Prospective, randomized, multicenter, double-blind placebo-controlled trial comparing adjuvant interferon alfa and isotretinoin with interferon alfa alone in stage IIA and IIB melanoma: European Cooperative Adjuvant Melanoma Treatment Study Group. Sentinel-node biopsy or nodal observation in melanoma. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of >= 1.5 mm tumor thickness: results of a randomized phase III DeCOG trial. Intensified high-dose intravenous interferon alpha 2b (IFNa2b) for adjuvant treatment of stage III melanoma: A randomized phase III Italian Melanoma Intergroup (IMI) trial [ISRCTN75125874]. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. Adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma: a phase III randomized controlled trial of health-related quality of life and symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group. Multiplex Analysis of Serum Cytokines in Melanoma Patients Treated with Interferon-α2b Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial. Quality of life and cost-effectiveness of interferon-alpha in malignant melanoma: results from randomised trial Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. 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. Adjuvant interferon alpha 2b in high risk melanoma – the Scottish study Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma. Prospective randomized multicenter adjuvant dermatologic cooperative oncology group trial of low-dose interferon alfa-2b with or without a modified high-dose interferon alfa-2b induction phase in patients with lymph node-negative melanoma. Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. Randomized trial of an allogeneic melanoma lysate vaccine with low-dose interferon Alfa-2b compared with high-dose interferon Alfa-2b for Resected stage III cutaneous melanoma. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. Interferon-Gamma or Granulocyte-Macrophage Colony-Stimulating Factor Administered as Adjuvants With a Vaccine of Irradiated Autologous Tumor Cells From Short-Term Cell Line Cultures: A Randomized Phase 2 Trial of the Cancer Biotherapy Research Group A randomised phase II trial of 1 month versus 1 year of adjuvant high-dose interferon α-2b in high-risk acral melanoma patients. A randomized phase III trial of biochemotherapy versus interferon-&agr;-2b for adjuvant therapy in patients at high risk for melanoma recurrence Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial Postsurgical adjuvant therapy for melanoma Health-related Quality of Life Before and During Adjuvant Interferon-&agr; Treatment for Patients With Malignant Melanoma (DeCOG-Trial) Quality-of-life-adjusted survival analysis of high-dose adjuvant interferon alpha-2b for high-risk melanoma patients using intergroup clinical trial data. 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. Randomized trial of adjuvant human interferon gamma versus observation in high-risk cutaneous melanoma: a Southwest Oncology Group study. Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study. Randomized phase III trial of high-dose interferon alfa-2b (HDI) for 4 weeks induction only in patients with intermediate- and high-risk melanoma (Intergroup trial E 1697) . Ulceration as a Predictive Marker for Response to Adjuvant Interferon Therapy in Melanoma The Impact of Surgery on Survival of Patients With Cutaneous Melanoma: Revisiting the Role of Primary Tumor Excision Margins 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. Results of a prospective randomized trial using DTIC and interferon as adjuvant therapy for stage I malignant melanoma. Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon. Adjuvant high‐dose interferon for cutaneous melanoma is most beneficial for patients with early stage III disease 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.
PURPOSE The combination of interferon alfa ( IFNalpha ) and isotretinoin has shown a direct antiproliferative effect on human melanoma cell lines , but it remained unclear whether this combination is more effective than IFNalpha alone in patients with metastatic melanoma . We evaluated safety and efficacy of IFNalpha and isotretinoin compared with IFNalpha alone as adjuvant treatment in patients with primary malignant melanoma stage IIA and IIB . PATIENTS AND METHODS In a prospect i ve , r and omized , double-blind , placebo-controlled trial , 407 melanoma patients in stage IIA ( 301 patients ) and IIB ( 106 patients ) were r and omly assigned to either IFNalpha and isotretinoin ( isotretinoin group ; 206 patients ) or IFNalpha and placebo ( placebo group ; 201 patients ) after excision of the primary tumor . IFNalpha was administered three times a week at a dose of 3 million units subcutaneously for 24 months . Isotretinoin at a dose of 20 mg for patients < or = 73 kg , 30 mg for patients greater than 73 kg , or placebo daily for 24 months . RESULTS A scheduled interim analysis revealed no significant differences in survival rates , with the isotretinoin group and the placebo group showing 5-year disease-free survival rates of 55 % ( 95 % CI , 46 % to 65 % ) and 67 % ( 95 % CI , 59 % to 75 % ) , respectively , and overall 5-year survival rates of 76 % ( 95 % CI , 67 % to 84 % ) and 81 % ( 95 % CI , 74 % to 88 % ) , respectively . The trial was stopped for futility . CONCLUSION The addition of isotretinoin to an adjuvant treatment of low-dose IFNalpha in patients with stage IIA and IIB melanoma had no significant effect on disease-free or overall survival and is therefore not recommended BACKGROUND We evaluated the contribution of sentinel-node biopsy to outcomes in patients with newly diagnosed melanoma . METHODS Patients with a primary cutaneous melanoma were r and omly assigned to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred , or to wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy . RESULTS Among 1269 patients with an intermediate-thickness primary melanoma , the mean ( + /-SE ) estimated 5-year disease-free survival rate for the population was 78.3+/-1.6 % in the biopsy group and 73.1+/-2.1 % in the observation group ( hazard ratio for recurrence[corrected ] , 0.74 ; 95 % confidence interval [ CI ] , 0.59 to 0.93 ; P=0.009 ) . Five-year melanoma-specific survival rates were similar in the two groups ( 87.1+/-1.3 % and 86.6+/-1.6 % , respectively ) . In the biopsy group , the presence of metastases in the sentinel node was the most important prognostic factor ; the 5-year survival rate was 72.3+/-4.6 % among patients with tumor-positive sentinel nodes and 90.2+/-1.3 % among those with tumor-negative sentinel nodes ( hazard ratio for death , 2.48 ; 95 % CI , 1.54 to 3.98 ; P<0.001 ) . The incidence of sentinel-node micrometastases was 16.0 % ( 122 of 764 patients ) , and the rate of nodal relapse in the observation group was 15.6 % ( 78 of 500 patients ) . The corresponding mean number of tumor-involved nodes was 1.4 in the biopsy group and 3.3 in the observation group ( P<0.001 ) , indicating disease progression during observation . Among patients with nodal metastases , the 5-year survival rate was higher among those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed ( 72.3+/-4.6 % vs. 52.4+/-5.9 % ; hazard ratio for death , 0.51 ; 95 % CI , 0.32 to 0.81 ; P=0.004 ) . CONCLUSIONS The staging of intermediate-thickness ( 1.2 to 3.5 mm ) primary melanomas according to the results of sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy . ( Clinical Trials.gov number , NCT00275496 [ Clinical Trials.gov ] . ) BACKGROUND Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment . Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability . METHODS 1256 patients with resected stage III melanoma were r and omly assigned to observation ( n=629 ) or pegylated interferon alfa-2b ( n=627 ) 6 mug/kg per week for 8 weeks ( induction ) then 3 mug/kg per week ( maintenance ) for an intended duration of 5 years . R and omisation was stratified for microscopic ( N1 ) versus macroscopic ( N2 ) nodal involvement , number of positive nodes , ulceration and tumour thickness , sex , and centre . R and omisation was done with a minimisation technique . The primary endpoint was recurrence-free survival . Analyses were done by intention to treat . This study is registered with Clinical Trials.gov , number NCT00006249 . FINDINGS All r and omised patients were included in the primary efficacy analysis . 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses . The median length of treatment with pegylated interferon alfa-2b was 12 ( IQR 3.8 - 33.4 ) months . At 3.8 ( 3.2 - 4.2 ) years median follow-up , 328 recurrence events had occurred in the interferon group compared with 368 in the observation group ( hazard ratio 0.82 , 95 % CI 0.71 - 0.96 ; p=0.01 ) ; the 4-year rate of recurrence-free survival was 45.6 % ( SE 2.2 ) in the interferon group and 38.9 % ( 2.2 ) in the observation group . There was no difference in overall survival between the groups . Grade 3 adverse events occurred in 246 ( 40 % ) patients in the interferon group and 60 ( 10 % ) in the observation group ; grade 4 adverse events occurred in 32 ( 5 % ) patients in the interferon group and 14 ( 2 % ) in the observation group . In the interferon group , the most common grade 3 or 4 adverse events were fatigue ( 97 patients , 16 % ) , hepatotoxicity ( 66 , 11 % ) , and depression ( 39 , 6 % ) . Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 ( 31 % ) patients . INTERPRETATION Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant , sustained effect on recurrence-free survival PURPOSE Low-dose ( LD ) interferon ( IFN ) alfa ( LDI ) has demonstrated a consistent disease-free survival benefit for patients with clinical ly lymph node-negative melanoma in clinical trials . However , the optimal duration of treatment is still under discussion , and no previous trial has evaluated this question specifically . A prolongation of LDI from 18 months to 60 months might be of clinical benefit for patients with intermediate or high-risk melanoma . PATIENTS AND METHODS Eight hundred fifty patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness were included in this prospect i ve r and omized , multicenter trial in Germany and Austria . Patients had to be clinical ly lymph node-negative , and sentinel node biopsy ( SLNB ) was performed in a majority of cases . They were r and omly assigned to receive 3 MU IFNalpha2a three times a week subcutaneously for either 18 months ( arm A ) or 60 months ( arm B ) . Results Of 850 r and omly assigned patients , 840 were eligible for evaluation after a median follow-up of 4.3 years . Tumor thickness and other relevant prognostic factors were well balanced between both groups . SLNB was performed in 635 patients ( 75.6 % ) , with a positivity rate of 18.0 % in arm A and 17.5 % in arm B. Neither relapse-free survival ( arm A , 75.6 % v arm B , 72.6 % ; P = .72 ; hazard ratio , 1.05 ; 95 % CI , 0.80 to 1.39 ) nor distant-metastasis-free survival ( 81.9 % v 79.7 % ; P = .56 ; HR , 1.10 ; 95 % CI , 0.80 to 1.52 ) or overall survival ( 85.9 % v 84.9 % ; P = .86 ; HR , 1.03 ; 95 % CI , 0.71 to 1.50 ) showed significant differences . CONCLUSION A prolongation of conventional LDI therapy from 18 to 60 months showed no clinical benefit in patients with intermediate and high-risk primary melanoma 8506 Background : High dose IFNalfa2b , according to the ECOG 1684 schedule , is the only approved adjuvant treatment for stage III melanoma . The risk/benefit profile has limited its use , while efficacy of intravenous ( iv ) phase and optimal duration have not been defined . The IMI Mel . A. trial evaluated the efficacy and safety of a pulsed high dose iv IFNa2b regimen . METHODS Following lymphadenectomy , stage III ( AJCC2002 ) patients ( pts ) , were r and omly assigned to either 4 courses of IFNa2b 20 MU/m2iv 5 d/wk for 4 wks every other month ( IHDI arm ) or the st and ard high dose regimen of a 4 week iv course followed by 10 MU/m2IFNa2b sc 3 times/wk for 11 months ( HDI Arm ) . Overall survival ( OS ) was the primary end point . The sample size of 328 pts and 118 deaths was determined assuming a 55 % 5-y OS for HDI and an increase of 15 % in IHDI ( β=20 % , α=5 % , 2-sided test ) . RESULTS From 1998 to 2010 , 336 pts were r and omized and 330 evaluated for OS : 172 in IHDI , 158 in HDI . Pts were well balanced according to age , sex , PS ( WHO ) , tumor ulceration ( 41 % vs 46 % ) and number of metastatic lymph-nodes ( N1 : 64 % vs 60 % , N2 : 22 % vs 28 % , N3 : 13 % vs 10 % ) . Relapse occurred in 87 ( IHDI : 50.6 % ) vs 80 ( HDI : 50,6 % ) pts with a median relapse free survival ( RFS ) time of 47.9 ( IHDI ) vs 35.6 ( HDI ) months , not statistically different and a 5-y RFS of 45.8 % ( 95%CI : 37.4;53.7 ) in IHDI vs 44.3 % ( 95%CI : 35.7;52.6 ) in HDI arm . 72 pts ( 40.8 % ) died in IHDI arm vs 64 ( 40.7 % ) in HDI arm . The median and 5-y OS were 88.7 months ( 95%CI : 61.2;- ) and 60.1 % ( 95%CI : 53;66.5 ) in IHDI vs 82.6 ( 95%CI : 45.8;- ) and 52.7 % ( 95%CI : 44.9;59.8 ) in HDI arm , and were not significantly different . Discontinuation due to toxicity or refusal was 20 % in IHDI vs 28 % in HDI with 66 % of pts in IHDI completing the treatment vs 49 % in HDI ( p=0.0026 ) . The distribution of all grade s of toxicity was similar in both groups , except for leucopenia , higher in IHDI arm ( 23 % vs 12 % , p=0.0331 ) . CONCLUSIONS Our data show that a shorter but more intensive HDI regimen is more feasible and not more toxic than conventional HDI . No significant differences in efficacy were observed and a meta- analysis of our and DeCog Ma-ADJ-5 trial data could better establish the role of iv HDI BACKGROUND Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib ( PLX4032 ) have shown response rates of more than 50 % in patients with metastatic melanoma with the BRAF V600E mutation . METHODS We conducted a phase 3 r and omized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated , metastatic melanoma with the BRAF V600E mutation . Patients were r and omly assigned to receive either vemurafenib ( 960 mg orally twice daily ) or dacarbazine ( 1000 mg per square meter of body-surface area intravenously every 3 weeks ) . Co primary end points were rates of overall and progression-free survival . Secondary end points included the response rate , response duration , and safety . A final analysis was planned after 196 deaths and an interim analysis after 98 deaths . RESULTS At 6 months , overall survival was 84 % ( 95 % confidence interval [ CI ] , 78 to 89 ) in the vemurafenib group and 64 % ( 95 % CI , 56 to 73 ) in the dacarbazine group . In the interim analysis for overall survival and final analysis for progression-free survival , vemurafenib was associated with a relative reduction of 63 % in the risk of death and of 74 % in the risk of either death or disease progression , as compared with dacarbazine ( P<0.001 for both comparisons ) . After review of the interim analysis by an independent data and safety monitoring board , crossover from dacarbazine to vemurafenib was recommended . Response rates were 48 % for vemurafenib and 5 % for dacarbazine . Common adverse events associated with vemurafenib were arthralgia , rash , fatigue , alopecia , keratoacanthoma or squamous-cell carcinoma , photosensitivity , nausea , and diarrhea ; 38 % of patients required dose modification because of toxic effects . CONCLUSIONS Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation . ( Funded by Hoffmann-La Roche ; BRIM-3 Clinical Trials.gov number , NCT01006980 . ) PURPOSE Interferon ( IFN ) -based adjuvant therapy in melanoma is associated with significant side effects , which necessitates evaluation of health-related quality of life ( HRQOL ) . Our trial examined the HRQOL effects of adjuvant pegylated IFN-alpha-2b ( PEG-IFN-alpha-2b ) versus observation in patients with stage III melanoma . METHODS A total of 1,256 patients with stage III melanoma were r and omly assigned after full lymphadenectomy to receive either observation ( n = 629 ) or PEG-IFN-alpha-2b ( n = 627 ) : induction 6 micrograms/kg/wk [ DOSAGE ERROR CORRECTED ] for 8 weeks then maintenance 3 micrograms/kg/wk [ DOSAGE ERROR CORRECTED ] for an intended total duration of 5 years . The European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 was used to assess HRQOL . RESULTS At 3.8 years of median follow-up , for the primary end point , recurrence-free survival ( RFS ) , risk was reduced by 18 % ( hazard rate = 0.82 ; P = .01 ) in the PEG-IFN-alpha-2b arm compared with observation . Significant and clinical ly meaningful differences occurred with the PEG-IFN-alpha-2b treatment arm compared with the observation group , showing decreased global HRQOL at month 3 ( -11.6 points ; 99 % CI , -8.2 to -15.0 ) and year 2 ( -10.5 points ; 99 % CI , -6.6 to -14.4 ) . Many of the other scales showed statistically significant differences between scores when comparing the two arms . From a clinical point of view , important differences were found for five scales : two functioning scales ( social and role functioning ) and three symptom scales ( appetite loss , fatigue , and dyspnea ) , with the PEG-IFN-alpha-2b arm being most impaired . CONCLUSION PEG-IFN-alpha-2b leads to a significant and sustained improvement in RFS . There is an expected negative effect on global HRQOL and selected symptoms when patients undergo PEG-IFN-alpha-2b treatment Purpose : Interferon (IFN)-α2b is the only Food and Drug Administration – approved treatment for operable high-risk melanoma that has been shown to significantly and durably prolong relapse-free survival ( RFS ) of patients with stage IIB-III melanoma . Development of reliable serum assays may contribute to the development of methods for earlier detection of melanoma and the selection of patients who may be most susceptible to current available interventions with IFNα . Experimental Design : A powerful high-throughput xMAP multiplex immunobead assay technology ( Luminex Corp. , Austin , TX ) was used to simultaneously test 29 cytokines , chemokines , angiogenic as well as growth factors , and soluble receptors in the sera of 179 patients with high-risk melanoma and 378 healthy individuals . Results : Serum concentrations of interleukin (IL)-1α , IL-1β , IL-6 , IL-8 , IL-12p40 , IL-13 , granulocyte colony-stimulating factor , monocyte chemoattractant protein 1 ( MCP-1 ) , macrophage inflammatory protein (MIP)-1α , MIP-1β , IFNα , tumor necrosis factor (TNF)-α , epidermal growth factor , vascular endothelial growth factor ( VEGF ) , and TNF receptor II were found to be significantly higher in patients with resected high-risk melanoma compared with healthy controls . Bayesian Network algorithm classification of the data offered 90 % sensitivity at 98 % specificity with 96.5 % of melanoma patients distinguished from healthy individuals . IFN-α2b therapy result ed in a significant decrease of serum levels of immunosuppressive and tumor angiogenic/growth stimulatory factors ( VEGF , epidermal growth factor , and hepatocyte growth factor ) and increased levels of antiangiogenic IFN-γ inducible protein 10 ( IP-10 ) and IFN-α . Pretreatment levels of proinflammatory cytokines IL-1β , IL-1α , IL-6 , TNF-α , and chemokines MIP-1α and MIP-1β were found to be significantly higher in the serum of patients with longer RFS values of 1 to 5 and > 5 years when compared with patients with shorter RFS of < 1 year . Conclusion : These data show that multiplexed analysis of serum biomarkers is useful for the evaluation of prognostic markers of clinical outcome and potential predictive markers of response to IFN-α2b in patients with high-risk operable melanoma BACKGROUND Adjuvant high-dose interferon alfa-2b improves relapse-free survival ( RFS ) in patients with high-risk melanoma , although benefits in overall survival are uncertain . Because of the toxic effects of high-dose regimens , intermediate doses are being explored . We investigated whether adjuvant therapy with intermediate-dose interferon alfa-2b for 1 or 2 years would improve outcomes in patients with stage IIB-IIC or III resected cutaneous melanoma . METHODS This r and omised , open-label , phase 3 , parallel-group trial was undertaken between 1996 and 2004 . 855 patients were r and omly assigned at 35 centres in the Nordic countries by block r and omisation to three groups : observation only ( group A ) ; 4 weeks of induction ( interferon alfa-2b 10 million units flat dose subcutaneously 5 days per week ) followed by 12 months of maintenance therapy ( interferon alfa-2b 10 million units flat dose subcutaneously 3 days per week ; group B ) ; or 1 month of induction and 24 months of maintenance ( group C ) . Neither investigators nor patients were masked to treatment assignment . Patients were stratified for country and tumour stage ; patients with stage III disease were further stratified for presence of metastatic lymph nodes at primary diagnosis versus at relapse , palpable versus non-palpable lymph-node metastases , and number of metastatic lymph nodes . The primary endpoint was overall survival in the two interferon alfa-2b groups combined . Analyses were by intention to treat . This study is registered with Clinical Trials.gov , number NCT01259934 . FINDINGS 284 patients were assigned to group A , 285 to group B , and 286 to group C ; all patients were analysed . The median follow-up time was 72·4 months ( IQR 46·9 - 98·0 ) . We recorded no significant improvement in overall survival in patients given interferon alfa-2b compared with observation : median overall survival was 56·1 months ( IQR 22·3 to > 120·0 ) in group A , 72·1 months ( 25·8 to > 120 ) in group B , and 64·3 months ( 24·7 to > 120 ) in group C ( p=0·600 ) . Hazard ratios ( HR ) for overall survival were 0·91 ( 95 % CI 0·74 - 1·10 ; p=0·642 ) for groups B and C combined versus observation ; 0·91 ( 0·72 - 1·14 ; p=0·652 ) for group B versus observation ; and 0·91 ( 0·72 - 1·15 ; p=0·858 ) for group C versus observation . Median RFS was 23·2 months ( IQR 5·6 to < 120 ) in group A , 37·8 months ( 10·8 to > 120 ) in group B , and 28·6 months ( 8·6 to > 120 ) in group C ( p=0·034 ) . HRs for RFS were 0·80 ( 0·67 - 0·96 ; p=0·030 ) for groups B and C combined versus observation , 0·77 ( 0·63 - 0·96 ; p=0·034 ) for group B versus observation , and 0·83 ( 0·68 - 1·03 ; p=0·178 ) for group C versus observation . The most common grade 3 and 4 adverse events were fatigue ( five in group A [ 1·8 % ] , 28 in group B [ 9·8 % ] , and 32 in group C [ 11·2 % ] ) , myalgia ( three [ 1·1 % ] , 15 [ 5·3 % ] , 14 [ 4·9 % ] , respectively ) , and thrombocytopenia ( 15 [ 5·3 % ] , 23 [ 8·1 % ] , eight [ 2·8 % ] , respectively ) . INTERPRETATION Adjuvant therapy with intermediate-dose interferon alfa-2b did not significantly improve overall survival . Interferon alfa-2b with 1-year maintenance therapy significantly improved RFS , but we recorded no significant effect for 2-year maintenance therapy . Further research is in progress to define the subgroup of patients who benefit from adjuvant interferon alfa-2b . FUNDING Schering-Plough ( now Merck ) ; the Radiumhemmet Research Funds , Stockholm ; the Stockholm County Council ; and the Swedish Cancer Society A definitive conclusion regarding the value of low-dose extended duration adjuvant interferon-alpha therapy in the treatment of malignant melanoma is only possible once data on health-related quality of life ( HRQoL ) and costs have been considered . This trial r and omised 674 patients to interferon alpha-2a  ( 3 megaunits three times per week for 2 years or until recurrence ) or placebo . Health-related quality of life ( QoL ) was to be assessed up to 60 months using the European Organisation for Research and Treatment of Cancer ( EORTC ) QLQ-C30 . Data for the economic analysis , including cost information and the EQ-5D were also collected . Patients in the observation ( OBS ) group had significantly better mean follow-up quality of on five dimensions of the EORTC QLQ-C30 functional scales : role functioning ( P=0.033 ) , emotional functioning ( P=0.003 ) , cognitive functioning ( P=0.001 ) , social functioning ( P=0.003 ) and global health status ( P=0.001 ) . Patients in the OBS group had significantly better mean follow-up symptom scores on seven dimensions of the EORTC QLQ-C30 V1 symptom scales . Economic data showed that costs were £ 3066 higher in the interferon group and produces an incremental cost per quality -adjusted life year of £ 41 432 at 5 years . The results show that interferon has significant effects on QoL and symptomatology and is unlikely to be cost-effective in this patient group in the UK PURPOSE Adjuvant high-dose interferon-alfa-2b ( HDI ) improves disease-free and overall survival in patients with high-risk melanoma . However , its mechanism of action is largely unknown . Therefore , HDI was investigated in the neoadjuvant setting to assess clinical and pathologic responses after 4 weeks of HDI and to perform immunohistochemical evaluation of immune cell subsets and melanoma-associated antigens . PATIENTS AND METHODS Patients with palpable regional lymph node metastases from melanoma ( American Joint Committee on Cancer stage IIIB-C ) underwent surgical biopsy at study entry and then received st and ard intravenous HDI ( 20 million units/m2 , 5 days per week ) for 4 weeks followed by complete lymphadenectomy and st and ard maintenance subcutaneous HDI ( 10 million units/m2 3 times per week ) for 48 weeks . Biopsy sample s were obtained before and after intravenous HDI and subjected to immunohistochemical analysis as well as routine pathologic study . RESULTS Twenty patients were enrolled , and biopsy sample s were informative for 17 . Eleven patients ( 55 % ) demonstrated objective clinical response , and 3 patients ( 15 % ) had complete pathologic response . At a median follow-up of 18.5 months ( range , 7 months to 50 months ) 10 patients had no evidence of recurrent disease . Clinical responders had significantly greater increases in endotumoral CD11c+ and CD3 + cells and significantly greater decreases in endotumoral CD83 + cells compared with nonresponders . No changes in the expression of melanoma-associated lineage antigens , tumor cell proliferation , angiogenesis , or apoptosis were evident . CONCLUSION Neoadjuvant HDI is highly effective for the treatment of palpable stage IIIB-C melanoma , and the findings of this study implicate an indirect immunomodulatory mechanism rather than a direct antitumor mechanism 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 prospect i ve , r and omized , 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 PURPOSE Vaccine alternatives to high-dose interferon alfa-2b therapy ( HDI ) , the current st and ard 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 prospect i ve , r and omized , 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 r and omized ( 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 In 1989 , the Scottish melanoma group initiated a r and omized trial , comparing observation alone with 6 months ' therapy with low dose interferon α ( given subcutaneously 3 MU day–1 , thrice weekly ) , for patients with primary melanomas of at least 3 mm Breslow thickness , or with evidence of regional node involvement . The trial was closed in 1993 with only 95 eligible patients r and omized . There were no toxic deaths , and no patient failed to complete the treatment for reasons of toxicity . 6 months ' treatment with low-dose interferon-α result ed in a statistically significant improved disease-free survival for up to 24 months after r and omization ( P < 0.05 ) . However , at a median follow-up of over 6 years , although there was an apparent improvement in disease-free survival ( from 9 to 22 months ) , and overall survival ( from 27 to 39 months ) , consistent with larger studies powered to detect such differences , these differences were not statistically significant . The data therefore suggest that 6 months of low-dose interferon is active , and confirm the importance of the large r and omized studies , such as the UKCCCR AIM -High and EORTC trials , that seek to confirm a possible survival advantage for low or intermediate dose interferon . © 2001 Cancer Research Campaign PURPOSE A high-dose interferon alfa ( IFN-alpha ) regimen as reported in E1684 was unique for the incorporation of an induction phase of maximally tolerated dosages of intravenous ( IV ) therapy for the initial 4 weeks . This is the only trial that has shown prolongation of overall survival and relapse-free survival ( RFS ) in comparison with observation . Analysis of the hazard curves for RFS and overall survival ( OS ) in E1684 revealed separation of the high-dose and observation arms , suggesting that the induction phase may represent a critical component of this regimen , although this has not been tested prospect ively . PATIENTS AND METHODS We conducted a prospect i ve r and omized study of IV induction therapy versus a full year of high-dose IFN , with primary end points of RFS and OS for patients with stage IIB , IIC , and III melanoma , within 56 days of curative surgery . Patients were r and omly assigned to receive IFN-alpha-2b 15 x 10(6 ) U/m2 IV x 5/7 days weekly x 4 weeks ( arm A ) versus the same regimen followed by IFN-alpha-2b 10 x 10(6 ) U ( flat dose ) administered subcutaneously three times a week for 48 weeks ( arm B ) . RESULTS Between 1998 and 2004 , 364 patients were enrolled ( 353 eligible : arm A , n = 177 ; arm B , n = 176 ) . At a median follow-up of 63 months ( 95 % CI , 58.1 to 67.7 ) , the median RFS was 24.1 months versus 27.9 months ( P = .9 ) and the median OS was 64.4 months versus 65.3 months ( P = .49 ) . Patients in arm B had more grade 1 to 2 hepatotoxicity , nausea/vomiting , alopecia , and neurologic toxicity . CONCLUSION There were no significant differences in OS and RFS between the regimens of 1 month and 1 year of treatment PURPOSE Interferon alfa ( IFN-alpha ) has shown clinical efficacy in the adjuvant treatment of patients with high-risk melanoma in several clinical trials , but optimal dosing and duration of treatment are still under discussion . It has been argued that in high-dose IFN-alpha ( HDI ) , the intravenous ( IV ) induction phase might be critical for the clinical benefit of the regimen . PATIENTS AND METHODS In an attempt to investigate the potential role of a modified high-dose induction phase , lymph node-negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness were included in this prospect i ve r and omized multicenter Dermatologic Cooperative Oncology Group trial . Six hundred seventy-four patients were r and omly assigned to receive 4 weeks of a modified HDI scheme . This schedule consisted of 5 times weekly 10 MU/m(2 ) IFN-alpha-2b IV for 2 weeks and 5 times weekly 10 MU/m(2 ) IFN-alpha-2b administered subcutaneously ( SC ) for another 2 weeks followed by 23 months of low-dose IFN-alpha-2b ( LDI ) 3 MU SC three times a week ( arm A ) . LDI 3 MU three times a week was given for 24 months in arm B. Results Of 650 assessable patients , there were 92 relapses among the 321 patients receiving high-dose induction as compared with 95 relapses among the 329 patients receiving LDI only . Five-year relapse-free survival rates were 68.0 % ( arm A ) and 67.1 % ( arm B ) , respectively . Likewise , melanoma-related fatalities were similar between both groups , result ing in 5-year overall survival rates of 80.2 % ( arm A ) and 82.9 % ( arm B ) . CONCLUSION The addition of a 4-week modified HDI induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome PURPOSE We conducted a r and omized prospect i ve trial in selected patients with fully resected high-risk stage I and II malignant melanoma . PATIENTS AND METHODS Interferon alfa-2a ( IFN-alpha 2a ) 20 x 10(6 ) U/m2 was administered three times each week for 12 weeks by the intramuscular route . Both the treatment group ( n = 131 ) and the control group ( n = 131 ) were evenly balanced with regard to relevant prognostic discriminants . RESULTS The median disease-free survival ( DFS ) time was 2.4 years for the IFN-alpha 2a group and 2.0 years for the observation group ( log-rank P = 0.19 ) . The median survival times were 6.6 years for IFN-alpha 2a and 5.0 years for observation ( log-rank P = .40 ) . For stage I patients ( n = 102 ) , there was no apparent therapeutic advantage from IFN-alpha 2a therapy . The DFS for stage II patients was a median of 10.8 months in the control group versus 17 months in the treatment group . The overall survival time was 4.1 years for the treatment group versus 2.7 years for the control group . The differences in DFS for stage II patient were significant in a Cox model . These results must be interpreted cautiously because of subset analysis . A severe flu-like toxicity occurred in 44 % of patients , 13 % lost at least 10 % of their baseline weight , and 45 % experienced a worsening of Eastern Cooperative Oncology Group ( ECOG ) performance score . CONCLUSION Our findings indicate trends that suggest a possible benefit for selected patients with high-risk malignant melanoma . The results will require further study in a larger patient population for confirmation PURPOSE To compare the overall survival ( OS ) of patients with resected stage III melanoma administered active specific immunotherapy and low-dose interferon alfa-2b ( IFN-alpha-2b ) with the OS achieved using high-dose IFN-alpha-2b . PATIENTS AND METHODS An Ad Hoc Melanoma Working Group of 25 investigators treated 604 patients from April 1997 to January 2003 . Patients were stratified by sex and number of nodes and were r and omly assigned to receive either 2 years of treatment with active specific immunotherapy with allogeneic melanoma lysates and low-dose IFN-alpha-2b ( arm 1 ) or high-dose IFN-alpha-2b alone for 1 year ( arm 2 ) . Active specific immunotherapy was injected subcutaneously ( SC ) weekly for 4 weeks , at week 8 , and bimonthly thereafter . IFN-alpha-2b SC was begun on week 4 and continued thrice weekly at 5 MU/m2 for 2 years . IFN-alpha-2b in arm 2 was administered according to the Eastern Cooperative Oncology Group 1684 study regimen . RESULTS Median follow-up time was 32 months for all patients and 42 months for surviving patients . Median OS time exceeds 84 months in arm 1 and is 83 months in arm 2 ( P = .56 ) . Five-year OS rate is 61 % in arm 1 and 57 % in arm 2 . Estimated 5-year relapse-free survival ( RFS ) rate is 50 % in arm 1 and 48 % in arm 2 , with median RFS times of 58 and 50 months , respectively . The incidence of serious adverse events as a result of treatment was the same in both arms , but more severe neuropsychiatric toxicity was seen in arm 2 . CONCLUSION OS and RFS achieved by active specific immunotherapy and low-dose IFN-alpha-2b were indistinguishable from those achieved by high-dose IFN-alpha-2b . Long RFS and OS times were observed in both treatment arms PURPOSE Interferon alfa-2b ( IFN alpha-2b ) exhibits antitumor activity in metastatic melanoma and on this basis has been evaluated as an adjuvant therapy following surgery for deep primary ( T4 ) or regionally metastatic ( N1 ) melanoma . METHODS A r and omized controlled study of IFN alpha-2b ( Schering-Plough , Kenilworth , NJ ) administered at maximum-tolerated doses of 20 MU/m2/d intravenously ( i.v . ) for 1 month and 10 MU/m2 three times per week subcutaneously ( SC ) for 48 weeks versus observation , was conducted by the Eastern Cooperative Oncology Group ( ECOG ) in 287 patients . RESULTS A significant prolongation of relapse-free survival ( P = .0023 , one-sided ) and prolongation of overall survival ( P = .0237 , one-sided ) was observed with IFN alpha-2b therapy in this trial , which is now mature with a median follow-up time of 6.9 years . The impact of treatment on relapse rate is most pronounced early during the treatment interval . The overall benefit of treatment in this trial was analyzed stratified by tumor burden and the presence or absence of microscopic nonpalpable and palpable regional lymph node metastasis . The benefit of therapy with IFN alpha-2b was greatest among node-positive strata . Toxicity of IFN alpha-2b required dose modification in the majority of patients , but treatment at > or = 80 % of the scheduled dose was feasible in the majority of patients through the IV phase of treatment , and for more than 3 months of SC maintenance therapy . Discontinuation of treatment due to toxicity was infrequent after the fourth month of therapy . CONCLUSION IFN alpha-2b prolongs the relapse-free interval and overall survival of high-risk resected melanoma patients . The increment in median disease-free survival ( from 1 to 1.7 years ) and overall survival ( from 2.8 to 3.8 years ) that results from this therapy is associated with a 42 % improvement in the fraction of patients who are continuously disease-free after treatment with IFN ( from 26 % to 37 % ) in comparison to observation . IFN alpha-2b is the first agent to show a significant benefit in relapse-free and overall survival of high-risk melanoma patients in a r and omized controlled trial The objective was to study the effects of patient-specific vaccine immunotherapy administered with either interferon-gamma ( IFN&ggr ; ) or granulocyte-macrophage colony stimulating factor ( GM-CSF ) in patients with metastatic cancer . Short-term cell lines were established from cancer tissue resected from patients with metastatic cancer for use as autologous tumor cell vaccines . Successful cultures were exp and ed to 1 to 2 × 108 cells , irradiated , and cryopreserved in aliquots of 106 cells for intradermal testing of delayed tumor hypersensitivity and 107 cells for subcutaneous vaccinations . The study design was that of a r and omized phase 2 trial . Patients were stratified by tumor type and by whether they had measurable disease at the time vaccination was to commence , and then r and omized to receive either 100 MIU IFN&ggr ; subcutaneously or 500 & mgr;g GM-CSF subcutaneously at the time of each tumor cell vaccination . Following a baseline test of delayed-type hypersensitivity ( DTH ) to an intradermal injection of 106 irradiated autologous tumor cells , patients received 3 weekly subcutaneous injections of 107 cells , had a repeat DTH test at week 4 , then received monthly vaccinations for 5 months . A positive DTH test was defined as at least 10 mm of in duration ; survival was determined from the first DTH test . There were 98 patients enrolled with a median follow-up of over 4 years . The most prevalent diagnoses were melanoma ( 51 ) , renal cell carcinoma ( 18 ) , and soft-tissue sarcoma ( 14 ) . There were 49 patients ( 26 men , 23 women , average age 50.4 years ) r and omized to IFN&ggr ;  and 49 ( 28 men , 21 women , average age 54.1 years ) to GM-CSF . The average numbers of vaccine and adjuvant injections were 6.3 and 5.9 , respectively . For the patients who received IFN&ggr ; , the objective response rate was 0 of 21 ; for patients who received GM-CSF the response rate was 1 of 26 . Only eight patients ( four from each arm ) had a positive baseline DTH reaction to autologous tumor . The tumor DTH test converted from negative to positive in 13 of 45 of the IFN&ggr ; group and 11 of 43 of the GM-CSF group . With 29 patients deceased in the IFN&ggr ;  arm and 31 in  the GM-CSF arm , the 2-year and 5-year survival rates were 45 % and 29 % for the IFN&ggr ; arm and 41 % and 23 % for the GM-CSF arm ( NSD ) . Both adjuvants were well tolerated and results were similar in both arms of the study . Both adjuvants were associated with a 25 % to 30 % rate of DTH conversion and a 25 % 5-year survival rate . Immune recognition of autologous tumor can be induced with this approach BACKGROUND High-dose Interferon-α-2b ( HD-IFN ) is an adjuvant treatment for melanoma . However , clinical trials for HD-IFN have not been reported in acral melanoma ( AM ) , the predominant subtype of cutaneous melanoma in Asian population . METHODS Patients with resected high-risk ( stage IIb-IIIc ) AM were r and omly assigned to a regimen of 4-week ( arm A : 15 × 10(6)U/m(2)d1 - 5/w × 4w ) or 1-year adjuvant HD-IFN ( arm B : 15 × 10(6)U/m(2)d1 - 5/w × 4w+9 × 10(6)Utiw × 48w ) , respectively . The endpoints were relapse-free survival ( RFS ) , overall survival ( OS ) and toxicities . RESULTS A total of 158 patients were enrolled in this study and 147 patients were eligible for survival analysis . With a median follow-up of 36.1 months , median RFS for arm A and arm B were 17.9 months and 22.5 months , respectively ( P=0.72 ) . Stratified analysis showed that RFS curves of patients in stage IIIb-IIIc were statistically different between arm A and arm B ( P=0.02 ) . The median RFS of patients with more nodal metastases ( n⩾3 ) was shorter ( P=0.004 ) in arm A ( 3.3 months ) than that in arm B ( 11.9 months ) . Grade 1/2 adverse effects were observed in both groups . However , patients in arm B showed higher incidence of reversible Grade 3/4 hepatotoxicity ( P=0.03 ) . CONCLUSIONS The induction dose of 15 × 10(6)U/m(2 ) and the maintenance dose of 9 × 10(6)U were tolerable , which may be the optional dose intensity for adjuvant IFN-α-2b  therapy in Chinese high risk AM population . No statistical significance was detected in RFS between the 4-week and 1-year regimen while a 1-year regimen may show clinical benefits in patients with stage IIIb-IIIc AM or with ≥ 3 nodal metastases The objective of this study was to compare the clinical benefit of biochemotherapy and interferon-&agr;-2b ( IFN ) as adjuvant therapy . Biochemotherapy has higher response rates than other regimens in patients with metastatic melanoma . We conducted a r and omized phase III study comparing the clinical benefit of biochemotherapy and IFN as adjuvant therapy . Patients who had undergone lymphadenectomy for melanoma metastatic to regional lymph nodes were r and omly assigned to either biochemotherapy or IFN , and IFN patients were further r and omized to either high-dose IFN ( HDI ) or intermediate-dose IFN ( IDI ) . The primary end point was relapse-free survival ( RFS ) ; the secondary end point was overall survival ( OS ) . The planned enrollment was 200 patients , the number required to have 80 % power to detect , at a significance level of 5 % , an improvement in median RFS from 18 to 36 months and an improvement in median OS from 40 to 80 months between the IFN and biochemotherapy groups . A futility analysis was performed because of slow accrual . One hundred and thirty-eight patients were enrolled – 71 in the biochemotherapy group , 34 in the HDI subgroup , and 33 in the IDI subgroup . No significant differences in median RFS or OS between the HDI and IDI subgroups were observed . With a median follow-up of 49.3 months , neither the biochemotherapy nor IFN group had reached median RFS or OS , and there were no significant differences in estimated median RFS or OS ( P=0.86 and 0.45 , respectively ) between the two groups . Biochemotherapy is not more effective than IFN as adjuvant therapy for melanoma . These findings support early termination of this trial PURPOSE Patients with primary cutaneous melanoma with a Breslow thickness > or = 1.5 mm have only a 30 % to 70 % probability of survival after surgery , and no adjuvant therapy has so far improved this outcome . Since interferon alfa-2a ( IFNalpha2a ) exhibits antitumor activity in metastatic melanoma , we investigated whether adjuvant IFNalpha2a diminishes the occurrence of metastases and thus prolongs disease-free survival in melanoma patients after excision of the primary tumor . PATIENTS AND METHODS In a prospect i ve r and omized study , 311 melanoma patients with a Breslow thickness > or = 1.5 mm were assigned to either adjuvant IFNalpha2a treatment ( n = 154 ) or observation ( n = 157 ) after excision of the primary tumor . IFNalpha2a was given daily at a dose of 3 mIU subcutaneously ( s.c . ) for 3 weeks ( induction phase ) , after which a dose of 3 mIU s.c . three times per week was given over 1 year ( maintenance phase ) . RESULTS Prolonged disease-free survival was observed in patients treated with IFNalpha2a versus those who underwent surgery alone . This difference was significant ( P = .02 ) for all patients enrolled onto the study ( intention-to-treat analysis ) at a mean observation time of 41 months . Subgroup analysis showed that Breslow tumor thickness had no influence on treatment results in the groups of patients investigated . CONCLUSION Adjuvant IFNalpha2a treatment diminishes the occurrence of metastases and thus prolongs disease-free survival in resected primary stage II cutaneous melanoma patients BACKGROUND Individuals affected by melanoma with thick primary tumours or regional node involvement have a poor outlook , with only 30 - 50 % alive at 5 years . High-dose and low-dose interferon alfa have been assessed for the treatment of these patients , with the former having considerable toxicity and a consistent effect on disease free survival , but not on overall survival , and the latter no consistent effect on either . Our aim was , therefore , to assess the effect of two regimens of interferon of intermediate dose versus observation alone on distant metastasis-free interval ( DMFI ) and overall survival in such patients . METHODS We did a r and omised controlled trial in 1388 patients who had had a thick primary tumour ( thickness > or = 4 mm ) resected ( stage IIb ) or regional lymph node metastases dissected ( stage III ) and had been assigned to 13-months ( n=553 ) or 25 months ( n=556 ) of treatment with subcutaneous interferon alfa 2b , or observation ( n=279 ) . Treatment comprised 4 weeks of 10 million units ( MU ) of interferon alfa ( 5 days per week ) followed by either 10 MU three times a week for 1 year or 5 MU three times a week for 2 years , to a total dose of 1760 MU . Our primary endpoint was DMFI . Analyses were by intent to treat . FINDINGS After a median follow-up of 4.65 years , we had recorded 760 distant metastases and 681 deaths . At 4.5 years , the 25-month interferon group showed a 7.2 % increase in rate of DMFI ( hazard ratio 0.83 , 97.5 % CI 0.66 - 1.03 ) and a 5.4 % improvement in overall survival . The 13-month interferon group showed a 3.2 % increase in rate of DMFI at 4.5 years ( 0.93 , 0.75 - 1.16 ) and no extension of overall survival . Toxicity was acceptable , with 18 % ( 195 of 1076 ) of patients going off study because of toxicity or as a result of refusal of treatment because of side-effects . INTERPRETATION Interferon alfa as used in the regimens studied does not improve outcome for patients with stage IIb/III melanomas , and can not be recommended . With respect to efficacy of the drug , duration of treatment seemed more important than dose , and should be assessed in future trials Early surgical intervention is still the most successful therapy for patients with melanoma . The results obtained with medical therapies are still quite disappointing , with better results observed in soft tissue and lymph node metastasis . There currently is no st and ardized adjuvant therapy for primary melanoma . On the basis of the activity demonstrated in vitro against melanoma cell lines and the results obtained in many clinical trials in patients with advanced melanoma , the authors chose to study the use of recombinant interferon‐α ( IFN‐α ) as adjuvant therapy for patients with Stage I and Stage II melanoma Adjuvant treatment with interferon-&agr ; ( IFN-&agr ; ) for patients with malignant melanoma can improve relapse-free and overall survival , but IFN-associated side effects may reduce patient 's quality of life . The aim of the study was to prospect ively evaluate health-related quality of life ( HRQoL ) in patients with melanoma before and during Low-Dose IFN-&agr ; therapy .  In a prospect i ve multicenter trial conducted by the Dermatologic Cooperative Oncology Group , 850 patients with cutaneous stage II malignant melanoma received a st and ard Low-Dose of IFN-&agr;-2a . We evaluated HRQoL using the European Organization for Research and Treatment of Cancer Quality of Life Core 30 question naire at baseline and after 3 , 6 , and 12 months of IFN-&agr ; treatment in 282 patients . Nine of 15 subscales showed significant poorer results after 3 months of adjuvant IFN treatment . Symptoms included reduced physical functioning , reduced cognitive functioning , fatigue , nausea , pain , dyspnea , insomnia , diarrhea , and loss of appetite . We did not find a significant change over time for role , emotional , or social functioning . Only cognitive functioning and dyspnea continuously worsened through the twelfth month . At baseline women had significantly lower scores for physical and emotional functioning and for fatigue compared with men . During treatment , women scored significantly poorer on physical functioning , emotional functioning , fatigue , pain , and constipation subscales . Patients who reported having a bad or very bad QoL before treatment were 5.8 times more likely to discontinue treatment early because of psychiatric problems . We conclude that adjuvant low-dose IFN treatment is associated with significant deterioration of HRQoL. Specific psychosocial care should be offered especially for patients who report lower HRQoL and emotional problems before treatment to prevent early discontinuation PURPOSE High-dose adjuvant interferon alpha-2b ( IFN alpha 2b ) for high-risk melanoma is a 1-year regimen that improves relapse-free and overall survival but has significant toxicity . A quality -of-life -- adjusted survival ( QAS ) analysis analysis of two cooperative group phase III trials , E1684 and E1690/S9111/C9190 , was performed , incorporating patient values ( utilities ) for the toxicity of IFN alpha 2b treatment and melanoma recurrence . PATIENTS AND METHODS Quality -Adjusted Time Without Symptoms or Toxicity methodology was used with melanoma patient utilities and trial data to estimate the effect of IFN alpha 2b on QAS . The increase or decrease in QAS that patients could expect from treatment was estimated based on their utilities . Eleven utility predictor questions were tested to identify patients with utilities that result in decreased QAS . RESULTS Using E1684 data , IFN alpha 2b would result in an increase in QAS for all sets of patient utilities . This benefit was significant ( P < .05 ) for 16 % of patients . Using E1690/S9111/C9190 data , 77 % of patients would experience a benefit in QAS from IFN alpha 2b and 23 % would experience a decrease in QAS ; neither of these effects was statistically significant . Using utility predictors and the E1690/S9111/C9190 analysis , a decision rule was formulated that helps identify patients in whom IFN alpha 2b may detract from QAS . CONCLUSION Most patients experienced improvement in QAS in both trials , but this benefit was statistically significant in only 16 % of patients in E1684 . Change in QAS depends more on the utility for IFN alpha 2b toxicity than on the utility for melanoma recurrence . Cancer patients probably have higher utilities for IFN alpha 2b toxicity than members of the general population and will tend to favor IFN alpha 2b treatment as a result PURPOSE To evaluate low-dose extended duration interferon alfa-2a as adjuvant therapy in patients with thick ( > or = 4 mm ) primary cutaneous melanoma and /or locoregional metastases . PATIENTS AND METHODS In this r and omized controlled trial involving 674 patients , the effect of interferon alfa-2a ( 3 megaunits three times per week for 2 years or until recurrence ) on overall survival ( OS ) and recurrence-free survival ( RFS ) was compared with that of no further treatment in radically resected stage IIB and stage III cutaneous malignant melanoma . RESULTS The OS and RFS rates at 5 years were 44 % ( SE , 2.6 ) and 32 % ( SE , 2.1 ) , respectively . There was no significant difference in OS or RFS between the interferon-treated and control arms ( odds ratio [ OR ] , 0.94 ; 95 % CI , 0.75 to 1.18 ; P = .6 ; and OR , 0.91 ; 95 % CI , 0.75 to 1.10 ; P = .3 ; respectively ) . Male sex ( P = .003 ) and regional lymph node involvement ( P = .0009 ) , but not age ( P = .7 ) , were statistically significant adverse features for OS . Subgroup analysis by disease stage , age , and sex did not show any clear differences between interferon-treated and control groups in either OS or RFS . Interferon-related toxicities were modest : grade 3 ( and in only one case , grade 4 ) fatigue or mood disturbance was seen in 7 % and 4 % respectively , of patients . However , there were 50 withdrawals ( 15 % ) from interferon treatment due to toxicity . CONCLUSION The results from this study , taken in isolation , do not indicate that extended- duration low-dose interferon is significantly better than observation alone in the initial treatment of completely resected high-risk malignant melanoma BRIEF COMMUNICATION R and omized Trial of Adjuvant Human Interferon Gamma Versus Observation in High-Risk Cutaneous Melanoma : a Southwest Oncology Group Study Frank L. Meyskens , Jr. , Kenneth J. Kopecky , Charles W. Taylor , R. Dirk Noyes , Ralph J. Tuthill , Evan M. Hersh , Lynn G. Feun , James H. Doroshow , Lawrence E. Flaherty , Vernon K. Sondak * The prognosis for patients with cu- taneous malignant melanoma worsens considerably if the primary tumor in- vades deeply ( > 1.5 mm , American Joint Committee on Cancer [ AJCC ] stage II ) and /or spreads to regional lymph nodes ( AJCC stage III ) ( J-3 ) . Such patients are therefore appropriate c and i date s for studies of postsurgical adjuvant therapy . Several observations suggest a role for immunologic mechanisms in controlling proliferation and spread of melanoma cells ( 4,5 ) . Nonetheless , clinical trials of nonspecific immunologic stimulants such as BCG , Corynebacterium parvum , le- vamisole , and transfer factor have been disappointing ( 6 - 11 ) , leading to con- sideration of more specific immuno- modulatory approaches . Interferon gamma ( IFN y ) induces a variety of immunomodulatory effects : increased natural killer cell-mediated cytotoxicity , macrophage activation , and enhancement of human leukocyte an- tigen class II antigen expression and shedding ( 12 - 15 ) . Phase I studies showed that IFN y was well tolerated and favorably affected immune parameters in patients with completely resected melanoma ( 16 - 18 ) . Although IFN y has 1710 BRIEF COMMUNICATION no documented activity against meta- static melanoma , such phase I results ar- gued for its evaluation in the adjuvant setting . Accordingly , the Southwest On- cology Group undertook a r and omized , phase III trial ( SWOG-8642 ) to test whether prognosis is improved with recombinant human IFN y ( Genentech , Inc. , South San Francisco , CA ) com- pared with observation following defini- tive surgery for cutaneous melanoma . Eligible patients were 18 years of age or older , had cutaneous melanoma of AJCC stage II ( primary thickness of > 1.5 mm , NO , MO ) or III ( any T , Nl-2 , MO ) , and a performance status ( Eastern Cooperative Oncology Group scale ) of 0 or 1 . Patients were required to have had complete excision of their tumors ( with at least 1-cm margins ) within 4 weeks after registration and to have no prior or concurrent nonsurgical therapy . Staging procedures were required to en- sure that patients were free of detectable residual disease . After giving written in- formed consent , patients were r and omly assigned to receive either IFN y or no treatment ( observation ) , stratified by stage . Optimal immunomodulatory ef- fects of IFN y in melanoma patients at high risk of recurrence following sur- gery have been reported at an intra- muscular or subcutaneous dose of 0.1 mg/m 2 per day ( 19 ) . For practicality , IFN y was given subcutaneously at 0.2 mg per day for 1 year or until disease recurrence . The slides of the tumors of all patients were review ed by one pa- thologist ( R. J. Tuthill ) , and there was central review of all relevant eligibility criteria , including surgical technique , to determine final eligibility . The protocol was approved by the institutional review boards of the participating institutions . The present analysis was based on data available August 2 , 1994 , and up date s an earlier preliminary report ( 20 ) . Since the stated aim of the study was to deter- mine whether treatment with IFN y im- proves outcome compared with that seen with observation , one-tailed P values ( P\ ) are reported except for un- planned post hoc analyses using two- tailed P values ( P 2 ) that were performed to investigate whether treatment with IFN y might actually be harmful . From October 1987 through Novem- ber 1989 , 284 patients were r and omly assigned ( 137 IFN y and 147 observa- tion ) by st and ard cooperative group pro- cedures performed central ly at the Southwest Oncology Group Statistical Center . Eighty-two ( 29 % ) were in- eligible , primarily because of failure to obtain required pre study tests or to meet required histologic or surgical criteria . Results for all 284 patients were similar to those for the 202 eligible patients ; the latter are emphasized here . Characteristics of and treatment out- comes for the eligible patients are shown in Table 1 . Disease-free survival and overall survival were not sig- nificantly better with IFN y ( Fig. 1 : for disease-free survival , P\ - .81 ; for over- all survival , P\ - .91 ; stage-stratified logrank test ) . Disease-free survival and overall survival were in fact somewhat poorer with IFN y , but not significantly so in post hoc analyses ( disease-free survival , P 2 - .38 ; overall survival , P 2 = .18 ) . Proportional hazards regression analysis found no significant interac- tions between treatment and stage , gender , age , primary site , body surface area , or weight . The study was original- ly design ed for 230 eligible patients . With 202 eligible patients , however , the alternative hypothesis that IFN y reduces the risk of relapse or death by 25 % ( i.e. , relative risk = 0.75 ) was con- vincingly rejected ( Pi = .007 ) , constitut- ing strong evidence against any clinical ly meaningful beneficial effect . Of the 137 patients r and omly as- signed to receive IFN y , 133 were asses- sable for toxic effects . There were no * Affiliations of authors : F. L. Meyskens , Jr. , University of California , Irvine ; K. J. Kopecky , Southwest Oncology Group Statistical Center , Seattle , WA ; C. W. Taylor , E. M. Hersh , Univer- sity of Arizona Cancer Center , Tucson ; R. D. Noyes , University of Utah Medical Center , Salt Lake City ; R. J. Tuthill , Clevel and Clinic Founda- tion , OH ; L. G. Feun , University of Miami School of Medicine , FL ; J. H. Doroshow , City of Hope National Medical Center , Duarte , CA ; L. E. Flaherty , Wayne State University Medical Center , Detroit , MI ; V. K. Sondak , University of Michigan Medical Center , Ann Arbor . Correspondence to : Vernon K. Sondak , M.D. , 2920 Taubman Center , 1500 East Medical Center Dr. , Ann Arbor , MI 48109 - 0331 . Reprint requests to : Southwest Oncology Group ( SWOG-8642 ) , Operations Office , Omicron Dr. , San Antonio , TX 78245 - 3217 . See Notes section following References . Journal of the National Cancer Institute , Vol . 87 , No. 22 , November 15 , PURPOSE To evaluate the quality -of-life effects of adjuvant high-dose interferon alfa-2b ( IFN alpha 2b ) treatment of high-risk melanoma . PATIENTS AND METHODS A quality -of-life-adjusted survival analysis ( Quality -Adjusted Time Without Symptoms , and Toxicity [ Q-TWiST ] ) was applied to the Eastern Cooperative Oncology Group Trial E1684 , which compared high-dose IFN alpha 2b treatment for 1 year versus observation in 280 high-risk patients .  IFN alpha 2b was administered at a dosage of 20 mU/m2 intravenously daily for 5 days per week for 4 weeks , and then three times weekly at 10 mU/m2 subcutaneously for 48 weeks . RESULTS After 84 months of median follow-up time , the IFN alpha 2b group gained a mean of 8.9 months without disease relapse ( P = .03 ) and 7.0 months of overall survival ( P = .07 ) as compared with the observation group , but had severe treatment-related toxicity for 5.8 months , on average . The IFN alpha 2b group had more quality -of-life-adjusted time than the observation group regardless of the relative valuations placed on time with toxicity ( Tox ) and time with relapse ( Rel ) . This gain was significant ( P < .05 ) for patients who consider Tox to have a high relative value and Rel to have a low relative value . In contrast , for patients who value Tox about the same as Rel , the quality -adjusted gain for IFN alpha 2b was not statistically significant . An analysis stratified according to tumor burden indicated that the benefit of IFN alpha 2b was greatest in the node-positive strata . CONCLUSION For patients with high-risk melanoma , the clinical benefits of high-dose IFN alpha 2b can offset the toxic effects . The optimal treatment for an individual patient depends on the patient 's tumor burden and preferences regarding toxicity and disease relapse 8505 Background : To assess the benefit of 4 weeks of HDI compared with observation ( obs ) in relation to the relapse free survival ( RFS ) and overall survival ( OS ) of patients ( pts ) with resectable intermediate and high-risk melanoma Methods : Pts with intermediate and high-risk melanoma defined as T3 ( AJCC 6th ed . > Breslow thickness 1.5 mm ( AJCC 7th ed . > 2.0 mm ) or any thickness with microscopically positive node disease ( N1a-N2a ) were r and omized to receive postoperative adjuvant Interferon ( IFN ) alfa2b 20 MU/m2/day for 5 days/week X 4 weeks or observation . Primary endpoints of the trial were RFS and OS . A sample size of 1420 pts was chosen to detect a 15 % relative increase in the median time-to-event for those not cured and a 7.5 % absolute increase in the cure rate with 88 % power at a 5 % level of significance , using a two-sided log-rank test . RESULTS Between December 1998 and October 2010 , 1150 pts were enrolled - 581 assigned to HDI and 596 to obs . The breakdown of stage at entry was as follows : T2N0 : 22 % , T3N0 : 45 % , T4N0 : 14 % , T1 - 4 , N1a-2a:19 % . Primary ulceration was present in 36 % of pts . A third interim analysis of this trial was carried out in August 2010 with RFS data in 838 and OS data in 1091 pts . The 234 RFS events correspond to 69.0 % information time , while the 134 OS events correspond to 74 % information time . Median RFS for Obs was 7.3 years ( 95 % CI 5.3 , 9.8 ; n=413 ) while for IFN , RFS was 6.8 years ( 95 % CI 5.1 , 9.0 ; n=425 ) . The 5-year survival rate for OBS was 0.85 ( 95 % CI .81 , .89 ; n=535 ) while for IFN induction-only the 5-year survival rate was 0.82 with ( 95 % CI .78 , .86 ; n=556 ) . Accrual to the trial has therefore been terminated . CONCLUSIONS Adjuvant HDI induction with only 4 weeks therapy neither improved RFS nor OS over observation for pts with intermediate and high-risk melanoma . This trial supports the importance of HDI treatment duration and argues that the approved 1 year Interferon regimen of induction followed by maintenance remains the st and ard of care for pts with T4N0 or node positive disease Objective : This analysis was performed to investigate the hypothesis that ulceration predicts improved response to adjuvant interferon ( IFN ) therapy . Summary background data : Several studies have demonstrated that adjuvant therapy for high-risk melanoma patients with IFN alfa-2b improves disease-free survival ( DFS ) , although the impact on overall survival ( OS ) is controversial . Recent data have suggested that IFN therapy may preferentially benefit patients with ulcerated primary melanomas . Methods : Post hoc analysis was performed by a prospect i ve multi-institutional r and omized study of observation versus adjuvant IFN therapy for melanoma . All patients underwent sentinel lymph node biopsy ;  completion lymphadenectomy was performed for patients with sentinel lymph node metastasis . Patients were stratified by Breslow thickness , ulceration , and nodal status . Kaplan-Meier analysis of DFS and OS was performed and included univariate and multivariate analyses . Results : A total of 1769 patients were analyzed ( 1311 without ulceration , 458 with ulceration ) with a median follow-up of 71 months . Ulceration was associated with significantly worse DFS and OS in both node-negative and node-positive patients . Kaplan-Meier analysis of node-negative and node-positive patients by ulceration status revealed that the only significant impact of interferon was improved DFS in the ulcerated node-positive patients ( P = 0.0169 ) . IFN therapy had no significant impact on OS regardless of ulceration status , however . On multivariate analysis , IFN treatment was a significant independent predictor of DFS among ulcerated patients ( odds ratio , 0.51 ; 95 % confidence interval , 0.30–0.83 ; P = 0.0053 ) , but not among patients without ulceration . Conclusions : These data support the conclusion that ulceration is a predictive marker for response to adjuvant IFN therapy . Future studies to evaluate specifically the differential effect of IFN on patients with ulcerated melanomas may allow us to focus this therapy on patients most likely to benefit from it OBJECTIVE To quantify the impact of excision margins on disease-specific survival of patients with primary cutaneous melanoma . BACKGROUND Current guidelines recommend narrow margins for the treatment of primary melanoma , although available evidence on this subject is not unequivocal and not always appropriately analyzed . METHODS A systematic review of r and omized controlled trials ( RCT ) addressing the issue of wide versus narrow excision margins was performed . Meta- analysis methods for time-to-event data were used to extract hazard ratios(HR ) and their 95 % confidence intervals ( CI ) from eligible studies , and ultimately to estimate the summary effect of excision margins on patients ' survival . RESULTS The 5 eligible RCT enrolled a total of 3295 patients who were allocated to wide ( 3 - 5 cm ) or narrow ( 1 - 2 cm ) excision of their primary tumor . The data of locoregional disease-free ( LDFS ) , disease-free (DFS),disease-specific ( DSS ) , and overall ( OS ) survival were available for 3 , 5 , 3 , and 5 RCT , respectively . The meta- analysis suggested that narrow margins might be associated with an increased risk of both locoregional disease recurrence ( HR : 1.30 , CI : 1.07 - 1.57 ; P = 0.01 ) and death by disease ( HR : 1.28 , CI:1.07 - 1.53 , P = 0.01 ) . As regards DFS , the borderline disadvantage ( HR:1.13 , CI : 0.995 - 1.28 ; P = 0.06 ) becomes significant when considering RCT that enrolled patients with thicker melanoma ( HR : 1.19 , CI : 1.02 - 1.39 , P = 0.03 ) . When death by any cause ( OS ) was analyzed , no risk difference was found . CONCLUSIONS The lack of DSS data from all the available RCT does not allow to draw definitive conclusions . However , current evidence appears sufficient to question the common belief that narrow excision margins are as safe as wide margins in the management of primary melanoma , that calls for further investigation in this field PURPOSE High-dose interferon alfa-2b ( IFNalpha2b ) is the only established adjuvant therapy of resectable high-risk melanoma . GM2-KLH/QS-21 ( GMK ) is a chemically defined vaccine that is one of the best developed of a range of vaccine c and i date s for melanoma . A single-institution phase III trial conducted at Memorial Hospital served as the impetus for an intergroup adjuvant E1694/S9512/C509801 trial , which recently completed enrollment of 880 patients . To build on the apparent benefit of IFNalpha2b in resectable high-risk American Joint Committee on Cancer ( AJCC ) stage IIB or III melanoma , this phase II study was design ed to evaluate the combination of GMK and IFNalpha2b . The E2696 trial was undertaken to evaluate the toxicity and other effects of the established adjuvant high-dose IFNalpha2b regimen in relation to immune responses to GMK and to evaluate the potential clinical and immunologic effects of the combined therapies . PATIENTS AND METHODS This trial enrolled 107 patients with resectable high- or very high-risk melanoma ( AJCC stages IIB , III , and IV ) . RESULTS The results demonstrate that IFNalpha2b does not significantly inhibit immunoglobulin M or G serologic responses to the vaccine and that the combination of high-dose IFNalpha2b and GMK is well tolerated in this patient population . CONCLUSION Cox analysis of the results of the combination with IFNalpha2b show improvement in the relapse-free survival of patients with very high-risk melanoma ( including those with resectable M1 disease ) This prospect i ve r and omized trial evaluated the effect of DTIC and interferon as adjuvant therapy for high risk stage 1 malignant melanoma in 26 patients . Both groups were well matched for depth of disease , site of melanoma and other prognostic criteria . Like other studies the findings of 2.6 times increased relative risk of mortality in the treatment arm do not support a rationale for adjuvant immuno-chemotherapy even in patients at high risk of recurrence BACKGROUND Appearance of autoantibodies and clinical manifestations of autoimmunity in melanoma patients treated with adjuvant interferon (IFN)-alpha2b  was reported to be associated with improved prognosis . We assessed the association of the appearance of autoantibodies after initiation of treatment with recurrence-free interval in two r and omized trials that compared intermediate doses of IFN with observation for the treatment of melanoma patients . METHODS Serum levels of anticardiolipin , antithyroglobulin , and antinuclear antibodies were determined using enzyme-linked immunosorbent assays in 187 and 356 patients in the European Organization for Research and Treatment of Cancer ( EORTC ) 18952 and Nordic IFN trials , respectively , immediately before and up to 3 years after r and om assignment . The association of the presence of at least one of the three autoantibodies with risk of recurrence was assessed by three Cox models in patients negative for all three autoantibodies at baseline ( 125 from the EORTC 18952 trial and 230 from the Nordic IFN trial ) : 1 ) a model that considered appearance of autoantibodies as a time-independent variable , 2 ) one that considered a patient autoantibody positive once a positive test for an autoantibody was obtained , and 3 ) a model in which the status of the patient was defined by the most recent autoantibody test . All statistical tests were two-sided . RESULTS When treated as a time-independent variable ( model 1 ) , appearance of autoantibodies was associated with improved relapse-free interval in both trials ( EORTC 18952 , hazard ratio [ HR ] = 0.41 , 95 % confidence interval [ CI ] = 0.25 to 0.68 , P < .001 ; and Nordic IFN , HR = 0.51 , 95 % CI = 0.34 to 0.76 , P < .001 ) . However , on correction for guarantee-time bias , the association was weaker and not statistically significant ( model 2 : EORTC 18952 , HR = 0.81 , 95 % CI = 0.46 to 1.40 , P = .44 ; and Nordic IFN , HR = 0.85 , 95 % CI = 0.55 to 1.30 , P = .45 ; model 3 : EORTC 18952 , HR = 1.05 , 95 % CI = 0.59 to 1.87 , P = .88 ; and Nordic IFN , HR = 0.78 , 95 % CI = 0.49 to 1.24 , P = .30 ) . CONCLUSIONS In two r and omized trials of IFN for the treatment of melanoma patients , appearance of autoantibodies was not strongly associated with improved relapse-free interval when correction was made for guarantee-time bias Evidence from r and omized trials in the pre‐sentinel lymph node biopsy era indicate that adjuvant treatment with high‐dose interferon‐α ( 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 PURPOSE To compare health-related quality of life ( HRQoL ) and side-effects in patients with high-risk melanoma participating in a r and omised phase III trial of adjuvant interferon alfa-2b ( IFN ) .  PATIENTS AND METHODS A 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 r and omised 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 Question naire ( EORTC QLQ-C30 ) before r and omisation and at 8 pre-defined time-points during 2 years . IFN-related side-effects were assessed by a study -specific question naire . RESULTS > 80 % of eligible patients returned question naires at the different assessment points . Statistically significant interactions between r and omisation arm and time after r and omisation 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 . CONCLUSION A significant negative impact on HRQoL of IFN treatment was demonstrated , however the impact were reversible when treatment was stopped
BACKGROUND Interferon alpha is the only agent approved for the postoperative adjuvant treatment of high-risk cutaneous melanoma .
However , the survival advantage associated with this treatment is unclear , especially in terms of overall survival .
Thus , adjuvant interferon is not universally considered a gold st and ard treatment by all oncologists .
OBJECTIVES To assess the disease-free survival and overall survival effects of interferon alpha as adjuvant treatment for people with high-risk cutaneous melanoma .