High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190.

PURPOSE: Pivotal trial E1684 of adjuvant high-dose interferon alfa-2b (IFNalpha2b) 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 IFNalpha2b (HDI) for 1 year and low-dose IFNalpha2b (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 (P(2) =.05); for LDI versus Obs, it was 1.19 (P(2) =.17). By Cox analysis, the impact of HDI on RFS achieved significance (P(2) =.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 IFNalpha-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 IFNalpha2b 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 IFNalpha2b that is dose-dependent and significant for HDI by Cox multivariable analysis.     

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.

PURPOSE: To correlate the presence of extracapsular spread (ECS) of regional nodal metastases, and micrometastasis near the primary tumor, with disease outcome in the intergroup study E1690 in relation to the impact of recombinant interferon-alfa (rIFN alpha)-2b. PATIENTS AND METHODS: E1690 included 642 patients with American Joint Committee on Cancer stage IIB or III cutaneous melanoma. Patients were randomized into high- and low-dose rIFN alpha-2b treatment arms and an observation arm. Pathologic slides were reviewed for selected parameters from at least half of the subjects in all three arms. Evaluation of the primary tumor included notations regarding ulceration, mitotic activity, thickness, microscopic satellites (MS), and nodal ECS on a standardized pathology form. These data were collated in relation to relapse-free survival (RFS) and overall survival (OS) at 50 months' follow-up and studied using Cox regression analysis. RESULTS: Ulceration, mitotic activity, thickness, and size of tumor-bearing lymph nodes did not show a statistically significant correlation with either OS or RFS across all treatment arms. The presence of MS was correlated with RFS (P =.0008) and OS (P =.05). ECS correlated with RFS (hazard ratio = 1.44, P =.032) but not OS (P =.11). CONCLUSION: The presence of MS (in 6% [18 of 308 patients]) had a significant adverse impact on both RFS (P =.0008) and OS (P =.053). Ulceration, mitotic activity, thickness, and number of positive lymph nodes had no significant effect on OS in this subset study (univariate or multivariate Cox analysis). The presence of ECS in lymph nodes had a significant adverse effect on RFS (P =.032) but not on OS.     

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.

PURPOSE: Vaccine alternatives to high-dose interferon alfa-2b therapy (HDI), the current standard adjuvant therapy for high-risk melanoma, are of interest because of toxicity associated with HDI. The GM2 ganglioside is a well-defined melanoma antigen, and anti-GM2 antibodies have been associated with improved prognosis. We conducted a prospective, randomized, intergroup trial to evaluate the efficacy of HDI for 1 year versus vaccination with GM2 conjugated to keyhole limpet hemocyanin and administered with QS-21 (GMK) for 96 weeks (weekly x 4 then every 12 weeks x 8). PATIENTS AND METHODS: Eligible patients had resected stage IIB/III melanoma. Patients were stratified by sex and number of positive nodes. Primary end points were relapse-free survival (RFS) and overall survival (OS). RESULTS: Eight hundred eighty patients were randomized (440 per treatment group); 774 patients were eligible for efficacy analysis. The trial was closed after interim analysis indicated inferiority of GMK compared with HDI. For eligible patients, HDI provided a statistically significant RFS benefit (hazard ratio [HR] = 1.47, P = .0015) and OS benefit (HR = 1.52, P = .009) for GMK versus HDI. Similar benefit was observed in the intent-to-treat analysis (RFS HR = 1.49; OS HR = 1.38). HDI was associated with a treatment benefit in all subsets of patients with zero to > or = four positive nodes, but the greatest benefit was observed in the node-negative subset (RFS HR = 2.07; OS HR = 2.71 [eligible population]). Antibody responses to GM2 (ie, titers > or = 1:80) at days 29, 85, 365, and 720 were associated with a trend toward improved RFS and OS (P2 = .068 at day 29). CONCLUSION: This trial demonstrated a significant treatment benefit of HDI versus GMK in terms of RFS and OS in melanoma patients at high risk of recurrence.     

Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial.

PURPOSE: Patients with high-risk melanoma treated by immunotherapy with vaccinia viral lysates were found in phase II studies to have improved survival compared with historical controls. We therefore elected to test this therapy in a phase III study. PATIENTS AND METHODS: A prospective, randomized, multicenter trial to determine whether immunotherapy with a vaccine prepared from vaccinia melanoma cell lysates (VMCL) over a 2-year period after definitive surgery would improve relapse-free survival (RFS) and overall survival (OS) in patients with American Joint Committee on Cancer stage IIB and III melanoma compared with a control group treated only with surgery. RESULTS: A total of 700 patients were randomized: 353 to VMCL and 347 to no immunotherapy. Seventy-seven percent had lymph node (LN) metastases and 66% had clinically detected LN metastases. Analysis on the basis of all eligible, randomized patients (n = 675) found, after a median follow-up period of 8 years, a median OS of 88 months in the control versus 151 months in the treated group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.64 to 1.02; P =.068 by stratified univariate Cox analysis). At 5 and 10 years, survival rates for control and treated patients were 54.8% v 60.6% and 41% v 53.4%, respectively. Median RFS was 43 months in the control group compared with 83 months in the treated group (HR, 0.86; 95% CI, 0.7 to 1.07; P =.17). RFS at 5 years was 50.9% for the treated group and 46.8% for the control group. There were no selective benefits from the vaccine for particular subsets of patients. CONCLUSION: Immunotherapy with VMCL was not associated with a statistically significant improvement in OS or RFS, with CIs not ruling out important gains from such treatment.     

Dose-dependent treatment benefit in high-risk melanoma patients receiving adjuvant high-dose interferon alfa-2b

This retrospective analysis of 150 consecutive high-risk melanoma patients treated with high-dose interferon alfa-2b at a single institution demonstrates similar relapse-free and overall survival data, as previously published from Eastern Cooperative Oncology Group (ECOG) and Intergroup trials. The data suggest at least a transient dose dependency of the treatment effect on relapse-free and overall survival with high-dose interferon in high-risk melanoma patients. BACKGROUND: Adjuvant high-dose interferon seems to be the best adjuvant treatment option for patients with high-risk melanoma (AJCC-stage IIC, III) after definitive surgery. METHODS: One-hundred fifty consecutive patients were treated at our institution during the period from September 1997 to March 2003 were retrospectively studied. RESULTS: After a median follow-up of 35 months, 63% of patients had developed a melanoma relapse, and 37% were relapse- free. Fifty-five percent of patients are still alive, and 45% had died-all but 3 patients from melanoma. Patients with stage IIC disease demonstrated a similar unfavorable course of disease as patients with stage IIIC disease (2-year relapse-free survival 18% and 26%). We identified two groups of patients with different cumulative interferon dose-levels (> or =90% and <90% of the projected dose, according to the protocol), who demonstrated at least transient differences, both in terms of relapse-free and overall survival; the predictive impact was statistically independent upon the Cox regression analysis. CONCLUSIONS: Our clinical data are consistent with the published ECOG and Intergroup data dealing with highdose interferon in high-risk melanoma patients. The data suggest a dose-dependency on the treatment effect and, therefore, support further prospective trials comparing different dose-distribution patterns in high-dose interferon.     

Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial.

PURPOSE: Phase II and III studies have shown that the addition of interleukin-2 (IL-2) and interferon alpha-2b (IFN alpha-2b) in multiagent chemotherapy (CT) for advanced melanoma increases overall response (OR), albeit without clear evidence of an improvement in overall survival (OS). Treatment with high-dose IL-2 can cause severe toxicity and is normally administered in an inpatient setting. We conducted a multicenter prospective randomized clinical trial in outpatients with metastatic melanoma to compare CT with biochemotherapy (bioCT) using immunomodulant doses of IL-2 and IFN alpha-2b. PATIENTS AND METHODS: One hundred seventy-six eligible patients with advanced melanoma were randomized to receive CT (cisplatin and dacarbazine with or without carmustine every 21 days) or bioCT comprising the same CT regimen followed by low-dose subcutaneous IL-2 for 8 days and IFN alpha-2b three times a week, both for six cycles. RESULTS: At a median follow-up of 18 (CT) and 16 (bioCT) months, median OS was 9.5 versus 11.0 months (P =.51), respectively. In the 89 CT-arm patients, 18 ORs (20.2%) (three complete responders [CRs] and 15 partial responders [PRs]) were observed according to World Health Organization criteria. In the 87 bioCT-arm patients, 22 ORs (25.3%) (three CRs and 19 PRs) (P =.70) were recorded. Treatment-related toxicity was fairly similar in both arms. CONCLUSION: The addition of low-dose immunotherapy did not produce a statistically significant advantage in OS, time to progression, or OR. However, the 11-month median OS in the bioCT arm does not differ greatly from the best results with high-dose IL-2-containing regimens reported in the literature. Furthermore, our treatment schedule was carried out on outpatients and had an acceptable level of toxicity.     

Adjuvant high-dose interferon for cutaneous melanoma is most beneficial for patients with early stage III disease

BACKGROUND: Evidence from randomized trials in the pre-sentinel lymph node biopsy era indicate that adjuvant treatment with high-dose interferon-alpha (IFN) increases recurrence-free survival (RFS) in patients with high-risk melanoma. However, to the authors' knowledge, the role of this treatment in selected patients with early stage III disease has not been well studied. METHODS: The clinical and pathologic characteristics of 486 patients undergoing surgical treatment for stage III melanoma were evaluated and the authors compared outcomes for those given adjuvant treatment with IFN with those patients who had surgery alone. A particular focus was on the effect of IFN therapy on RFS and overall survival (OS) among those patients with stage IIIA disease. RESULTS: The median follow-up for the entire cohort was 5.2 years; the 5-year RFS and OS rates for the entire group were 41% and 53%, respectively. Adjuvant IFN was given to 141 patients (29%). On multivariate analysis, IFN was found to be the only independent predictor for RFS in patients with stage IIIA disease (hazards ratio of 0.4; 95% confidence interval, 0.2-0.9 [P = .02]). IFN was not found to be associated with increased RFS in patients with more advanced lymph node disease (stage IIIB and stage IIIC). IFN appeared to have no effect on OS in any patient with stage III disease. CONCLUSIONS: Adjuvant treatment with IFN improves RFS in melanoma patients with early stage III disease. The results of the current study should help guide management when considering adjuvant treatment for these patients.     

Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macrometastatic nodes: An open-label,randomised, phase 3 European Association for Dermato-Oncology (EADO) study

AimBoth low-dose interferon (IFN) alfa-2b and pegylated interferon (Peg-IFN) alfa-2b have been shown to be superior to observation in the adjuvant treatment of melanoma without macrometastatic nodes, but have never been directly compared. Peg-IFN facilitates prolongation of treatment, which could provide additional benefit. This multicentre, open-label, randomised, phase 3 trial compared standard low-dose interferon IFN and prolonged treatment with Peg-IFN.Patients and methodsPatients with resected melanoma ?1.5 mm thick and without clinically detectable node metastases were randomised 1:1 to treatment with IFN 3 MU subcutaneously (SC) three times weekly for 18 months or Peg-IFN 100 μg SC once weekly for 36 months. Sentinel lymph node dissection (SLND) was optional. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS) and adverse events (AEs) grade 3–4.ResultsOf 898 patients enrolled, 896 (443 Peg-IFN, 453 IFN) were eligible for evaluation (median follow-up 4.7 years). SLND was performed in 68.2% of patients. There were no statistical differences between the two arms for the primary outcome of DFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.73–1.15) or the secondary outcomes of DMFS (HR 1.02, 95% CI 0.80–1.32) and OS (HR 1.09, 95% CI 0.82–1.45). Peg-IFN was associated with higher rates of grade 3–4 AEs (47.3% versus 25.2%; p < 0.0001) and discontinuations (54.3% versus 30.4%) compared with IFN.ConclusionThis trial did not show superiority for adjuvant Peg-IFN over conventional low-dose IFN in melanoma patients without clinically detectable nodes. ClinicalTrials.gov identifier: NCT00221702.     

A phase II evaluation of all-trans-retinoic acid plus interferon alfa-2a in stage IV melanoma: a Southwest Oncology Group study

BACKGROUND: Interferon alfa has modest but definite activity in the treatment of metastatic melanoma and is the only agent currently available for adjuvant therapy of high-risk resected disease. A variety of retinoic acid derivatives have been shown to be synergistic with interferon alfa in vitro and in vivo, with nonoverlapping toxicities. If promising combinations of interferon alfa and retinoids could be developed for melanoma patients, they would have clinical relevance for the treatment of advanced as well as localized disease. PURPOSE: To determine the efficacy and toxicity of a combination of interferon alfa-2a and all-trans-retinoic acid in patients with measurable metastatic melanoma, the South-west Oncology Group conducted a phase II clinical trial. PATIENTS AND METHODS: Fifty-seven patients with measurable metastatic melanoma (American Joint Committee on Cancer stage IV) were entered; five patients were unevaluable. Treatment consisted of oral all-trans-retinoic acid (37.5 to 75 mg/m2 orally twice daily for 21 days followed by 7 days' rest) plus subcutaneously administered interferon alfa-2a (6 MU/m2 three times a week). RESULTS: Two complete and three partial responses were observed among 52 evaluable patients, for an objective response rate of 10% (95% confidence interval 3% to 21%). Responses were seen only in patients with pulmonary, nodal, or subcutaneous metastases, and lasted from 4 to 23+ months. Median survival for the 52 patients was 8 months. Side effects were tolerable but significant, with one case of grade IV anemia and 92% of patients experiencing at least grade II toxicity. Flu-like symptoms were the most commonly reported side effects. There was one case of grade III hyperlipidemia. CONCLUSION: The combination of recombinant human interferon alfa-2a with all-trans-retinoic acid did not result in a greater percentage of objective responses or a longer overall survival than that associated with interferon alfa alone. This combination cannot be recommended for further evaluation in melanoma in either the advanced disease or the adjuvant settings.     

Health-related quality of life in patients with high-risk melanoma randomised in the Nordic phase 3 trial with adjuvant intermediate-dose interferon alfa-2b

PurposeTo compare health-related quality of life (HRQoL) and side-effects in patients with high-risk melanoma participating in a randomised phase III trial of adjuvant interferon alfa-2b (IFN).Patients and methodsA total of 855 patients with histologically verified resected cutaneous melanoma in AJCC stage IIb (T4 N0 M0) or stage III (Tx N1-3 M0) were randomised to: Arm A: observation only (n = 284); Arm B: 1-year treatment: induction: IFN alfa-2b, 10 MU (flat dose), SC, 5 days/week, 4 weeks, maintenance: IFN alfa-2b, 10 MU (flat dose), SC, 3 days/week for 12 months (n = 285); or Arm C: 2 years of same treatment as Arm B. HRQoL was assessed using The European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) before randomisation and at 8 pre-defined time-points during 2 years. IFN-related side-effects were assessed by a study-specific questionnaire.Results>80% of eligible patients returned questionnaires at the different assessment points. Statistically significant interactions between randomisation arm and time after randomisation were found for almost all EORTC QLQ-30 variables. While patients in Arm A improved or remained at baseline levels; patients in Arms B and C reported decreased functioning and quality of life, and an increase in side-effects during their treatment. Patients in Arm B improved after the 12th month assessment, when IFN treatment was scheduled to end, to the 16th month assessment (p < 0.001). The same pattern of improvement was found for 5 of 7 interferon-related side-effects.ConclusionA significant negative impact on HRQoL of IFN treatment was demonstrated, however the impact were reversible when treatment was stopped.     

Update on adjuvant interferon therapy for high-risk melanoma

Melanoma is almost 100% curable when diagnosed early, but when metastatic to distant organs, it is associated with a poor survival. The interferons have shown the mostpromise in the treatment of melanoma and interferon-alpha has been the most extensively studied. In recent trials, interferon alfa-2b (Intron A) administered at maximally tolerated doses for 1 year produced improvements in both relapse-free and overall survival. The importance and impact of the IV induction component of high-dose interferon regimens is currently being evaluated in an Intergroup randomized trial. A trial of the GMK vaccine vs high-dose interferon in patients with high-risk melanoma closed early when an interim analysis detected a markedly inferior response in the GMK arm compared to the high-dose interferon arm. The use of surgical staging will help to better define prognostic groups and support ongoing efforts for more effective adjuvant therapy.     

Health management program: factors influencing completion of therapy with high-dose interferon alfa-2b for high-risk melanoma

The goal of the 1-year observational, multicentre, open-label study reported here was to identify factors influencing adherence to high-dose interferon alfa-2b adjuvant therapy in patients at high risk of recurrence following surgical excision of malignant melanoma. The study was carried out in 23 tertiary-care centres across Canada.The 225 patients enrolled in the study all had malignant melanoma that was surgically excised and that required adjuvant treatment with interferon alfa-2b. Of these patients, 64% were men. Mean age was 51.7 years. All patients received interferon alfa-2b treatment during a 4-week induction phase (20 MU/m(2) intravenously 5 days per week) followed by a 48-week maintenance phase (10 MU/m(2) subcutaneously 3 days per week).Oncology nurses reviewed side-effect management with the patients before the induction and maintenance phases. Patients were provided with daily diaries, comprehensive educational materials, and ongoing nursing support. Data on side effects and discontinuations were obtained from patient interviews and diaries. THE MAIN OUTCOME MEASUREMENTS WERE RELATED TO TREATMENT DISCONTINUATION: rate, timing, reason, and prevention. Of the 225 patients, 75 (33.3%) discontinued interferon during the induction phase, and 58 (25.8%) discontinued during the maintenance phase. The main reasons for discontinuation were adverse events (58%) and disease progression (26%). Patients with a daily fluid intake greater than 1.5 L were more likely to complete therapy than were those with an intake less than 1.5 L (64% vs. 36%, p < 0.0001).Of 225 patients enrolled in the interferon alfa-2b health management program, 41% completed the 1-year treatment course. Higher fluid intake (>1.5 L daily) was associated with increased adherence to therapy.     

Adjuvant high-dose interferon alfa-2b in patients with high-risk melanoma

We performed an analysis of toxicity and survival in stage III melanoma patients receiving adjuvant interferon alfa-2b (IFN). This was a retrospective single-arm analysis of 40 patients with stage III melanoma who received (IFN) administered at maximum tolerated doses of 20 mU/m2/day intravenously (i.v.) for 1 month and 10 mU/m2 three times per week subcutaneously (s.c.) for 48 weeks. Toxicity in our series is comparable to that experienced in the Eastern Cooperative Oncology Group (ECOG) 1684 trial, except for higher rates of dose-limiting myelosuppression and hepatotoxicity. All 40 patients experienced constitutional symptoms, but only 14/40 (35%) experienced grade 3 to 4 symptoms. Of the 40 patients, 36 (90%) experienced neurologic symptoms, but only seven (17.5%) experienced grade 3 to 4 neurotoxicity. Two patients stopped treatment because of severe psychiatric symptoms; one patient attempted suicide, and a psychosis developed in another. Thirty-nine (97.5%) patients experienced myelosuppression; 31 (77.5%) developing grade 3 to 4 myelosuppression. Hepatotoxicity was evident in 39 (97.5%) patients, and 26 (65%) experienced grade 3 to 4 hepatotoxicity. Three patients (7.5%) experienced mild renal toxicity. At a median follow-up of 27 months from initiation of therapy, there have been 19 relapses (47.5% disease-free survival [DFS]) and 10 deaths (75% OS) resulting from progression of disease. The DFS compares with the treatment arm in ECOG 1684 at 27 months, but overall survival is higher in our series of patients at the same time point. In a single program setting, IFN can be administered with similar side effects and outcome profiles seen in multi-institutional studies. Modifications in the induction regimen resulted in notably higher hematologic and hepatic toxicities but did not preclude administering further therapy and did not result in increased attrition rate among patients: only nine patients (22.5%) had their treatment stopped as a result of IFN-related toxicity. In comparison, 26% of patients had to have their treatment discontinued because of toxicity in ECOG 1684.     

Adjuvant treatment with pegylated interferon α-2a versus low-dose interferon α-2a in patients with high-risk melanoma: a randomized phase III DeCOG trial

BackgroundAdjuvant treatment with interferon (IFN)-α-2a improved disease-free survival (DFS) and showed a trend for improving overall survival (OS) in melanoma. This trial was designed to examine whether PEG-IFN is superior to IFN with regard to distant metastasis-free survival (DMFS), DFS and OS.Patients and methodsIn this multicenter, open-label, prospective randomized phase III trial, patients with resected cutaneous melanoma stage IIA(T3a)–IIIB (AJCC 2002) were randomized to receive PEG-IFN (180 μg subcutaneously 1×/week; 24 months) or IFN α-2a (3MIU subcutaneously 3×/week; 24 months). Randomization was stratified for stage, number of metastatic nodes, age and previous IFN treatment. The primary end point was DMFS; secondary end points were OS, DFS, quality of life (QoL) and tolerability.ResultsA total of 909 patients were enrolled (451 PEG-IFN versus 458 IFN). Neither 5-year DMFS [PEG-IFN 61.0% versus IFN 67.3%; hazard ratio (HR) 1.16, P = 0.21] nor 5-year OS (PEG-IFN 73.2% versus IFN 75.2%; HR 1.05, P = 0.70) nor 5-year DFS (PEG-IFN 57.3% versus IFN 60.9%; HR 1.09, P = 0.40) showed significant differences. Subgroup analyses in patients ± ulcerated primaries and of different tumor stages did not find differences in DMFS, OS or DFS between the treatment groups. One hundred and eighteen patients (26.2%) in the PEG-IFN and 61 patients (13.3%) in the IFN population did not receive the full dosage and length of treatment due to adverse events (P < 0.001). Leukopenia and elevation of liver enzymes were more common in the PEG-IFN arm (56% versus 23.5% LCP; 19.1% versus 9.4% AST; 33.0% versus 16.5% ALT). QoL was identical for nearly all domains.ConclusionPEG-IFN did not improve the outcome over IFN. A higher percentage of patients under PEG-IFN discontinued treatment due to toxicity.Clinical Trials.gov IdentifierNCT00204529.     

A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma.

PURPOSE: Nearly 2000 patients with stage IIB and III melanoma have participated in four multicenter, randomized trials, conducted by the Eastern Cooperative Oncology Group and the Intergroup, investigating adjuvant high-dose IFN-alpha 2b therapy. The objectives of this study were to update the analyses of each individual trial and to analyze prognostic factors and treatment effects based on pooled data. EXPERIMENTAL DESIGN: Survival and disease status were updated to April 2001. Analysis of prognostic factors using optimized statistical models was based on data from patients in E1684, E1690, E1694, and E2696. Analysis of treatment effects versus observation (Obs) was based on data from 713 patients randomized to high-dose IFN-alpha 2b (HDI) or Obs in Trials E1684 and E1690. RESULTS: Updated analysis of E1684, E1690, and E1694 confirmed their original conclusions, now at median follow-up intervals of 2.1-12.6 years. Based on two-sided univariate log-rank analysis of pooled data from E1684 and E1690 (median follow-up, 7.2 years), relapse-free survival (RFS)-but not overall survival (OS)-was significantly prolonged (two-sided log-rank P value = 0.006) for patients treated with HDI versus Obs. Among all patients, prognostic factors that significantly negatively impacted RFS and OS included ulceration, recurrent disease at entry, enrollment in E1684, and age > 49 years. Multivariate statistical models adjusting for these factors confirmed the statistically significant RFS benefit of HDI versus Obs but did not demonstrate a significant OS benefit in the pooled populations. CONCLUSIONS: In patients with high-risk resected melanoma, HDI is effective adjuvant therapy with strong evidence for improved RFS and evidence for moderate improvement in OS based on two prospective randomized studies but not the pooled analysis. Analyses of predictors of relapse and response are now needed to improve the therapeutic value of this modality.     

Intermediate- and high-risk melanoma

Opinion statement Intermediate and high risk for recurrence melanoma comprise a unique subset of patients with surgically treatable melanoma for whom cure is possible but relapse and distant metastases likely. Strategies to improve the prognosis for such patients with effective adjuvant therapies are critical. In recent randomized trials conducted by the cooperative groups in the United States of patients at high risk for recurrence (patients with thick primary melanomas and those with regional lymph node metastases) administered adjuvant therapy with high-dose interferon alfa-2b (HDI), relapse-free survival and overall survival rates improved significantly. Research efforts in this area continue to assess the role of intermediate-dose interferon, but there is no convincing evidence of success of the lower-dose regimens, despite the reduction in toxicity. For a subset of patients at highest risk (two or more involved lymph nodes), a regimen of therapy for metastatic stage IV melanoma (interleukin-2 based biochemotherapy) is being compared with HDI in an ongoing phase III trial. For intermediate-risk melanoma, no effective adjuvant therapy is available. For such patients, enrollment in ongoing clinical trials assessing the role of shorter courses of HDI or vaccines should be encouraged.     

Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: impact of HLA class I antigen expression on outcome.

PURPOSE: An association between expression of > or = two of five HLA class I antigens (HLA-A2, HLA-A28, HLA-B44, HLA-B45, and HLA-C3; collectively called M5) and response to an allogeneic melanoma vaccine (Melacine; Corixa Corporation, Seattle, WA) has been described in stage IV melanoma. This study investigated whether class I antigen expression impacted relapse-free survival (RFS) after adjuvant therapy with this vaccine. PATIENTS AND METHODS: We performed class I (HLA-A, HLA-B, and HLA-C) serotyping on patients enrolled onto Southwest Oncology Group Trial 9035, a randomized, observation-controlled, phase III trial of adjuvant Melacine. All patients had clinically node-negative cutaneous melanoma (1.5 to 4.0 mm). Interactions between treatment and class I antigen expression were tested. Analyses involved all serotyped patients and were adjusted for tumor thickness, method of nodal staging, sex, ulceration, and primary tumor site. RESULTS: HLA typing was performed on 553 (80%) of the 689 enrolled patients (294 vaccinated and 259 observed). Expression of > or = two M5 antigens was associated with a superior vaccine treatment effect. Among patients who matched > or = two of the M5, the 97 vaccine-treated patients had improved RFS compared with the 78 observation patients (5-year relapse-free survival, 83% v 59%; P =.0002). The major components of this effect were contributed by HLA-A2 and HLA-C3. Among those who were HLA-A2-positive and/or HLA-C3-positive, the 5-year RFS for vaccinated patients was 77%, compared with 64% for observation (P =.004). There was no impact of HLA-A2 and/or HLA-C3 expression among observation patients. CONCLUSION: This prospective analysis indicates a highly significant benefit of adjuvant therapy with Melacine among patients expressing > or = two of the M5 class I antigens, validating a prior observation in stage IV disease. HLA-A2 and HLA-C3 contributed most to this effect. Processed melanoma peptides found in Melacine may be presented by HLA-A2 and HLA-C3 and play a role in preventing relapse in vaccinated patients.     

Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial.

PURPOSE: The addition of cytokines to chemotherapy has produced encouraging results in advanced melanoma. In this phase III trial, we compared the effects of chemotherapy (cisplatin, vinblastine, and dacarbazine [CVD]) with those of sequential biochemotherapy consisting of CVD plus interleukin-2 and interferon alfa-2b. PATIENTS AND METHODS: Metastatic melanoma patients who had not previously received chemotherapy were stratified by prognostic factors and given chemotherapy or biochemotherapy. CVD consisted of dacarbazine (days 1 and 22) and cisplatin and vinblastine (days 1 to 4 and 22 to 25). Biochemotherapy involved CVD with vinblastine reduced 25% plus interleukin-2 by 24-hour continuous infusion (on days 5 to 8, 17 to 20, and 26 to 29) and interferon alfa-2b by subcutaneous injection (on days 5 to 9, 17 to 21, and 26 to 30). Response was assessed every 6 weeks. RESULTS: Among 190 patients enrolled, 91 were assessable for biochemotherapy and 92 for chemotherapy. Ten percent of the patients were alive a median of 52 months from start of therapy. Response rates were 48% for biochemotherapy and 25% for chemotherapy (P =.001); six patients given biochemotherapy and two given chemotherapy had complete responses. Median time to progression (TTP) was 4.9 months for biochemotherapy and 2.4 months for chemotherapy (P =.008); median survival was 11.9 and 9.2 months, respectively (P =.06). The influence of treatment on TTP and survival was confirmed in multivariate analyses with other prognostic factors not included in the original stratification. Biochemotherapy produced substantially more constitutional, hemodynamic, and myelosuppressive toxic effects. CONCLUSION: Cytokines substantially augment the antitumor activity of chemotherapy at the expense of considerable toxicity in patients with metastatic melanoma.