title: Randomized phase II study comparing mitomycin, cisplatin plus doxifluridine with cisplatin plus doxifluridine in advanced unresectable gastric cancer. Randomized phase II study of irinotecan, leucovorin and 5-fluorouracil (ILF) versus cisplatin plus ILF (PILF) combination chemotherapy for advanced gastric cancer. Cyclophosphamide plus 5-FU versus 5-FU alone in advanced gastric carcinoma. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. 5-Fluorouracil vs. epirubicin vs. 5-fluorouracil plus epirubicin in advanced gastric carcinoma Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial 5-Fluorouracil, epirubicin, and mitomycin C versus 5-fluorouracil, epirubicin, mitomycin C, and leucovorin in advanced gastric carcinoma. A randomized trial. Docetaxel and continuous-infusion fluorouracil versus epirubicin, cisplatin, and fluorouracil for advanced gastric adenocarcinoma: a randomized phase II study. A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. Bimonthly 24 h Infusion of High-Dose 5-Fluorouracil vs EAP Regimen in Patients with Advanced Gastric Cancer Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Randomized study of combination chemotherapy in unresectable gastric cancer A Cooperative Randomized Study on Tegafur plus Mitomycin C versus Combined Tegafur and Uracil plus Mitomycin C in the Treatment of Advanced Gastric Cancer High Doses of 5-Fluorouracil and Epirubicin with or without Cisplatin in Advanced Gastric Cancer: A Randomized Study Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. A comparative clinical assessment of combination chemotherapy in the management of advanced gastric carcinoma Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. Sequential high-dose methotrexate and fluorouracil combined with doxorubicin--a step ahead in the treatment of advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Capecitabine and oxaliplatin for advanced esophagogastric cancer. Treatment of patients with advanced gastric carcinoma with a 5‐fluorouracil‐based or a cisplatin‐based regimen Chemotherapy of gastric and pancreatic carcinoma: a controlled evaluation of combinations of 5-fluorouracil with nitrosoureas and "lactones". Controlled evaluation of three drug combination regimens versus fluorouracil alone for the therapy of advanced gastric cancer. North Central Cancer Treatment Group. Fluorouracil, doxorubicin, and mitomycin combination versus PELF chemotherapy in advanced gastric cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. Sequential and combination chemotherapy of advanced gastric cancer FAMTX versus etoposide, doxorubicin, and cisplatin: a random assignment trial in gastric cancer. 5 FU infusion with mitomycin‐C vs. 5 FU infusion with methyl‐CCNU in the treatment of advanced upper gastrointestinal cancer. A Southwest oncology group study Cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) is more active than 5-fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastric carcinoma. Treatment of advanced gastric carcinoma with 5-fluorouracil: a randomized comparison of two routes of delivery. Randomised trial of epirubicin versus fluorouracil in advanced gastric cancer. An International Collaborative Cancer Group (ICCG) study. Irinotecan in combination with 5-fluorouracil and folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric junction adenocarcinoma: results of a randomized phase II study. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. Treatment of advanced gastric cancer with 5-fluorouracil versus mitomycin C. A randomized phase II trial of irinotecan plus oxaliplatin versus oxaliplatin, fluorouracil (5 FU), leukovorin (LV) as first-line treatment in advanced gastric cancer. Etoposide (E) + epirubicin (E) + cisplatin (P) combination chemotherapy (EEP) in advanced gastric cancer: negative impact on clinical outcome. Spanish Cooperative Group for GI Tumor Therapy (T.T.D.). An EORTC Gastrointestinal Group phase III evaluation of combinations of methyl-CCNU, 5-fluorouracil, and adriamycin in advanced gastric cancer. Sequence-dependence of cisplatin and 5-fluorouracil in advanced and recurrent gastric cancer. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). Paclitaxel versus docetaxel for advanced gastric cancer: a randomized phase II trial in combination with infusional 5-fluorouracil Analysis of a prospectively randomized comparison of doxorubicin versus 5-fluorouracil, doxorubicin, and BCNU in advanced gastric cancer: implications for future studies. Weekly infusional high-dose fluorouracil (HD-FU), HD-FU plus folinic acid (HD-FU/FA), or HD-FU/FA plus biweekly cisplatin in advanced gastric cancer: randomized phase II trial 40953 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group and the Arbeitsgemeinschaft I Efficacy of the association of folinic acid and 5-fluorouracil alone versus folinic acid and 5-fluorouracil plus 4-epidoxorubicin in the treatment of advanced gastric carcinoma. Chemotherapy of disseminated gastric cancer. A joint effort of the Northern California oncology group and the Japanese gastric cancer chemotherapy group AVAGAST: A randomized, double-blind, placebo-controlled, phase III study of first-line capecitabine and cisplatin plus bevacizumab or placebo in patients with advanced gastric cancer (AGC). Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer.
abstract: UNLABELLED Various chemotherapies have been used to treat inoperable gastric cancer . Most combination therapies include cisplatin ( CDDP ) and fluoropyrimidine ( 5-FUs ) , which are thought of as key drugs . In the present study , we r and omly compared mitomycin ( MMC ) and CDDP plus doxifluridine ( 5'-DFUR ) , which is an oral 5-FU and an intermediate metabolite of capecitabine ( Xeloda ) , with CDDP plus 5'-DFUR in advanced unresectable gastric cancer . Regimen A was CDDP ( 70 mg/m2 , by 2-hour intravenous drip infusion on day 1 ) , MMC ( 7 mg/m2 , injected intravenously on day 2 ) , and oral 5'-DFUR ( 1200 mg/m2 , on days 4 to 7 , 11 to 14 , 18 to 21 and 25 to 28 ; 3 days rest and 4 days administration ) . Regimen B was identical to regimen A without MMC . RESULTS The response rate was 25.0 % ( 8/32 patients ) in Regimen A , 17.2 % ( 5/29 ) in Regimen B ( p=0.541 ) . The median survival time was 241 days in Regimen A and 179 days in Regimen B ( p=0.498 ) . In Regimen A , although no significant difference was observed , end points such as response rate and suvival improved . Thus , we concluded that a r and omized controlled phase III study with more subjects should be conducted BACKGROUND Irinotecan , in combination with 5-fluorouracil ( 5-FU ) or cisplatin , has demonstrated efficacy against advanced gastric cancer ( AGC ) . PATIENTS AND METHODS Chemotherapy-naive AGC patients were r and omly assigned to receive irinotecan 150 mg/m(2 ) on day 1 , leucovorin 20 mg/m(2 ) and a 22-h infusion of 5-FU 1000 mg/m(2 ) on days 1 and 2 ( ILF ) or ILF plus cisplatin 30 mg/m(2 ) on day 2 ( PILF ) . Treatment was repeated every 2 weeks . RESULTS Of 91 registered patients , 45 patients were treated with ILF and 45 with PILF .  For both arms , 687 chemotherapy cycles were delivered ( median = 7 for ILF and 8 for PILF ) . Both ILF and PILF were generally well tolerated and there was no relevant difference in the occurrence of overall grade 3/4 toxic effects between the two arms . Four patients died during treatment : one in the ILF and three in the PILF arm . The objective response rate was 42 % for both arms . There was no significant difference in therapeutic efficacy between ILF and PILF with respect to progression-free survival ( 4.8 versus 6.2 months ; P = 0.523 ) and overall survival ( 10.7 versus 10.5 months ; P = 0.850 ) . CONCLUSION Both ILF and PILF are active as first-line chemotherapy for AGC . The addition of cisplatin , however , has no clear advantage over ILF 30 patients with advanced metastatic gastric adenocarcinoma , having a measurable indicator lesion , were r and omized ( 1:2 ) to receive ( intravenously ) either weekly 5-fluorouracil alone ( 15 mg/kg ) or combination treatment with cyclophosphamide ( 20 mg/kg ) given on day 1 and 5-FU ( 15 mg/kg ) given weekly on weeks 2 - 5 , beginning on day 8 . The combination cycle was repeated at 6-week intervals . Although the toxic effects of therapy were similar in both arms , the addition of cyclophosphamide to the single-agent 5-FU regimen did not increase either the frequency of objective response ( 5-FU 18 % , combination 16 % ) or improve the median survival of patients with advanced measurable gastric carcinoma ( 5-FU 4.4 months , combination 5.2 months ) . Patients with pretreatment weight loss greater than 10 % had significantly ( p less than 0.05 ) shorter median survival ( 2.8 versus 5.6 months ) compared to patients without weight loss BACKGROUND To compare capecitabine/cisplatin with 5-fluorouracil/cisplatin as first-line treatment for advanced gastric cancer ( AGC ) . PATIENTS AND METHODS In this r and omised , open-label , phase III study , patients received cisplatin ( 80 mg/m(2 ) i.v . day 1 ) plus oral capecitabine ( 1000 mg/m(2 ) b.i.d . , days 1 - 14 ) ( XP ) or 5-FU ( 800 mg/m(2)/day by continuous infusion , days 1 - 5 ) ( FP ) every 3 weeks . The primary end point was to confirm noninferiority of XP versus FP for progression-free survival ( PFS ) . RESULTS A total of 316 patients were r and omised to XP ( n = 160 ) or FP ( n = 156 ) . In the per- protocol population , median PFS for XP ( n = 139 ) versus FP ( n = 137 ) was 5.6 versus 5.0 months . The primary end point was met with an unadjusted hazard ratio ( HR ) of 0.81 [ 95 % confidence interval ( CI ) 0.63 - 1.04 , P < 0.001 versus noninferiority margin of 1.25 ] . Median overall survival was 10.5 versus 9.3 months for XP versus FP ( unadjusted HR = 0.85 , 95 % CI 0.64 - 1.13 , P = 0.008 versus noninferiority margin of 1.25 ) . The most common treatment-related grade 3/4 adverse events in XP versus FP patients were as follows : neutropenia ( 16 % versus 19 % ) , vomiting ( 7 % versus 8 % ) , and stomatitis ( 2 % versus 6 % ) . CONCLUSIONS XP showed significant noninferiority for PFS versus FP in the first-line treatment of AGC . XP can be considered an effective alternative to FP BACKGROUND We aim ed to establish the superiority ( or noninferiority if superiority was not achieved ) in terms of time to progression ( TTP ) of irinotecan/5-fluorouracil ( IF ) over cisplatin/5-fluorouracil ( CF ) in chemonaive patients with adenocarcinoma of the stomach/esophagogastric junction . PATIENTS AND METHODS Patients received either IF : i.v . irinotecan 80 mg/m(2 ) 30 min , folinic acid 500 mg/m(2 ) 2 h , 5-fluorouracil ( 5-FU ) 2000 mg/m(2 ) 22 h , for 6/7 weeks or CF : cisplatin 100 mg/m(2 ) 1 - 3 h , with 5-FU 1000 mg/m(2)/day 24 h , days 1 - 5 , every 4 weeks . RESULTS In all , 333 patients were r and omized and treated ( IF 170 , CF 163 ) . Patient characteristics were balanced except more IF patients had Karnofsky performance status 100 % . TTP for IF was 5.0 months [ 95 % confidence interval ( CI ) 3.8 - 5.8 ] and 4.2 months ( 95 % CI 3.7 - 5.5 ) for CF ( P = 0.088 ) . Overall survival ( OS ) was 9.0 versus 8.7 months , response rate 31.8 % versus 25.8 % , time to treatment failure ( TTF ) 4.0 versus 3.4 months for IF and CF , respectively . The difference in TTF was statistically significant ( P = 0.018 ) . IF was better in terms of toxic deaths ( 0.6 % versus 3 % ) , discontinuation for toxicity ( 10.0 % versus 21.5 % ) , severe neutropenia , thrombocytopenia and stomatitis , but not diarrhea . CONCLUSION IF did not yield a significant TTP or OS superiority over CF , and the results of noninferiority of IF were borderline . However , IF may provide a viable , platinum-free front-line treatment alternative for metastatic gastric cancer From January , 1985 , through January , 1987 , 165 patients with advanced gastric cancer were r and omized to receive epirubicin ( E ) alone ( 90 mg/m2 day 1 ) , 5-Fluorouracil ( 5-FU ) alone ( 500 mg/m2 days 1–5 ) , or the combination of E ( 90 mg/m2 day 1 ) and 5-FU ( 400 mg/m2 days 1–5 ) . Courses were repeated every four weeks . Patients were stratified by extent ( locally advanced vs. metastatic ) , evaluability ( measurable vs. non-measurable ) and by history of prior radiotherapy ( yes vs. no ) . R and omization to single arm epirubicin was stopped after 26 patients were enrolled . Objective responses occurred in only 1/16 ( 6 % ) of the patients treated with E alone , 1/40 ( 5 % ) with 5-FU alone and 4/33 ( 12 % ) with both 5-FU and E. There were no significant differences in all eligible patients with respect to time to progression or overall survival in the three treatment arms . Toxicity was primarily hematologic and more pronounced in the combination arm . Neither 5-FU alone , epirubicin alone , or the combination have a major impact in the treatment of gastric carcinoma BACKGROUND Trastuzumab , a monoclonal antibody against human epidermal growth factor receptor 2 ( HER2 ; also known as ERBB2 ) , was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer . METHODS ToGA ( Trastuzumab for Gastric Cancer ) was an open-label , international , phase 3 , r and omised controlled trial undertaken in 122 centres in 24 countries . Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation . Participants were r and omly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab . Allocation was by block r and omisation stratified by Eastern Cooperative Oncology Group performance status , chemotherapy regimen , extent of disease , primary cancer site , and measurability of disease , implemented with a central interactive voice recognition system . The primary endpoint was overall survival in all r and omised patients who received study medication at least once . This trial is registered with Clinical Trials.gov , number NCT01041404 . FINDINGS 594 patients were r and omly assigned to study treatment ( trastuzumab plus chemotherapy , n=298 ; chemotherapy alone , n=296 ) , of whom 584 were included in the primary analysis ( n=294 ; n=290 ) . Median follow-up was 18.6 months ( IQR 11 - 25 ) in the trastuzumab plus chemotherapy group and 17.1 months ( 9 - 25 ) in the chemotherapy alone group . Median overall survival was 13.8 months ( 95 % CI 12 - 16 ) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months ( 10 - 13 ) in those assigned to chemotherapy alone ( hazard ratio 0.74 ; 95 % CI 0.60 - 0.91 ; p=0.0046 ) . The most common adverse events in both groups were nausea  ( trastuzumab plus chemotherapy , 197 [ 67 % ] vs chemotherapy alone , 184 [ 63 % ] ) , vomiting ( 147 [ 50 % ] vs 134 [ 46 % ] ) , and neutropenia ( 157 [ 53 % ] vs 165 [ 57 % ] ) . Rates of overall grade 3 or 4 adverse events ( 201 [ 68 % ] vs 198 [ 68 % ] ) and cardiac adverse events ( 17 [ 6 % ] vs 18 [ 6 % ] ) did not differ between groups . INTERPRETATION Trastuzumab in combination with chemotherapy can be considered as a new st and ard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer . FUNDING F Hoffmann-La Roche Leucovorin ( LV ) enhances the activity of 5-fluorouracil ( 5FU ) . Based on these data , we performed a r and omized trial with 5FU , epirubicin ( EPI ) , mitomycin C(MMC ) with/ without LV in advanced gastric cancer ( AGC ) . The purpose of our study was to investigate if the addition of LV improved the response rate of the combination 5FU EPI , MMC ( FEM ) over FEM . From January 1988 until April 1994 , 88 patients with recurrent or metastatic AGC were r and omly received  5FU , EPI , MMC with ( group A ) or without ( group B ) LV . Between the two arms of the study no difference was noticed in sex , performance status , primary site of tumor , and lymph node metastases . Therapy included group A ( 5FU 600 mg/m2/day , i.v . bolus , on days 1 , 8 , 29 , 36 , and EPI 45 mg/m2/day , i.v . bolus , on days 1 and 29 , MMC 10 mg/m2/day , i.v . bolus , on day 1 ) and group B ( the same as group A plus LV 200 mg/m2/day by 2 h intravenous infusion with 5FU intravenous push at midinfusion ) . No significant difference in response rate was noticed between the two treatment arms ; there were two ( 5 % ) patients with complete response in group A , and five ( 12 % ) in A and 11 ( 26 % ) partial responders in group B ( p < 0.1 ) . A significantly higher number of patients achieving stable disease was observed in group B ; 19 ( 44 % ) in comparison to group A 10 ( 24 % ) ( p < 0.048 ) . There were more patients with progressive disease in group A 25 ( 59 % ) than in group B 12 ( 28 % ) ( p < 0.003 ) ( Table 2 ) . No difference was noted in mean duration of response : group A , 15.8 ( 6 - 31 ) weeks ; and group B , 17.6 ( 6 - 28 ) weeks . The mean time to progression was for group A [ 11.4 ( 6 - 35 ) weeks ] and for group B [ 17.6 ( 8 - 33 ) weeks ] . Mean survival was for group A [ 27.4 ( 12 - 59 ) weeks ] and for group B [ 30.6 ( 17 - 53 ) weeks ] , for 50 % of patients . Causes of death were , for group A , 40 patients from disease progression and two sudden deaths ; for group B , causes of death were for 41 patients disease progression and two sudden deaths . There were two patients in group A and one in group B that were not evaluable because they ab and oned therapy after the first cycle . Toxicity was increased in group B ; anemia , nausea and vomiting , and alopecia ( p < 0.055 ) were more severe in group B , but not statistically different when compared to group A. Neutropenia , thrombocytopenia , mucositis , and fatigue of any grade were significantly more common and severe in group B. Significant dose reductions due to toxicity were required more commonly in group B. We conclude that the response rate was increased in the schedule with the addition of LV , at the cost of increased toxicity and with no difference in survival . A r and omized trial comparing FEM-LV with new generation regimens would determine whether the addition of LV qualifies FAM equally active with these PURPOSE A combination of docetaxel and fluorouracil ( DF ) was evaluated in an outpatient setting and compared with epirubicin , cisplatin , and fluorouracil ( ECF ) , which served as an internal control arm to avoid selection bias . PATIENTS AND METHODS Patients with metastatic or locally advanced gastric adenocarcinoma without prior chemotherapy were r and omly assigned to receive either ECF ( epirubicin 50 mg/m(2 ) day 1 , cisplatin 60 mg/m(2 ) day 1 , and fluorouracil 200 mg/m(2 ) days 1 through 21 , every 3 weeks ) or DF ( docetaxel 75 mg/m(2 ) day 1 , and fluorouracil 200 mg/m(2 ) days 1 through 21 , every 3 weeks ) . RESULTS Ninety patients were r and omly assigned . Toxicity was rarely severe . Major toxic effects included diarrhea , stomatitis , and leukopenia in the DF arm and nausea , vomiting , and leukopenia in the ECF arm . Forty-three of 45 patients in each arm were assessable . In the DF arm , two patients ( 4.4 % , intent to treat ) experienced a confirmed complete tumor remission as best response , and 15 patients ( 33.3 % ) experienced a confirmed partial remission ( overall response rate [ ORR ] , 37.8 % ; 95 % CI , 25.9 % to 51.9 % ) . Two patients ( 4.4 % ) in the ECF arm showed confirmed complete remission , and 14 ( 31.1 % ) showed confirmed partial remission ( ORR , 35.6 % ; 95 % CI , 24.8 % to 48.7 % ) . For the DF and ECF arms , the median survival was 9.5 and 9.7 months , and the median time to tumor progression 5.5 and 5.3 months , respectively . CONCLUSION DF can be safely given in an ambulant setting . Compared with ECF , the dual combination of DF shows promising efficacy and may be an alternative treatment option that avoids cisplatin Three hundred five patients with advanced pancreatic and gastric carcinoma were r and omly assigned to treatment with fluorouracil , fluorouracil plus doxorubicin ( Adriamycin ) ( FA ) , or fluorouracil plus doxorubicin plus mitomycin ( mitomycin C ) ( FAM ) . All regimens were equivalent with regard to patient survival . There is no reasonable likelihood that either the FA or FAM regimen could produce a meaningful survival advantage over fluorouracil alone . Interval to disease progression , objective response rates , and palliative effects ( improved performance , body weight , or symptoms ) were essentially equivalent among the three regimens . With regard to toxicity , the FAM regimen produced more anorexia , nausea , vomiting , leukopenia , thrombocytopenia , and cumulative bone marrow suppression . Fluorouracil alone produced more stomatitis and diarrhea . Because of a failure to produce improved survival or palliation , unrewarded toxicity , and excessive cost , neither the FA nor FAM regimen can be recommended for the treatment of advanced pancreatic or gastric cancer Abstract Background : To investigate the activity and toxicity of high dose ( HD ) infusional 5-FU in comparison to EAP regimen as first-line chemotherapy in patients with advanced gastric cancer . Patients and methods : Histologically confirmed measurable advanced gastric cancer , age < 72 yr , ECOG performance status 0–2 , no prior chemo- and radiotherapy , adequate organ functions . Treatment : EAP arm : doxorubicin ( 40 mg/m2 ) , etoposide ( 360 mg/m2 ) , and cisplatin ( 80 mg/m2 ) every 28 d ; HD 5-FU arm : 5-FU 2.6 g/m2 24 h infusion , biweekly . Results : Sixty patients were r and omized . Patient characteristics ( arms EAP/HD 5-FU ) : Median age 57/55 yr , median PS 1/1 , LAD ( patients ) 3/8 , M1 ( patients ) 27/22 .  Median number of cycles ( range ) : EAP arm 4 ( 2–8 ) , HD 5-FU arm 2 ( 1–8 ) . Worst toxicity per cycle ( grade 3 and 4 in% ) : Neutropenia 20/3 , thrombocytopenia 9/0 , anemia 9/13 , diarrhea 3/10 , nausea 17/7 , vomiting 10/0 for EAP and HD 5-FU arms , respectively . All patients were eligible for response in both arms .  Confirmed response rate ( 95%CI ) : EAP arm 34 % [16–50%]/HD 5-FU arm 10 % ( 0–21 % ) , no change : 46/40 % , progression of disease : 20/50 , respectively . Overall survival ( range ) : EAP arm A 7 mo [ 3–27 ] , HD 5-FU arm 6 mo ( 4–25 ) . Conclusions : Infusional HD 5-FU showed a low incidence of severe toxicity . But given the low efficacy of 5-FU in the dosage we applied in the study , it can not be recommended as a single treatment for further studies . Assessment of higher dose intensity and /or dose density of 5-FU , with introduction of other active drugs in combination , could be an option for further studies PURPOSE To compare the efficacy and tolerability of etoposide , leucovorin , and bolus fluorouracil ( ELF ) or infusional fluorouracil plus cisplatin ( FUP ) with that of the reference protocol of fluorouracil , doxorubicin , and methotrexate ( FAMTX ) in advanced gastric cancer . PATIENTS AND METHODS A total of 399 patients with advanced adenocarcinoma of the stomach were r and omized and analyzed for toxicity , tumor response , and progression-free and overall survival . Only review ed and confirmed responses were considered . The analysis of remission was based on assessable patients with documented measurable lesions . The intent-to-treat principle , log-rank test , and Cox regression model were used for the statistical analysis of time-to-event end points . RESULTS The overall response rate for 245 eligible patients with measurable disease was 9 % with ELF , 20 % with FUP , and 12 % with FAMTX , with no significant differences . One hundred twelve patients were eligible for efficacy  in assessable , nonmeasurable disease . No change was observed in 66 % of patients treated with ELF , 56 % with FUP , and 55 % with FAMTX . Two patients achieved a complete tumor regression ( one each for ELF and FAMTX ) . With a median follow-up time of 4.5 years , the median survival times were 7.2 months with ELF , 7.2 months with FUP , and 6.7 months with FAMTX , respectively , with no significant differences . Nonhematologic and hematologic toxicities of ELF , FUP , and FAMTX were acceptable , with neutropenia being the major toxicity for all three regimens . Seven treatment-related deaths occurred ( two with FUP and five with FAMTX ) . CONCLUSION All three investigated regimens demonstrate modest clinical efficacy and should not be regarded as st and ard treatment for advanced gastric cancer . New strategies should be considered to achieve a better clinical efficacy in the treatment of advanced gastric cancer Two hundred forty‐one patients with unresectable gastric adenocarcinoma were entered between December 1978 and March 1981 , into a prospect ively r and omized comparison of three chemotherapy regimens to identify therapeutic activity and determine patient tolerability : ( 1 ) 5‐fluorouracil plus Adriamycin ( FA ) ; ( 2 ) FA plus methyl‐CCNU ( FAMe ) ; and ( 3 ) FA plus mitomycin C ( FAMi ) . Patients were stratified by stage and performance status prior to r and omization . Treatment groups were well balanced with respect to known prognostic discriminants . The primary endpoint to evaluate treatment effect was patient survival . Pair‐wise comparisions using a proportional hazards model adjusted for stage and performance status documented a significant survival advantage for FAMe compared with FA ( P < 0.03 ) . Toxicity was primarily hematologic and was seen more frequently in patients receiving FAMe . Further investigations of the FAMe regimen in the surgical adjuvant setting and combined with radiotherapy for patients with locally unresectable gastric cancer are under development . Cancer 53:13‐17 , 1984 A r and omized controlled trial involving 13 institutions in Japan was conducted in order to compare the efficacy of tegafur plus mitomycin C ( MMC ) ( Regimen A ) and UFT ( a combination of uracil and tegafur at a molar ratio of 4 to 1 ) plus MMC ( Regimen B ) for patients with advanced gastric cancer , who had not received any prior cancer chemotherapy . Regimen A ( tegafur+MMC ) consisted of 5 mg of MMC/m2/week given intravenously , and 500 mg of tegafur/m2/day given orally . Regimen B consisted of the same schedule of MMC and 375 mg of UFT/m2/day given orally . One hundred and eighty‐six patients with primary gastric cancer were entered ; 183 were eligible and 3 were ineligible for the study . A total of 169 were evaluable for efficacy of the treatment , including 90 patients with Regimen A and 79 with Regimen B. A response rate of 7.8 % ( 7/90 cases ) for Regimen A and one of 25.3 % ( 20/79 cases ) for Regimen B were obtained , indicating a significantly higher response rate for Regimen B according to the Criteria for Evaluating Efficacy of Chemotherapy /Radiation Therapy in the Treatment of Gastric Cancer ( P= 0.004 ) , Regarding side effects , no marked differences in either severity or incidence were observed between the two groups . The group assigned to Regimen B showed a significant survival advantage after adjustment for major prognostic factors using a proportional hazards model ( P=0.0398 ) . Moreover , a close correlation of antitumor effect and survival duration was found when the above criteria were used Background A prospect i ve r and omized clinical study was performed in patients with locally advanced or metastatic gastric cancer . The purpose of the study was to determine the activity of high doses of 5-fluorouracil and epirubicin ( FE ) vs the same combination + cisplatin ( FEP ) , and particularly the value of cisplatin in the combination . Patients and Methods A total of 122 patients was included in the study ; 110 of them were assessable . In the FE arm , the treatment involved 1000 mg/m2 in a 6-hr infusion of 5-fluorouracil on days 1 , 2 , 3 , 4 and 5 and 120 mg/m2 of epirubicin iv on day 1 . In the FEP arm , the same combination of cytostatics + cisplatin ( 30 mg/m2 ) was administered on days 2 and 4 . The cycles were repeated after 4 weeks . Altogether , 468 cycles of chemotherapy were given ( FE , 240 ; FEP , 228 ) . Results In the FE arm , 56 patients were assessable , with 2 complete and 14 partial remissions ( 28.6 % ) ; in the FEP arm , 4 complete and 19 partial remissions ( 42.6 % ) were observed in 54 assessable patients . Median survival in the FE group was 7.1 months and in the FEP group 9.6 months . The survival difference was statistically significant ( Cox 's test , P<0.05 ) . The most frequent side effects included grade 2 and 3 alopecia ( FE , 93 % ; FEP , 94 % ) and grade 2 and 3 vomiting ( FE , 20 % ; FEP , 35 % ) . Grade 3 and 4 leukopenia was observed in 9 % of patients in the FE group and in 13 % of patients in the FEP group , with 6 cases of febrile neutropenia ( FE , 4 % ; FEP , 7 % ) . Stenocardia was registered in 1 patient in the FE group and in 2 patients in the FEP group . No treatment-related death was registered . Conclusions The addition of cisplatin to high doses of 5-fluorouracil and epirubicin result ed in a statistically significant better survival of treated patients PURPOSE We report the results of a prospect ively r and omized study that compared the combination of epirubicin , cisplatin , and protracted venous infusion fluorouracil ( 5-FU ) ( ECF regimen ) with the st and ard combination of 5-FU , doxorubicin , and methotrexate ( FAMTX ) in previously untreated patients with advanced esophagogastric cancer . PATIENTS AND METHODS Two hundred seventy-four patients with adenocarcinoma or undifferentiated carcinoma were r and omized and analyzed for survival , tumor response , toxicity , and quality of life ( QL ) . RESULTS The overall response rate was 45 % ( 95 % confidence interval [ CI ] , 36 % to 54 % ) with ECF and 21 % ( 95 % CI , 13 % to 29 % ) with FAMTX ( P = .0002 ) . Toxicity was tolerable and there were only three toxic deaths . The FAMTX regimen caused more hematologic toxicity and serious infections , but ECF caused more emesis and alopecia . The median survival duration was 8.9 months with ECF and 5.7 months with FAMTX ( P = .0009 ) ; at 1 year , 36 % ( 95 % CI , 27 % to 45 % ) of ECF and 21 % ( 95 % CI , 14 % to 29 % ) of FAMTX patients were alive . The median failure-free survival duration was 7.4 months with ECF and 3.4 months with FAMTX ( P = .00006 ) . The global QL scores were better for ECF at 24 weeks , but the remaining QL data showed no differences between either arm of the study . Hospital-based cost analysis on a subset of patients was similar for each arm and translated into an increment cost of $ 975 per life-year gained . CONCLUSION The ECF regimen results in a survival and response advantage , tolerable toxicity , better QL and cost-effectiveness compared with FAMTX chemotherapy . This regimen should now be considered the st and ard treatment for advanced esophagogastric cancer This report summarizes the results of a r and omized multi‐institutional clinical trial in advanced gastric carcinoma comparing four combination chemotherapy regimens : 5‐FU , Adriamycin + mitomycin C ( FAMi ) ; 5‐FU , Adriamycin + methyl‐CCNU ( FAMe ) ; 5‐FU , ICRF‐159 + methyl‐CCNU ( FIMe ) ; and 5‐FU + methyl‐CCNU ( FMe ) .  One‐hundred‐eighty‐one evaluable patients received chemotherapy . These objective tumor response rates were observed among the 59 patients with measurable indicator lesions : FAMi , 3/12 ( 25 % ) ; FAMe , 3/10 ( 30 % ) ; FIMe , 4/19 ( 21 % ) ; FMe , 1/18 ( 6 % ) . The survival distributions for the four treatment groups were significantly different ( P < 0.05 ) , with these median survivals observed ( in weeks from the onset of chemotherapy ) : FAMi , 29.6 ; FAMe , 34.4 ; FMe , 22.9 ; FIMe , 17.4 . Two nontreatment variables were found to be significantly associated with survival when analyzed using the Cox covariate model : pretreatment performance status ( P < 0.0001 ) , and presence or absence of measurable metastatic disease ( P < 0.001 ) . After adjustments for the effects of these and other clinical variables , two treatment regimens were found to be associated with improved survival  : FAMi therapy ( P < 0.01 ) , and FAMe therapy ( P = 0.07 ) . Toxicity was , in general , moderate and consisted primarily of gastrointestinal side effects and myelosuppression . We conclude that the FAMi and FAMe regimens are superior to the FIMe and FMe regimens in the management of advanced gastric cancer PURPOSE Patients with advanced gastric or gastroesophageal adenocarcinoma need more efficacious and safer treatments than established today . S-1 , a contemporary oral fluoropyrimidine , can provide that advantage . PATIENTS AND METHODS This study was conducted in 24 countries and 146 centers . One thous and fifty-three patients were stratified ( center , number of metastatic sites , prior adjuvant therapy , and measurable cancer ) and r and omly assigned . Patients received either S-1 at 50 mg/m(2 ) divided in two daily doses for 21 days and cisplatin at 75 mg/m(2 ) intravenously on day 1 , repeated every 28 days ( 527 patients ) or infusional fluorouracil at 1,000 mg/m(2)/24 hours for 120 hours and cisplatin at 100 mg/m(2 ) intravenously on day 1 , repeated every 28 days ( 526 patients ) . The primary end point was superiority in overall survival ( OS ) from cisplatin/S-1 compared with cisplatin/infusional fluorouracil in patients with advanced , untreated gastric , or gastroesophageal adenocarcinoma . The secondary end points were response rate , progression-free survival , time to treatment failure , and safety . RESULTS The median OS was 8.6 months in the cisplatin/S-1 arm and 7.9 months in the cisplatin/infusional fluorouracil arm ( HR , 0.92 ; 95 % CI , 0.80 to 1.05 ; P = .20 ) . Significant safety advantages were observed in the cisplatin/S-1 arm compared with the cisplatin/infusional fluorouracil arm for the rates of grade 3/4 neutropenia ( 32.3 % v 63.6 % ) , complicated neutropenia ( 5.0 % v 14.4 % ) , stomatitis ( 1.3 % v 13.6 % ) , hypokalemia ( 3.6 % v 10.8 % ) , and treatment-related deaths ( 2.5 % v 4.9 % ; P < .05 ) . CONCLUSION Cisplatin/S-1 did not prolong OS of patients with advanced gastric or gastroesophageal adenocarcinoma compared with cisplatin/infusional fluorouracil , but it did result in a significantly improved safety profile In a prospect i ve phase III multicenter trial , 213 patients with advanced measurable or nonmeasurable gastric cancer were r and omized to receive methotrexate ( MTX ) , fluorouracil ( 5-FU ) , and Adriamycin ( doxorubicin ; Farmitalia Carlo Erba , Milan , Italy ) ( FAMTX ) or 5-FU , Adriamycin , and mitomycin ( FAM ) . The results show a significantly superior response rate ( 41 % v 9 % [ P less than .0001 ] ) , and survival ( median , 42 weeks v 29 weeks [ P = .004 ] ) for FAMTX . There was a cumulative thrombocytopenia in FAM and not in FAMTX . The FAMTX protocol should be the reference treatment in future clinical trials that seek to improve the therapeutic outcome in advanced gastric cancer PURPOSE The purpose of this study was to define the contribution of docetaxel to combination chemotherapy in the outcome of patients with advanced gastric or gastroesophageal adenocarcinoma . We compared the overall response rate ( ORR ) and safety of docetaxel plus cisplatin ( DC ) with DC plus fluorouracil ( DCF ) to select either DC or DCF as the experimental treatment in the ensuing phase III part of trial V-325 . PATIENTS AND METHODS In this phase II r and omized study , untreated patients with confirmed advanced gastric or gastroesophageal adenocarcinoma received either DCF ( docetaxel 75 mg/m2 , cisplatin 75 mg/m2 on day 1 , and fluorouracil 750 mg/m2/d as continuous infusion on days 1 to 5 ) or DC ( docetaxel 85 mg/m2 and cisplatin 75 mg/m2 on day 1 ) every 3 weeks . An independent data monitoring committee ( IDMC ) was to select one of the two regimens based primarily on ORR and safety profile . RESULTS Of 158 r and omly assigned patients , 155 ( DCF , n = 79 ; DC , n = 76 ) received treatment . The confirmed ORR was 43 % for DCF ( n = 79 ) and 26 % for DC ( n = 76 ) . Median time to progression was 5.9 months for DCF and 5.0 months for DC .  Median overall survival time was 9.6 months for DCF and 10.5 months for DC . The most frequent grade 3 and 4 events per patient included neutropenia  ( DCF = 86 % ; DC = 87 % ) and GI ( DCF = 56 % ; DC = 30 % ) . CONCLUSION Both regimens were active , but DCF produced a higher confirmed ORR than DC .  Toxicity profiles of DCF were considered manageable . The IDMC chose DCF for the phase III part of V-325 , which compares DCF with cisplatin plus fluorouracil BACKGROUND Phase I/II clinical trials of S-1 plus cisplatin for advanced gastric cancer have yielded good responses and the treatment was well tolerated . In this S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer ( SPIRITS ) trial , we aim ed to verify that overall survival was better in patients with advanced gastric cancer treated with S-1 plus cisplatin  than with  S-1 alone . METHODS In this phase III trial , chemotherapy-naive patients with advanced gastric cancer were enrolled between March 26 , 2002 , and Nov 30 , 2004 , at 38 centres in Japan , and r and omly assigned to S-1 plus cisplatin or S-1 alone .  In patients assigned to S-1 plus cisplatin , S-1 ( 40 - 60 mg depending on patient 's body surface area ) was given orally , twice daily for 3 consecutive weeks , and 60 mg/m(2 ) cisplatin was given intravenously on day 8 , followed by a 2-week rest period , within a 5-week cycle . Those assigned to S-1 alone received the same dose of S-1 twice daily for 4 consecutive weeks , followed by a 2-week rest period , within a 6-week cycle . The primary endpoint was overall survival . Secondary endpoints were progression-free survival , proportions of responders , and safety . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00150670 . FINDINGS 305 patients were enrolled ; seven patients were ineligible or withdrew consent , therefore , 148 patients were assigned to S-1 plus cisplatin and 150 patients were assigned to S-1 alone .  Median overall survival was significantly longer in patients assigned to S-1 plus cisplatin ( 13.0 months [ IQR 7.6 - 21.9 ] ) than in those assigned to S-1 alone ( 11.0 months [ 5.6 - 19.8 ] ; hazard ratio for death , 0.77 ; 95 % CI 0.61 - 0.98 ; p=0.04 ) . Progression-free survival was significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to S-1 alone ( median progression-free survival 6.0 months [ 3.3 - 12.9 ] vs 4.0 months [ 2.1 - 6.8 ] ; p<0.0001 ) . Additionally , of 87 patients assigned S-1 plus cisplatin who had target tumours , one patient had a complete response and 46 patients had partial responses , ie , a total of 54 % ( range 43 - 65 ) . Of 106 patients assigned S-1 alone who had target tumours , one patient had a complete response and 32 had partial responses , ie , a total of 31 % ( 23 - 41 ) . We recorded more grade 3 or 4 adverse events including leucopenia , neutropenia , anaemia , nausea , and anorexia , in the group assigned to S-1 plus cisplatin than in the group assigned to S-1 alone . There were no treatment-related deaths in either group . INTERPRETATION S-1 plus cisplatin holds promise of becoming a st and ard first-line treatment for patients with advanced gastric cancer BACKGROUND We evaluated capecitabine ( an oral fluoropyrimidine ) and oxaliplatin ( a platinum compound ) as alternatives to infused fluorouracil and cisplatin , respectively , for untreated advanced esophagogastric cancer . METHODS In a two-by-two design , we r and omly assigned 1002 patients to receive triplet therapy with epirubicin and cisplatin plus either fluorouracil ( ECF ) or capecitabine ( ECX ) or triplet therapy with epirubicin and oxaliplatin plus either fluorouracil ( EOF ) or capecitabine ( EOX ) . The primary end point was noninferiority in overall survival for the triplet therapies containing capecitabine as compared with fluorouracil and for those containing oxaliplatin as compared with cisplatin . RESULTS For the capecitabine-fluorouracil comparison , the hazard ratio for death in the capecitabine group was 0.86 ( 95 % confidence interval [ CI ] , 0.80 to 0.99 ) ; for the oxaliplatin-cisplatin comparison , the hazard ratio for the oxaliplatin group was 0.92 ( 95 % CI , 0.80 to 1.10 ) . The upper limit of the confidence intervals for both hazard ratios excluded the predefined noninferiority margin of 1.23 . Median survival times in the ECF , ECX , EOF , and EOX groups were 9.9 months , 9.9 months , 9.3 months , and 11.2 months , respectively ; survival rates at 1 year were 37.7 % , 40.8 % , 40.4 % , and 46.8 % , respectively . In the secondary analysis , overall survival was longer with EOX than with ECF , with a hazard ratio for death of 0.80 in the EOX group ( 95 % CI , 0.66 to 0.97 ; P=0.02 ) . Progression-free survival and response rates did not differ significantly among the regimens . Toxic effects of capecitabine and fluorouracil were similar . As compared with cisplatin , oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia , alopecia , renal toxicity , and thromboembolism but with slightly higher incidences of grade 3 or 4 diarrhea and neuropathy . CONCLUSIONS Capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin , respectively , in patients with previously untreated esophagogastric cancer . ( Current Controlled Trials number , IS RCT N51678883 [ controlled-trials.com ] . ) Although many drug combination therapies have been proposed , there is no st and ard therapy for patients with advanced gastric carcinoma . The superiority of combination therapy over monochemotherapy has not been demonstrated convincingly . To explore the role of monochemotherapy , the authors evaluated 5‐fluorouracil ( 5‐FU ) , modulated by 6S‐leucovorin ( 6S‐LV ) and a cisplatin‐containing regimen , which was comprised of epirubicin , etoposide , and cisplatin with the addition of the reversal agent lonidamine ( EEP‐L ) By r and om assignment a total of 176 eligible patients with advanced nonmeasurable pancreatic carcinoma were treated with 5-fluorouracil ( 5-FU ) either alone or in combination with a nitrosourea ( streptozotocin ) , in combination with a " lactone " ( spironolactone ) , or in combination with both . By r and om assignment a total of 179 patients with advanced nonmeasurable gastric carcinoma were treated with 5-FU either alone or in combination with a nitrosourea ( methyl CCNU ) , in combination with a lactone ( testolactone ) , or in combination with both . The median survival period for all pancreatic carcinoma patients was 17 weeks , and for all gastric carcinoma patients 30 weeks . The addition of the nitrosoureas or the lactones or a combination of both produced no improvement in length of patient survival for either primary carcinoma when compared to treatment with 5-FU alone PURPOSE The purpose of this study was to evaluate the therapeutic effectiveness of fluorouracil ( 5-FU ) , doxorubicin , and methyl lomustine ( CCNU ) ( FAMe ) , 5-FU , doxorubicin , and cisplatin ( FAP ) , and FAMe alternating with triazinate ( TZT ) when compared with a st and ard therapy of 5-FU alone in patients with advanced gastric cancer . PATIENTS AND METHODS Two hundred fifty-two eligible patients selected for study had proven locally unresectable and /or metastatic gastric adenocarcinoma . The majority had nonmeasureable disease . They were r and omly assigned to receive one of the three drug combination regimens or to 5-FU alone administered by rapid injection in 5-day course . Survival was the primary study end point . RESULTS None of the three drug combinations showed a significant advantage over 5-FU alone in improved performance score , weight gain , or patient survival . Each of the three combinations was more toxic than 5-FU alone . CONCLUSION FAMe , FAP , or FAMe alternating with TZT can not be recommended for the therapy of advanced gastric carcinoma . Therapy of this disease should remain an experimental endeavor . It would seem reasonable to prove the value of any new treatment approach by a r and omized comparison to simple therapy with 5-FU alone PURPOSE The combination of cisplatin , epirubicin , and leucovorin preceding fluorouracil ( PELF ) includes three novel agents compared with the st and ard combination of fluorouracil , doxorubicin , and mitomycin ( FAM ) in the treatment of advanced gastric carcinoma . We report the results of a prospect i ve r and omized comparison of the two combinations in previously untreated patients . PATIENTS AND METHODS One hundred thirty assessable patients were entered onto the trial ; 52 received FAM and 85 PELF . A 1:2 unbalanced r and omization in favor of the experimental treatment was chosen . Approximately 90 % of patients had measurable tumor masses . RESULTS The overall response rates ( complete responses [ CRs ] and partial responses [ PRs ] ) were 15 % and 43 % for the FAM and the PELF regimens , respectively , with a statistically significant advantage for the experimental treatment ( P = .001 ) . Time to progression ( median , 2.6 and 4.7 months ) , duration of response ( median , 10.7 and 10.2 months ) , and survival duration s ( median , 5.6 and 8.1 months ) were not significantly different between the FAM and PELF regimens , respectively . The PELF combination was more toxic compared with FAM , but generally tolerable . CONCLUSION This study showed that the PELF combination is about three times more effective than the FAM combination in inducing objective responses . Due to tolerability , it is not recommended for routine clinical use . However , it should be considered , among other second-generation chemotherapy combinations , in future r and omized studies aim ed to improve the therapeutic outcome in gastric carcinoma PURPOSE This r and omized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate ( ORR ) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil ( ECF ) as first-line advanced gastric cancer therapy . PATIENTS AND METHODS Chemotherapy-naïve patients with measurable unresectable and /or metastatic gastric carcinoma , a performance status < or= 1 , and adequate hematologic , hepatic , and renal function r and omly received < or= eight 3-weekly cycles of ECF ( epirubicin 50 mg/m(2 ) on day 1 , cisplatin 60 mg/m(2 ) on day 1 , and fluorouracil [ FU ] 200 mg/m(2)/d on days 1 to 21 ) , TC ( docetaxel initially 85 mg/m(2 ) on day 1 [ later reduced to 75 mg/m(2 ) as a result of toxicity ] and cisplatin 75 mg/m(2 ) on day 1 ) , or TCF ( TC plus FU 300 mg/m(2)/d on days 1 to 14 ) . Study objectives included response ( primary ) , survival , toxicity , and quality of life ( QOL ) . RESULTS ORR was 25.0 % ( 95 % CI , 13 % to 41 % ) for ECF , 18.5 % ( 95 % CI , 9 % to 34 % ) for TC , and 36.6 % ( 95 % CI , 23 % to 53 % ) for TCF ( n = 119 ) . Median overall survival times were 8.3 , 11.0 , and 10.4 months for ECF , TC , and TCF , respectively . Toxicity was acceptable , with one toxic death ( TC arm ) . Grade 3 or 4 neutropenia occurred in more treatment cycles with docetaxel ( TC , 49 % ; TCF , 57 % ; ECF , 34 % ) . Global health status/QOL substantially improved with ECF and remained similar to baseline with both docetaxel regimens . CONCLUSION Time to response and ORR favor TCF over TC for further evaluation , particularly in the neoadjuvant setting . A trend towards increased myelosuppression and infectious complications with TCF versus TC or ECF was observed One hundred and forty‐six previously untreated patients with advanced gastric cancer were assigned at r and om to therapy with the following regimens : 1 ) Methyl CCNU alone ; 2 ) Methyl CCNU with cyclophosphamide induction ; 3 ) 5‐fluorouracil ( 5‐FU ) + methyl CCNU ; and 4 ) 5‐FU + methyl CCNU with cyclophosphamide induction . Cyclophosphamide induction produced an objective response rate of only 8 % . In addition , it added to hematologic toxicity and detracted from the therapeutic activity of subsequent treatment . Methyl CCNU was relatively ineffective therapy with an overall objective response rate of 8 % . The response rate  to 5‐FU + methyl CCNU without cyclophosphamide induction was 40 % and this was significantly superior to all other regimens . The survival time of all patients treated with 5‐FU + methyl CCNU was significantly superior to that of all patients treated with methyl CCNU alone PURPOSE The chemotherapy regimens of high-dose methotrexate , high-dose fluorouracil ( FU ) , Adriamycin ( doxorubicin ; Adria Laboratories , Columbus , OH ) , and leucovorin ( FAMTX ) and etoposide , Adriamycin , and cisplatin ( EAP ) have both been reported in nonr and om assignment trials to have high overall response rates and substantial complete response rates in patients with gastric cancer , as well as major toxicities of myelosuppression . Here we report a prospect i ve , stratified , r and om-assignment comparison of the two combinations in previously untreated patients with advanced gastric cancer . PATIENTS AND METHODS Sixty patients were entered onto the trial , 30 receiving EAP and 30 FAMTX . All patients had measurable or assessable tumor masses . Patient entry was stopped at the point when significant toxicity differences were seen at interim analysis . RESULTS Response rates were similar between the two arms ( FAMTX , 33 % [ 95 % confidence interval ( CI ) , 16 % to 50 % ] ; EAP , 20 % [ 95 % Cl , 6 % to 34 % ] ) . Three FAMTX and no EAP patients had complete remissions . The median survival for the two arms were similar ( EAP , 6.1 months ; FAMTX , 7.3 months ) . At 1 year , 7 % of EAP and 17 % of FAMTX patients were alive . EAP caused significantly more myelosuppression ( leukopenia , P = .002 ; anemia , P = .03 ; thrombocytopenia , P = .0001 ) than did FAMTX . EAP also result ed in significantly longer hospitalizations per study month ( 8 v 5 days ) . Four EAP patients died of lethal toxicity , whereas no FAMTX patients died of treatment-related causes ( P = .04 ) . CONCLUSIONS FAMTX is at least as active as EAP and is significantly less toxic . Although both regimens remain investigational , the toxicities of FAMTX are more manageable . Further studies involving FAMTX in both the adjuvant and advanced disease setting are underway A r and omized trial was conducted by the Southwest Oncology Group ( SWOG ) in advanced carcinoma of the stomach and pancreas . Patients were assigned to receive monthly 5‐fluorouracil 96‐hour continuous infusions with either bolus mitomycin‐C or oral methyl‐CCNU . Mitomycin‐C and methyl‐CCNU were administered every eight weeks . The 5 FU‐mitomycin combination produced a 14 % and 22 % response rate in disseminated stomach and pancreatic carcinoma , respectively . The combination of infusion 5 FU and methyl‐CCNU achieved responses in 9 % and 5 % of stomach and pancreatic tumors , respectively . There was ho significant difference in survival between limbs for either tumor . Median survival in gastric carcinoma on the 5 FU‐mitomycin regimen was 25 weeks vs. 18 weeks on the 5 FU‐methyl‐CCNU arm . In pancreatic carcinoma median survival on the mitomycin limb was 19 weeks as compared to 17 weeks on the methyl‐CCNU program . Leukopenia was greater for the first course on the mitomycin limb . Regression analysis demonstrated that performance status was the most important pretreatment characteristic for predicting survival in both tumors . Neither 5 FU infusion combination appears to significantly alter the dismal prognosis of advanced upper gastrointestinal neoplasms BACKGROUND 5-Fluorouracil ( 5-FU ) , doxorubicin and methotrexate ( FAMTX ) and cisplatin , epirubicin , leucovorin and 5-FU ( PELF ) have both been reported to be superior to the combination 5-FU , doxorubicin and mitomycin C ( FAM ) in advanced gastric carcinoma . On the basis of the presence and dose intensity of the included agents , we hypothesised that PELF would be superior to FAMTX . PATIENTS AND METHODS Two hundred patients with untreated advanced gastric carcinoma were r and omised to receive PELF or FAMTX for a maximum of six cycles or until disease progression . RESULTS The complete response ( CR ) rates to PELF and FAMTX were , respectively , 13 % [ 95 % confidence intervals ( CI ) 6 % to 20 % ] and 2 % ( 95 % CI 0 % to 5 % ; P = 0.003 ) , and the objective response rates [ CR plus partial response ( PR ) rates ] 39 % ( 95 % CI 29 % to 49 % ) and 22 % ( 95 % CI 13 % to 30 % ; P = 0.009 ) , thus significantly favouring the PELF combination . The survival rates after 12 months ( 30.8 % versus 22.4 % ) and 24 months ( 15.7 % versus 9.5 % ) were also higher among patients receiving PELF , but these differences were not statistically significant . The toxicities were qualitatively different but quantitatively similar . Both regimens seem to be feasible provided that careful patient monitoring is assured . CONCLUSIONS PELF is significantly more active than FAMTX and deserves further research in the adjuvant setting Fifty-seven patients with advanced gastric carcinoma were r and omized to receive 15 mg/kg/week of 5-fluorouracil by either the iv or oral route . Toxic effects of treatment included nausea and vomiting ( 40 % with the oral route versus 35 % with the iv route ) and myelosuppression , with a wbc count of less than 4000/mm3 ( 28 % with the oral route versus 32 % with the iv route ) . The frequency of partial response was 12 % ( three of 25 patients ) for the oral route and 16 % ( five of 32 patients ) for the iv route . Only two of 36 patients with liver metastases responded . No advantage was seen for the oral versus the iv route of 5-fluorouracil in the treatment of advanced gastric carcinoma BACKGROUND It is not yet established whether doses of epirubicin equitoxic to adriamycin are more effective in the treatment of locally advanced or metastatic gastric cancer . PATIENTS AND METHODS Seventy patients with advanced gastric cancer were r and omised to receive fluorouracil ( 500 mg/m2 days 1 - 5 every three weeks ) or epirubicin ( 100 mg/m2 every three weeks ) , with doses escalating to a maximum dose of 700 mg/m2 of fluorouracil or 140 mg/m2 of epirubicin . RESULTS No patients attained complete response . Partial response was seen in 3 patients in the epirubicin arm ( 8 % ) compared with 2 patients in the fluorouracil arm ( 6 % ) . No statistically significant difference between the two treatments was seen in either response or survival . Severe side effects , particularly alopecia , and nausea and vomiting were more common in the epirubicin arm ( 45 % and 37 % , respectively ) compared with the fluorouracil arm ( 12 % and 8 % , respectively ) . CONCLUSIONS Our trial demonstrates that fluorouracil and epirubicin as single agents have comparable but insufficient activity in advanced gastric cancer BACKGROUND To identify the most effective of two combinations , irinotecan/5-fluorouracil (5-FU)/folinic acid ( FA ) and irinotecan/cisplatin , in the treatment of advanced gastric cancer , for investigation in a phase III trial . PATIENTS AND METHODS Patients were r and omized to receive irinotecan [ 80 mg/m2 intravenously ( i.v . ) ] , FA ( 500 mg/m2 i.v . ) and a 22-h infusion of 5-FU ( 2000 mg/m2 i.v . ) , weekly for 6 weeks with a 1-week rest , or  irinotecan ( 200 mg/m2 i.v . ) and  cisplatin ( 60 mg/m2 i.v . ) , on day 1 for 3 weeks . RESULTS A total of 115 patients were eligible for analysis in the per- protocol population . The overall response rate in the irinotecan/5-FU/FA arm ( n=59 ) was 42.4 % , with a complete response rate of 5.1 % . Corresponding figures for the irinotecan/cisplatin arm ( n=56 ) were 32.1 % and 1.8 % , respectively . The median time to progression was 6.5 months ( irinotecan/5-FU/FA ) and 4.2 months ( irinotecan/cisplatin ) ( P < 0.0001 ) , with median survival times of 10.7 and 6.9 months , respectively ( P=0.0018 ) . The major toxicity was grade 3/4 neutropenia , which was more pronounced with irinotecan/cisplatin than with irinotecan/5-FU/FA ( 65.7 % versus 27 % ) . Diarrhea was the main grade 3/4 non-hematological toxicity with both irinotecan/5-FU/FA ( 27.0 % ) and irinotecan/cisplatin ( 18.1 % ) . CONCLUSIONS Both combinations were active , with acceptable safety profiles . Irinotecan/5-FU/FA was selected as the most effective combination for investigation in a phase III trial in advanced gastric cancer PURPOSE In the r and omized , multinational phase II/III trial ( V325 ) of untreated advanced gastric cancer patients , the phase II part selected docetaxel , cisplatin , and fluorouracil ( DCF ) over docetaxel and cisplatin for comparison against cisplatin and fluorouracil ( CF ; reference regimen ) in the phase III part . PATIENTS AND METHODS Advanced gastric cancer patients were r and omly assigned to docetaxel 75 mg/m2 and cisplatin 75 mg/m2 ( day 1 ) plus fluorouracil 750 mg/m2/d ( days 1 to 5 ) every 3 weeks or cisplatin 100 mg/m2 ( day 1 ) plus fluorouracil 1,000 mg/m2/d ( days 1 to 5 ) every 4 weeks . The primary end point was time-to-progression ( TTP ) . RESULTS In 445 r and omly assigned and treated patients ( DCF = 221 ; CF = 224 ) , TTP was longer with DCF versus CF ( 32 % risk reduction ; log-rank P < .001 ) . Overall survival was longer with DCF versus CF ( 23 % risk reduction ; log-rank P = .02 ) . Two-year survival rate was 18 % with DCF and 9 % with CF .  Overall response rate was higher with DCF ( chi2 P = .01 ) . Grade 3 to 4 treatment-related adverse events occurred in 69 % ( DCF ) v 59 % ( CF ) of patients . Frequent grade 3 to 4 toxicities for DCF v CF were : neutropenia ( 82 % v 57 % ) , stomatitis ( 21 % v 27 % ) , diarrhea ( 19 % v 8 % ) , lethargy ( 19 % v 14 % ) . Complicated neutropenia was more frequent with DCF than CF ( 29 % v 12 % ) . CONCLUSION Adding docetaxel to CF significantly improved TTP , survival , and response rate in gastric cancer patients , but result ed in some increase in toxicity . Incorporation of docetaxel , as in DCF or with other active drug(s ) , is a new therapy option for patients with untreated advanced gastric cancer Thirty-eight patients of advanced adenocarcinoma of the stomach were r and omly administered intensive courses of either 5-FU or mitomycin C by intravenous route , The 5-FU administration result ed in a slightly better response than mitomycin C , although the toxic effects of the two drugs were more or less the same . The selection of drug regime in the present study has been based on cost , availability , potential toxicity , and minimal alteration of the patients ' life style 4536 Background : To compare the efficacy and tolerance of two oxaliplatin-based regimens as first-line treatment of advanced gastric cancer . METHODS Chemotherapy-naïve patients with measurable recurrent or metastatic gastric adenocarcinoma , PS ( ECOG ) 0 - 2 and adequate organ functions were r and omly assigned to receive either irinotecan 200mg/m2 and oxaliplatin 80mg/m2 ( IO ) , every 21 days or oxaliplatin 85mg/m2 on day 1 , 5-FU 400 mg/m2 ( over 1 hour infusion ) + 600mg/m2 ( over 22 hours infusion ) on days 1 and 2 , leucovorin ( LV ) 200mg/m2 on days 1 and 2 ( FOLFOX4 ) every 2 weeks . Study endpoints : Overall Response Rate ( ORR ) , Toxicity Time to Progression ( TTP ) and Survival ( S ) . RESULTS 138 patients were enrolled and all were evaluable for response . Median number of cycles administered was 5.5 ( range 1 - 10 ) for IO and 7 ( range 1 - 18 ) for FOLFOX4 . In an intent-to treat analysis the ORR ( RR+CR ) was 29.4 % for IO arm and 34.3 % for FOLFOX4 arm ( p= 0.587 ) . The median response duration was 5.63 months ( mo ) for IO arm and 6,6mo for FOLFOX4 arm . Median TTP was 4.2mo and 6,1mo for IO and FOLFOX4 arm respectively ( p= 0.012 ) . Median OS was 9.4mo for IO and 11.97mo for FOLFOX4 ( p= 0.456 ) . Toxicity was acceptable , with one toxic death in each arm . Grade 3 - 4 vomiting ( 7.3 % ) , diarrhea ( 11.8 % ) , neutropenia ( 22 % ) and febrile neutropenia ( 5.9 % ) occurred more frequently in IO arm , while anaemia ( 4.3 % ) and grade II neurotoxicity ( 11.4 % ) was more frequent in FOLFOX4 arm . CONCLUSIONS Both regimens are well tolerated and active in advanced gastric cancer . Based on the TTP and toxicity profile , the FOLFOX4 regimen merits to be further evaluated in prospect i ve phase III trials . No significant financial relationships to disclose One  hundred nineteen patients with advanced gastric cancer were included in a study comparing EEP vs. FEM chemotherapy . The response rate was higher ( 30 % ) in patients on EEP than in those treated with FEM ( p = 0.05 ) . Severe leukopenia , anemia , alopecia and infection were significantly more frequent on EEP . In addition , because of its intrinsic toxicity , EEP chemotherapy has a negative impact on the performance status of patients treated with this regimen , more than half of whom presented at least one episode of severe symptomatic toxicity while on EEP chemotherapy . The median time to progression and median survival for EEP-FEM were 2.08 - 3.4 and 4.2 - 7.9 months , respectively . Our data do not support the use of EEP chemotherapy in patients with AGC In a prospect i ve phase III multicenter trial , 189 patients with advanced measurable and nonmeasurable gastric cancer were r and omized to receive 5-fluorouracil ( 5-FU ) combined with Adriamycin ( FA ) or FA plus methyl-CCNU ( MeFA ) . The response rate in patients with measurable disease was 10 % ( three of 29 ) , and 18 % ( five of 28 ) , respectively . No difference in the duration of survival was detected ( P = .14 ; log rank test ) . Median survivals were 21 and 32 weeks , respectively . Toxicity was moderate , but there have been two toxic deaths among the patients who received FA . Because of the low response rate and the short survival , neither regimen can be recommended for the treatment of advanced gastric cancer This r and omized controlled clinical trial was design ed to compare the safety and effectiveness of different sequences of treatment with cisplatin ( CDDP ) and 5-fluorouracil ( 5-FU ) in patients with unresectable advanced and post-operative recurrent gastric cancer . Patients with unresectable advanced or post-operative recurrent gastric cancer were r and omly assigned by a registration center to group A or B. Group A received CDDP ( 80 mg/m(2 ) ) as a continuous 2-h intravenous infusion on day 1 and 5-FU ( 700 mg/m(2 ) ) as a continuous intravenous infusion on days 2 - 5 . Group B was given 5-FU ( 700 mg/m(2 ) ) as a continuous intravenous infusion on days 1 - 4 , followed by CDDP ( 80 mg/m(2 ) ) as a continuous 2-h intravenous infusion on day 5 . Each course of chemotherapy was repeated every 28 days . A total of 74 patients were enrolled . One patient died accidentally , and 5 could not be evaluated . Response was assessable in 68 patients . The response rate was 31.3 % ( 10/32 ) in group A as compared with 13.9 % ( 5/36 ) in group B. Although the response rate was higher in Group A , the difference was not significant ( p=0.085 ) . The response rate in  patients with diffuse type tumors was significantly lower in group B. There was no difference between the groups in response among patients with intestinal type tumors . The median overall survival was 239 and 174 days and time to progression was 175 and 140 days in group A and group B , respectively . Although there were trends toward longer survival and time to progression in group A , the differences between the groups were not statistically significant . There was also no difference in the type or incidence of adverse reactions . The results of this controlled study indicate that the overall response rate was slightly but not significantly higher in patients who received CDDP before 5-FU . Among patients with diffuse type tumors , the response rate was significantly lower when 5-FU was administered before CDDP . Our results suggest that CDDP should be given before 5-FU in patients with gastric cancer when treated with a combination of CDDP and 5-FU PURPOSE To compare fluorouracil ( FU ) alone with FU plus cisplatin ( FP ) and with uracil and tegafur plus mitomycin ( UFTM ) for patients with advanced gastric cancer in a prospect i ve , r and omized , controlled trial . PATIENTS AND METHODS A total of 280 patients with advanced gastric cancer were r and omly allocated and analyzed for survival , response , and toxicity . The survival curves were compared between groups by log-rank test on an intent-to-treat basis . RESULTS At the interim analysis , the UFTM arm showed a significantly inferior survival with higher incidences of hematologic toxic effects than did control arm FU alone , and the registration to UFTM was terminated . Both investigational regimens , FP and UFTM , had a significantly higher incidence of hematologic toxic effects than FU alone , although the effects were manageable . The overall response rates of the FU-alone , FP , and UFTM arms were 11 % , 34 % , and 9 % , respectively . The median progression-free survival was 1.9 months with FU alone , 3.9 months with FP , and 2.4 months with UFTM , respectively . Although FP demonstrated a higher response rate ( P < .001 ) and longer progression-free survival than did FU alone ( P < .001 ) , no differences in overall survival were observed between the arms . The median survival times and 1-year survival rates were 7.1 months and 28 % with FU , 7.3 months and 29 % with FP , and 6.0 months and 16 % with UFTM , respectively . CONCLUSION Neither investigational regimen , FP nor UFTM , showed a survival advantage as compared with FU alone . FU alone will remain a reference arm in our future trial for advanced gastric cancer Taxanes have clearly demonstrated activities against gastric cancer . We compared the combination of paclitaxel plus 5-fluorouracil ( 5-FU ) ( PF ) with docetaxel plus 5-FU ( DF ) as first-line chemotherapy in patients with measurable metastatic gastric cancer . Seventy-seven patients were r and omly assigned to receive paclitaxel 175 mg/m2 or docetaxel 75 mg/m2 on day 1 , in combination with 5-FU 500 mg/m2 continuous infusion on days 1–5 . Treatment was repeated every 3 weeks . Of 314 chemotherapy cycles delivered ( median 5 in both groups ) , dose reduction was required more frequently in the DF group , being 9 and 19 % , respectively ( P<0.01 ) . PF was associated with , although statistically insignificant , substantially less grade 3 or 4 toxicities than DF ( 68 versus 85 % ; P=0.09 ) . Global quality of life was similar in both groups , but substantive differences in many symptom scores including pain , dyspnea , constipation and diarrhea favored PF . There were no significant differences in therapeutic efficacy between PF and DF with respect to response rate ( 42 versus 33 % , respectively ; P=0.53 ) , and failure-free ( 3.6 versus 4.2 months ; P=0.92 ) and overall survival ( 9.9 versus 9.3 months ; P=0.42 ) . Both PF and DF appear to have efficacy against metastatic gastric cancer , with different , but acceptable , safety profiles A multi-institutional cooperative study of patients with locally advanced , recurrent , or metastatic gastric adenocarcinoma who had not previously received chemotherapy  was conducted , prospect ively r and omizing patients to receive either doxorubicin or the three-drug combination , 5-fluorouracil ( 5-FU ) , doxorubicin ( Adriamycin ; Adria Laboratories , Columbus , Ohio ) , and BCNU ( FAB ) . The 187 evaluable patients were initially stratified according to the presence of measurable or evaluable disease and performance status . There was a significantly higher response rate observed for FAB ( 40 % ) compared with doxorubicin ( 13 % ) among the 145 measurable-disease patients . Duration of response and survival were significantly longer for FAB in the measurable-disease group , but for the total patient population an early advantage for FAB in time to disease progression and survival was lost with continued follow-up . Median survival was 33 weeks for patients receiving FAB and 19 weeks for those receiving doxorubicin . Significant pretreatment factors adversely affecting survival included poor performance status , weight loss of greater than 10 % , and more than two sites of metastases . Toxicity was not severe in either treatment arm , and only thrombocytopenia occurred significantly more often with FAB . It is contended that in the treatment of advanced gastric cancer , chemotherapy only exerts a relatively short-term and modest beneficial effect , most apparent in patients with intermediate tumor bulk . 5-FU remains the most active single agent , and combination chemotherapy has not yet proven its overall worth . Further studies are indicated comparing the most active combinations with 5-FU using optimal doses and schedules , and consideration must be given to the incorporation of no-treatment controls PURPOSE This multicentric , r and omized , two-stage phase II trial evaluated three simplified weekly infusional regimens of fluorouracil ( FU ) or FU plus folinic acid ( FA ) and cisplatin ( Cis ) with the aim to select a regimen for future phase III trials . PATIENTS AND METHODS A total of 145 patients with advanced gastric cancer where r and omly assigned to weekly  FU 3,000 mg/m2/24 hours ( HD-FU ) , FU 2,600 mg/m2/24 hours plus dl-FA 500 mg/m2 or l-FA 250 mg/m2 ( HD-FU/FA ) , or FU 2000 mg/m2/24 hours plus FA plus biweekly Cis 50 mg/m2 , each administered for 6 weeks with a 1-week rest . The primary end point was the response rate . RESULTS Confirmed responses were observed in 6.1 % ( two of 33 ) of the eligible patients treated with HD-FU , in 25 % ( 12 of 48 , including one complete remission [ CR ] ) with HD-FU/FA , and in 45.7 % ( 21 of 46 , including four CRs ) with HD-FU/FA/Cis . The HD-FU arm was closed after stage 1 because the required minimum number of responses was not met . The median progression-free survival of all patients in the HD-FU , HD-FU/FA , and HD-FU/FA/Cis arm was 1.9 , 4.0 , and 6.1 months , respectively . The median overall survival was 7.1 , 8.9 , and 9.7 months , and the survival rate at 1 year was 24.3 % , 30.3 % , and 45.3 % , respectively . Grade 4 toxicities were rare . The most relevant grade 3/4 toxicities were neutropenia in 1.9 % , 5.4 % , and 19.6 % , and diarrhea in 2.7 % , 1.9 % , and 3.9 % of the cycles in the HD-FU , HD-FU/FA , and HD-/FU/Cis arms , respectively . CONCLUSION Weekly infusional FU/FA plus biweekly Cis is effective and safe in patients with gastric cancer A total of 71 patients with advanced gastric carcinoma were r and omized to receive either folinic acid + fluorouracil ( arm A ) or the same combination with the addition of 4-epidoxorubicin ( arm B ) . Of the 62 evaluable patients ( 31 in both arms ) , six patients achieved a CR ( 10 % ) and 16 a PR ( 25.5 % ) with an overall response rate of 35.5 % ( 29 % in arm A and 42 % in arm B ; p = .28 ) . Median duration of response was 6 and 7 months for arm A and B , respectively ( p = .6 ) . Responder patients showed a significantly better median survival duration than nonresponders ( p = .01 ) ; in arm B the median survival duration was 16 months for responder patients in contrast to 7 months for nonresponders ( p = .004 ) . Toxicity was mild without significant differences between the two groups . There was one death due to hematological toxicity ( arm A ) . The EPI-FA-FU combination appears effective and well tolerated with the additional advantage of being able to be administered in the outpatient clinic A consortium of Northern California and Japanese investigators studied 142 patients with advanced gastric adenocarcinoma . Patients were r and omized to one of two combination chemotherapy programs in each nation ( one common therapy shared and one therapy  unique to each nation ) . Median duration of survial ranged between 5 and 45 weeks , depending on performance status , extent of disease , and chemotherapy program . More importantly , there was considerable comparability with respect to toxicity and outcome between patients in the US and Japan .  Overall median survival was 26 weeks for Japanese and 27 weeks for US patients . This study helps provide the basis for future comparative multinational trials LBA4007 Background : The median survival for patients ( pts ) with AGC in most phase III studies is less than 1 year . The addition of bevacizumab ( bev ) to chemotherapy ( chemo ) is supported by a strong pre clinical rationale and by phase II evaluation . AVAGAST is the first r and omized study to compare the efficacy and safety of bev + chemo vs placebo + chemo . METHODS Pts with inoperable , locally advanced or metastatic stomach/gastroesophageal junction adenocarcinoma with no prior therapy were r and omized 1:1 to capecitabine ( cape , or 5-FU ) + cisplatin ( cis ) and either bev ( 7.5 mg/kg iv ) or placebo q3w . Stratification variables : geographical region , fluoropyrimidine treatment , disease status . Cis was given for 6 cycles ; bev/placebo + cape/5-FU were given until disease progression or unmanageable toxicity . PRIMARY OBJECTIVE compare overall survival ( OS ) ; secondary objectives : compare progression-free survival ( PFS ) , overall response rate ( ORR ) , and safety ( as overseen by an independent DSMB ) . RESULTS From Sep 2007 to Dec 2008 , 774 pts were enrolled . Treatment arms were balanced . Approx 95 % of pts were metastatic . Two-thirds of pts were male , 49 % of pts were from Asia/Pacific , 32 % from Europe and 19 % from the Americas . Median OS was 10.1 months with chemo + placebo and 12.1 months with chemo + bev in the intent-to-treat population ( HR 0.87 ; p=0.1002 ) . Median OS according to geographical region was 6.8 vs. 11.5 months ( HR 0.63 ) in the Americas , 8.6 vs. 11.1 months ( HR 0.85 ) in Europe and 12.1 vs. 13.9 months in Asia-Pacific ( HR 0.97 ) . Secondary endpoints and AEs of special interest for Bev are summarized below ( Table ) . CONCLUSIONS While the primary endpoint was not met ( median OS HR 0.87 ; p=0.1002 ) , there was a significant improvement in PFS and ORR and an acceptable safety profile for bev + chemo in patients with AGC . [ Table : see text ] [ Table : see text ] PURPOSE We report the results of a prospect ively r and omized study that compared the combination of epirubicin , cisplatin , and protracted venous-infusion fluorouracil ( PVI 5-FU ) ( ECF ) with the combination of mitomycin , cisplatin , and PVI 5-FU ( MCF ) in previously untreated patients with advanced esophagogastric cancer . PATIENTS AND METHODS Five hundred eighty patients with adenocarcinoma , squamous carcinoma , or undifferentiated carcinoma were r and omized to receive either ECF ( epirubicin 50 mg/m(2 ) every 3 weeks , cisplatin 60 mg/m(2 ) every 3 weeks and PVI 5-FU 200 mg/m(2)/d ) or MCF ( mitomycin 7 mg/m(2 ) every 6 weeks , cisplatin 60 mg/m(2 ) every 3 weeks , and PVI 5-FU 300 mg/m(2)/d ) and analyzed for survival , response , toxicity , and quality of life ( QOL ) . RESULTS The overall response rate was 42.4 % ( 95 % confidence interval [ CI ] , 37 % to 48 % ) with ECF and 44.1 % ( 95 % CI , 38 % to 50 % ) with MCF ( P = .692 ) . Toxicity was tolerable , and there were only two toxic deaths .  ECF result ed in more grade 3/4 neutropenia and grade 2 alopecia , but MCF caused more thrombocytopenia and plantar-palmar erythema . Median survival was 9.4 months with ECF and 8.7 months with MCF ( P = .315 ) ; at 1 year , 40.2 % ( 95 % CI , 34 % to 46 % ) of ECF and 32.7 % ( 95 % CI , 27 % to 38 % ) of MCF patients were alive . Median failure-free survival was 7 months with both regimens . Global QOL scores were better with ECF at 3 and 6 months . CONCLUSION This study confirms response , survival , and QOL benefits of ECF observed in a previous r and omized study . The equivalent efficacy of MCF was demonstrated , but QOL was superior with ECF . ECF remains one of the reference treatments for advanced esophagogastric cancer
target: Within a combination chemotherapy regimen , oral capecitabine is preferred over intravenous 5-fluorouracil (5fu)-that is , epirubicin-cisplatin-capecitabine is preferred over the prior st and ard regimen , epirubicin-cisplatin-5fu (ecf).Epirubicin-oxaliplatin-capecitabine ( eox ) is a reasonable alternative to ecf .
background: QUESTION What is the optimal chemotherapy regimen in advanced gastric cancer ?
  PERSPECTIVES Gastric cancer is the second leading cause of cancer mortality worldwide .
  Despite low incidence rates for gastric cancer in Ontario , the overall prognosis is bleak , with 5-year survival rates of approximately 23 % in Canada .
  Even with the considerable body of research available on chemotherapy for advanced gastric cancer , uncertainty remains .
  There is no recognized st and ard treatment , and there appears to be geographic variation in practice .