A multicentre, randomised phase III trial comparing protracted venous infusion (PVI) 5-fluorouracil (5-FU) with PVI 5-FU plus mitomycin C in patients with inoperable oesophago-gastric cancer. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial Effect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. A randomised phase II trial and feasibility study of palliative chemotherapy in frail or elderly patients with advanced gastroesophageal cancer (321GO) Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Matuzumab plus epirubicin, cisplatin and capecitabine (ECX) compared with epirubicin, cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophago-gastric cancer: a randomised, multicentre open-label phase II study. 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 The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Randomised, non-comparative phase II study of weekly docetaxel with cisplatin and 5-fluorouracil or with capecitabine in oesophagogastric cancer: the AGITG ATTAX trial Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first-line therapy for advanced or locally recurrent gastric cancer Panitumumab added to docetaxel, cisplatin and fluoropyrimidine in oesophagogastric cancer: ATTAX3 phase II trial S-1 combined with cisplatin versus cisplatin alone for the treatment of advanced gastric cancer: a pilot randomized-controlled trial Randomized phase II trial of first-line treatment with tailored irinotecan and S-1 therapy versus S-1 monotherapy for advanced or recurrent gastric carcinoma (JFMC31-0301) S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial. The feasibility of triple-drug chemotherapy combination in older adult patients with oesophagogastric cancer: a randomised trial of the Arbeitsgemeinschaft Internistische Onkologie (FLOT65+). Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial 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. Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter Phase II trial.
BACKGROUND This r and omised study compared protracted venous infusion ( PVI ) fluorouracil ( 5-FU ) with PVI 5-FU plus mitomycin C ( MMC ) in patients with advanced oesophago-gastric cancer . PATIENTS AND METHODS Two hundred and fifty-four patients with adenocarcinoma , squamous cell carcinoma or undifferentiated carcinoma involving the oesophagus , oesophago-gastric junction or the stomach were r and omised . The major end points were tumour response , survival , toxicity and quality of life . RESULTS The median age of patients treated was 72 years and the two arms were well-balanced for baseline demographic factors . The overall response rate was 16.1 % [ 95 % confidence interval ( CI ) 9.5 % to 22.7 % ] in patients treated with PVI 5-FU alone compared with 19.1 % ( 95 % CI 12.0 % to 26.0 % ) for those treated with PVI 5-FU plus MMC ( P = 0.555 ) . Median time to treatment failure was 3.9 months for PVI 5-FU and 3.8 months for PVI 5-FU plus MMC ( P = 0.195 ) . Median survival was 6.3 months for PVI 5-FU and 5.3 months for PVI 5-FU plus MMC ( P = 1.0 ) . Toxicity was mild for both treatments . Symptomatic benefit measured by improvement in pain control , weight loss , dysphagia and oesophageal reflux was observed in over 64 % of patients in each arm . Quality of life scores were comparable in each arm . CONCLUSIONS PVI 5-FU is a safe , effective form of palliation for patients with advanced oesophago-gastric cancer although the addition of MMC adds little extra benefit We report the final 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 oesophagogastric cancer . Between 1992 and 1995 , 274 patients with adenocarcinoma or undifferentiated carcinoma were r and omized from eight oncology centres in the UK and analysed for response and survival . The overall response rate was 46 % ( 95 % confidence interval ( CI ) , 37–55 % ) with ECF , and 21 % ( 95 % CI , 13–28 % ) with FAMTX ( P = 0.00003 ) . The median survival was 8.7 months with ECF and 6.1 months with FAMTX ( P = 0.0005 ) . The 2-year survival rates were 14 % ( 95 % CI , 8–20 % ) for the ECF arm , and 5 % ( 95 % CI , 2–10 % ) for the FAMTX arm ( P = 0.03 ) . Histologically complete surgical resection following chemotherapy was achieved in ten patients in the ECF arm ( three pathological complete responses to chemotherapy ) and three patients in the FAMTX arm ( no pathological complete responses ) . The ECF regimen result ed in a response and survival advantage compared with FAMTX chemotherapy . The probability of long-term survival following surgical resection of residual disease is increased by this treatment . The high response rates seen with ECF support its use in the neoadjuvant setting Importance Dysregulation of the mesenchymal-epithelial transition ( MET ) signaling pathway is associated with poor prognosis in gastroesophageal adenocarcinoma ( GEC ) . We report results of METGastric , a phase 3 trial of the MET inhibitor onartuzumab plus st and ard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative , MET-positive , advanced GEC . Objective To determine whether the addition of onartuzumab to first-line fluorouracil , leucovorin , and oxaliplatin ( mFOLFOX6 ) improves efficacy compared with mFOLFOX6 plus placebo in HER2-negative , MET-positive GEC . Design , Setting , and Participants R and omized , double-blind , multicenter trial conducted from November 2012 to March 2014 . Patients were 18 years or older with an adenocarcinoma of the stomach or gastroesophageal junction with metastatic disease not amenable for curative therapy . Tumor sample s were central ly tested for MET expression using Ventana anti-Total c-MET ( SP44 ) rabbit monoclonal antibody , HER2 status , and Lauren histologic subtype . MET-positive tumors were defined as at least 50 % of tumor cells showing weak , moderate , and /or strong staining intensity ( MET 1+/2+/3 + , respectively ) by immunohistochemistry . Interventions Patients with HER2-negative , MET-positive GEC were enrolled and r and omized 1:1 to receive mFOLFOX6 with or without onartuzumab ( 10 mg/kg ) . Main Outcomes and Measures Co– primary end points : overall survival in the intent-to-treat ( ITT ) population and in patients with MET 2+/3 + GEC . Secondary end points : progression-free survival ( PFS ) , overall response rate ( ORR ) , and safety . Results Enrollment was stopped early due to sponsor decision , which was agreed with an independent data monitoring committee . At the data cutoff ( April 25 , 2014 ) there were 562 patients in the ITT population ( n = 283 placebo plus mFOLFOX6 [ median age , 58 y ; 65 % male ] ; n = 279 onartuzumab plus mFOLFOX6 [ median age , 60 y ; 67 % male ] ) ; 109 ( 38.5 % ) and 105 ( 37.6 % ) of the ITT population were MET 2+/3 + , respectively . Addition of onartuzumab to mFOLFOX6 did not significantly improve OS , PFS , or ORR vs placebo plus mFOLFOX6 in the ITT ( OS hazard ratio [ HR ] , 0.82 ; 95 % CI , 0.59 - 1.15 ; P = .24 ; PFS HR , 0.90 ; 95 % CI , 0.71 - 1.16 ; P = .43 ; ORR , 46.1 % vs 40.6 % ) or MET 2+/3 + population s ( OS HR , 0.64 ; 95 % CI , 0.40 - 1.03 ; P = .06 ; PFS HR , 0.79 ; 95 % CI , 0.54 - 1.15 ; P = .22 ; ORR , 53.8 % vs 44.6 % ) . Safety was as expected for onartuzumab . Conclusions and Relevance Addition of onartuzumab to first-line mFOLFOX6 did not significantly improve clinical benefits in the ITT or MET 2+/3 + population s. Trial Registration clinical trials.gov Identifier : OBJECTIVES More than half of cases of gastric cancer ( GC ) are diagnosed in elderly patients ( ≥70years ) . While doublet combination with fluoropyrimidines and platinum is currently considered st and ard first-line chemotherapy in advanced GC , the main goal of chemotherapy remains palliation . MATERIAL S AND METHODS In a multi-center phase III trial , patients with chemotherapy-naïve , metastatic GC , aged 70years or older were r and omized 1:1 to receive X monotherapy ( capecitabine 1000mg/m2 bid po on days one to fourteen ) or XELOX ( X plus oxaliplatin 110mg/m2 iv on D1 ) . Treatment was repeated every 21days until disease progression , unacceptable toxicity , or withdrawal . Primary endpoint was overall survival ( OS ) . RESULTS In total , 50 patients with a median age of 77 ( range , 70 to 84 ) were enrolled ( X , n=26 ; XELOX , n=24 ) . No treatment-related serious adverse events or unexpected toxicities were observed . The most frequently observed toxicities were nausea and h and -foot syndrome , with fatigue and peripheral neuropathy more common in XELOX than in X patients . Median OS was 11.1months for XELOX arm and 6.3months for X arm ( HR 0.58 , 95 % CI 0.30 - 1.12 , P=0.108 ) . Although the difference was not significant , on the basis of evidence of superiority of XELOX seen in the first interim analysis , an independent data monitoring committee recommended early stopping of the trial . PFS was significantly longer ( HR 0.32 , 95 % CI 0.17 - 0.61 , P<0.001 ) with XELOX ( 7.1months ) than with X ( 2.6months ) . CONCLUSION Platinum-based combination chemotherapy was associated with survival benefit , as compared with X monotherapy in elderly patients with GC Background : Elderly patients are commonly under-represented in cancer clinical trials . The 321GO was undertaken in preparation for a definitive phase three trial assessing different chemotherapy regimens in a frail and /or elderly population with advanced gastroesophageal ( GO ) cancer . Methods : Patients with advanced GO cancer considered unfit for conventional dose chemotherapy were r and omly assigned in a 1 : 1 : 1 ratio to : epirubicin , oxaliplatin and capecitabine ( EOX ) ; oxaliplatin and capecitabine ( OX ) ; and capecitabine alone ( X ) ( all 80 % of full dose and unblinded ) . The primary end point was patient recruitment over an 18-month period . A registration study recorded treatment choice for all patients with advanced GO cancer at trial centres . Results : A total of 313 patients were considered for palliative chemotherapy for GO cancer over the 18-month period : 115 received full dose treatment , 89 less than st and ard treatment or entered 321GO and 111 no treatment . Within 321GO , 55 patients were r and omly assigned ( 19 to OX and X ; 17 to EOX ) . Progression-free survival ( PFS ) for all patients was 4.4 months and by arm 5.4 , 5.6 and 3.0 months for EOX , OX and X , respectively . The number of patients with a good overall treatment utility ( OTU ) , a novel patient-centred endpoint , at 12 weeks was 3 ( 18 % ) , 6 ( 32 % ) and 1 ( 6 % ) for EOX , OX and X , respectively . At 6 weeks , 22 patients ( 41 % ) had experienced a non-haematologic toxicity ⩾ grade 3 , most commonly lethargy or diarrhoea . The OTU was prognostic for overall survival in patients alive at week 12 ( logrank test P=0.0001 ) . Conclusions : It is feasible to recruit elderly and /or frail patients with advanced GO cancer to a r and omised clinical trial . The OX is the preferred regimen for further study . Overall treatment utility shows promise as a comparator between treatment regimens for feasibility and r and omised trials in the elderly and /or frail GO cancer population BACKGROUND Rilotumumab is a fully human monoclonal antibody that selectively targets the lig and of the MET receptor , hepatocyte growth factor ( HGF ) . We aim ed to assess the efficacy , safety , and pharmacokinetics of rilotumumab combined with epirubicin , cisplatin , and capecitabine , and to assess potential biomarkers , in patients with advanced MET-positive gastric or gastro-oesophageal junction adenocarcinoma . METHODS This multicentre , r and omised , double-blind , placebo-controlled , phase 3 study was done at 152 centres in 27 countries . We recruited adults ( aged ≥18 years ) with unresectable locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma , an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 or 1 , MET-positive tumours ( ≥25 % of tumour cells with membrane staining of ≥1 + staining intensity ) , and evaluable disease , who had not received previous systemic therapy . Eligible patients were r and omly assigned ( 1:1 ) via a computerised voice response system to receive rilotumumab 15 mg/kg intravenously or placebo in combination with open-label chemotherapy ( epirubicin 50 mg/m2 intravenously ; cisplatin 60 mg/m2 intravenously ; capecitabine 625 mg/m2 orally twice daily ) in 21-day cycles for up to ten cycles . After completion of chemotherapy , patients continued to receive rilotumumab or placebo monotherapy until disease progression , intolerability , withdrawal of consent , or study termination . R and omisation was stratified by disease extent and ECOG performance status . Both patients and physicians were masked to study treatment assignment . The primary endpoint was overall survival , analysed by intention to treat . We report the final analysis . This study is registered with Clinical Trials.gov , number NCT01697072 . FINDINGS Between Nov 7 , 2012 , and Nov 21 , 2014 , 609 patients were r and omly assigned to rilotumumab plus epirubicin , cisplatin , and capecitabine ( rilotumumab group ; n=304 ) or placebo plus epirubicin , cisplatin , and capecitabine ( placebo group ; n=305 ) . Study treatment was stopped early after an independent data monitoring committee found a higher number of deaths in the rilotumumab group than in the placebo group ; all patients in the rilotumumab group subsequently discontinued all study treatment . Median follow-up was 7·7 months ( IQR 3·6 - 12·0 ) for patients in the rilotumumab group and 9·4 months ( 5·3 - 13·1 ) for patients in the placebo group . Median overall survival was 8·8 months ( 95 % CI 7·7 - 10·2 ) in the rilotumumab group compared with 10·7 months ( 9·6 - 12·4 ) in the placebo group ( stratified hazard ratio 1·34 , 95 % CI 1·10 - 1·63 ; p=0·003 ) . The most common grade 3 or worse adverse events in the rilotumumab and placebo groups were neutropenia ( 86 [ 29 % ] of 298 patients vs 97 [ 32 % ] of 299 patients ) , anaemia ( 37 [ 12 % ] vs 43 [ 14 % ] ) , and fatigue ( 30 [ 10 % ] vs 35 [ 12 % ] ) . The frequency of serious adverse events was similar in the rilotumumab and placebo groups ( 142 [ 48 % ] vs 149 [ 50 % ] ) . More deaths due to adverse events occurred in the rilotumumab group than the placebo group ( 42 [ 14 % ] vs 31 [ 10 % ] ) . In the rilotumumab group , 33 ( 11 % ) of 298 patients had fatal adverse events due to disease progression , and nine ( 3 % ) had fatal events not due to disease progression . In the placebo group , 23 ( 8 % ) of 299 patients had fatal adverse events due to disease progression , and eight ( 3 % ) had fatal events not due to disease progression . INTERPRETATION Lig and -blocking inhibition of the MET pathway with rilotumumab is not effective in improving clinical outcomes in patients with MET-positive gastric or gastro-oesophageal adenocarcinoma . FUNDING Amgen BACKGROUND Clinical data showed promising antitumour activity with feasible tolerability for matuzumab plus epirubicin , cisplatin and capecitabine ( ECX ) chemotherapy in untreated advanced oesophago-gastric ( OG ) cancer . The aim was to evaluate the efficacy of matuzumab plus ECX versus ECX alone . PATIENTS AND METHODS In this multicentre , r and omised open-label phase II study , 72 patients with metastatic OG cancer were r and omly assigned to either 800 mg matuzumab weekly plus epirubicin 50 mg/m² , cisplatin 60 mg/m² on day 1 and capecitabine 1250 mg/m² daily in a 21-day cycle ( ECX ) or the same ECX regimen alone . The primary end point was objective response . Secondary end points included progression-free survival ( PFS ) , overall survival ( OS ) , quality of life , safety and tolerability . RESULTS Following r and om assignment , 35 patients ( median age 59 years ) received ECX/matuzumab and 36 patients ( median age 64 years ) ECX . The addition of matuzumab to ECX did not improve objective response : 31 % for ECX/matuzumab [ 95 % confidence interval ( CI ) 17 - 49 ] compared with 58 % for the ECX arm ( 95 % CI 41 - 74 ) P = 0.994 ( one sided ) . There was no significant difference in median PFS : 4.8 months ( 95 % CI 2.9 - 8.1 ) for ECX/matuzumab versus 7.1 months ( 95 % CI 4.4 - 8.5 ) for ECX , or in median OS : 9.4 months ( 95 % CI 7.5 - 16.2 ) , compared with 12.2 months ( 95 % CI 9.8 - 13.8 months ) . Grade 3/4 treatment-related toxicity was observed in 27 and 25 patients in the ECX/matuzumab and ECX groups , respectively . CONCLUSION Matuzumab 800 mg weekly combined with ECX chemotherapy does not increase response or survival for patients with advanced OG cancer .  Therefore , ECX/matuzumab should not be examined further in phase III trials 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 Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background : Docetaxel administered 3-weekly with cisplatin and 5-fluorouracil leads to better survival than does st and ard therapy in patients with oesophagogastric cancer , but leads to high rates of haematological toxicity . Weekly docetaxel is associated with less haematological toxicity . This r and omised phase II study tested weekly docetaxel-based combination chemotherapy regimens , with the aim of maintaining their activity while reducing toxicity . Methods : Patients with histologically confirmed metastatic oesophageal or gastric carcinoma were r and omised to receive weekly docetaxel ( 30 mg m−2 ) on days 1 and 8 , cisplatin ( 60 mg m−2 ) on day 1 , and 5-fluorouracil ( 200 mg m−2 per day ) continuously , every 3 weeks ( weekly TCF , wTCF ) ; or docetaxel ( 30 mg m−2 ) on days 1 and 8 and capecitabine ( 1600 mg m−2 per day ) on days 1–14 , every 3 weeks ( weekly TX , wTX ) . Results : A total of 106 patients were enrolled ( wTCF , n=50 ; wTX , n=56 ) . Response rates , the primary end point , were 47 % with wTCF and 26 % with wTX . Rates of febrile neutropenia were low in each arm . Median progression-free and overall survival times were 5.9 and 11.2 months for wTCF and 4.6 and 10.1 months for wTX , respectively . Conclusion : Weekly TCF and TX have encouraging activity and less haematological toxicity than TCF administered 3-weekly . Weekly docetaxel-based combination regimens warrant further evaluation in this disease Background The V325 study showed that docetaxel , cisplatin , and fluorouracil ( DCF ) prolonged overall survival ( OS ) of patients with advanced gastric cancer , but with a high incidence of dose-limiting toxicities . We investigated the efficacy and safety of a modified DCF ( mDCF ) regimen for Chinese patients with advanced gastric cancer . Methods Untreated advanced gastric cancer patients r and omly received docetaxel and cisplatin at 60 mg/m2 ( day 1 ) followed by fluorouracil at 600 mg/m2/day ( days 1–5 ; mDCF regimen ) or cisplatin at 75 mg/m2 ( day 1 ) followed by fluorouracil at 600 mg/m2/day ( days 1–5 ; CF ) every 3 weeks . The primary end point was progression-free survival ( PFS ) . The secondary end points were OS , overall response rate ( ORR ) , time-to-treatment failure ( TTF ) , and safety . Results In total , 243 patients were r and omized to treatment ( mDCF regimen 121 ; CF 122 ) . Compared with CF , the mDCF regimen significantly improved PFS and OS : the median PFS was 7.2 and 4.9 months , respectively [ hazard ratio ( HR ) 0.58 , log-rank P = 0.0008 ] , and the median OS was 10.2 and 8.5 months , respectively ( HR = 0.71 , P = 0.0319 ) . Additionally , the mDCF regimen improved the parameters used as secondary objectives : the ORR was 48.7 % with the mDCF regimen versus 33.9 % with CF ( P = 0.0244 ) ; the median TTF was 3.4 months with the mDCF regimen and 2.4 months with CF ( HR = 0.67 , P = 0.0027 ) . Grade 3 and grade 4 treatment-related adverse events occurred in 77.3 % of patients who received the mDCF regimen versus 46.1 % of patients who received CF ( P < 0.001 ) . Conclusions The mDCF regimen , compared with CF , significantly prolonged PFS and OS and enhanced ORR of Chinese patients with advanced gastric cancer .  The mDCF regimen achieved efficacy comparable to that of DCF but with fewer toxicities , which is appropriate for the Chinese population Background : This r and omised phase II study evaluated the efficacy and safety of panitumumab added to docetaxel-based chemotherapy in advanced oesophagogastric cancer . Methods : Patients with metastatic or locally recurrent cancer of the oesophagus , oesophagogastric junction or stomach received docetaxel and a fluoropyrimidine with or without panitumumab for 8 cycles or until progression . The primary end point was response rate ( RECIST1.1 ) . We planned to enrol 100 patients , with 50 % expected response rate for combination therapy . Results : A total of 77 patients were enrolled . A safety alert from the REAL3 trial prompted a review of data that found no evidence of adverse outcomes associated with panitumumab but question able efficacy , and new enrolment was ceased . Enrolled patients were treated according to protocol . Response rates were 49 % ( 95 % CI 34–64 % ) in the chemotherapy arm and 58 % ( 95 % CI 42–72 % ) in the combination arm . Common grade 3 and 4 toxicities included infection , anorexia , vomiting , diarrhoea and fatigue . At 23.7 months of median follow-up , median progression-free survival was 6.9 months vs 6.0 months and median overall survival was 11.7 months vs 10.0 months in the chemotherapy arm and the combination arm , respectively . Conclusions : Adding panitumumab to docetaxel-based chemotherapy for advanced oesophagogastric cancer did not improve efficacy and increased toxicities We aim ed to assess the efficacy and safety of S-1 combined with cisplatin ( SC ) over cisplatin alone ( C ) for the treatment of advanced gastric cancer in China . Between July 2009 and June 2011 , 72 eligible patients with advanced gastric cancer were selected and divided r and omly into two groups . Thirty-six patients received SC , with S-1 on days 1 through 14 of a 21-day cycle and cisplatin ( 60 mg/m2 on day 1 ) every 4 weeks for two cycles . The other 36 patients were administered only cisplatin ( in the same manner as SC ) . The primary outcome was overall survival . The secondary outcomes were progression-free survival and adverse events . The 2-year overall response rate was 51.5 and 42.3 % for the SC and C groups , respectively , and the difference was statistically significant , whereas the median overall survival was 9.4 months ( range , 1.9–24.4 months ) and 7.6 months ( range , 1.7–21.4 months ) , respectively ( P=0.039 ) . The median progression-free survival was 7.7 months for SC ( range , 1.8–19.4 months ) , whereas it was 6.5 months ( range , 1.5–16.4 months ) for C ( P=0.047 ) . The toxicity profile was similar in both groups . In summary , we have shown that S-1 combined with cisplatin is more effective , with acceptable toxicity in comparison with cisplatin alone in Chinese patients with advanced gastric cancer . Chinese Clinical Trials Register : ChiCTR-TRC-13003993 The pharmacokinetics of irinotecan vary markedly between individuals . This study sought to compare tailored irinotecan and S-1 therapy with S-1 monotherapy for the treatment of patients with advanced/recurrent gastric cancer . Patients with advanced/recurrent gastric cancer were r and omized to receive tailored irinotecan and S-1 ( arm A ) therapy or S-1 therapy alone ( arm B ) . Arm A received S-1 ( 80–120 mg/m2/day ) for 14 days , with irinotecan on days 1 and 15 . The initial irinotecan dose of 75 mg/m2 ( level 0 ) was adjusted for toxicity during an earlier course . In arm B , S-1 ( 80–120 mg/day ) was administered alone for 28 days , followed by 14 days without therapy . Ninety-five patients were r and omized ( 48 patients to arm A and 47 patients to arm B ) .  The response rate of the primary tumor ( Japanese criteria ) was 25.0 % in arm A ( 12 of 48 patients ) and 14.9 % in arm B ( seven of 47 patients ) , whereas the response rates according to Response Evaluation Criteria In Solid Tumors were 27.8 % ( 10 of 36 ) versus 21.9 % ( seven of 32 ) . Hematological toxicity , anorexia , and diarrhea were significantly more common in arm A , but both arms had similar grade s 3–4 toxicities . These findings suggest the usefulness of tailored irinotecan and S-1 therapy for gastric cancer BACKGROUND Although leucovorin enhances the efficacy of fluorouracil , the anti-tumour activity of S-1 and leucovorin and their combination with oxaliplatin for patients with advanced gastric cancer is unknown . We compared the activity and safety of S-1 plus leucovorin , S-1 plus leucovorin and oxaliplatin , and S-1 plus cisplatin as first-line chemotherapy for advanced gastric cancer . METHODS In this multicentre , r and omised , open-label , phase 2 trial , we recruited chemotherapy-naive patients with unresectable or recurrent gastric cancer with measurable lesions aged 20 years or older from 25 general hospitals and specialist centres in Japan . Patients were r and omly assigned ( 1:1:1 ) central ly to receive S-1 plus leucovorin ( S-1 40 - 60 mg orally plus oral leucovorin 25 mg twice a day for 1 week , every 2 weeks ) , S-1 plus leucovorin and oxaliplatin ( S-1 plus leucovorin and intravenous oxaliplatin 85 mg/m(2 ) on day 1 , every 2 weeks ) , or S-1 plus cisplatin ( S-1 40 - 60 mg orally twice a day for 3 weeks , plus intravenous cisplatin 60 mg/m(2 ) on day 8 , every 5 weeks ) . R and omisation was done with the minimisation method using performance status ( 0 vs 1 ) and tumour stage ( stage IV vs recurrent ) as stratification factors . The primary endpoint was independently review ed overall response in the full analysis set . This trial is registered with Japic CTI , number 111635 . FINDINGS Between Oct 20 , 2011 , and Dec 17 , 2012 , we enrolled and r and omly assigned 145 patients : 49 patients were assigned to S-1 plus leucovorin , 47 to S-1 plus leucovorin and oxaliplatin , and 49 to S-1 plus cisplatin . An objective response assessed by the independent review committee was achieved in 20 ( 43 % [ 95 % CI 28·3 - 57·8 ] ) of the 47 patients in the S-1 plus leucovorin group , 31 ( 66 % [ 50·7 - 79·1 ] ) of the 47 patients in the S-1 plus leucovorin and oxaliplatin group , and 22 ( 46 % [ 31·4 - 60·8 ] ) of the 48 patients in the S-1 plus cisplatin group ( Fisher 's exact test , p=0·84 for S-1 plus leucovorin vs S-1 plus cisplatin , p=0·063 for S-1 plus leucovorin and oxaliplatin vs S-1 plus cisplatin , and p=0·038 for S-1 plus leucovorin and oxaliplatin vs S-1 plus leucovorin ) . The most common grade 3 - 4 adverse events were neutropenia ( three [ 6 % ] of 48 patients in the S-1 plus leucovorin group vs 12 [ 26 % ] of 47 patients in the S-1 plus leucovorin and oxaliplatin group vs 17 [ 35 % ] of 49 patients in the S-1 plus cisplatin group ) , decreased appetite ( six [ 13 % ] vs 14 [ 30 % ] vs 12 [ 24 % ] ) , anaemia ( five [ 10 % ] vs seven [ 15 % ] vs 13 [ 27 % ] ) , and hyponatraemia ( two [ 4 % ] vs two [ 4 % ] vs nine [ 18 % ] ) . INTERPRETATION S-1 plus leucovorin and oxaliplatin was more active than S-1 plus leucovorin or S-1 plus cisplatin with acceptable toxic effects for patients with advanced gastric cancer . A phase 3 trial comparing S-1 plus leucovorin and oxaliplatin with S-1 plus cisplatin is underway . FUNDING Taiho Pharmaceutical BACKGROUND We evaluated the feasibility and tolerability of triple- versus double-drug chemotherapy in elderly patients with oesophagogastric cancer . METHODS Patients aged 65 years or older with locally advanced or metastatic oesophagogastric cancer were stratified and r and omised to infusional 5-FU , leucovorin and oxaliplatin without ( FLO ) or with docetaxel 50 mg/m(2 ) ( FLOT ) every 2 weeks . The study is registered at Clinical Trials.gov , identifier NCT00737373 . FINDINGS One hundred and forty three ( FLO , 71 ; FLOT , 72 ) patients with a median age of 70 years were enrolled . The triple combination was associated with more treatment-related National Cancer Institute Common Toxicity Criteria ( NCI-CTC ) grade 3/4 adverse events ( FLOT , 81.9 % ; FLO , 38.6 % ; P<.001 ) and more patients experiencing a ≥10-points deterioration of European Organization for Research and Treatment of Cancer Quality of Life ( EORTC QoL ) global health status scores ( FLOT , 47.5 % ; FLO 20.5 % ; p=.011 ) . The triple combination was associated with more alopecia ( P<.001 ) , neutropenia ( P<.001 ) , leukopenia ( P<.001 ) , diarrhoea ( P=.006 ) and nausea ( P=.029 ) . ) . No differences were observed in treatment duration and discontinuation due to toxicity , cumulative doses or toxic deaths between arms . The triple combination improved response rates and progression-free survival in the locally advanced subgroup and in the subgroup of patients aged between 65 and 70 years but not in the metastatic group or in patients aged 70 years and older . INTERPRETATION The triple-drug chemotherapy was feasible in elderly patients with oesophagogastric cancer . However , toxicity was significantly increased and QoL deteriorated in a relevant proportion of patients . FUNDING The study was partially funded by Sanofi-Aventis Summary Background EGFR overexpression occurs in 27–55 % of oesophagogastric adenocarcinomas , and correlates with poor prognosis . We aim ed to assess addition of the anti-EGFR antibody panitumumab to epirubicin , oxaliplatin , and capecitabine ( EOC ) in patients with advanced oesophagogastric adenocarcinoma . Methods In this r and omised , open-label phase 3 trial ( REAL3 ) , we enrolled patients with untreated , metastatic , or locally advanced oesophagogastric adenocarcinoma at 63 centres ( tertiary referral centres , teaching hospitals , and district general hospitals ) in the UK . Eligible patients were r and omly allocated ( 1:1 ) to receive up to eight 21-day cycles of open-label EOC ( epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 and capecitabine 1250 mg/m2 per day on days 1–21 ) or modified-dose EOC plus panitumumab ( mEOC+P ; epirubicin 50 mg/m2 and oxaliplatin 100 mg/m2 on day 1 , capecitabine 1000 mg/m2 per day on days 1–21 , and panitumumab 9 mg/kg on day 1 ) . R and omisation was blocked and stratified for centre region , extent of disease , and performance status . The primary endpoint was overall survival in the intention-to-treat population . We assessed safety in all patients who received at least one dose of study drug . After a preplanned independent data monitoring committee review in October , 2011 , trial recruitment was halted and panitumumab withdrawn . Data for patients on treatment were censored at this timepoint . This study is registered with Clinical Trials.gov , number NCT00824785 . Findings Between June 2 , 2008 , and Oct 17 , 2011 , we enrolled 553 eligible patients . Median overall survival in 275 patients allocated EOC was 11·3 months ( 95 % CI 9·6–13·0 ) compared with 8·8 months ( 7·7–9·8 ) in 278 patients allocated mEOC+P ( hazard ratio [ HR ] 1·37 , 95 % CI 1·07–1·76 ; p=0·013 ) . mEOC+P was associated with increased incidence of grade 3–4 diarrhoea ( 48 [ 17 % ] of 276 patients allocated mEOC+P vs 29 [ 11 % ] of 266 patients allocated EOC ) , rash ( 29 [ 11 % ] vs two [ 1 % ] ) , mucositis ( 14 [ 5 % ] vs none ) , and hypomagnesaemia ( 13 [ 5 % ] vs none ) but reduced incidence of haematological toxicity ( grade ≥3 neutropenia 35 [ 13 % ] vs 74 [ 28 % ] ) . Interpretation Addition of panitumumab to EOC chemotherapy does not increase overall survival and can not be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma . Funding Amgen , UK National Institute for Health Research Biomedical Research Centre 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 BACKGROUND We report the first r and omized , Phase II trial of ramucirumab , an anti-vascular endothelial growth factor receptor-2 monoclonal antibody , as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction ( GEJ ) . PATIENTS AND METHODS Patients from the USA with advanced esophageal , gastric , or GEJ adenocarcinoma r and omly received ( 1:1 ) mFOLFOX6 plus ramucirumab ( 8 mg/kg ) or mFOLFOX6 plus placebo every 2 weeks . The primary end point was progression-free survival ( PFS ) with 80 % power to detect a hazard ratio ( HR ) of 0.71 ( one-sided α = 0.15 ) . Secondary end points included evaluation of response and overall survival ( OS ) ; an exploratory ramucirumab exposure-response analysis was undertaken . RESULTS Of 168 r and omized patients , 52 % of tumors were located in the stomach/GEJ and 48 % in the esophagus . The trial did not meet the primary end point of PFS [ 6.4 versus 6.7 months , HR 0.98 ( 95 % confidence interval 0.69 - 1.37 ) ] or the secondary end point of OS ( 11.7 versus 11.5 months ) in the intent-to-treat ( ITT ) population . Objective response rates ( 45.2 % versus 46.4 % ) were similar between arms . Most Grade ≥3 toxicities did not differ significantly between arms , yet premature discontinuation of FOLFOX and ramucirumab ( for reasons other than progressive disease ) was more common among ramucirumab- versus placebo-treated patients . In an exploratory analysis that censored for premature discontinuation , the HR for PFS favored the ramucirumab arm ( HR 0.76 ) , particularly in patients with gastric/GEJ cancer . An exploratory exposure-response analysis indicated that patients with higher ramucirumab exposure had longer OS . CONCLUSION The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population . CLINICAL TRIALSGOV IDENTIFIER NCT01246960
Background : Systemic therapy is the st and ard treatment against advanced gastric cancer .
Fluoropyrimidine plus platinum doublet has been recommended as the preferred first-line strategy .
However , there is still a lack of a comprehensive and hierarchical evidence that compares all eligible literature simultaneously .