human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    