria for determining treatment effect were relapse-free interval and OS time from study entry. The sites of all recurrences were documented with attention to regional nodal relapse. Histologic and cytologic confirmation of relapse was attempted in all cases.
The study design involved two primary comparisons for the RFS end point: HDI versus Obs, and LDI versus Obs. Each comparison was to be conducted at a type I error rate of 0.025, thus yielding an overall error rate of 0.05. A group-sequential design using the cure rate model determined the sample size and power. The design was based on a desire to detect a 10% increase in the cure rate and a 50% relative increase in the median RFS (or OS) for those not cured with an 83% power. Target accrual was set at 625 patients, anticipating 252 relapses and 199 deaths at 100% information. Interim analyses were scheduled at four times corresponding to quarters of the statistical information accrued. At the recommendation of the independent data safety monitoring committee, E1690 was unblinded in May 1998 before reaching 100% of the events originally stipulated in its design. This decision was reached based on estimates of the protracted time that would be required to reach the original targets and the low likelihood of demonstrating a significant improvement in OS for either treatment arm even with deferred analysis. The database was subsequently audited internally by ECOG and externally by a panel of four international surgical and medical experts in the field for end points and eligibility (see Acknowledgment).
Statistical Analysis
Efficacy comparisons between the HDI or LDI and Obs arms were performed using stratified as well as nonstratified two-sided log-rank test statistics based on eligible patients and the intent-to-treat (ITT) population. The levels of significance are presented using both two-sided and one-sided tests for comparison to E1684. The probability of RFS and OS was estimated by the Kaplan-Meier method and a cure rate model.12 The hazard ratio (HR) for relapse or death was calculated by Cox proportional hazards regression after adjusting for stage of disease and number of involved nodes. The comparison between treatment arms based on HRs was performed as indicated. Throughout, we have defined HR to denote the ratio of the hazard of the Obs arm relative to that of the treatment arm. An HR greater than 1 indicates that the risk of relapse or death was greater in the Obs arm than in the treatment arm.
All comparisons between trials E1690 and E1684 were based on the ITT populations. The median follow-up for E1690 has reached 52 months (4.3 years), and these results are compared with analyses of E1684 based on 6.9 years’ median follow-up. These comparisons use HRs for relapse or death calculated as the ratio for Obs versus HDI in E1684 divided by the HR for Obs versus HDI in E1690. A value of 1 indicates that the hazard of relapse or death was equivalent in both trials, whereas a value greater than 1 indicates a relative improvement in the prognosis of patients in trial E1690 compared with those in trial E1684. Dose-intensity was calculated as the fraction of the scheduled dose actually delivered for patients relative to 100% of scheduled dosage.
Analysis of Salvage Therapy
Information on postrelapse salvage therapy was not originally collected in E1690. A sweep of all institutions with more than one patient retrieved data for 331 (93%) of 357 assessable patients who had relapsed on E1690 (114 patients in the HDI arm, 122 patients in the LDI arm, and 121 patients in the Obs arm). Information was collected on any postrelapse therapy (surgery, radiation therapy, chemotherapy, biologic therapy, or combination biochemotherapy) given to patients from the time of first recurrence until death or last follow-up. If IFN-based therapy was administered, the IFN dosage was noted. Seventy-one of 73 institutions with two or more relapsed patients were site-visited; 118 institutions with only one relapsed patient were queried by the respective cooperative group data centers. The proportion of patients who received surgical and medical salvage therapy of various types was compared between the HDI and Obs arms. Postrelapse survival from the date of relapse to the date of death or last follow-up (censored) was estimated using the Kaplan-Meier method; HRs and confidence intervals (CIs) were used to compare postrelapse survival among patients who received IFN-containing salvage therapy versus those who did not.
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RESULTS
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Patient Characteristics
Of 642 patients entered onto the study, 34 patients were ineligible, resulting in an eligible population of 608 patients (95%). Ineligibility occurred as a result of violations of specified time intervals (n = 12), inappropriate disease stage (n = 9), incomplete work-up (n = 8), or inadequate surgery (n = 5). Twelve patients in each IFN treatment arm and 10 patients in the Obs arm were ineligible for the efficacy analysis. Randomization achieved an excellent balance of all known prognostic factors between treatment arms. Table 1 shows the distribution of patient characteristics, including the major prognostic factors, across treatment arms for the ITT population. The majority of patients (80% to 90%) in each treatment arm had an ECOG performance status of 0. Pathologically proven regional lymph node involvement (stage III disease) was documented in 477 patients (75%) at study entry; 163 patients (25%) entered this study with T4N0 disease. Only 39 (24%) of the patients with T4N0 disease were electively dissected, and only eight (5%) were evaluated by sentinel node mapping techniques. The largest stratification group, comprising 51% of the total ITT population, had recurrent disease in regional nodes after a wide excision for primary cutaneous melanoma (Table 4).
Impact of IFN2b on RFS and OS
Among the 642 patients comprising the ITT analysis, there were 363 recurrences (114 on HDI, 122 on LDI, and 127 on Obs). There were 287 deaths (96% of the targeted number of events, ie, 98 on HDI, 96 on LDI, and 93 on Obs). The Kaplan-Meier estimate of RFS in the eligible population (n = 608) is shown in Fig 2. The estimated 5-year RFS rates for patients in the HDI and LDI arms were 44% and 40%, respectively, compared with 35% in the Obs arm for the ITT analysis. Comparison of the HRs for RFS between treatment arms based on both the ITT and eligible populations more accurately estimates the impact of treatment with IFN2b on the risk of relapse (Table 2). According to a log-rank test using a cure rate model for the statistical design, the HR for Obs versus HDI was 1.28 (P2 = .05; P1 = .025; 95% CI, 1.0 to 1.65) in the ITT analysis and 1.27 (95% CI, 0.98 to 1.65) for eligible cases. This implies a 28% greater risk of recurrence on the Obs arm compared with HDI (ITT analysis). A Cox model analysis adjusting for significant prognostic variables, including stage of disease and number of positive nodes, also demonstrated an RFS benefit for HDI versus Obs (P2 = .03; P1 = .015). In contrast, HR analysis of patients treated with LDI demonstrated a 19% (ITT population) to 23% (eligible cases) difference in the risk of relapse compared with Obs (HR, 1.19 and 95% CI, 0.93 to 1.53 in the ITT analysis; HR, 1.23 and 95% CI, 0.95 to 1.59 for eligible cases). The Cox model analysis for the RFS benefit of LDI adjusting for stage and number of positive nodes did not reach significance (P2 = .17; P1 = .085).
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Fig 2. Kaplan-Meier estimate of RFS and estimated hazard of relapse over time by treatment arm based on eligible cases (n = 608).
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The Kaplan-Meier estimate of OS based on analysis of the eligible population is shown in Fig 3. The estimated 5-year survival rates for the HDI, LDI, and Obs arms were 52%, 53%, and 55% (eligible population), respectively. Treatment with IFN2b had no apparent impact on OS compared with Obs, and HRs were approximately 1 for both treatment arms versus Obs (Table 3).
The impact of HDI on RFS compared with Obs was also calculated for each stratification group based on stage of disease and number of involved lymph nodes (Table 4). No difference in the benefit of HDI was apparent in node-negative and node-positive patients. Subset analyses achieved statistical significance only for the group with two to three positive nodes (HR, 1.92; P2 = .02; P1 = .01). These patients had an estimated 5-year RFS rate of 50% in the HDI arm compared with only 28% in the Obs arm (Fig 4). In contrast, HDI did not seem to have an impact upon RFS among patients with only one positive node (HR, 1.0). Analysis of the frequency of relapses according to treatment in various regional and distant organs is presented in Table 5. There was no significant or consistent difference in skin, nodal, or visceral sites of relapse for the HDI or LDI and Obs arms. In particular, the frequency of distant relapse demonstrated no significant difference between the HDI or LDI and Obs arms.
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Fig 4. Kaplan-Meier estimate of RFS in the subset of patients with two to three nodal metastases in the HDI arm versus Obs arm.
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Comparison With E1684
The results of E1690 were compared with those of E1684 based on 6.9 years’ median follow-up. Results based on an updated 10-year follow-up of E1684 were similar. Comparisons were performed to determine (1) whether the results of the treatment intervention were different between the studies and (2) whether the Obs arms in the two studies differed in terms of relapse and survival outcomes. Comparison of the Kaplan-Meier estimates for RFS and OS in the HDI arms (ITT populations) of trials E1690 and E1684 revealed that both RFS and OS for patients on E1690 were improved compared with E1684. As shown in Fig 5, patients treated with HDI had an estimated 5-year RFS rate of 44% on E1690 versus 37% on E1684. The HR for the RFS comparison was 1.21. Similarly, the estimated 5-year OS rate was 53% for patients treated with HDI on E1690 versus 46% for those on E1684, with an HR of 1.23. This comparison indicates a 21% improvement in RFS and a 23% improvement in OS for patients treated with HDI on E1690 compared with the pivotal E1684 trial. Comparison of the two trials using a Cox multivariate regression model demonstrated that the treatment arms were consistent between these trials, without any apparent study effect (P2 = .5 to .9).
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Fig 5. Kaplan-Meier estimate of RFS and OS in the HDI arms of E1690 compared with E1684 based on the ITT population.
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In contrast, the comparison of RFS and OS outcomes for patients on the Obs arms of trials E1690 and E1684 demonstrated a substantial study effect, which was two-fold greater for the OS than for the RFS comparison. Patients who were observed on E1690 had an estimated 5-year RFS rate of 35% versus 26% on E1684 (Fig 6); the HR for this comparison was 1.31. The estimated 5-year OS rate was 54% for patients who were observed on E1690 versus only 37% for those on E1684; the HR for this comparison was 1.64. A Cox model analysis of the Obs arms of the two studies showed highly significant RFS (P2 = .01) and OS (P2 = .001) study differences.
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Fig 6. Kaplan-Meier estimate of RFS and OS in the Obs arms of E1690 compared with E1684 based on the ITT population.
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The reasons for the marked (31%) improvement in relapse rate and the more profound (64%) improvement for OS of the patients on the Obs arm in E1690 compared with the E1684 pivotal trial are not fully understood. Three possibilities have been considered: the demographic profile of patients who were entered onto the study; definitive surgical interventions used; and the salvage medical therapies administered. The demographics for accepted risk factors favor the E1690 trial, which had larger numbers of T4N0 (25% v 11%) and smaller numbers of node positive (75% v 89%) and recurrent (51% v 64%) patients compared with E1684. Analysis of the role of newer surgical procedures, such as sentinel lymph node mapping, revealed a minor (< 5%) fraction of patients having undergone sentinel node mapping surgery as the possible basis of improved RFS (data not shown).
Analysis of the average daily dose and the distribution of total dose received by patients on E1690 compared with E1684 demonstrated that a slightly larger average daily dose of IFN2b was delivered during induction and maintenance on trial E1690; conversely, a larger proportion of patients on trial E1684 received  400 megaunits/m2 total dose (Table 6). Thus, the IFN2b treatment on protocol does not seem to have differed in a way that could explain the outcome differences. Rather, differences in salvage therapy with IFN2 and/or other agents may represent a more plausible explanation, as presented later in this article.
Safety Summary
Treatment with HDI was associated with significant toxicity consistent with the adverse events that have been reported by others and those observed in trial E1684.6,7,13,14 The most common WHO grade 3 and 4 adverse events are listed in Table 7. The majority of adverse events were grade 3. No treatment-related deaths occurred in the HDI arm.
The number of treatment delays and dose reductions necessitated for toxicity or any reason in patients receiving HDI on E1690 is listed in Table 8. Dose reductions were planned in two tiers (33% and 66% from starting dosage) in E1690, compared with only one tier (50%) in E1684. The median and mean IFN2b dosages delivered in the HDI arm of E1690 exceeded those for patients on E1684 (Table 6), but the number of treatment delays and dose reductions was greater on trial E1690. During the induction phase, 58% of patients in the HDI arm of E1690 required delays or dose reductions (44% due to toxicity) compared with 50% of patients on E1684 (37% due to toxicity). Likewise, during the maintenance phase, 59% of patients in the HDI arm of E1690 required delays or dose reductions (52% due to toxicity) compared with 48% of patients on E1684 (36% due to toxicity).
Postrelapse Salvage Therapy
The median OS of patients in the E1690 Obs arm was 6 years, compared with only 2.8 years for the E1684 Obs arm (Table 9), whereas the median RFS of the Obs arms in E1690 and E1684 were quite similar (1.6 years v 1.0 years, respectively). The E1690 Obs arm showed a more than two-fold increase in postrelapse survival compared with the E1684 Obs arm (4.3 years, compared with 1.8 years). In contrast, postrelapse survival in the HDI arm was comparable between the E1690 and E1684 trials (2.6 v 2.1 years, respectively). To understand what factors might have contributed to the unusual postrelapse survival of the E1690 Obs arm, we compared the proportion of relapsed patients in each treatment arm who received various kinds of salvage therapy and analyzed the potential effects of these therapies on postrelapse survival. These data were not collected in the original data set, nor was this analysis anticipated in the original plan for analysis of this trial. However, given the difference in the eligibility criteria and removal of lymphadenectomy requirements, resulting in a more than two-fold larger accrual of T4cN0 patients in E1690, this analysis seems warranted to deal with the clear and apparent double opportunity for the application of adjuvant IFN2b for patients with T4, clinically node-negative, but undissected disease.
There was no statistically significant difference between treatment arms with respect to the site of first recurrence; 53 (46%) of 114 patients in the HDI arm had distant metastasis at first recurrence compared with 66 (55%) of 121 patients in the Obs arm. Table 5 shows the proportion of patients in the HDI, LDI, and Obs arms with either regional/superficial or distant/visceral recurrence. With respect to postrelapse salvage therapy, similar proportions of patients in each treatment arm received surgery, chemotherapy, radiotherapy, or no treatment at relapse. However, a significantly larger proportion of relapsed patients from the Obs arm (31%) received an IFN-containing salvage regimen, compared with only 15% of patients from the HDI arm (P = .003,  2 test; Table 10). Patients in the Obs arm were also twice as likely to receive higher doses IFN therapy (> 10 megaunits/m2 SC TIW) at relapse compared with those failing on the HDI arm (21% v 10%). Similarly, a greater proportion of patients in the Obs arm was treated with a biochemotherapy regimen compared with the HDI arm (17% v 6%; P = .013, 2 test). There were no important differences in the proportion of patients in each treatment arm who received interleukin-2–containing salvage therapy (either single-agent or combination therapy).
Impact of Salvage Therapy on Survival
Kaplan-Meier estimates of OS were performed on subgroups of relapsed patients in the Obs and HDI arms who either received an IFN-containing salvage regimen or did not. As shown in Fig 7, relapsed patients in the E1690 Obs arm who received IFN-containing salvage therapy (n = 38) had an apparent postrelapse survival advantage compared with 83 patients who did not receive IFN-containing salvage therapy (median, 2.2 years v 0.8 year; P = .0024, log-rank test). The HR for this comparison was 2.13 (95% CI, 1.29 to 3.53). In contrast to the Obs arm, no apparent survival advantage was associated with IFN-containing salvage therapy in the HDI arm; however, the number of patients in the HDI arm who received IFN-containing salvage therapy was small (n = 17).
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Fig 7. Post-relapse survival for the Obs arm (relapsed patients only) with and without IFN-containing salvage therapy.
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The assumption in this analysis is that patients in the Obs arm who received IFN-containing salvage therapy were clinically comparable at relapse to those who did not. This assumption is supported by the findings of a Cox regression analysis and data on site of relapse. Cox regression analysis was performed to determine whether prognostic factors differed between patients in the E1690 Obs arm who did or did not receive IFN-containing salvage therapy. Variables included in this analysis were age, sex, performance status, ulceration, and disease stage and number of positive nodes at randomization. Adjusting for these variables, only salvage therapy with an IFN-containing regimen had a meaningful effect on survival (HR, 2.14; 95% CI, 1.28 to 3.61). Moreover, the median time from randomization to initial relapse of the 38 patients in the Obs arm who received IFN-containing salvage therapy was not substantially different from the median RFS of the 83 patients who did not receive IFN-containing salvage therapy (0.9 years v 0.5 years, respectively; HR, 1.34; 95% CI, 0.91 to 1.98). These data suggest that IFN-containing salvage therapy may account for the prolonged postrelapse survival of the 38 patients in the Obs arm who received it. Indeed, 17 of these patients received IFN2 therapy for resectable regional relapse that was indistinguishable from the setting in which the original E1684 trial tested the role of IFN.
Effect of IFN Salvage Therapy on Patients With Regional Versus Distant Recurrence
Among 121 patients in the E1690 Obs arm who experienced a relapse, 51 patients (42%) had regional or superficial recurrences, and 66 patients (55%) had distant or visceral recurrences (four patients had unknown sites of recurrence). The distribution of regional and distant recurrence was similar for the subgroup of patients who received IFN2b therapy for resectable regional relapse that contained salvage therapy and those who did not (45% v 41% regional recurrence and 53% v 55% distant recurrence, respectively). These subsets were further analyzed with respect to the impact of IFN-containing salvage therapy on postrelapse survival. The impact of IFN-containing salvage therapy was noted in both subsets but greatest for patients with regional recurrence (Fig 8). Indeed, 17 of these patients received IFN2b therapy for resectable regional relapse that was indistinguishable from the setting in which the original E1684 trial tested the role of IFN2b. The median postrelapse survival for these patients has not been reached, whereas it is 1.5 years for the 34 treated without IFN2 (HR, 2.2; 95% CI, 0.89 to 5.44). In patients with distant recurrence, the median survival was 1.0 year with IFN-containing salvage therapy versus 0.5 years without it (HR, 2.38; 95% CI, 1.29 to 4.40).
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Fig 8. Post-relapse survival for the Obs arm (relapsed patients only) with and without IFN-containing salvage therapy by site of recurrence.
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DISCUSSION
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HDI therapy for 1 year was approved in 1995 by the US Food and Drug Administration for adjuvant therapy in high-risk (ie, AJCC stage IIB and stage III) melanoma, based on the observed improvement in RFS and OS for patients on trial E1684.6,7 Intergroup trial E1690 was designed in 1990, at a time when interim analysis of the E1684 trial demonstrated a consistent and pronounced impact of HDI on the RFS of high-risk melanoma patients at 4 years’ median follow-up. The E1690 study was initiated before a significant impact on survival had been noted in E1684 and used a cure rate model powered to detect a 10% increase in cure rate and a 50% relative increase in RFS or OS. The sample size was calculated on the basis of the Obs arm of the E1684 trial. At the recommendation of the Data Safety and Monitoring Committee, E1690 was unblinded after meeting its accrual target but before reaching 100% of the events stipulated in its original design. This was decided as a consequence of the prolonged time estimated to reach the planned number of events, as well as the low likelihood of demonstrating a significant survival benefit, even at full maturity. The diminished event rate and improved prognosis of patients on the E1690 trial for both recurrence-free interval and OS are notable, beyond the evaluation of the effects of IFN2b therapy reported here. The results stress the importance of concurrent randomized controlled trials for adjuvant therapy evaluation.
Based upon the ITT analysis with more than 90% of expected events now reached for RFS, E1690 has confirmed the clinical benefit of HDI with respect to continuous RFS (P2 = .03 by Cox multivariate analysis and P2 = .05 by log-rank analysis) at 52 months’ median follow-up. The benefit of HDI in E1690 was equivalent in both node-negative and node-positive patients. The trial demonstrated an advantage for HDI for 1 year compared with the low-dose regimen for 2 years in terms of continuous RFS, but it has not demonstrated a survival benefit for either HDI or LDI therapy at this time.
A variety of factors may have contributed to the absence of a survival impact in this trial. It may be that the magnitude of the treatment effect of HDI was less than the estimates generated from the E1684 trial and that this more modest treatment effect was sufficient to delay recurrence but not to prevent death. The HR for RFS on the HDI arm of E1690 was 1.28 (signifying a 28% improvement in RFS compared with Obs), which is somewhat less than the RFS HR for benefit of IFN2b in E1684 (1.42). However, the CIs for these HRs overlap one another, and the HDI arms of the two trials were not distinguishable in a multivariate analysis. There was no evidence of a study effect between E1684 and E1690 with respect to the HDI arms. Direct comparison of the HDI arms of E1690 and E1684 revealed an improvement in RFS and OS (HR, 1.21 to 1.23) for patients treated with HDI on E1690 relative to E1684. However, patients on the E1690 Obs arm also fared better in terms of RFS and more so in terms of OS relative to the E1684 Obs arm. HR analysis revealed that the study effect (trial outcome difference) between the Obs arms of E1690 and E1684 was two-fold larger (64%) than the treatment effect for HDI versus Obs on E1690 (28%).
Several factors were considered to account for the study outcome differences in relation to the Obs arms, including the following: (1) the improved demographic profile of E1690, along with the use of more accurate staging methods resulting in stage migration; (2) better or more aggressive surgical intervention at initial treatment or subsequent relapse; and (3) improved systemic medical postrelapse therapy, including IFN2b or interleukin-2, both of which were approved for use by the Food and Drug Administration during the conduct of this trial. With regard to the demographic profile of patients on this trial, it is clear that E1690 included a more favorable population of melanoma patients in that 75% of accrued patients were node-positive, of whom 51% entered with nodal recurrence; in contrast, in E1684 89% of accrued patients were node-positive, and 64% of them entered with nodal recurrence. There is no evidence of any systematic differences in staging or surgery between E1684 and E1690. An audit of surgical procedures revealed that only 5% of patients received any form of sentinel node mapping during definitive surgery. The last possibility was retrospectively evaluated, and given the data, it seems that the disproportionate use of IFN-containing salvage therapy, particularly in patients who had nodal relapse from stratum I (ie, T4cN0), may have influenced the OS of the E1690 Obs arm compared with the HDI arm. The subset of relapsed patients in the E1690 Obs arm who received IFN-containing salvage therapy had significantly improved OS compared with patients in the Obs arm who did not receive IFN-containing salvage therapy, and this survival benefit could not be accounted for by any other clinical variable.
The absence of a survival benefit in E1690, and the strikingly prolonged postrelapse survival of patients assigned to Obs in E1690 compared with E1684, was analyzed in relation to the different criteria for entry of T4 patients, who were only required to be clinically staged as N0 in E1690, whereas all of these patients underwent regional lymphadenectomy for pathologic staging in E1684. Among the 163 T4"N0" patients in E1690, 125 patients (76.6%) did not undergo lymphadenectomy. More importantly, the 56 T4N0 patients in the Obs arm, who had the opportunity to undergo surgical salvage and subsequent "second-round" adjuvant IFN2b therapy off protocol for regional relapses, had no counterpart in the E1684 trial. In fact, analysis of the 121 patients who relapsed from the Obs arm demonstrated that 51 patients had regional nonvisceral disease relapses, amenable to surgical salvage, and that 38 patients then received IFN2b, compared with the 17 of 114 patients who failed HDI therapy (P = .003). Thus, the opportunity for curative surgical intervention and postrelapse adjuvant therapy with IFN2b has potentially confounded the survival outcome analysis of E1690.
The significant improvement in the prognosis of Obs arm patients in the E1690 trial compared with E1684 has increased the number of patients who would be required to detect the improvements in RFS and OS seen as a consequence of HDI in E1684. In this context, it is notable that the subsequent intergroup trial E1694/S9512, comparing a defined vaccine (ganglioside GM2) to HDI in 880 patients fulfilling the same eligibility criteria, will provide additional data regarding HDI for twice as many patients as the E1684 or E1690 trials. Future clinical trials of adjuvant therapy in melanoma will need to have the power to detect smaller increases in cure rates, in reference to a substantially improved prognosis of high-risk melanoma patients with current management strategies. Future trials will also need to anticipate the use of IFN2b as salvage therapy and may need to focus upon primary end points of RFS.
Among the four large randomized studies of adjuvant IFN therapy that have been conducted in high-risk melanoma patients, E1684 is the only trial that has demonstrated a statistically significant RFS and OS benefit in the entire study population. However, other studies have demonstrated a treatment benefit associated with IFN therapy in high-risk patients that is consistent with the effects noted in E1684 and the current E1690 trial. With respect to HDI, NCCTG trial 83-7052 demonstrated an RFS benefit of high-dose IM IFN2a for stage III patients that was significant in Cox multivariate analysis. The high-risk node-positive subgroup comprised two thirds of the study population (160 of 262 patients) but was smaller than that of the E1684 trial, and there was no evidence of an RFS benefit in the study population as a whole. With respect to LDI in high-risk patients, neither the E1690 nor the WHO 16 trial demonstrated a significant overall treatment benefit with LDI administered for 2 or 3 years. Comparing and contrasting the outcome of the HDI arms of E1684 and E1690 with the LDI arm of E1690, the RFS analysis suggests that both the nature and magnitude of the therapeutic benefit differ. The RFS benefit associated with LDI was transient, enduring for little more than the interval of therapy, as previously reported preliminarily from WHO trial 16. In intermediate-risk node-negative stage II patients, two randomized controlled trials of LDI for 12 to 18 months demonstrated an RFS benefit but no OS benefit.15,16 A sustained RFS benefit may require prolonged administration of LDI. In contrast to the transient effects of LDI, the continuous RFS observed with 1 year of HDI in E1690 and the E1684 trial, now updated to 10 years’ median follow-up, suggests a benefit that endures for many years after the completion of therapy. This allows patients and physicians to consider the possibility of a curative goal for this therapy in high-risk patients. No other randomized controlled adjuvant trial of chemotherapy, vaccines, or other biologic agents has shown a significant effect upon either RFS or OS. Taken together, this argues that HDI continues to be the standard for adjuvant therapy of high-risk stage IIB and stage III melanoma patients, who are treated off investigational protocols, and the most appropriate comparator for clinical trials of promising new modalities under evaluation in randomized controlled trials. Toxicity has been a major obstacle for broader adoption of HDI, but it is notable that no toxic deaths occurred among patients treated with HDI in E1690. Greater experience with the high-dose regimen has resulted in a complete absence of the lethal hepatotoxicity earlier observed during the E1684 trial. Still, given the toxicity and cost of HDI, the data from E1690 may be construed by some to mean that Obs is reasonable for patients with high-risk melanoma. However, the generally poor survival for patients who relapse after lymphadenectomy and the poor survival of patients with visceral relapses in E1690, regardless of whether they were treated with IFN2 at relapse, support the earlier use of adjuvant IFN2b therapy. The salvage therapy analysis performed in E1690 suggests a survival benefit for systemic IFN2b therapy of advanced metastatic melanoma. Follow-up analyses of the mature data from E1690 and further prospective trials will be of interest in this regard. Evaluation of the quality of life (Q-TWiST) and cost-efficacy benefits of HDI in E1690 is also warranted and may provide further assistance to physicians and patients who are considering the risks and benefits of HDI.
HDI is the best-evaluated and most effective available option for reducing the risk of relapse in patients with high-risk melanoma. Clearly, however, we need to improve upon the results of these trials. A corollary immunologic evaluation of 143 patients treated in the E1690 trial and analyzed for immunologic effects of IFN2b at low and high dosages offers an opportunity to define intermediate end points of HDI and LDI and their correlation to RFS. This would permit the application of this modality for those patients most likely to benefit. Conversely, efforts to define molecular and immunologic markers of risk would allow us to refine the application of IFN2b for those at more precisely defined levels of risk. The comparative trial of the ganglioside GM2 vaccination versus HDI (intergroup trial E1694/S9512) was recently completed, along with an evaluation of combinations of GM2 and IFN2b, laying the groundwork for future trials as these data mature. In addition, combinations of IFN2b with interleukin-2 and polychemotherapy are now under evaluation and may provide alternate approaches to investigational adjuvant therapy for patients with resected high-risk melanoma.
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ACKNOWLEDGMENTS
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Supported by Eastern Cooperative Organization Group grant no. U10CA392294.
We gratefully acknowledge the efforts of the external data review panel, including Ian Quirt, MD, Princess Margaret Hospital, Montreal, Providence of Quebec, Canada; James Rusthoven, MD, National Cancer Institute of Canada Melanoma Clinical Trials Group, Hamilton, Ontario, Canada (currently at Eli Lilly Pharmaceuticals, Indianapolis, IN); Marshall Urist, MD, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL; and Alexander Eggermont, MD, PhD, European Organization for Research and Treatment of Cancer Melanoma Cooperative Group, Rotterdam, the Netherlands. The authors gratefully acknowledge the expert protocol coordination and data management performed by Sandra Donnelly, RN, OCN, University of Pittsburgh Melanoma Center, Pittsburgh, PA, and Laura Kandziolka, ECOG Operations Office, Boston, MA, the editorial assistance of Jeffrey Riegel, ProEd Communications, Cleveland, OH, and the assistance of Schering-Plough Research Institute and Schering-Plough Oncology Biotech with posttrial data collection.
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NOTES
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J.M.K., J.I., T.J.S., U.R., M.S., and R.H.B. are affiliated with the Eastern Cooperative Oncology Group. V.K.S. and L.E.F. are affiliated with the Southwest Oncology Group. J.R. and M.S.E. are affiliated with Cancer and Leukemia Group B.
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Submitted October 12, 1999;
accepted February 22, 2000.
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H. Tsao, M. B. Atkins, and A. J. Sober
Management of Cutaneous Melanoma
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G. B. Lesinski, B. Badgwell, J. Zimmerer, T. Crespin, Y. Hu, G. Abood, and W. E. Carson III
IL-12 Pretreatments Enhance IFN-{alpha}-Induced Janus Kinase-STAT Signaling and Potentiate the Antitumor Effects of IFN-{alpha} in a Murine Model of Malignant Melanoma
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J. M. Kirkwood, J. Manola, J. Ibrahim, V. Sondak, M. S. Ernstoff, and U. Rao
A Pooled Analysis of Eastern Cooperative Oncology Group and Intergroup Trials of Adjuvant High-Dose Interferon for Melanoma
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J. A. Sparano, R. Gray, B. Giantonio, P. O'Dwyer, and R. L. Comis
Evaluating Antiangiogenesis Agents in the Clinic: The Eastern Cooperative Oncology Group Portfolio of Clinical Trials
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L. M. Schuchter
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B.W. Hancock, K. Wheatley, S. Harris, N. Ives, G. Harrison, J.M. Horsman, M.R. Middleton, N. Thatcher, P.C. Lorigan, J.R. Marsden, et al.
Adjuvant Interferon in High-Risk Melanoma: The AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research Randomized Study of Adjuvant Low-Dose Extended-Duration Interferon Alfa-2a in High-Risk Resected Malignant Melanoma
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[Abstract]
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S. J. Moschos, J. M. Kirkwood, and P. A. Konstantinopoulos
Present Status and Future Prospects for Adjuvant Therapy of Melanoma: Time to Build upon the Foundation of High-dose Interferon Alfa-2b
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N. Ready and M. A. Weinstock
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Amplification of Virus-Induced Antimelanoma T-Cell Reactivity by High-Dose Interferon-{alpha}2b: Implications for Cancer Vaccines
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M. S. Sabel and V. K. Sondak
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Prospective Randomized Trial of Interferon Alfa-2b and Interleukin-2 as Adjuvant Treatment for Resected Intermediate- and High-Risk Primary Melanoma Without Clinically Detectable Node Metastasis
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Characterization of Methylthioadenosin Phosphorylase (MTAP) Expression in Malignant Melanoma
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A. Ribas, L. H. Butterfield, J. A. Glaspy, and J. S. Economou
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P. Hersey, A. S. Coates, W. H. McCarthy, J. F. Thompson, R. W. Sillar, R. McLeod, P. G. Gill, B. J. Coventry, A. McMullen, H. Dillon, et al.
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J. M. Kirkwood, J. Ibrahim, V. K. Sondak, M. S. Ernstoff, L. Flaherty, F. J. Haluska, M.B. Lens, and M. Dawes
Use and Abuse of Statistics in Evidence-Based Medicine
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R. Bukowski, M. S. Ernstoff, M. E. Gore, J. J. Nemunaitis, R. Amato, S. K. Gupta, and C. L. Tendler
Pegylated Interferon Alfa-2b Treatment for Patients With Solid Tumors: A Phase I/II Study
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J. M. Kirkwood, C. Bender, S. Agarwala, A. Tarhini, J. Shipe-Spotloe, B. Smelko, S. Donnelly, and L. Stover
Mechanisms and Management of Toxicities Associated With High-Dose Interferon Alfa-2b Therapy
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S. D. Thome, C. L. Loprinzi, and M. P. Heldebrant
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M. Islam, R. F. Frye, T. J. Richards, I. Sbeitan, S. S. Donnelly, P. Glue, S. S. Agarwala, and J. M. Kirkwood
Differential Effect of IFN{alpha}-2b on the Cytochrome P450 Enzyme System: A Potential Basis of IFN Toxicity and Its Modulation by Other Drugs
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U.N.M. Rao, J. Ibrahim, L.E. Flaherty, J. Richards, and J.M. Kirkwood
Implications of Microscopic Satellites of the Primary and Extracapsular Lymph Node Spread in Patients With High-Risk Melanoma: Pathologic Corollary of Eastern Cooperative Oncology Group Trial E1690
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L. Kretschmer, C. Neumann, B. Coldiron, S. Dinehart, J. M. Kirkwood, S. S. Agarwala, J. Ibrahim, J. Manola, V. K. Sondak, M. S. Ernstoff, et al.
Sentinel-Node Technique Will Change the Design of Clinical Trials in Malignant Melanoma
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M. B. Lens and M. Dawes
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K. L. Kilbridge, B. F. Cole, J. M. Kirkwood, F. G. Haluska, M. A. Atkins, J. C. Ruckdeschel, D. E. Sock, R. F. Nease Jr, and J. C. Weeks
Quality-of-Life-Adjusted Survival Analysis of High-Dose Adjuvant Interferon Alfa-2b for High-Risk Melanoma Patients Using Intergroup Clinical Trial Data
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Phase I Trial of a Melanoma Vaccine with gp100280-288 Peptide and Tetanus Helper Peptide in Adjuvant: Immunologic and Clinical Outcomes
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R. W. Dubois, S. M. Swetter, M. Atkins, K. McMasters, R. Halbert, S. J. Miller, R. Shiell, and J. Kirkwood
Developing Indications for the Use of Sentinel Lymph Node Biopsy and Adjuvant High-Dose Interferon Alfa-2b in Melanoma
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C. M. Balch, S.-J. Soong, J. E. Gershenwald, J. F. Thompson, D. S. Reintgen, N. Cascinelli, M. Urist, K. M. McMasters, M. I. Ross, J. M. Kirkwood, et al.
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High-Dose Interferon Alfa-2b Significantly Prolongs Relapse-Free and Overall Survival Compared With the GM2-KLH/QS-21 Vaccine in Patients With Resected Stage IIB-III Melanoma: Results of Intergroup Trial E1694/S9512/C509801
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J. M. Kirkwood, J. Ibrahim, D. H. Lawson, M. B. Atkins, S. S. Agarwala, K. Collins, R. Mascari, D. M. Morrissey, and P. B. Chapman
High-Dose Interferon Alfa-2b Does Not Diminish Antibody Response to GM2 Vaccination in Patients With Resected Melanoma: Results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696
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TOP
ABSTRACT
INTRODUCTION
