Adjuvant chemotherapy with a nitrosourea-based protocol in advanced malignant melanoma. DTIC and combination therapy for melanoma: III. DTIC (NSC 45388) surgical adjuvant study COG PROTOCOL 7040 Clinical trials of chemotherapy and chemoimmunotherapy in primary malignant melanoma. Adjuvant immunotherapy or chemotherapy for malignant melanoma. Preliminary report of the National Cancer Institute randomized clinical trial. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. Adjuvant treatment of malignant melanoma with DTIC + estracyt or BCG. 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. Double-blind trial of a polyvalent, shed-antigen, melanoma vaccine. Adjuvant interferon alpha 2b in high risk melanoma – the Scottish study Double blind randomized prospective trial of levamisole/placebo in stage I cutaneous malignant melanoma. Significant impact of HLA class I allele expression on outcome in melanoma patients treated with an allogeneic melanoma cell lysate vaccine. Final analysis of SWOG-9035. Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial. A randomized trial of levamisole versus placebo as adjuvant therapy in malignant melanoma. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. 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. Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: the final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial. Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada Clinical Trials Group. Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the Southwest Oncology Group. 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. Improved survival in stage III melanoma patients with GM2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside. The Sunbelt Melanoma Trial Results of a prospective randomized trial using DTIC and interferon as adjuvant therapy for stage I malignant melanoma. Lack of benefit of adjunctive chemotherapy in stage I malignant melanoma: a Southwest Oncology Group Study. Controlled trial of active immunotherapy in management of stage IIB malignant melanoma.
173 patients with regional lymphatic metastases ( n = 139 ) or distant disease ( n = 34 ) were prospect ively r and omised , following resection of all clinical ly detectable tumour , to observation ( n = 88 ) or adjuvant chemotherapy ( n = 85 ) . The treatment group received 1 , 3-bis(2-chloroethyl)-1-nitrosourea ( BCNU ) 80 mg/m2 intravenously ( i.v . ) every 4 weeks , and actinomycin-D 10 micrograms/kg , vincristine 1.0 mg/m2 i.v . every 2 weeks for 6 months . The disease-free survival curves between the two groups were significantly different ( P = 0.03 ) . The estimated 5-year disease-free survival rate for the observation group was 9 % and for the treatment group 29 % . However , the overall survival curves were not significantly different for the two groups . Nitrosoureas may have a weak effect as adjuvant treatment in malignant melanoma A prospect ively r and omized study of postoperative chemotherapy with dimethyl triazeno imidazole carboxamide ( DTIC ) was conducted by the Central Oncology Group from 1972 until 1976 . Of 174 patients operated upon for melanoma and entered into the study , 87 were r and omly selected to receive DTIC , four courses in 12 months , at 4.5 mg/kg/d × 10 . One‐hundred‐sixty‐five ( 95 % ) of the cases were evaluable , including 40 high risk Stage I , 96 Stage II , and 29 Stage III cases . At a median follow‐up period of 2.5 years , the control group had a better median disease‐free interval ( 40 weeks vs. 73 weeks ) , median survival time ( 103 weeks vs. 133 weeks ) , and percentage of patients living free of disease ( 28 % vs. 44 % ) than the DTIC‐treated group . While disease‐free interval appeared to be improved in the 25 % of patients on DTIC therapy who developed thrombocytopenia , the overall effect of postoperative DTIC therapy was apparently not beneficial ( P < 0.05 ) We report here two r and omized prospect i ve clinical trials of adjuvant treatment in the management of primary malignant melanoma of Clark 's level III , IV or V. All patients had curative resection of the primary tumor . In the first trial , 117 patients were r and omized between control ( surgery alone ) systemic chemotherapy and intraarterial chemotherapy . Intraarterial chemotherapy consisted of DTIC 80 mg/m2 + 8 days prior to surgery . Systemic chemotherapy consisted of courses of vinblastine ( 6 mg/m2 ) , thiotepa ( 6 mg/m2 ) , rufocromycine ( 60 microgram/m2 ) , methotrexate ( 15 mg/m2 ) on day 1 , and procarbazine ( 30 mg/m12 X 7 days . Courses were repeated every 2 weeks X 6 , then every 4 weeks X 15 . Twenty-two of 55 patients relapsed in the control group versus 22 of 67 in the chemotherapy group ( NS ) . For male patients , the difference in disease-free survival was significant ( P less than 0.005 , log rank test ) , though not in women . In the second trial , 352 patients were entered from July , 1976 . Men were r and omized between chemotherapy and chemoimmunotherapy . Women were r and omized between surgery alone and chemoimmunotherapy .  Chemotherapy was identical , except for the addition of DTIC ( 300 mg/m2 ) for each course . Immunotherapy consisted of BCG every 4 weeks and C. parvum every week . Immunotherapy seemed to be of no additional benefit A preliminary analysis is presented of a clinical trial to determine whether adjuvant immunotherapy or chemotherapy can prolong the disease-free interval and survival of patients with poor prognosis Stage I malignant melanoma or Stage II melanoma . Postsurgical patients were r and omized to receive either no further treatment , bacille Calmette Guerin ( BCG ) ; BCG plus neuraminidase-treated , allogeneic , tissue-cultured melanoma cells ; or methyl-CCNU . No statistically significant improvement in disease-free interval or overall survival has been noted 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 Eighty-two patients with invasive malignant melanoma and no distant metastases were prospect ively r and omized following their surgical treatment to 1 ) observation ; 2 ) chemotherapy with Dacarbazine ( DTIC ) 200 mg/M2 I.V. daily X 5 every 4 weeks and Estracyt 15 mg/kg orally daily for 1 year ; and 3 ) immunotherapy with TICE BCG 1 ml to an area of scarification near the primary site , every 4 weeks for 1 year . At a median follow-up of 73.4 months 31 patients ( 38 % ) have relapsed . There was no significant difference in survival according to the treatment , but a weak effect on the course of the disease by either of the treatment protocol s can not be ruled out due to the small sample of patients . Survival and disease-free interval varied significantly according to the histologic status of the regional nodes . The estimated 5-year disease-free rate of patients with negative nodes was 85 % and for those with positive nodes it was 35 % ( P less than 0.0001 ) 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 A polyvalent melanoma vaccine prepared from shed antigens stimulates humoral and cellular immune responses and improves survival compared with historical controls . We conducted a double-blind , prospect ively r and omized , placebo-controlled trial to assess whether this vaccine could slow the progression of resected melanoma . Thirty-eight patients with resected melanoma metastatic to regional nodes ( American Joint Committee on Cancer stage III ) who had a particularly poor prognosis on the basis of the nodes being clinical ly positive or two or more histologically positive nodes were r and omly assigned in a 2:1 ratio to treatment with 40 microg of melanoma or placebo ( human albumin ) vaccine , both of which were bound to alum as an adjuvant . Immunizations were given intradermally into the extremities every 3 weeks x 4 , monthly x 3 , every 3 months x 2 , and then every 6 months for 5 years or until disease progression . Twenty-four patients were treated with the melanoma , and 14 patients were treated with the placebo vaccine .  The groups were evenly balanced with respect to prognostic factors . Median length of observation was 2.5 years . There was no local or systemic toxicity . By Kaplan-Meier analysis , median time to disease progression was two and a half times longer in patients treated with melanoma vaccine compared with that in patients treated with placebo vaccine , i.e. , 1.6 years ( 95 % confidence interval , 1.0 - 3.0 years ) compared with 0.6 year [ 95 % confidence interval , 0.3 - 1.9 year(s ) ] . By Cox proportional hazards analysis , this difference was significant at P = 0.03 . Overall survival was 40 % longer in the melanoma vaccine-treated group ( median overall survival of 3.8 years versus 2.7 years ) , but this difference was not statistically significant . In a double-blind and placebo-controlled trial , these results suggest that immunization with a melanoma vaccine may be able to slow the progression of melanoma . Although statistically significant , these results must be interpreted with caution because they are based on a small number of patients 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 One hundred and fifty-six Stage I , Clark 's Level III , IV , and V cutaneous malignant melanoma patients were r and omized , 83 to Levamisole and 73 to placebo .  One hundred and thirty-seven patients were evaluable . Their median follow-up time was 5 years . The 2 groups were comparable in terms of patient characteristics , except for a slightly higher percentage of Clark 's level III in the placebo group ( 57.8 vs 52 % ) . Severe toxicity leading to discontinuation of the medication occurred in 32 patients in the Levamisole arm , versus 10 in the placebo arm . Thirty per cent of patients receiving Levamisole have recurred in comparison with 26 % of those on placebo treatment , and despite a trend in the delay of appearance of distant metastasis in the patients receiving Levamisole ( 30 months versus 9 months in the placebo patients ) , this drug does not appear to be effective in altering the disease-free survival or the survival of Stage I patients in the dosage schedule utilized in this study 7501 Background : SWOG-9035 compared 2 years of an allogeneic melanoma lysate ( Melacine ™ ) to  observation in patients ( pts ) with stage II melanoma 1.5 - 4.0 mm thick . We also analyzed the effects of expression of certain HLA antigens ( ≥2 of HLA-A2 , A28 , B44 , B45 , C3 - called M5 - or either HLA-A2 and or C3 ) . Now we report the mature overall survival ( OS ) analysis as planned . METHODS Primary analyses were conducted on the eligible pt population ( intent to treat , ITT ) using a Cox model adjusted for stratification and recognized prognostic factors . HLA analyses were [ Formula : see text ] , involved all typed pts and were adjusted for stratification and prognostic factors . RESULTS In total , 689 pts were entered over 4.5 years ( 598 eligible ) . Median follow-up time is 7.8 years ( maximum 10.9 years ) . Ninety-one patients are ineligible , mostly ( n=75 ) by pathology ( tumor too thin or too thick ) . For the ITT analysis , the 5-year OS for the observation arm is 77 % and for the vaccine arm is 81 % ( p=.98 ) . For all r and omized pts , the 5-year OS for the observation arm is 76 % and for the vaccine arm is 82 % ( p=.49 ) . We HLA typed 553 of the total 689 pts enrolled ( 80 % of the total ) . There was a significant interaction of M5 status ( ≥2 vs 0 - 1 ) and treatment ( p=.02 ) . Among pts with 2 or more of the M5 , 5-year OS for vaccine pts is 93 % and for observation pts is 74 % ( p=.009 ) . Among patients with 0 - 1 of the M5 , 5-year OS for vaccine pts is 83 % and for observation pts is 82 % ( p=.68 ) . The interaction remained significant when only HLA A2/C3 status was considered ( A2 + and /or C3 + vs A2- and C3- , p=.004 ) . In the A2 + and /or C3 + group , 5-year OS for vaccine pts is 90 % and for observation pts is 76 % ( p=.007 ) . In the A2- and C3- group , 5-year OS for vaccine pts is 80 % and for observation pts is 84 % ( p=.16 ) . CONCLUSION There was no significant benefit of vaccine therapy overall , but this prospect i ve analysis indicates significant survival benefit of vaccine therapy among early-stage melanoma pts expressing ≥2 of the M5 alleles . HLA-A2 and C3 were the predominant alleles contributing to this effect . A prospect i ve confirmatory trial in pts expressing HLA-A2 and /or HLA-C3 is planned . No significant financial relationships to disclose 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 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 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 prospect i ve , r and omized , 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 r and omized : 353 to VMCL and 347 to no immunotherapy .  Seventy-seven percent had lymph node ( LN ) metastases and 66 % had clinical ly detected LN metastases . Analysis on the basis of all eligible , r and omized 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 We conducted a r and omized double-blind trial of levamisole versus placebo as adjuvant therapy for surgical treatment of melanoma . Of 203 patients entered into the study , 104 received levamisole  and 99 placebo .  The distribution of prognostic variables was similar in both groups , indicating the efficacy of the r and omization and the absence of bias . Three end points were analyzed : disease-free interval , time to appearance of visceral metastasis , and survival . There was no statistically significant difference between the groups regarding any of these end points . In patients with Stage I disease , there was a trend in favor of levamisole regarding time to first visceral recurrence and survival ( P = 0.07 ) . We conclude that levamisole has no benefit , as compared with placebo , as adjuvant therapy for malignant melanoma 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 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 BACKGROUND A phase III , r and omized , double-blind , multicenter trial of active specific immunotherapy ( ASI ) using vaccinia melanoma oncolysate ( VMO ) was performed in patients with stage III ( American Joint Commission on Cancer ) melanoma to determine the efficacy of VMO to increase the disease-free interval ( DFI ) or overall survival ( OS ) in these patients . Two interim analyses of data from this trial were performed in May 1994 and June 1995 . Although the results from these analyses showed no statistically significant improvement in DFI or OS in all patients using  VMO  , two subsets-men aged 44 - 57 years with one to five positive nodes and all patients with clinical stage I and pathologic stage II disease-showed an overall survival advantage with VMO therapy . A final analysis of data from this trial was performed in May 1996 and is reported here . The design of future melanoma vaccine trials is discussed based on information learned from this first r and omized , multicenter trial of ASI therapy . STUDY DESIGN A polyvalent VMO was prepared using melanoma cells derived from four melanoma cell lines and vaccinia vaccine virus ( V ) . Patients were accrued from 11 United States institutions and were r and omized by the Statistical Center at the University of Alabama , Birmingham . Two hundred fifty patients were r and omized to treatment with either VMO ( 1 U containing 2 mg of total protein derived from 5 x 10(6 ) melanoma cells and 10(5.6 ) 50 % tissue culture infectious dose of vaccinia virus ) or control V ( 1 U containing 10(5.4 ) 50 % tissue culture infectious dose of vaccinia virus ) once a week for 13 weeks and then once every 2 weeks for a total of 12 months , or until recurrence . Patient data were collected by the Statistical Center and analyzed as of May 1996 for DFI and OS using Wilcoxon test and log-rank analysis . RESULTS Two hundred seventeen patients were found to be eligible according to the inclusion criteria . Data from these patients were analyzed for DFI and OS after a median followup of 46.3 months ( 50.2 months for VMO and 41.3 months for V ) . This final analysis showed no statistically significant increase in either DFI ( p = 0.61 ) or OS ( p = 0.79 ) of patients treated with VMO ( n = 104 ) compared with V ( n = 113 ) . At 2- , 3- , and 5-year intervals , 47.8 % , 43.8 % , and 41.7 % of patients treated with VMO were disease-free , respectively , compared with 51.2 % , 44.8 % , and 40.4 % of patients treated with V. At the same intervals , 70.0 % , 60.0 % , and 48.6 % of patients treated with VMO  survived , compared with 65.4 % , 55.6 % , and 48.2 % of patients treated with V. In a retrospective subset analysis , male patients aged 44 - 57 years ( n = 20 ) with one to five positive nodes showed 18.9 % , 26.82 % , and 21.3 % improvement in survival at 2- , 3- , and 5-year intervals , respectively , after treatment with VMO when compared with V ( n = 18 ) ( p = 0.046 ) . CONCLUSIONS This study was a r and omized , multicenter , placebo-controlled evaluation of an active specific immunotherapeutic agent to increase the DFI or OS of patients with stage III melanoma in a surgical adjuvant setting . In this trial , ASI with VMO when compared with V showed no difference in either DFI or OS . In a retrospective subset analysis , however , a subset of men with one to five positive nodes , between the ages of 44 and 57 years , showed a survival advantage with VMO . This result suggests that one must include a detailed subset analysis in the design of future trials of ASI for patients with American Joint Commission on Cancer stage III melanoma . An appropriate control arm also must be included in ASI trials Five hundred forty-three patients with completely resected malignant melanoma who were considered to have a significant risk of developing recurrent disease were r and omized to one of four study groups . One group received levamisole 2.5 mg/kg on 2 consecutive days weekly for 3 years , a second group received bacillus Calmette-Guérin ( BCG ) for 3 years . A third group alternated 8-week courses of BCG and levamisole for 3 years and a fourth group underwent clinical assessment at the same frequency as the three treatment groups . The median duration of follow-up is 8.5 years . The percentage of reduction in the death rate and the recurrence rate in the treatment groups compared with the control group was calculated using the Cox proportional hazards model and adjusted for age , sex , and stage as covariants . The patients treated with levamisole were estimated to have a 29 % reduction in both the death rate ( P = .08 ) and the recurrence rate ( P = .09 ) compared with patients receiving no further treatment . Fifty-five patients discontinued levamisole early because of gastrointestinal intolerance or arthralgia , myalgia , fever , and immune leukopenia . The patients treated with BCG alternating with levamisole experienced a 10 % reduction in the death rate and a 6 % reduction in the recurrence rate , and the patients treated with BCG alone experienced a 4 % reduction in the death rate and a 3 % increase in the recurrence rate compared with the control group . The degree of improvement experienced by the patients that were treated by levamisole is of sufficient magnitude to warrant further investigation of this dose of levamisole as adjuvant treatment in patients with melanoma PURPOSE Patients with clinical ly negative nodes constitute over 85 % of new melanoma cases . There is no adjuvant therapy for intermediate-thickness , node-negative melanoma patients . PATIENTS AND METHODS The Southwest Oncology Group conducted a r and omized phase III trial of an allogeneic melanoma vaccine for 2 years versus observation in patients with intermediate-thickness ( 1.5 to 4.0 mm or Clark 's level IV if thickness unknown ) , clinical ly or pathologically node-negative melanoma ( T3N0M0 ) . RESULTS Six hundred eighty-nine patients were accrued over 4.5 years ; 89 patients ( 13 % ) were ineligible . Surgical node staging was performed in 24 % , the remainder were clinical N0 . Thirteen eligible patients refused assigned treatment : seven on the observation arm and six on the vaccine arm . Most vaccine patients experienced mild to moderate local toxicity , but 26 ( 9 % ) experienced grade 3 toxicity . After a median follow-up of 5.6 years , there were 107 events ( tumor recurrences or deaths ) among the 300 eligible patients r and omized to vaccine compared with 114 among the 300 eligible patients r and omized to observation ( hazard ratio , 0.92 ; Cox-adjusted P(2 ) = 0.51 ) . There was no difference in vaccine efficacy among patients with tumors < or = 3 mm or > 3 mm . CONCLUSION This represents one of the largest r and omized , controlled trials of adjuvant vaccine therapy in human cancer reported to date . Compliance with r and omization was excellent , with only 2 % refusing assigned therapy . There is no evidence of improved disease-free survival among patients r and omized to receive vaccine , although the power to detect a small but clinical ly significant difference was low . Future investigations of adjuvant vaccine approaches for patients with intermediate-thickness melanoma should involve larger numbers of patients and ideally should include sentinel node biopsy staging 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 PURPOSE To perform a double-blind r and omized trial with American Joint Commission on Cancer ( AJCC ) stage III melanoma patients for the following reasons : ( 1 ) to confirm our previous finding that patients with antibodies against the melanoma differentiation antigen GM2 have an improved prognosis , and ( 2 ) to demonstrate clinical benefit from GM2 antibody induction . PATIENTS AND METHODS One hundred twenty-two patients with AJCC stage III melanoma who were free of disease after surgery were r and omized : 58 to receive treatment with the GM2/BCG vaccine , and 64 to receive treatment with bacille Calmette-Guèrin ( BCG ) alone . All patients were pretreated with low-dose cyclophosphamide ( Cy ) .  RESULTS GM2 antibody was detected in 50 of 58 patients treated with GM2/BCG and seven of 64 patients treated with BCG alone . With a minimum follow-up period of 51 months , there was a highly significant increase in the disease-free interval ( P = .004 ) and a 17 % increase in overall survival ( P = .02 ) in these 57 antibody-positive patients , confirming our earlier experience . Exclusion of all patients with preexisting GM2 antibodies ( one in the GM2/BCG group and five in the BCG group ) from statistical analysis result ed in a 23 % increase in disease-free interval ( P = .02 ) and a 14 % increase in overall survival ( P = .15 ) at 51 months for patients treated with the GM2/BCG vaccine . However , when all patients in the two treatment groups were compared as r and omized , these increases were 18 % for disease-free interval and 11 % for survival in the GM2/BCG treatment group , with neither result showing statistical significance . CONCLUSION ( 1 ) Vaccination with GM2/BCG induced immunoglobulin M ( IgM ) antibodies in most patients . ( 2 ) GM2 antibody production was associated with a prolonged disease-free interval and survival . ( 3 ) Comparison of the two arms of this trial as r and omized fails to show a statistically significant improvement in disease-free interval or survival for patients treated with GM2/BCG vaccines The Sunbelt Melanoma Trial , a multicenter , prospect i ve r and omized clinical study , evaluated the role of high-dose interferon alfa-2b ( HDI ) therapy for patients with a single positive sentinel lymph node ( SLN ) metastasis treated with a completion lymph node dissection ( CLND ) .  A second protocol in the trial evaluated the prognostic significance of using molecular markers to identify su bmi croscopic metastases in sentinel lymph nodes that were negative by routine pathologic analysis . The role of CLND with or without adjuvant HDI was evaluated in this group of patients . The results of the study demonstrated that adjuvant HDI offered no survival benefit for patients with a single positive SLN in terms of disease-free or overall survival . Molecular staging using polymerase chain reaction ( PCR ) for melanoma markers did not identify a high-risk group of patients at increased risk of melanoma recurrence . Additional treatment of these patients who were PCR-positive with either CLND alone or CLND plus HDI did not improve their survival . Additional studies from the Sunbelt Melanoma Trial helped to vali date the operational st and ards of the SLN biopsy procedure and defined the complication rates for both SLN biopsy and CLND . A prognostic risk calculator has been developed from trial data , and the importance of different micrometastatic tumor burden measurements was reported . Although the Sunbelt Melanoma Trial did not demonstrate an improvement in survival with HDI , it is an important trial that highlights the significance of surgeon-initiated r and omized clinical trials that incorporate surgical techniques , molecular biomarkers , and adjuvant therapy 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 In 1975 , the Southwest Oncology Group initiated an adjuvant study in localized malignant melanoma testing the value of aggressive chemotherapy using carmustine , hydroxyurea , and dacarbazine versus a control arm .  Median disease-free survival was 7.1 years for the control arm and 6 years for the treatment arm . Survival was identical for both arms with 65 % of the patients alive at 6 years . We conclude that carmustine , hydroxyurea , and dacarbazine chemotherapy is of no value as adjuvant treatment for localized melanoma The prognosis for patients who undergo surgery for stage IIB malignant melanoma is poor . Animal studies have suggested that BCG and tumour cell vaccines given together may provide effective immunotherapy . To assess the effectiveness of this treatment 15 patients with stage IIB malignant melanoma who had their tumour excised were studied . Seven were treated conservatively , and eight were vaccinated with BCG and autologous irradiated cells . Three vaccinated patients suffered widespread recurrence within three months . All four vaccinated patients who suffered a recurrence within the first year died , while none of the three controls with recurrent disease died . In view of this alarming trend the trial was stopped after a year . BCG and the tumour cells may have enhanced the tumour growth , although there was no apparent reason for this . The results of uncontrolled or unr and omised trials that have suggested that this treatment is beneficial should be treated with scepticism
The authors examined the role of systemic adjuvant therapy in patients with high-risk , resected , primary melanoma .
Outcomes of interest included overall survival , disease-free survival , adverse effects , and quality of life .