Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: A randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second scandinavian trial in esophageal cancer Randomized trial of adjuvant chemotherapy with mitomycin plus ftorafur versus mitomycin alone in resected locally advanced gastric cancer. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. A prospective, randomized trial of pre-operative and intraoperative radiotherapy versus surgery alone in resectable gastric cancer. NEOSCOPE: A randomised phase II study of induction chemotherapy followed by oxaliplatin/capecitabine or carboplatin/paclitaxel based pre-operative chemoradiation for resectable oesophageal adenocarcinoma A randomized trial comparing adjuvant fluorouracil, epirubicin, and mitomycin with no treatment in operable gastric cancer. Short-term curative effect of S-1 plus oxaliplatin as perioperative chemotherapy for locally advanced gastric cancer: a prospective comparison study. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multice Perioperative chemotherapy with or without epidermal growth factor receptor blockade in unselected patients with locally advanced oesophagogastric adenocarcinoma: Randomized phase II study with advanced biomarker program of the German Cancer Society (AIO/CAO STO-0801). Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08) Adjuvant Chemoradiotherapy With Epirubicin, Cisplatin, and Fluorouracil Compared With Adjuvant Chemoradiotherapy With Fluorouracil and Leucovorin After Curative Resection of Gastric Cancer: Results From CALGB 80101 (Alliance). Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. Morbidity and mortality after surgery for cancer of the oesophagus and gastro-oesophageal junction: A randomized clinical trial of neoadjuvant chemotherapy vs. neoadjuvant chemoradiation. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2–3 trial Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial Concurrent Neoadjuvant Chemoradiotherapy for Siewert II and III Adenocarcinoma at Gastroesophageal Junction A randomized, controlled, multicenter study comparing intensity-modulated radiotherapy plus concurrent chemotherapy with chemotherapy alone in gastric cancer patients with D2 resection. Prospective, randomized trial comparing 5-FU/LV with or without oxaliplatin as adjuvant treatment following curative resection of gastric adenocarcinoma. Multicentre randomised study of adjuvant chemotherapy with mitomycin C and tegafur or tegafur-uracil in gastric cancer. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial Adjuvant chemotherapy with 5-fluorouracil and cisplatin compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801). A PILOT STUDY OF PREOPERATIVE AND POSTOPERATIVE CHEMOTHERAPY IN PATIENTS WITH OPERABLE GASTRIC CANCER: AUSTRALASIAN GASTROINTESTINAL TRIALS GROUP STUDY 9601 Combined 5-fluorouracil and radiation therapy as a surgical adjuvant for poor prognosis gastric carcinoma. Positive results of adjuvant mitomycin-C in resected gastric cancer: a randomised trial on 134 patients. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Effects of adjuvant radiotherapy on completely resected gastric cancer: A radiation oncologist's view of the ARTIST randomized phase III trial. A randomized phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in patients with gastric cancer Comparing Efficacy of Preoperative neo-Adjuvant Chemotherapy and Surgery versus Surgery Alone in Patients with Resectable Gastroesophageal Cancer Adjuvant treatment of high-risk, radically resected gastric cancer patients with 5-fluorouracil, leucovorin, cisplatin, and epidoxorubicin in a randomized controlled trial. Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): Long-term results of a controlled randomised trial. Adjuvant chemotherapy for gastric cancer: a randomised phase 3 trial of mitomycin-C plus either short-term doxifluridine or long-term doxifluridine plus cisplatin after curative D2 gastrectomy (AMC0201) Preoperative chemoradiotherapy for esophageal or junctional cancer. Feasibility of perioperative chemotherapy with infusional 5-FU, leucovorin, and oxaliplatin with (FLOT) or without (FLO) docetaxel in elderly patients with locally advanced esophagogastric cancer A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer. Adjuvant chemotherapy after gastric resection in node-positive cancer patients: a multicentre randomised study. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)--report on 370 patients. Preoperative versus postoperative docetaxel-cisplatin-fluorouracil (TCF) chemotherapy in locally advanced resectable gastric carcinoma: 10-year follow-up of the SAKK 43/99 phase III trial. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A southwest oncology group study Comparison of 5-fluorouracil with ftorafur in adjuvant chemotherapies with combined inductive and maintenance therapies for gastric cancer. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. Controlled trial of adjuvant chemotherapy following curative resection for gastric cancer Feasibility of Preoperative Chemotherapy with Docetaxel, Cisplatin, and 5-Fluorouracil versus Adriamycin, Cisplatin, and 5-Fluorouracil for Resectable Advanced Esophageal Cancer Eastern Cooperative Oncology Group and American College of Radiology Imaging Network Randomized Phase 2 Trial of Neoadjuvant Preoperative Paclitaxel/Cisplatin/Radiation Therapy (RT) or Irinotecan/Cisplatin/RT in Esophageal Adenocarcinoma: Long-Term Outcome and Implications for Trial Design. Randomized trial of adjuvant chemotherapy versus control after curative resection for gastric cancer: 5-year follow-up Chemotherapy for operable gastric cancer: results of the Dutch randomised FAMTX trial. The Dutch Gastric Cancer Group (DGCG). Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. S-1 Based Doublet as an Adjuvant Chemotherapy for Curatively Resected Stage III Gastric Cancer: Results from the Randomized Phase III POST Trial A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. A phase III randomized trial of 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil and mitomycin C versus 5-fluorouracil alone in curatively resected gastric cancer. Adjuvant chemotherapy with epirubicin, leucovorin, 5-fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale (GOIM 9602 Study). Feasibility of Sequential Therapy with FOLFIRI Followed by Docetaxel/Cisplatin in Patients with Radically Resected Gastric Adenocarcinoma Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer. Adjuvant Chemotherapy with Etoposide, Adriamycin and Cisplatin Compared with Surgery Alone in the Treatment of Gastric Cancer: A Phase III Randomized, Multicenter, Clinical Trial Preoperative therapy for esophageal cancer: a randomized comparison of chemotherapy versus radiation therapy. A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer. International Collaborative Cancer Group. Neoadjuvant treatment of advanced stage esophageal adenocarcinoma increases survival. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954. A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction. A prospective, randomized evaluation of intensive‐course 5‐fluorouracil plus doxorubicin as surgical adjuvant chemotherapy for resected gastric cancer Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Neo-adjuvant chemotherapy for operable gastric cancer: long term results of the Dutch randomised FAMTX trial. Adjuvant radiotherapy and chemotherapy in resectable gastric cancer. A randomized trial of the gastro-intestinal tract cancer cooperative group of the EORTC. Enhanced efficacy of postoperative adjuvant chemotherapy in advanced gastric cancer: results from a phase 3 randomized trial (AMC0101) Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: a randomised trial Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Final results of a phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer. A randomized trial of 5-fluorouracil, leucovorin, cisplatin and epirubicin (PELF) versus 5-fluorouracil, leucovorin and etoposide (ELF) given as adjuvant chemotherapy to patients with resected advanced gastric adenocarcinomas. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer. A phase III randomized study comparing oral doxifluridine and oral 5-fluorouracil after curative resection of gastric cancer. Phase III Trial to Compare Adjuvant Chemotherapy With Capecitabine and Cisplatin Versus Concurrent Chemoradiotherapy in Gastric Cancer: Final Report of the Adjuvant Chemoradiotherapy in Stomach Tumors Trial, Including Survival and Subset Analyses. ADJUVANT CHEMOTHERAPY IN OPERABLE GASTRIC CANCER: 5 Year Follow-up of First British Stomach Cancer Group Trial [Efficacy of oxaliplatin plus 5-fluorouracil/leucovorin calcium combined with concurrent radiotherapy for local advanced gastric cancer]. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. Preoperative radioactive therapy for esophageal carcinoma. Randomized evaluation trial in eight institutions. Postoperative radiotherapy for carcinoma of the esophagus: a prospective, randomized controlled study. Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the esophagus or gastroesophageal junction: long-term results of a randomized clinical trial. Prolonged Time to Surgery After Neoadjuvant Chemoradiotherapy Increases Histopathological Response Without Affecting Survival in Patients With Esophageal or Junctional Cancer Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. Survival results of a randomised two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) followed by D2 gastrectomy for resectable advanced gastric cancer.
In a prospect i ve multicenter study , 186 patients with squamous cell esophageal carcinoma , who after evaluation were considered suitable for surgery , were r and omized to 4 treatment groups : Group 1 , surgery alone ; Group 2 , pre-operative chemotherapy ( cisplatin and bleomycin ) and surgery ; Group 3 , pre-operative irradiation ( 35 Gy ) and surgery ; Group 4 , pre-operative chemotherapy , radiotherapy , and surgery .  Three-year survival was significantly higher in the pooled groups receiving radiotherapy as compared with the pooled groups not receiving radiotherapy . Comparison of the groups having pre-operative chemotherapy with those not having chemotherapy showed no significant difference in survival .  Female patients had a significantly better survival than males . The results indicate that pre-operative irradiation had a beneficial effect on intermediate term survival , whereas the chemotherapy regime used did not influence survival . RésuméDans une étude prospect i ve , multicentrique , 186 patients ayant un cancer épidermoïde de l'oesophage ont été r and omisée dans quatre groupes : le groupe 1 a eu la chirurgie seule ; le groupe 2 , une chimiothérapie préopératoire ( cis-platine et bléomycine ) ; le groupe 3 , une radiothérapie préopératoire suivie de chirurgie ; et le groupe 4 , une chimiothérapie et une radiothérapie préopératoires suivies de chirurgie . La survie à trois ans a été supérieure chez l'ensemble des patients ayant reçu la radiothérapie préopératoire par rapport à ceux qui n'en ont pas eu . Aucune différence de survie n'a pu être mise en évidence dans les groupes ayant eu ou pas de chimiothérapie . La survie des femmes a été significativement supérieure à celle des hommes . Ces résultats indiquent que la radiothérapie préopératoire apporte un plus en ce qui concerne la survie à moyen terme , alors que la chimiothérapie n'influence pas la survie . ResumenEn un estudio prospect ivo multicéntrico sobre 186 pacientes con carcinoma escamocelular del esófago c and idatos para cirugía , se constituyeron cuatro grupos para r and omización : Grupo 1 , cirugía solamente ; Grupo 2 , quimioterapia preoperatoria ( cisplatino y bleomicina ) y cirugía ; Grupo 3 , irradiación preoperatoria ( 35 Gy ) y cirugía ; Grupo 4 , quimioterapia preoperatoria , radioterapia y cirugía . La comparación entre el grupo que recibió quimioterapia y el que no la recibió no demostró diferencia significativa en cuanto a supervivencia . Las pacientes femeninas exhibieron una mejor supervivencia que los pacientes masculinos . Los result ados indican que la irradiación preoperatoria tuvo un efecto benéfico sobre la sobrevida a término medio , en tanto que la quimioterapia , en el regimen utilizado , no tuvo influencia sobre la supervivencia PURPOSE We performed a clinical trial to determine whether postoperative adjuvant chemotherapy with two drugs versus one drug could prolong survival . PATIENTS AND METHODS From 1985 to 1996 , 85 patients with completely resected locally advanced gastric cancer were enrolled . The subjects were r and omized into two treatment groups , as follows : mitomycin ( MMC ) 10 to 20 mg/m2 intravenously ( i.v . ) on day 1 every 6 weeks plus ftorafur ( FT ) 500 mg/m2/d for 36 consecutive days ; or MMC alone , 10 to 20 mg/m2 i.v . every 6 weeks . All courses were repeated four times . RESULTS After a median follow-up duration of 62 months , the overall 5-year survival rates were 67 % for the MMC-FT group versus 44 % for the MMC group ( P = .04 ) . Subgroup analysis to compare survival curves using the method of Mantel-Cox showed survival rates significantly in favor of the MMC-FT group in the subsets of patients with node-negative disease ( P = .01 ) and those whose disease was stage IB or II ( P = .008 ) . CONCLUSION Significantly better survival results were observed for MMC-FT versus MMC alone . Subset analysis suggest a strong benefit in patients with node-negative and early-stage resected gastric cancer PURPOSE The first planned interim analysis ( median follow-up , 3 years ) of the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer confirmed that the oral fluoropyrimidine derivative S-1 significantly improved overall survival , the primary end point . The results were therefore opened at the recommendation of an independent data and safety monitoring committee . We report 5-year follow-up data on patients enrolled onto the ACTS-GC study . PATIENTS AND METHODS Patients with histologically confirmed stage II or III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were r and omly assigned to receive S-1 after surgery or surgery only . S-1 ( 80 to 120 mg per day ) was given for 4 weeks , followed by 2 weeks of rest . This 6-week cycle was repeated for 1 year . The primary end point was overall survival , and the secondary end points were relapse-free survival and safety . RESULTS The overall survival rate at 5 years was 71.7 % in the S-1 group and 61.1 % in the surgery-only group ( hazard ratio [ HR ] , 0.669 ; 95 % CI , 0.540 to 0.828 ) . The relapse-free survival rate at 5 years was 65.4 % in the S-1 group and 53.1 % in the surgery-only group ( HR , 0.653 ; 95 % CI , 0.537 to 0.793 ) . Subgroup analyses according to principal demographic factors such as sex , age , disease stage , and histologic type showed no interaction between treatment and any characteristic . CONCLUSION On the basis of 5-year follow-up data , postoperative adjuvant therapy with S-1 was confirmed to improve overall survival and relapse-free survival in patients with stage II or III gastric cancer who had undergone D2 gastrectomy BACKGROUND The prognosis for locally advanced gastric cancer is poor despite advances in adjuvant chemotherapy . We did the Stomach cancer Adjuvant Multi-Institutional group Trial ( SAMIT ) to assess the superiority of sequential treatment ( paclitaxel then tegafur and uracil [ UFT ] or paclitaxel then S-1 ) compared with monotherapy ( UFT or S-1 ) and also the non-inferiority of UFT compared with S-1 . METHODS We did this r and omised phase 3 trial with a two-by-two factorial design at 230 hospitals in Japan . We enrolled patients aged 20 - 80 years with T4a or T4b gastric cancer , who had had D2 dissection and a ECOG performance score of 0 - 1 . Patients were r and omly assigned to one of four treatment groups with minimisation for tumour size , lymph node metastasis , and study site . Patients received UFT only ( 267 mg/m(2 ) per day ) , S-1 only ( 80 mg/m(2 ) per day ) for 14 days , with a 7-day rest period or three courses of intermittent weekly paclitaxel ( 80 mg/m(2 ) ) followed by either UFT , or S-1 . Treatment lasted 48 weeks in monotherapy groups and 49 weeks in the sequential treatment groups . The primary endpoint was disease-free survival assessed by intention to treat . We assessed whether UFT was non-inferior to S-1 with a non-inferiority margin of 1·33 . This trial was registered at UMIN Clinical Trials Registry , number C000000082 . FINDINGS We r and omly assigned 1495 patients between Aug 3 , 2004 , and Sept 29 , 2009 . 374 patients were assigned to receive UFT alone , 374 to receive S-1 alone , 374 to received paclitaxel then UFT , and 373 to receive paclitaxel then S-1 . We included 1433 patients in the primary analysis after at least 3 years of follow-up ( 359 , 364 , 355 , and 355 in each group respectively ) . Protocol treatment was completed by 215 ( 60 % ) patients in the UFT group , 224 ( 62 % ) in the S-1 group , 242 ( 68 % ) in the paclitaxel then UFT group , and 250 ( 70 % ) in the paclitaxel then S-1  group . 3-year disease-free survival for monotherapy was 54·0 % ( 95 % CI 50·2 - 57·6 ) and that of sequential treatment was 57·2 % ( 53·4 - 60·8 ; hazard ratio [ HR ] 0·92 , 95 % CI 0·80 - 1·07 , p=0·273 ) . 3-year disease-free survival for the UFT group was 53·0 % ( 95 % CI 49·2 - 56·6 ) and that of the S-1 group was 58·2 % ( 54·4 - 61·8 ; HR 0·81 , 95 % CI 0·70 - 0·93 , p=0·0048 ; pnon-inferiority=0·151 ) . The most common grade 3 - 4 haematological adverse event was neutropenia ( 41 [ 11 % ] of 359 patients in the UFT group , 48 [ 13 % ] of 363 in the S-1 group , 46 [ 13 % ] of 355 in the paclitaxel then UFT group , and 83 [ 23 % ] of 356 in the paclitaxel then S-1  group ) . The most common grade 3 - 4 non-haematological adverse event was anorexia ( 21 [ 6 % ] , 24 [ 7 % ] , seven [ 2 % ] , and 18 [ 5 % ] , respectively ) . INTERPRETATION Sequential treatment did not improve disease-free survival , and UFT was not non-inferior to S-1 ( and S-1 was superior to UFT ) , therefore S-1 monotherapy should remain the st and ard treatment for locally advanced gastric cancer in Japan . FUNDING Epidemiological and Clinical Research Information Network PURPOSE OEO2 is a r and omized , controlled trial of preoperative chemotherapy in patients undergoing radical surgery for esophageal cancer . R and om assignment was to surgery alone ( S ) or to two cycles of combination cisplatin and fluorouracil before surgery ( CS ) . Initial results reported in 2002 demonstrated an advantage for both disease-free and overall survival in the CS group . The analysis has now been up date d after a median follow-up of 6 years . PATIENTS AND METHODS OEO2 recruited 802 patients , 400 on CS and 402 on S. The nature of the first recurrence event and cause of death are detailed . Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test . Survival by extent of resection is presented . RESULTS There were 655 deaths , 335 for S and 320 for CS . The survival benefit has been maintained with a hazard ratio ( HR ) of 0.84 ( 95 % CI , 0.72 to 0.98 ; P = .03 ) which in absolute terms is a 5-year survival of 23.0 % for CS compared with 17.1 % for S. The treatment effect is consistent in both adenocarcinoma and squamous cell carcinoma . The first disease-free survival event was macroscopic residual disease from incomplete resection ( R2 ) or no resection in 26.4 % of the S group versus 14.3 % of the CS P < .001 . Three-year survival by type of resection was R0 42.4 % , R1 was 18.0 % , and R2 was 8.6 % . CONCLUSION Long-term follow-up confirms that preoperative chemotherapy improves survival in operable esophageal cancer and should be considered as a st and ard of care INTRODUCTION Worldwide , gastric cancer remains one of the most common malignancies . Discouraging survival rates after surgical treatment promote the study of adjuvant therapy . A prospect ively , r and omized , controlled clinical trial was performed in order to determine whether pre-operative and intraoperative radiotherapy improves treatment results of gastrectomy for stomach carcinoma . METHODS From 1993 to 1998 , 112 patients were r and omized and underwent exploratory laparotomy ; among them 78 satisfied protocol requirements and entered in the trial . Patients in the experimental group were treated with pre-operative radiotherapy ( 20 Gy/5 days ) , gastrectomy and intraoperative radiotherapy ( 20 Gy using 8 - 12 electrons ) . Patients in the control group underwent surgery alone . RESULTS Incidence and distribution of post-operative complications were similar in both groups except significantly higher incidence of pancreatitis after surgical treatment . No late radiation-related morbidity was registered . There was no significant difference in survival between the two treatment groups ( Chi(2)=1.026 , df=1 , P=0 . 311 ) as well as in N0 ( Chi(2)=0.0029 , df=1 , P=0.956 ) and T1 - 2 subgroups ( Chi(2)=0.1928 , df=1 , P=0.660 ) . In contrast , combined treatment had marked survival advantage in more advanced stages : in the case of lymph-node involvement ( Chi(2)=4.19 , df=1 , P=0.04 ) and extragastric tumour extension ( Chi(2)=4.118 , df=1 , P=0.042 ) . CONCLUSION The proposed intensive treatment programme is feasible , shows good acute and late tolerance and has the potential to improve survival in patients with locally advanced gastric cancer Background Oxaliplatin-capecitabine ( OxCap ) and carboplatin-paclitaxel ( CarPac ) based neo-adjuvant chemoradiotherapy ( nCRT ) have shown promising activity in localised , resectable oesophageal cancer . Patients and methods A non-blinded , r and omised ( 1:1 via a central ised computer system ) , ‘ pick a winner ’ phase II trial . Patients with resectable oesophageal adenocarcinoma ≥ cT3 and /or ≥ cN1 were r and omised to OxCapRT ( oxaliplatin 85 mg/m2 day 1 , 15 , 29 ; capecitabine 625 mg/m2 bd on days of radiotherapy ) or CarPacRT ( carboplatin AUC2 ; paclitaxel 50 mg/m2 day 1 , 8 , 15 , 22 , 29 ) . Radiotherapy dose was 45 Gy/25 fractions/5 weeks . Both arms received induction OxCap chemotherapy ( 2 × 3 week cycles of oxaliplatin 130 mg/m2 day 1 , capecitabine 625 mg/m2 bd days 1–21 ) . Surgery was performed 6–8 weeks after nCRT . Primary end-point was pathological complete response ( pCR ) . Secondary end-points included toxicity , surgical morbidity/mortality , resection rate and overall survival . Statistics Based on pCR ≤ 15 % not warranting future investigation , but pCR ≥ 35 % would , 76 patients ( 38/arm ) gave 90 % power ( one-sided alpha 10 % ) , implying that arm(s ) having ≥10 pCR out of first 38 patients could be considered for phase III trials . Clinical Trials.gov : NCT01843829 . Funder : Cancer Research UK ( C44694/A14614 ) . Results Eighty five patients were r and omised between October 2013 and February 2015 from 17 UK centres . Three of 85 ( 3.5 % ) died during induction chemotherapy . Seventy-seven patients ( OxCapRT = 36 ; CarPacRT = 41 ) underwent surgery . The 30-d post-operative mortality was 2/77 ( 2.6 % ) . Grade III/IV toxicity was comparable between arms , although neutropenia was higher in the CarPacRT arm ( 21.4 % versus 2.6 % , p = 0.01 ) . Twelve of 41 ( 29.3 % ) ( 10 of first 38 patients ) and 4/36 ( 11.1 % ) achieved pCR in the CarPacRT and OxcapRT arms , respectively . Corresponding R0 resection rates were 33/41 ( 80.5 % ) and 26/36 ( 72.2 % ) , respectively . Conclusion Both regimens were well tolerated . Only CarPacRT passed the predefined pCR criteria for further investigation Combination chemotherapy ( CT ) has , in some groups of patients with gastric cancer ( GC ) , who are at a high risk for relapse , result ed in a small but measurable improvement in palliation and patient survival not reaching statistical significance and therefore remaining applicable in an investigational setting . Based on the above data , we studied adjuvant CT with FEM ( 5-fluorouracil ( 5-FU ) , epirubicin , mitomycin C ) in a r and omized study of patients with completely resected stage III GC and patients with stages T1 - 3 with a low histologic grade .  CT was started 2 - 3 weeks after surgery . From August 1988 until February 1994 , 84 patients with completely resected tumors and lymph nodes were r and omized to either group A  ( FEM ) or group B ( no treatment ) .  Patients were eligible for r and omization if they had a Karnofsky score > 60 , no postoperative evidence of residual tumor , and normal cardiac , hepatic and renal functions . Forty-two patients were r and omized to each group , with no significant differences regarding : age distribution , group A 53 years ( 41 - 65 ) , group B 57 years ( 35 - 66 ) ; sex , group A 32/10 , group B 25/17 ( men/women ) ; site of primary tumor , group A 22/20 , group B 25/17 ( pylorus/antrum ) ; histologic grade , group A 0/19/23 , group B 0/25/17 ( grade s I/II/III ) ; lymph node metastases , group A 30 , group B 32 , and surgical procedure , group A 33/9/6 , group B 35/7/9 ( total gastrectomy/partial gastrectomy/splenectomy ) . Group A received 5-FU 600 mg/m2/day i.v . on days 1 , 8 , 29 and 36 , epirubicin 45 mg/m2/day i.v . on days 1 and 29 , and mitomycin C 10 mg/m2 i.v . on day 1 . The schedule was repeated every 56 days for 3 cycles . Group B received no treatment odd was only subjected to the regular follow-up . At the last follow-up at 66 months , 27/42 patients in group A ( 64 % ) had relapsed or died , compared to 34/42 patients in group B ( 81 % ) . The differences in the relapse and the disease-free and the overall survival rates were not statistically significant . Only the subgroup of patients with histologic grade III tumors receiving adjuvant FEM  demonstrated a trend towards improved survival ( p = 0.085 ) . Main therapy-related toxicities for the treatment group were grade I-II anemia , neutropenia , and throbocytopenia in 16 , 45 , and 22 % of patients , respectively , and grade I-II nausea and vomiting in 29 % of patients . Based on the present findings and those of previous studies , even if one considers the difference reaching statistical significance in the latter for histologic grade III tumors , it becomes evident that with current therapeutic modalities adjuvant therapy has no established role in the management of resectable GC . Studies of new-generation regimens , such as FAMTX ( 5-FU , Adriamycin and methotrexate ) as well as ELF ( etoposide , Leucoverin , and 5-FU ) , should be conducted in the adjuvant therapy setting with a nontherapy control group , in order to clarify the issue of adjuvant CT in resectable GC This research aim ed to investigate the efficacy of S-1 plus oxaliplatin ( SOX ) as perioperative chemotherapy for locally advanced gastric cancer . We enrolled 102 patients with preoperative clinical stage T3 - 4N × M0 gastric cancer who were then r and omly assigned to receive SOX as either perioperative chemotherapy ( group A , 50 patients ) or postoperative adjuvant chemotherapy ( group B , 52 patients ) . Short-term curative efficacy and adverse effects of perioperative chemotherapy were analyzed . The rates of R0 resection , surgical complications , combined multiple organ resection , overall survival ( OS ) , and disease-free survival ( DFS ) were compared between the groups . Results showed an overall response rate in group A of 42 % , with a disease control rate of 94 % and a tumor down-staging rate of 50 % . An R0 resection rate of 90 % was achieved in group A , which was significantly higher than that in group B ( 75 % ) . No surgical mortality was observed , and the differences in surgical complications and combined multiple organ resection rates between the groups were not significant . The postoperative pathological examination of 4 patients in group A did not show any cancer cells in the tumor bed , result ing in a histological complete remission rate of 8 % . The average OS and DFS for group A patients were 17.928 and 16.134 months , respectively , which were both longer than that of group B patients . However , the differences were not significant . In all , our results shows that in locally advanced gastric carcinoma , SOX perioperative chemotherapy is effective and results in a significantly improved R0 resection rate compared to postoperative SOX administration . Perioperative SOX does not cause additional surgical complications and has low adverse reaction rates ; moreover , it appears to prolong survival BACKGROUND Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma , but has not yet been evaluated in the context of resectable patients . Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial , which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection . METHODS In this r and omised , open-label , phase 2/3 study , eligible participants were recruited from 28 German oncology centres . Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher , nodal positive ( cN+ ) disease , or both were r and omly assigned ( 1:1 ) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m2 on day 1 , intravenous cisplatin 60 mg/m2 on day 1 , and either fluorouracil 200 mg/m2 as continuous intravenous infusion or capecitabine 1250 mg/m2 orally ( two doses of 625 mg/m2 per day ) on days 1 to 21 ( ECF/ECX group ) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m2 , intravenous oxaliplatin 85 mg/m2 , intravenous leucovorin 200 mg/m2 , and fluorouracil 2600 mg/m2 as a 24 h infusion , all on day 1 ( FLOT group ) . R and omisation was done central ly with an interactive web-response system based on a sequence generated with blocks ( block size 2 ) stratified by Eastern Cooperative Oncology Group performance status , location of primary tumour , age , and nodal status . No masking was done . Central assessment of pathological regression was done according to the Becker criteria . The primary endpoint was pathological complete regression ( tumour regression grade TRG1a ) and was analysed in the modified intention-to-treat population , defined as all patients who were r and omly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation . The study ( including the phase 3 part ) has completed enrolment , but follow-up is ongoing and this is an interim analysis . The trial is registered with Clinical Trials.gov , number NCT01216644 . FINDINGS Between Aug 18 , 2010 , and Aug 10 , 2012 , 300 patients ( 152 patients in the ECF/ECX group ; 148 patients in the FLOT group ) were enrolled into the phase 2 part of the study , 265 of whom ( 137 in the ECF/ECX group ; 128 in the  FLOT group ) were assessable on a modified intention-to-treat basis . 119 ( 93 % ) of 128 patients in the FLOT group and 126 ( 92 % ) of 137 patients in the ECF/ECX group were given all planned preoperative cycles of treatment . FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX ( 20 [ 16 % ; 95 % CI 10 - 23 ] of 128 patients vs eight [ 6 % ; 3 - 11 ] of 137 patients ; p=0·02 ) . 44 ( 40 % ) of 111 patients in the ECF/ECX group and 30 ( 25 % ) of 119 patients in the FLOT group had at least one serious adverse event involving a perioperative medical or surgical complication . The most common non-surgical grade 3 - 4 adverse events were neutropenia ( 52 [ 38 % ] of 137 patients in the ECF/ECX group vs 67 [ 52 % ] of 128 patients in the FLOT  group ) , leucopenia ( 28 [ 20 % ] vs 36 [ 28 % ] ) , nausea ( 23 [ 17 % ] vs 12 [ 9 % ] ) , infection ( 16 [ 12 % ] vs 15 [ 12 % ] ) , fatigue ( 19 [ 14 % ] vs 11 [ 9 % ] ) , and vomiting ( 13 [ 10 % ] vs four [ 3 % ] ) . INTERPRETATION Perioperative FLOT was active and feasible to administer , and might represent an option for patients with locally advanced , resectable gastric or gastro-eosophageal junction adenocarcinoma . FUNDING None BACKGROUND Perioperative chemotherapy significantly improves survival in patients with locally advanced oesophagogastric cancer ( EGC ) . However , as approximately 60 % of patients will die from their disease , new therapeutic agents such as molecular-targeted drugs are needed . PATIENTS AND METHODS To evaluate the role of panitumumab with perioperative chemotherapy , previously untreated patients with locally advanced EGC received , in an open-label r and omised phase II study ( NEOPECX ) , st and ard epirubicin , cisplatin , capecitabine ( ECX ) chemotherapy with or without panitumumab . The primary end-point was the histological response rate after neoadjuvant therapy . The expression status and gene copy number of EGFR , HER2 , and MET were determined by immunohistochemistry and fluorescence in situ hybridization ( FISH ) . Plasma sample s were collected before the first cycle of neoadjuvant chemotherapy . RESULTS Overall , 160 patients ( 80 versus 80 ) were eligible . The majority ( 82 % versus 80 % ) showed lymph node involvement . Rate of R0-resection , percentage of patients with downstaging to ypT0 - 2 at pathohistological evaluation , and rate of major histological response was equal in both arms . Toxicity was increased by panitumumab with regard to thromboembolic events and skin toxicity .  Patients with tumour EGFR , HER2 or MET expression had shorter progression-free and overall survival . FISH positivity for these markers was associated with shorter survival independent of therapy . High levels of soluble EGFR in particular predicted poor survival in the panitumumab arm . CONCLUSION The addition of panitumumab to ECX did not improve downstaging of locally advanced EGC . Low plasma levels of pathway-associated proteins such as sEGFR may identify a group of patients that benefit from EGFR-directed therapy . CLINICAL TRIALS.GOV : NCT01234324 BACKGROUND Both perioperative chemotherapy and postoperative chemoradiotherapy improve survival in patients with resectable gastric cancer from Europe and North America . To our knowledge , these treatment strategies have not been investigated in a head to head comparison . We aim ed to compare perioperative chemotherapy with preoperative chemotherapy and postoperative chemoradiotherapy in patients with resectable gastric adenocarcinoma . METHODS In this investigator-initiated , open-label , r and omised phase 3 trial , we enrolled patients aged 18 years or older who had stage IB- IVA resectable gastric or gastro-oesophageal adenocarcinoma ( as defined by the American Joint Committee on Cancer , sixth edition ) , with a WHO performance status of 0 or 1 , and adequate cardiac , bone marrow , liver , and kidney function . Patients were enrolled from 56 hospitals in the Netherl and s , Sweden , and Denmark , and were r and omly assigned ( 1:1 ) with a computerised minimisation programme with a r and om element to either perioperative chemotherapy ( chemotherapy group ) or preoperative chemotherapy with postoperative chemoradiotherapy ( chemoradiotherapy group ) . R and omisation was done before patients were given any preoperative chemotherapy treatment and was stratified by histological subtype , tumour localisation , and hospital . Patients and investigators were not masked to treatment allocation . Surgery consisted of a radical resection of the primary tumour and at least a D1 + lymph node dissection . Postoperative treatment started within 4 - 12 weeks after surgery . Chemotherapy consisted of three preoperative 21-day cycles and three postoperative cycles of intravenous epirubicin ( 50 mg/m2 on day 1 ) , cisplatin ( 60 mg/m2 on day 1 ) or oxaliplatin ( 130 mg/m2 on day 1 ) , and capecitabine ( 1000 mg/m2 orally as tablets twice daily for 14 days in combination with epirubicin and cisplatin , or 625 mg/m2 orally as tablets twice daily for 21 days in combination with epirubicin and oxaliplatin ) , received once every three weeks . Chemoradiotherapy consisted of 45 Gy in 25 fractions of 1·8 Gy , for 5 weeks , five daily fractions per week , combined with capecitabine ( 575 mg/m2 orally twice daily on radiotherapy days ) and cisplatin ( 20 mg/m2 intravenously on day 1 of each 5 weeks of radiation treatment ) . The primary endpoint was overall survival , analysed by intention-to-treat . The CRITICS trial is registered at Clinical Trials.gov , number NCT00407186 ; EudraCT , number 2006 - 004130 - 32 ; and CKTO , 2006 - 02 . FINDINGS Between Jan 11 , 2007 , and April 17 , 2015 , 788 patients were enrolled and r and omly assigned to chemotherapy ( n=393 ) or chemoradiotherapy ( n=395 ) . After preoperative chemotherapy , 372 ( 95 % ) of 393 patients in the chemotherapy group and 369 ( 93 % ) of 395 patients in the chemoradiotherapy group proceeded to surgery , with a potentially curative resection done in 310 ( 79 % ) of 393 patients in the chemotherapy group and 326 ( 83 % ) of 395 in the chemoradiotherapy group . Postoperatively , 233 ( 59 % ) of 393 patients started chemotherapy and 245 ( 62 % ) of 395 started chemoradiotherapy . At a median follow-up of 61·4 months ( IQR 43·3 - 82·8 ) , median overall survival was 43 months ( 95 % CI 31 - 57 ) in the chemotherapy group and 37 months ( 30 - 48 ) in the chemoradiotherapy group ( hazard ratio from stratified analysis 1·01 ( 95 % CI 0·84 - 1·22 ; p=0·90 ) . After preoperative chemotherapy , in the total safety population of 781 patients ( assessed together ) , there were 368 ( 47 % ) grade 3 adverse events ; 130 ( 17 % ) grade 4 adverse events , and 13 ( 2 % ) deaths . Causes of death during preoperative treatment were diarrhoea ( n=2 ) , dihydropyrimidine deficiency ( n=1 ) , sudden death ( n=1 ) , cardiovascular events ( n=8 ) , and functional bowel obstruction ( n=1 ) . During postoperative treatment , grade 3 and 4 adverse events occurred in 113 ( 48 % ) and 22 ( 9 % ) of 233 patients in the chemotherapy group , respectively , and in 101 ( 41 % ) and ten ( 4 % ) of 245 patients in the chemoradiotherapy group , respectively . Non-febrile neutropenia occurred more frequently during postoperative chemotherapy ( 79 [ 34 % ] of 233 ) than during postoperative chemoradiotherapy ( 11 [ 4 % ] of 245 ) . No deaths were observed during postoperative treatment . INTERPRETATION Postoperative chemoradiotherapy did not improve overall survival compared with postoperative chemotherapy in patients with resectable gastric cancer treated with adequate preoperative chemotherapy and surgery . In view of the poor postoperative patient compliance in both treatment groups , future studies should focus on optimising preoperative treatment strategies . FUNDING Dutch Cancer Society , Dutch Colorectal Cancer Group , and Hoffmann-La Roche Background This open-label , phase III trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma . Patients and methods Patients were r and omly assigned ( 1 : 1 ) to two cycles of chemotherapy ( docetaxel 75 mg/m2 , cisplatin 75 mg/m2 ) followed by chemoradiation ( 45 Gy , docetaxel 20 mg/m2 and cisplatin 25 mg/m2 , weekly for 5 weeks ) and surgery , with or without neoadjuvant cetuximab 250 mg/m2 weekly and adjuvant cetuximab 500 mg/m2 fortnightly for 3 months . The primary end point was progression-free survival ( PFS ) . Results In total , 300 patients ( median age , 61 years ; 88 % male ; 63 % adenocarcinoma ; 85 % cT3/4a , 90 % cN+ ) were assigned to cetuximab ( n = 149 ) or control ( n = 151 ) . The R0-resection rate was 95 % for cetuximab versus 97 % for control . Postoperative treatment-related mortality was 6 % in both arms . Median PFS was 2.9 years [ 95 % confidence interval ( CI ) , 2.0 to not reached ] with cetuximab and 2.0 years ( 95 % CI , 1.5 - 2.8 ) with control [ hazard ratio ( HR ) , 0.79 ; 95 % CI , 0.58 - 1.07 ; P = 0.13 ] . Median overall survival ( OS ) time was 5.1 years ( 95 % CI , 3.7 to not reached ) versus 3.0 years ( 95 % CI , 2.2 - 4.2 ) for cetuximab and control , respectively ( HR , 0.73 ; 95 % CI , 0.52 - 1.01 ; P = 0.055 ) . Time to loco-regional failure after R0-resection was significantly longer for cetuximab ( HR 0.53 ; 95 % CI , 0.31 - 0.90 ; P = 0.017 ) ; time to distant failure did not differ between arms ( HR , 1.01 ; 95 % CI , 0.64 - 1.59 , P = 0.97 ) . Cetuximab did not increase adverse events in neoadjuvant or postoperative setting s. Conclusion Adding cetuximab to multimodal therapy significantly improved loco-regional control , and led to clinical ly relevant , but not-significant improvements in PFS and OS in resectable esophageal carcinoma . Clinical trial information NCT01107639 Purpose After curative resection of gastric or gastroesophageal junction adenocarcinoma , Intergroup Trial 0116 ( Phase III trial of postoperative adjuvant radiochemotherapy for high risk gastric and gastroesophageal junction adenocarcinoma : Demonstrated superior survival for patients who received postoperative chemoradiotherapy with bolus fluorouracil ( FU ) and leucovorin ( LV ) compared with surgery alone . CALGB 80101 ( Alliance ; Phase III Intergroup Trial of Adjuvant Chemoradiation After Resection of Gastric or Gastroesophageal Adenocarcinoma ) assessed whether a postoperative chemoradiotherapy regimen that replaced FU plus LV with a potentially more active systemic therapy could further improve overall survival . Patients and Methods Between April 2002 and May 2009 , 546 patients who had undergone a curative resection of stage IB through IV ( M0 ) gastric or gastroesophageal junction adenocarcinoma were r and omly assigned to receive either postoperative FU plus LV before and after combined FU and radiotherapy ( FU plus LV arm ) or postoperative epirubicin , cisplatin , and infusional FU ( ECF ) before and after combined FU and radiotherapy ( ECF arm ) . Results With a median follow-up duration of 6.5 years , 5-year overall survival rates were 44 % in the FU plus LV arm and 44 % in the ECF arm ( Plogrank = .69 ; multivariable hazard ratio , 0.98 ; 95 % CI , 0.78 to 1.24 comparing ECF with FU plus LV ) . Five-year disease-free survival rates were 39 % in the FU plus LV arm and 37 % in the ECF arm ( Plogrank = .94 ; multivariable hazard ratio , 0.96 ; 95 % CI , 0.77 to 1.20 ) . In post hoc analyses , the effect of treatment seemed to be similar across all examined patient subgroups . Conclusion After a curative resection of gastric or gastroesophageal junction adenocarcinoma , postoperative chemoradiotherapy using a multiagent regimen of ECF before and after radiotherapy does not improve survival compared with st and ard FU and LV before and after radiotherapy PURPOSE Preoperative chemotherapy is an accepted st and ard in the treatment of localized esophagogastric adenocarcinoma . Adding radiation therapy to preoperative chemotherapy appears promising , but its definitive value remains unknown . PATIENTS AND METHODS Patients with locally advanced ( uT3 - 4NXM0 ) adenocarcinoma of the lower esophagus or gastric cardia were r and omly allocated to one of two treatment groups : induction chemotherapy ( 15 weeks ) followed by surgery ( arm A ) ; or chemotherapy ( 12 weeks ) followed by chemoradiotherapy ( 3 weeks ) followed by surgery ( arm B ) . Primary outcome was overall survival time . A total of 354 patients were needed to detect a 10 % increase in 3-year survival from 25 % to 35 % by addition of radiation therapy . The study was prematurely closed due to low accrual . RESULTS The median observation time was 46 months . A total of 126 patients were r and omly assigned and 119 eligible patients were evaluated . The number of patients undergoing complete tumor resection was not different between treatment groups ( 69.5 % v 71.5 % ) . Patients in arm B had a significant higher probability of showing pathologic complete response ( 15.6 % v 2.0 % ) or tumor-free lymph nodes ( 64.4 % v 37.7 % ) at resection . Preoperative radiation therapy improved 3-year survival rate from 27.7 % to 47.4 % ( log-rank P = .07 , hazard ratio adjusted for r and omization strata variables 0.67 , 95 % CI , 0.41 to 1.07 ) . Postoperative mortality was nonsignificantly increased in the chemoradiotherapy group ( 10.2 % v 3.8 % ; P = .26 ) . CONCLUSION Although the study was closed early and statistical significance was not achieved , results point to a survival advantage for preoperative chemoradiotherapy compared with preoperative chemotherapy in adenocarcinomas of the esophagogastric junction OBJECTIVE To compare the incidence and severity of postoperative complications after  oesophagectomy for carcinoma of the oesophagus and gastro-oesophageal junction ( GOJ ) after r and omized accrual to neoadjuvant chemotherapy ( nCT )  or neoadjuvant chemoradiotherapy ( nCRT ) . BACKGROUND Neoadjuvant therapy improves long-term survival after oesophagectomy . To date , evidence is insufficient to determine whether combined nCT , or nCRT alone , is the most beneficial . METHODS Patients with carcinoma of the oesophagus or GOJ , resectable with a curative intention , were enrolled in this multicenter trial conducted at seven centres in Sweden and Norway . Study participants were r and omized to nCT or nCRT followed by surgery with two-field lymphadenectomy .  Three cycles of cisplatin/5-fluorouracil was administered in all patients , while 40 Gy of concomitant radiotherapy was administered in the nCRT group . RESULTS Of the r and omized 181 patients , 91 were assigned to nCT and 90 to nCRT .  One-hundred- and -fifty-five patients , 78 nCT and 77 nCRT , underwent resection . There was no statistically significant difference between the groups in the incidence of surgical or nonsurgical complications ( P-value = 0.69 and 0.13 , respectively ) . There was no 30-day mortality , while the 90-day mortality was 3 % ( 2/78 ) in the nCT group and 6 % ( 5/77 ) in the nCRT group ( P = 0.24 ) . The median Clavien-Dindo complication severity grade was significantly higher in the nCRT group ( P = 0.001 ) . CONCLUSION There was no significant difference in the incidence of complications between patients r and omized to nCT and nCRT . However , complications were significantly more severe after nCRT . REGISTRATION TRIAL DATA BASE The trial was registered in the Clinical Trials Data base ( registration number NCT01362127 ) Summary Background Peri-operative chemotherapy and surgery is a st and ard of care for patients with resectable oesophagogastric adenocarcinoma . Bevacizumab , a monoclonal antibody against VEGF , improves the proportion of patients responding to treatment in advanced gastric cancer . We aim ed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric , oesophagogastric junction , or lower oesophageal adenocarcinoma . Methods In this multicentre , r and omised , open-label phase 2–3 trial , we recruited patients aged 18 years and older with histologically proven , resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres . We r and omly assigned patients 1:1 to receive peri-operative epirubicin , cisplatin , and capecitabine chemotherapy or chemotherapy plus bevacizumab , in addition to surgery . Patients in the control group ( chemotherapy alone ) received three pre-operative and three post-operative cycles of epirubicin , cisplatin , and capecitabine chemotherapy : 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1–21 . Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy , as maintenance treatment . R and omisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit , where staff used a computer programme that implemented a minimisation algorithm with a r and om element to establish the allocation for the patient at the point of r and omisation . Patients were stratified by chemotherapy centre , site of tumour , and tumour stage . The primary outcome for the phase 3 stage of the trial was overall survival ( defined as the time from r and omisation until death from any cause ) , analysed in the intention-to-treat population . Here , we report the primary analysis results of the trial ; all patients have completed treatment and the required number of primary outcome events has been reached . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N 46020948 , and with Clinical Trials.gov , number NCT00450203 . Findings Between Oct 31 , 2007 , and March 25 , 2014 , 1063 patients were enrolled and r and omly assigned to receive chemotherapy alone ( n=533 ) or chemotherapy plus bevacizumab ( n=530 ) . At the time of analysis , 508 deaths were recorded ( 248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group ) . 3-year overall survival was 50·3 % ( 95 % CI 45·5–54·9 ) in the chemotherapy alone group and 48·1 % ( 43·2–52·7 ) in the chemotherapy plus bevacizumab group ( hazard ratio [ HR ] 1·08 , 95 % CI 0·91–1·29 ; p=0·36 ) . Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10 % of patients in either group . Wound healing complications were more prevalent in the bevacizumab group , occurring in 53 ( 12 % ) patients in this group compared with 33 ( 7 % ) patients in the chemotherapy alone group . In patients who underwent oesophagogastrectomy  , post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group ( 23 [ 10 % ] of 233 in the chemotherapy alone group vs 52 [ 24 % ] of 220 in the chemotherapy plus bevacizumab group ) ; therefore , recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial . Serious adverse events for all patients included anastomotic leaks ( 30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group ) , and infections with normal neutrophil count ( 42 events vs 53 ) . Interpretation The results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin , cisplatin , and capecitabine chemotherapy for patients with resectable gastric , oesophagogastric junction , or lower oesophageal adenocarcinoma  . Bevacizumab might also be associated with impaired wound healing . Funding Cancer Research UK , MRC Clinical Trials Unit at University College London , and F Hoffmann-La Roche Limited Summary Background Neoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer . The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current st and ard regimen . Methods OE05 was an open-label , phase 3 , r and omised clinical trial . Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1 , cT2N1 , cT3N0/N1 , or cT4N0/N1 were recruited from 72 UK hospitals . Eligibility criteria included WHO performance status 0 or 1 , adequate respiratory , cardiac , and liver function , white blood cell count at least 3 × 109 cells per L , platelet count at least 100 × 109 platelets per L , and a glomerular filtration rate at least 60 mL/min . Participants were r and omly allocated ( 1:1 ) using a computerised minimisation program with a r and om element and stratified by centre and tumour stage , to receive two cycles of cisplatin and fluorouracil ( CF ; two 3-weekly cycles of cisplatin [ 80 mg/m2 intravenously on day 1 ] and fluorouracil [ 1 g/m2 per day intravenously on days 1–4 ] ) or four cycles of epirubicin , cisplatin , and capecitabine ( ECX ; four 3-weekly cycles of epirubicin [ 50 mg/m2 ] and cisplatin [ 60 mg/m2 ] intravenously on day 1 , and capecitabine [ 1250 mg/m2 ] daily throughout the four cycles ) before surgery , stratified according to centre and clinical disease stage . Neither patients nor study staff were masked to treatment allocation . Two-phase oesophagectomy with two-field ( abdomen and thorax ) lymphadenectomy was done within 4–6 weeks of completion of chemotherapy . The primary outcome measure was overall survival , and primary and safety analyses were done in the intention-to-treat population . This trial is registered with the IS RCT N registry ( number 01852072 ) and Clinical Trials.gov ( NCT00041262 ) , and is completed . Findings Between Jan 13 , 2005 , and Oct 31 , 2011 , 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group . By Nov 14 , 2016 , 327 ( 73 % ) of 451 patients in the CF group and 302 ( 68 % ) of 446 in the ECX group had died . Median survival was 23·4 months ( 95 % CI 20·6–26·3 ) with CF and 26·1 months ( 22·5–29·7 ) with ECX ( hazard ratio 0·90 ( 95 % CI 0·77–1·05 , p=0·19 ) . No unexpected chemotherapy toxicity was seen , and neutropenia was the most commonly reported event ( grade 3 or 4 neutropenia : 74 [ 17 % ] of 446 patients in the CF group vs 101 [ 23 % ] of 441 people in the ECX group ) . The proportions of patients with postoperative complications ( 224 [ 56 % ] of 398 people for whom data were available in the CF group and 233 [ 62 % ] of 374 in the ECX group ; p=0·089 ) were similar between the two groups . One patient in the ECX group died of suspected treatment-related neutropenic sepsis . Interpretation Four cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival , and can not be considered st and ard of care . Our study involved a large number of centres and detailed protocol with comprehensive prospect i ve assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction ( Siewert types 1 and 2 ) . Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma . Funding Cancer Research UK and Medical Research Council Clinical Trials Unit at University College London Objective : This study was conducted to investigate the efficacy and safety of using a concurrent neoadjuvant chemoradiotherapy ( a XELOX regimen ) to treat adenocarcinoma of the gastroesophageal junction . Methods : Seventy-six patients having resectable adenocarcinoma at the gastroesophageal junction ( T3/4 , N+ , M0 ) were recruited to participate and r and omly assigned to either a chemoradiotherapy group or a surgery group . Patients in the chemoradiotherapy group were orally given capecitabine ( 1,000 mg/m2 , twice daily for 14 days , days 1–14 ) and intravenous oxaliplatin ( 130 mg/m2 on day 1 ) for 2 cycles . Radiotherapy was performed with a total of 45 Gy administered in 25 sessions for 5 weeks . Patients in the surgery group received only surgical intervention . Results : In the concurrent chemoradiotherapy group , the overall response rate was 55.6 % ( 20/36 ) , tumor control rate was 100 % and a pathological complete response was achieved in 16.7 % ( 6/36 ) . The entire chemoradiotherapy group had R0 resections as did 80 % of the surgery group ( 32/40 ) ( P < 0.05 ) . In the concurrent chemoradiotherapy group , 6 patients developed grade 3 side effects . Treatment was either discontinued or the dose adjusted . Major hematological side effects in the chemoradiotherapy group included leukopenia , neutropenia , anemia and thrombocytopenia . Nonhematological side effects included nausea , vomiting and appetite loss . Chemoradiotherapy-related death was not observed . Conclusions : Concurrent neoadjuvant chemoradiotherapy administration increased the rate of R0 resection and demonstrated favorable safety in patients with Siewert II or III adenocarcinoma at the gastroesophageal junction . These results support the use of neoadjunctive chemoradiotherapy in the treatment of adenocarcinoma of the gastroesophageal junction BACKGROUND AND PURPOSE The role of postoperative chemoradiotherapy in the treatment of patients with gastric cancer with D2 lymph node curative dissection is not well established . In this study , we compared postoperative intensity-modulated radiotherapy plus chemotherapy ( IMRT-C ) with chemotherapy-only in this patient population . MATERIAL S AND METHODS We r and omly assigned patients with D2 lymph node dissection in gastric cancer to  IMRT-C or chemotherapy-only groups . The adjuvant IMRT-C consisted of 400 mg of fluorouracil per square meter of body-surface area per day plus 20 mg of leucovorin per square meter of body-surface area per day for 5 days , followed by 45 Gy of IMRT for 5 weeks , with fluorouracil and leucovorin on the first 4 and the last 3 days of radiotherapy . Two 5-day cycles of fluorouracil and leucovorin were given 4 weeks after the completion of IMRT . Chemotherapy-only group was given the same chemotherapy regimens as IMRT-C group . RESULTS The median overall survival ( OS ) in the chemotherapy-only group was 48 months , as compared with 58 months in the IMRT-C group ; the hazard ratio for death was 1.24 ( 95 % confidence interval , 0.94 - 1.65 ; P=0.122 ) . IMRT-C was associated with increases in the median duration of recurrence-free survival ( RFS ) ( 36 months vs. 50 months ) , the hazard ratio for recurrence was 1.35 ( 95 % confidence interval , 1.03 - 1.78 ; P=0.029 ) . COX multivariate regression analysis showed that lymph node metastasis and TNM stage were both the independent prognostic factors . Rates of all grade adverse events were similar in the two treatment groups . CONCLUSIONS IMRT-C improved RFS , but did not significantly improve OS among patients with D2 lymph node dissection in gastric cancer . Using IMRT plus chemotherapy was feasible and well tolerated in patients with gastric cancer after D2 resection BACKGROUND To investigate the efficacy and toxicity of FOLFOX4 regimen and LV5Fu2 regimen in patients with advanced gastric adenocarcinoma after curative gastrectomy . METHODS Eighty patients with gastric adenocarcinoma after curative gastrectomy were r and omized to receive a 2-h infusion of leucovorin ( LV ; 200mg/m(2)/d ) followed by a 5-fluorouracil ( 5-FU ) bolus ( 400mg/m(2)/d ) and 22-h infusion ( 600 mg/m(2)/d ) for 2 consecutive days every 2 weeks , either alone or together with oxaliplatin 85 mg/m(2 ) as a 2-h infusion on day 1 ( FOLFOX4 regimen or LV5Fu2 regimen ) . The observation points were recurrence free survival , overall survival and toxicity of the two groups . RESULTS All patients had received curative gastrectomy ( R0 resection ) before received either of the two regimens . The 3-year recurrence free survival rate and the 3-year overall survival rate in FOLFOX4 group were all significantly better than those in the control group ( median , 30.0 months vs. 16.0 months , P<0.05 ; 36.0 months vs. 28.0 months , P<0.05 ) . COX multivariant analysis was used to evaluate the prognostic factors and oxaliplatin was found to be the independent prognostic factor and could improve the survival rate in FOLFOX4 group . Grade 3/4 peripheral neuropathy occurred in 19 % in FOLFOX4 group . There was no significant difference between the two groups in neutropenia , leukopenia , anemia , gastrointestinal reaction and so on . Three patients in each group were lost to follow up during treatment . CONCLUSION FOLFOX4 regimen showed good efficacy and an acceptable safety profile for patients with advanced gastric adenocarcinoma after curative gastrectomy compared with the control group . It may prove to be a suitable alterative regimen in this indication OBJECTIVE To compare therapeutic results and five year survival after two regimens of adjuvant chemotherapy after resections for gastric cancer . DESIGN Prospect i ve r and omised multicentre trial . SETTING S 21 departments of surgery . SUBJECTS 243 patients with stage II , III , or IV gastric cancer . INTERVENTIONS All patients received an intravenous bolus of mitomycin C 20 mg on the day of operation , and 10 mg on the first postoperative day . They were then r and omised to receive either tegafur 600 mg or tegafur-uracil 600 mg orally daily beginning two weeks after operation and continuing for two years . Patients with histological confirmed stage IV disease also received mitomycin C 10 mg every three months starting one month after operation . MAIN OUTCOME MEASURES Survival and side effects . RESULTS 13 patients ( 5 % ) were withdrawn from the study , leaving 230 for analysis . There were no serious side effects and both drugs were safe when given continuously for two years . There were no significant differences in 5 year survival ( though patients who were given tegafur-uracil tended to live longer ) , except when patients who had histological curative resections were compared with and those with poorly differentiated adenocarcinoma ( p = 0.04 ) BACKGROUND D2 gastrectomy is recommended in US and European guidelines , and is preferred in east Asia , for patients with resectable gastric cancer .  Adjuvant chemotherapy improves patient outcomes after surgery , but the benefits after a D2 resection have not been extensively investigated in large-scale trials . We investigated the effect on disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared with D2 gastrectomy only in patients with stage II-IIIB gastric cancer . METHODS The capecitabine and oxaliplatin adjuvant study in stomach cancer ( CLASSIC ) study was an open-label , parallel-group , phase 3 , r and omised controlled trial undertaken in 37 centres in South Korea , China , and Taiwan . Patients with stage II-IIIB gastric cancer who had had curative D2 gastrectomy were r and omly assigned to receive adjuvant chemotherapy of eight 3-week cycles of oral capecitabine ( 1000 mg/m(2 ) twice daily on days 1 to 14 of each cycle ) plus intravenous oxaliplatin ( 130 mg/m(2 ) on day 1 of each cycle ) for 6 months or surgery only . Block r and omisation was done by a central interactive computerised system , stratified by country and disease stage . Patients , and investigators giving interventions , assessing outcomes , and analysing data were not masked . The primary endpoint was 3 year disease-free survival , analysed by intention to treat . This study reports a prespecified interim efficacy analysis , after which the trial was stopped after a recommendation by the data monitoring committee . The trial is registered at Clinical Trials.gov ( NCT00411229 ) . FINDINGS 1035 patients were r and omised ( 520 to receive chemotherapy and surgery , 515 surgery only ) . Median follow-up was 34·2 months ( 25·4 - 41·7 ) in the chemotherapy and surgery group and 34·3 months ( 25·6 - 41·9 ) in the surgery only group . 3 year disease-free survival was 74 % ( 95 % CI 69 - 79 ) in the chemotherapy and surgery group and 59 % ( 53 - 64 ) in the surgery only group ( hazard ratio 0·56 , 95 % CI 0·44 - 0·72 ; p<0·0001 ) . Grade 3 or 4 adverse events were reported in 279 of 496 patients ( 56 % ) in the chemotherapy and surgery group and in 30 of 478 patients ( 6 % ) in the surgery only group . The most common adverse events in the intervention group were nausea ( n=326 ) , neutropenia ( n=300 ) , and decreased appetite ( n=294 ) . INTERPRETATION Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer . FUNDING F Hoffmann-La Roche and Sanofi-Aventis BACKGROUND The aim of this study was to evaluate the efficacy of adjuvant chemotherapy after resection for gastric cancer in a r and omized controlled trial . PATIENTS AND METHODS After curative resection , stage II-III-IVM0 gastric cancer patients were r and omly assigned to postoperative chemotherapy or surgery alone . 5-Fluorouracil ( 5-FU ) 800 mg/m(2 ) daily ( 5-day continuous infusion ) was initiated before day 14 after resection . One month later , four 5-day cycles of 5-FU ( 1 g/m(2 ) per day ) plus cisplatin ( 100 mg/m(2 ) on day 2 ) were administered every 4 weeks . RESULTS The study was closed prematurely after enrollment of 260 patients ( 79.7 % N+ ) , owing to poor accrual . At 97.8 months median follow-up , 5- and 7-year overall survival were 41.9 % and 34.9 % in the control group versus 46.6 % and 44.6 % in the chemotherapy group ( P=0.22 ) . Cox model hazard ratios were 0.74 [ 95 % confidence interval ( CI ) 0.54 - 1.02 ; P=0.063 ] for death and 0.70 ( 95 % CI 0.51 - 0.97 ; P=0.032 ) for recurrence . An invaded/removed lymph nodes ratio > 0.3 was the main independent poor prognostic factor identified by multivariate analysis ( P=0.0001 ) . Because of toxicity , only 48.8 % of patients received more than 80 % of the planned dose . CONCLUSION There was no statistically significant survival benefit with this toxic cisplatin-based adjuvant chemotherapy , but a risk reduction in recurrence was observed Background : With poor cure rates in gastric cancer using surgery alone , the safety , efficacy and feasibility of preoperative and postoperative chemotherapy was investigated Sixty-two patients with resectable but poor-prognosis gastric carcinoma were r and omized to either no surgical adjuvant therapy or treatment with 5-fluorouracil ( 15 mg/kg by rapid intravenous injection X 3 ) plus radiation ( 3,750 rad in 24 fractions ) initiated 3 1/2 to six weeks postoperatively . Informed consent was obtained after r and omization and only from the 39 r and omized to treatment . Ten patients refused their treatment assignment . The five-year survival rate for patients r and omized to treatment was 23 % , and for those r and omized to no treatment , 4 % ( P less than .05 ) . Both the survival distributions and the alive-without-recurrence distributions were significantly different for the two groups ( P = .024 ) and favored treatment assignment . When the treatment assignment group was broken down to those patients actually receiving treatment and those refusing , five-year survival rates were : treated , 20 % ; treatment refusal , 30 % ; controls , 4 % ; the three survival distributions were not significantly different . Thirty-nine percent of patients actually treated had a local-regional component of first clinical recurrence compared with 54 % of those who received no treatment . This study does not establish 5-fluorouracil plus radiation  as effective surgical adjuvant therapy  for gastric cancer but suggests this approach as a possible fruitful area for continued research . This study also illustrates the potential problems that may be encountered in interpreting results when patients are r and omized to a study before consent is obtained In order to evaluate the results on successful adjuvant chemotherapy in resected gastric cancer we performed a r and omised trial on 134 patients in two arms : a control one with no further treatment after surgery versus a treatment arm given mitomycin-C ( MMC ) , 20 mg/m2 intravenously one day every 6 weeks for four courses , starting before the sixth week after surgery . The median follow-up was 105 months . In the control arm , 49 out of 66 patients died due to recurrence , versus 40 out of 68 patients in treatment arm .  Actuarial survival curve was statistically significant ( P < 0.025 ) in favour of the treatment group . Liver metastases were lower in adjuvant group than in the control group ( 8/68 versus 19/66 ) . Toxicity was mild . Main toxic effects were thrombocytopenia , leukopenia , nausea and vomiting . A pelvis renal cancer as a second malignancy 8 years after gastric cancer was observed . In that particular case MMC was given after surgery . We conclude that adjuvant chemotherapy based on MMC given in the early period after surgery , improves survival rate in gastric cancer resected patients BACKGROUND The CLASSIC trial was done to compare adjuvant capecitabine plus oxaliplatin versus observation after D2 gastrectomy for patients with stage II or III gastric cancer . The planned interim analysis of CLASSIC ( median follow-up 34 months ) showed that adjuvant capecitabine plus oxaliplatin significantly improved disease-free survival , the primary endpoint , compared with observation after D2 gastrectomy . We report the 5-year follow-up data from the trial . METHODS CLASSIC was a phase 3 , r and omised , open-label study done at 35 cancer centres , medical centres , and hospitals in China , South Korea , and Taiwan . Patients with stage II-IIIB gastric cancer who underwent curative D2 gastrectomy were r and omly assigned ( 1:1 ) after surgery to receive adjuvant chemotherapy with capecitabine and oxaliplatin ( eight 3-week cycles of oral capecitabine 1000 mg/m(2 ) twice daily on days 1 - 14 plus intravenous oxaliplatin 130 mg/m(2 ) on day 1 ) for 6 months or observation alone . R and omisation was stratified by country and disease stage with a permuted block ( size four ) design . Neither patients nor investigators were masked to treatment assignment . The primary outcome was 3-year disease-free survival in the intention-to-treat population . This analysis presents the final preplanned assessment of outcomes after 5 years . The study is registered with Clinical Trials.gov , NCT00411229 . FINDINGS We enrolled 1035 patients : 520 were r and omly assigned to adjuvant capecitabine and oxaliplatin , and 515 to observation . Median follow-up for this analysis in the intention-to-treat population was 62·4 months ( IQR 54 - 70 ) . 139 ( 27 % ) patients had disease-free survival events in the adjuvant capecitabine and oxaliplatin group versus 203 ( 39 % ) patients in the observation group ( stratified hazard ratio [ HR ] 0·58 , 95 % CI 0·47 - 0·72 ; p<0·0001 ) . Estimated 5-year disease-free survival was 68 % ( 95 % CI 63 - 73 ) in the adjuvant capecitabine and oxaliplatin group versus 53 % ( 47 - 58 ) in the observation alone group . By the clinical cutoff date , 103 patients ( 20 % ) had died in the adjuvant capecitabine and oxaliplatin group versus 141 patients ( 27 % ) in the observation group ( stratified HR 0·66 , 95 % CI 0·51 - 0·85 ; p=0·0015 ) . Estimated 5-year overall survival was 78 % ( 95 % CI 74 - 82 ) in the adjuvant capecitabine and oxaliplatin group versus 69 % ( 64 - 73 ) in the observation group . Adverse event data were not collected after the primary analysis . INTERPRETATION Adjuvant treatment with capecitabine plus oxaliplatin after D2 gastrectomy should be considered for patients with operable stage II or III gastric cancer . FUNDING F Hoffmann La-Roche and Sanofi 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 PURPOSE We investigated which subgroups might benefit from adjuvant radiotherapy ( RT ) and suggested optimal RT targets by analyzing the results of the Adjuvant Chemoradiation Therapy in Stomach Cancer ( ARTIST ) trial . METHODS We conducted r and omized controlled trial in 458 gastric cancer patients . Patients were r and omly assigned to XP ( 6 cycles of capecitabine and ) or XPRT ( 2 cycles of XP+RT 45Gy/25 fraction with capecitabine+2 cycles of XP ) groups after D2 resection . Minimum follow-up was 5years . RESULTS During follow-up , 77 patients ( 33.8 % ) in the XP arm and 60 ( 26.1 % ) in the XPRT arm experienced recurrence . Among these patients , locoregional recurrence ( LRR ) developed in 44 ( 9.6 % ; 29 in XP , 15 in XPRT ; P=0.03 ) . The local recurrence rate ( 4.8 % ) did not vary between arms . Regional recurrence was the most important difference between the two groups ( 23 in the XP arm , 5 in the XPRT arm , P<0.001 ) . LRR-free survival ( LRRFS ) was significantly different between study arms ( P=0.03 ) , especially in patients with LN metastasis ( P=0.009 ) . CONCLUSIONS Adjuvant RT after D2 resection in gastric cancer reduced LRR , especially in group 3 LNs , and improved LRRFS . Patients with LN metastasis benefited more from the adjuvant RT treatment than the other subgroups The optimal adjuvant treatment for gastric cancer remains controversial . We compared the efficacy of a docetaxel and platinum adjuvant chemotherapy regimen , in patients with high-risk gastric cancer , with that of the same chemotherapy plus radiation therapy ( RT ) . In addition , we evaluated the prognostic and /or predictive value of a panel of molecular markers . Patients with histologically proven , radically resected gastric cancer , stage ≥T3 and /or N+ were r and omized to 6 cycles of docetaxel with cisplatin , both at 75 mg/m2 every 3 weeks ( arm A ) or the same treatment with RT ( arm B ; 45 Gy ) . Due to excessive nausea and vomiting , cisplatin was substituted by carboplatin at AUC ( area under the curve ) of 5 after the first 45 patients ( 22 group A , 23 group B ) . The prognostic value of EGFR , ERCC1 , HER2 , MET/HGFR , MAP-Tau , and PTEN expression was also studied in a subset of 67 patients using immunohistochemistry on tissue microarrays ( TMAs ) . A total of 147 patients were r and omized . After a median follow-up of 53.7 months , no differences in overall ( OS ) and disease-free survival ( DFS ) were found between the two arms . The most common grade 3/4 toxicities for arms A and B ( excluding alopecia ) were non-febrile neutropenia ( 11 and 17 % , respectively ) , febrile neutropenia ( 9 and 7 % ) and diarrhea ( 7 and 4 % , respectively ) . Patients with ERCC1 positive tumors had significantly longer median DFS ( 33.1 vs. 11.8 months , Wald P = 0.016 ) and OS ( 63.2 vs. 18.8 months , Wald P = 0.046 ) . Our results indicate that the addition of RT to platinum/docetaxel adjuvant chemotherapy does not appear to improve survival in high-risk , radically resected gastric cancer . However , the possibility that a benefit by the addition of RT was not detected due to decreased power of the study should not be excluded Background Recent research es have led to find strategies to prevent relapse and to improve survival for gastric cancer patients , including preoperative neo-adjuvant approaches . However , the efficacy of some neo-adjuvant regimens including 5-fluorouracil , cisplatin , and docetaxel have been less investigated . The present study evaluated the outcome and mid-term survival of patients with gastric cancer who undergoing this regimen . Methods In a r and omized double-blinded controlled trial performed at the Firoozgar hospital in Tehran in 2011 - 12 , 61 patients were r and omly assigned to treatment ( 32 to neo-adjuvant chemotherapy with docetaxel , cisplatin and 5-fluorouracil ( 5-FU ) before surgery and 27 to surgery alone ) . The present study tried to assess the efficacy of neoadjuvant chemotherapy regarding improvement of mid-term survival , complications , and R0 resection status . Results The two groups were matched in terms of gender , mean age , cancer location , and TNM staging . However , R0 resection in the former group was 85.7 % ; while this indicator in the isolated surgery group was significantly lower ( 61.5 % ) . Regarding WHO performance , no significant difference was observed across the two groups . Patients in  neo-adjuvant chemotherapy group were followed for mean follow-up time 10.32 months and those who categorized in isolated surgery group were followed for mean follow-up time 10.88 months . Mid-term mortality rate in the two groups was 14.3 % and 15.4 % , respectively ( p = 0.866 ) . In this regard , 3- , 6- , and 9-month survival rate in neo-adjuvant chemotherapy group was 96.4 % , 89.3 % , and 85.7 % , respectively . These survival rates in the surgery group were 92.3 % , 88.5 % , and 84.6 % , respectively . Multivariable logistic regression analysis showed that among all study variables , only R0 resection status could predict mid-term mortality .  Conclusion Neo-adjuvant chemotherapy and surgery compare to surgery alone more improve R0 resection status , but mid-term survival rate is similar in the two regiments . R0 resection status can effectively predict appropriate mid-term survival in undertreated patients BACKGROUND Promising findings obtained using a weekly regimen of 5-fluorouracil ( 5-FU ) , epidoxorubicin , leucovorin ( LV ) , and cisplatin ( PELFw ) to treat locally advanced and metastatic gastric cancer prompted the Italian Group for the Study of Digestive Tract Cancer ( GISCAD ) to investigate the efficacy of this regimen as adjuvant treatment for high-risk radically resected gastric cancer patients . METHODS From January 1998 to January 2003 , 400 gastric cancer patients at high risk for recurrence including patients with serosal invasion ( stage pT3 N0 ) and /or lymph node metastasis ( stage pT2 or pT3 N1 , N2 , or N3 ) , were enrolled in a trial of adjuvant chemotherapies ; 201 patients were r and omly assigned to receive the  PELFw regimen , consisting of eight weekly administrations of cisplatin ( 40 mg/m2 ) , LV ( 250 mg/m2 ) , epidoxorubicin ( 35 mg/m2 ) , 5-FU ( 500 mg/m2 ) , and glutathione ( 1.5 g/m2 ) with the support of filgrastim , and 196 patients were assigned to a regimen consisting of six monthly administrations of a 5-day course of 5-FU ( 375 mg/m2 daily ) and LV ( 20 mg/m2 daily , 5-FU/LV ) . Disease-free and overall survival were estimated and compared between arms using hazard ratios ( HRs ) and Kaplan-Meier estimates . All statistical tests were two-sided . RESULTS The 5-year survival rates were 52 % in the PELFw arm and 50 % in the 5-FU/LV arm . Compared with the 5-FU/LV regimen , the PELFw regimen did not reduce the risk of death ( HR = 0.95 , 95 % confidence interval [ CI ] = 0.70 to 1.29 ) or relapse ( HR = 0.98 , 95 % CI = 0.75 to 1.29 ) . Less than 10 % of patients in either arm experienced a grade 3 or 4 toxic episode . Neutropenia ( occurring more often in the PELFw arm ) and diarrhea and mucositis ( more prevalent in the 5-FU/LV arm ) were the most common serious side effects . Nevertheless , only 19 patients ( 9.4 % ) completed the treatment in the PELFw arm and 85 ( 43 % ) patients completed the treatment in the 5-FU/LV arm . CONCLUSIONS Our study found no benefit from an intensive weekly chemotherapy in gastric cancer . The extent of toxicity experienced by the patients in the adjuvant setting suggests that , in gastric cancer , chemotherapy may be more safely administered preoperatively Thirty-nine patients with potentially resectable cancer of the middle or lower esophagus who had not previously been treated were r and omly assigned to receive either immediate operation  ( n = 20 ) or operation plus preoperative and postoperative therapy with cisplatin , vindesine , and bleomycin  ( n = 19 ) . Patients were stratified by tumor size and location and by sex , with no significant differences appearing between the two treatment groups . Median follow-up for both groups was 30 months . The preoperative response rate to chemotherapy was 47 % . The postoperative complication rate for patients in the operation-only group was 47 % ; it was 29 % for patients receiving chemotherapy . The overall resectability rates were similar for the two groups . Patients responding to chemotherapy preoperatively had significantly prolonged survival ( median greater than 20 months ) when compared with either nonresponders ( median 6.2 months ) or patients receiving only operation ( median 8.6 months ) . A highly significant correlation was noted between a weight loss of less than 10 % and response to chemotherapy , which suggested that responses occurred in patients with less advanced disease . We conclude that preoperative and postoperative cisplatin , vindesine , and bleomycin chemotherapy has acceptable toxicity and does not increase the incidence of postoperative complications . The natural history of epidermoid carcinoma of the esophagus is altered and overall survival is prolonged for patients responding to preoperative chemotherapy . Potential responding patients can be identified by the degree of preoperative weight loss INTRODUCTION Preoperative chemotherapy ( CT ) and preoperative chemoradiation therapy ( CRT ) for resectable oesophageal cancer have been shown to improve overall survival in meta-analyses . There are limited data comparing these preoperative therapies . We report the outcomes of a r and omised phase II trial comparing preoperative CT and CRT for resectable adenocarcinoma of the oesophagus and gastro-oesophageal junction . METHODS Patients were r and omised to receive  preoperative CT with cisplatin ( 80 mg/m(2 ) ) and infusional 5 fluorouracil ( 1000 mg/m(2)/d ) on days 1 and 21 , or preoperative CRT with the same drugs accompanied by concurrent radiation therapy commencing on day 21 of chemotherapy and the 5 fluorouracil reduced to 800 mg/m(2)/d . The radiation dose was 35 Gy in 15 fractions over 3 weeks . The endpoints were toxicity , response rates , resection ( R ) status , progression-free survival ( PFS ) , overall survival ( OS ) and quality of life . RESULTS Seventy-five patients were enrolled on the study : 36 received preoperative CT and 39 preoperative CRT .  Toxicity was similar for CT and CRT . Eight patients ( 11 % ) did not proceed to resection . The histopathological response rate ( CRT 31 % versus CT 8 % , p = 0.01 ) and R1 resection rate ( CRT 0 % versus CT 11 % , p = 0.04 ) favoured those receiving CRT . The median PFS was 14 and 26 months for CT and CRT respectively ( p = 0.37 ) . The median OS was 29 months for CT compared with 32 months for CRT ( p = 0.83 ) . CONCLUSIONS Despite no difference in survival , the improvement from preoperative CRT with respect to margin involvement makes this treatment a reasonable option for bulky , locally advanced resectable adenocarcinoma of the oesophagus BACKGROUND Results of the PreOperative therapy in Esophagogastric adenocarcinoma Trial ( POET ) showed some benefits when including radiotherapy into the preoperative treatment . This article is reporting long-term results of this phase III study . PATIENTS AND METHODS Patients with locally advanced adenocarcinomas of the oesophagogastric junction ( Siewert types I-III ) were eligible . R and omisation was done to chemotherapy ( group A ) or induction chemotherapy and chemoradiotherapy ( CRT ; group B ) followed by surgery . RESULTS The primary end-point of the study was overall survival at 3 years . The study was closed early after 119 patients having been r and omised and were eligible .  Local progression-free survival after tumour resection was significantly improved by CRT ( hazard ratio [ HR ] 0.37 ; 0.16 - 0.85 , p = value 0.01 ) and 20 versus 12 patients were free of local tumour progression at 5 years ( p = 0.03 ) . Although the rate of postoperative in-hospital mortality was somewhat higher with CRT ( 10.2 % versus 3.8 % , p = 0.26 ) , more patients were alive at 3 and 5 years after CRT ( 46.7 % and 39.5 % ) compared with chemotherapy ( 26.1 % and 24.4 % ) . Thus , overall survival showed a trend in favour of preoperative CRT ( HR 0.65 , 95 % confidence interval [ CI ] 0.42 - 1.01 , p = 0.055 ) . CONCLUSION Although the primary end-point overall survival of the study was not met , our long-term follow-up data suggest a benefit in local progression-free survival when radiotherapy was added to preoperative chemotherapy in patients with locally advanced adenocarcinoma of the oesophagogastric junction Background : This phase 3 study evaluated the efficacy of new adjuvant chemotherapy ( MFP ) , which intensified the mitomycin-C ( MMC ) plus short-term doxifluridine ( Mf ) for gastric cancer . Patients and methods : A total of 855 patients ( 424 in Mf , 431 in MFP ) with pathological stage II – IV ( M0 ) gastric cancer after D2 gastrectomy were r and omly assigned to receive either Mf ( MMC 20 mg m−2 , followed by oral doxifluridine 460–600 mg m−2 per day for 3 months ) or MFP ( MMC 20 mg m−2 , followed by oral doxifluridine 460–600 mg m−2 per day for 12 months with 6 monthly infusions of 60 mg m−2 of cisplatin ) chemotherapy . Results : With a median follow-up of 6.6 years , there was no difference between the two groups in recurrence-free survival ( RFS ) ( 5-year RFS 61.1 % in Mf and 57.9 % in MFP ; hazard ratio 1.10 ( 95 % CI 0.89–1.35 ) ; P=0.39 ) and overall survival ( OS ) ( 5-year OS 66.5 % in Mf and 65.0 % in MFP ; hazard ratio 1.11 ( 95 % CI 0.89–1.39 ) ; P=0.33 ) . Conclusion : Intensification of Mf adjuvant chemotherapy by prolonging the duration of oral fluoropyrimidine and adding cisplatin was safe but not effective to improve the survivals in curatively resected gastric cancer patients BACKGROUND The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established . We compared chemoradiotherapy followed by surgery with surgery alone in this patient population . METHODS We r and omly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin ( doses titrated to achieve an area under the curve of 2 mg per milliliter per minute ) and paclitaxel ( 50 mg per square meter of body-surface area ) for 5 weeks and concurrent radiotherapy ( 41.4 Gy in 23 fractions , 5 days per week ) , followed by surgery . RESULTS From March 2004 through December 2008 , we enrolled 368 patients , 366 of whom were included in the analysis : 275 ( 75 % ) had adenocarcinoma , 84 ( 23 % ) had squamous-cell carcinoma , and 7 ( 2 % ) had large-cell undifferentiated carcinoma . Of the 366 patients , 178 were r and omly assigned to chemoradiotherapy followed by surgery  , and 188 to surgery alone . The most common major hematologic toxic effects in the chemoradiotherapy-surgery group were leukopenia ( 6 % ) and neutropenia ( 2 % ) ; the most common major nonhematologic toxic effects were anorexia ( 5 % ) and fatigue ( 3 % ) . Complete resection with no tumor within 1 mm of the resection margins ( R0 ) was achieved in 92 % of patients in the chemoradiotherapy-surgery group versus 69 % in the surgery group ( P<0.001 ) . A pathological complete response was achieved in 47 of 161 patients ( 29 % ) who underwent resection after chemoradiotherapy . Postoperative complications were similar in the two treatment groups , and in-hospital mortality was 4 % in both . Median overall survival was 49.4 months in the chemoradiotherapy-surgery group versus 24.0 months in the surgery group . Overall survival was significantly better in the chemoradiotherapy-surgery group ( hazard ratio , 0.657 ; 95 % confidence interval , 0.495 to 0.871 ; P=0.003 ) . CONCLUSIONS Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer . The regimen was associated with acceptable adverse-event rates . ( Funded by the Dutch Cancer Foundation [ KWF Kankerbestrijding ] ; Netherl and s Trial Register number , NTR487 . ) Background : The aim of this exploratory subgroup analysis of the fluorouracil , oxaliplatin , docetaxel (FLOT)65 + trial was to determine tolerability and feasibility of perioperative chemotherapy in elderly , potentially operable esophagogastric cancer patients . Methods : Patients aged ⩾65 with locally advanced esophagogastric adenocarcinoma were r and omized to perioperative chemotherapy consisting of four pre- and four postoperative cycles of infusional 5-FU , leucovorin , and oxaliplatin ( FLO ) without or with docetaxel 50 mg m−2 ( FLOT ) , every 2 weeks . Results : Forty-four patients with a median age of 70 years were r and omized and 43 patients started preoperative chemotherapy ( FLO , 22 ; FLOT , 21 ) . Thirty-eight ( 86.4 % ) patients completed four cycles of preoperative chemotherapy and 32 ( 74.4 % ) proceeded to surgery , with 67.4 % R0 resections on intent-to-treat analysis ( 90.1 % of the 32 patients who underwent resection ) . Median overall survival was not reached and median progression-free survival ( PFS ) was 17.3 months . Compared with the FLO group , the FLOT group showed a trend towards an improved median PFS ( 21.1 vs 12.0 months ; P=0.09 ) , however , associated with increased chemotherapy related toxicity . No perioperative mortality was observed . Postoperative morbidity was observed in 46.9 % of patients ( FLO , 35.3 % ; FLOT , 60 % ) . Conclusion : Neoadjuvant FLO or FLOT may offer a reasonable chance of curative surgery in elderly patients with locally advanced resectable gastroesophageal cancer . However , the increase in side effects with the FLOT regimen and postoperative morbidity should be carefully considered when an intensive chemotherapy regimen is planned BACKGROUND The contribution of induction chemotherapy ( IC ) before preoperative chemoradiation for esophageal cancer ( EC ) is not known . We hypothesized that IC would increase the rate of pathologic complete response ( pathCR ) . METHODS Trimodality-eligibile patients were r and omized to receive no IC ( Arm A ) or IC ( oxaliplatin/FU ; Arm B ) before oxaliplatin/FU/radiation . Surgery was attempted ∼5 - 6 weeks after chemoradiation . The pathCR rate , post-surgery 30-day mortality , overall survival ( OS ) , and toxic effects were assessed . Bayesian methods and Fisher 's exact test were used . RESULTS One hundred twenty-six patients were r and omized dynamically to balance the two arms for histology , baseline stage , gender , race , and age . Fifty-five patients in Arm A and 54 in Arm B underwent surgery . The median actuarial OS for all patients ( 54 deaths ) was 45.62 months [ 95 % confidence interval ( CI ) , 27.63-NA ] , with median OS 45.62 months ( 95 % CI 25.56-NA ) in Arm A and 43.68 months ( 95 % CI 27.63-NA ) in Arm B ( P = 0.69 ) . The pathCR rate in Arm A was 13 % ( 7 of 55 ) and 26 % ( 14 of 54 ) in Arm B ( two-sided Fisher 's exact test , P = 0.094 ) . Safety was similar in both arms . CONCLUSIONS These data suggest that IC  produces non-significant increase in the pathCR rate and does not prolong OS . Further development of IC before chemoradiation may not be beneficial . Clinical trial no. : NCT 00525915 ( www . clinical trials.gov ) After curative resection for gastric adenocarcinoma , 103 patients , all with positive nodes , were r and omised so that 48 received adjuvant chemotherapy of epidoxorubicin ( EPI ) 75 mg m-2 on day 1 , leucovorin ( LV ) 200 mg m-2 on days 1 - 3 and 5-fluorouracil ( 5-FU ) 450 mg m-2 on days 1 - 3 , every 21 days for 7 months , whereas the remaining 55 did not . During the first year of observation , 21 control patients ( 38 % ) and five treated patients had recurrences . After a follow-up period of 36 months , 12 of the treated patients ( 25 % ) and only seven controls ( 13 % ) were still alive . At that point , the median survival was 13.6 months for the 55 untreated patients and 20.4 months for the 48 treated patients , a significant difference . We found a survival advantage for patients treated with the EPI-LV-5-FU regimen and a consistent delay in the appearance of recurrent or metastatic cancer . Acute toxicity was mild and treatment was well accepted by all patients . There was no long-term toxicity or any cardiac toxicity . We conclude that this particular chemotherapy , administered shortly after gastric resection , improves survival rate in node-positive gastric cancer patients , even although final assessment of this particular adjuvant approach must await completion of the trial BACKGROUND Definitive chemoradiotherapy ( CRT ) is an alternative to surgery for the curative treatment of oesophageal carcinoma . The SCOPE1 trial aim ed to investigate the addition of cetuximab to cisplatin and fluoropyrimidine-based definitive CRT in patients with localised oesophageal squamous-cell cancer and adenocarcinomas to assess activity , safety , and feasibility of use . METHODS In this multicentre , r and omised , open-label , phase 2/3 trial , we recruited patients aged 18 years and older from UK radiotherapy centres who had non-metastatic , histologically confirmed carcinoma of the oesophagus ( adenocarcinoma , squamous-cell , or undifferentiated ; WHO status 0 - 1 ; stage I-III disease ) and been selected to receive definitive CRT .  Patients were r and omly assigned ( 1:1 ) via a central computerised system using stratified minimisation ( with an 80:20 r and om element ) to receive CRT alone or CRT with cetuximab ( 400 mg/m(2 ) on day 1 followed by 250 mg/m(2 ) weekly ) , stratified by recruiting hospital , primary reason for not having surgery , tumour histology , and tumour stage . CRT consisted of cisplatin 60 mg/m(2 ) ( day 1 ) and capecitabine 625 mg/m(2 ) twice daily ( days 1 - 21 ) for four cycles ; cycles three and four were given concurrently with 50 Gy in 25 fractions of radiotherapy . The primary endpoint was the proportion of patients who were treatment failure free at week 24 for the phase 2 trial and overall survival for the phase 3 trial , both measured from r and omisation . We analysed data by intention to treat . This trial is an International St and ard R and omised Controlled Trial , number 47718479 . FINDINGS 258 patients ( 129 assigned to each treatment group ) from 36 UK centres were recruited between Feb 7 , 2008 , and Feb 22 , 2012 . Recruitment was stopped without continuation to phase 3 because the trial met criteria for futility , but we continued to follow-up recruited patients until all had reached at least 24-week follow-up ( median follow-up of patients who survived was 16.8 months [ IQR 11.2 - 24.5 ] ) . Fewer patients were treatment failure free at 24 weeks in the CRT plus cetuximab group ( 79 of 119 patients [ 66·4 % , 90 % CI 58·6 - 73·6 ] ) than in the CRT only group ( 93 of 121 patients [ 76.9 % , 69.7 - 83.0 ] ) . The CRT plus cetuximab group also had shorter median overall survival ( 22.1 months [ 95 % CI 15.1 - 24.5 ] vs 25.4 months [ 20.5 - 37.9 ] ; adjusted HR 1.53 [ 95 % CI 1.03 - 2.27 ] ; p=0.035 ) . Patients who received CRT plus cetuximab had more non-haematological grade 3 or 4 toxicities ( 102 [ 79 % ] of 129 patients vs 81 [ 63 % ] of 129 patients ; p=0.004 ) . The most common grade 3 or 4 toxicities were low white blood cell count ( 14 [ 11 % ] in the CRT plus cetuximab group vs 21 [ 16 % ] in the CRT only group ) , low absolute neutrophil count ( 15 [ 12 % ] vs 24 [ 19 % ] ) , fatigue ( 26 [ 20 % ] vs 25 [ 19 % ] ) , and dysphagia ( 35 [ 27 % ] vs 37 [ 29 % ] ) . INTERPRETATION The addition of cetuximab to st and ard chemotherapy and radiotherapy can not be recommended for patients with oesophageal cancer suitable for definitive CRT . FUNDING Cancer Research UK BACKGROUND Complete surgical resection of gastric cancer is potentially curative , but long-term survival is poor . METHODS Patients with histologically proven adenocarcinoma of the stomach of stages IB , II , IIIA and B , or IV ( T4N2M0 ) and treated with potentially curative surgery  were r and omly assigned to follow-up alone or to intravenous treatment with four cycles ( repeated every 21 days ) of PELF ( cisplatin [ 40 mg/m(2 ) , on days 1 and 5 ] , epirubicin [ 30 mg/m(2 ) , days 1 and 5 ] , L-leucovorin [ 100 mg/m(2 ) , days 1 - 4 ] , and 5-fluorouracil [ 300 mg/m(2 ) , days 1 - 4 ] in a hospital setting . Frequencies and severity of adverse events were determined . Overall survival ( OS ) and disease-free survival ( DFS ) were compared between the treatment arms using Kaplan-Meier analysis and a Cox proportional hazards regression model . All statistical tests were two-sided . RESULTS From January 1995 through September 2000 , 258 patients were r and omly assigned to chemotherapy ( n = 130 ) or surgery alone ( n = 128 ) . Patient characteristics were well balanced between the two arms . Among those who received chemotherapy , grade 3 or 4 toxic effects including vomiting , mucositis , and diarrhea were experienced by 21.1 % , 8.4 % , and 11.8 % of patients , respectively . Leucopenia , anemia , and thrombocytopenia of grade 3 or 4 were experienced by 20.3 % , 3.3 % , and 4.2 % of patients , respectively . After a median follow-up of 72.8 months , 128 patients ( 49.6 % ) experienced recurrence and 139 ( 53.9 % ) deaths were observed , one toxicity-related . Relative to treatment with surgery alone , adjuvant chemotherapy did not increase disease-free survival ( hazard ratio [ HR ] of recurrence = 0.92 ; 95 % confidence interval [ CI ] = 0.66 to 1.27 ) or overall survival ( HR of death = 0.90 ; 95 % CI = 0.64 to 1.26 ) . CONCLUSIONS Our results failed to provide proof of an effect of adjuvant chemotherapy with PELF on overall survival or disease-free survival . The estimated effect of chemotherapy ( 10 % reduction in the hazard of death or relapse ) is modest and consistent with the results of meta-analyses of adjuvant chemotherapy without platinum agents PURPOSE An attempt was made to define the role of radiotherapy before operation for AGC . METHODS AND MATERIAL S From January 1978 to May 1989 , a prospect i ve r and omized trial on preoperative radiotherapy ( R+S ) vs. surgery alone ( S ) for AGC was carried out in 370 patients . Patients were r and omized into a combined group ( R+S , 171 patients ) or a surgery alone group ( S , 199 patients ) by the envelope method . 8-MV photon or telecobalt was used for the preoperative radiation therapy , using anterior-posterior opposing parallel fields to deliver 40 Gy to the cardia , lower segment of the esophagus , fundus , lesser curvature , and hepatogastric ligament . Surgery was performed after 2 to 4 weeks rest . RESULTS The 5- and 10-year survival rates of the R+S Group and the S Alone Group were 30.10 % and 19.75 % , 20.26 % and 13.30 % , respectively . The survival curves of these two groups diverged right from the beginning after the operation over the ninth year . Statistics by Kaplan-Meier log rank test proves that the difference is significant ( chi2 = 6.74 , p = 0.0094 ) . The immediate results were : resection rate 89.5 % and 79.4 % ( p < 0.01 ) ; pathologic stage after resection T2 12.9 % and 4.5 % ( p < 0.01 ) , T4 40.3 % and 51.3 % ( p < 0.05 ) , lymph node metastasis rates 64.3 % and 84.9 % ( p < 0.001 ) ; operative mortality rates 0.6 % and 2.5 % ; intrathoracic leak rates 1.8 % and 4.0 % , respectively . The causes of failure were : local uncontrol and recurrence 38.6 % vs. 51.7 % ( p < 0.025 ) , regional lymph node metastasis 38.6 % vs. 54.6 % ( p < 0.005 ) , distant metastasis 24.3 % vs. 24.7 % . CONCLUSION Preoperative radiation therapy is able to improve the results of surgery for adenocarcinoma of the gastric cardia BACKGROUND Fluorouracil-based adjuvant chemotherapy in gastric cancer has been reported to be effective by several meta-analyses . Perioperative chemotherapy in locally advanced resectable gastric cancer ( RGC ) has been reported improving survival by two large r and omized trials and recent meta-analyses but the role of neoadjuvant chemotherapy and optimal regimen remains to be determined . We compared a neoadjuvant with adjuvant docetaxel-based regimen in a prospect i ve r and omized phase III trial , of which we present the 10-year follow-up data . PATIENTS AND METHODS Patients with cT3 - 4 anyN M0 or anyT cN1 - 3 M0 gastric carcinoma , staged with endoscopic ultrasound , computed tomography , bone scan , and laparoscopy , were assigned to receive four 21-day/cycles of docetaxel 75 mg/m(2 ) day 1 , cisplatin 75 mg/m(2 ) day 1 , and fluorouracil 300 mg/m(2)/day over days 1 - 14 , either before ( arm A ) or after ( arm B ) gastrectomy . Event-free survival was the primary end point , whereas secondary end points included overall survival , toxicity , down-staging , pathological response , quality of life , and feasibility of adjuvant chemotherapy . RESULTS This trial was activated in November 1999 and closed in November 2005 due to insufficient accrual . Of the 70 enrolled patients , 69 were r and omized , 34 to arm A and 35 to arm B. No difference in EFS ( 2.5 years in both arms ) or OS ( 4.3 versus 3.7 years , in arms A and B , respectively ) was found . A higher dose intensity of chemotherapy was observed in arm A and more frequent chemotherapy-related serious adverse events occurred in arm B. Surgery was safe after preoperative chemotherapy . A 12 % pathological complete response was observed in arm A. CONCLUSION Docetaxel/cisplatin/fluorouracil chemotherapy is promising in preoperative setting of locally advanced RGC . The early stopping could mask the real effectiveness of neoadjuvant treatment . However , the complete pathological tumour responses , feasibility , and safe surgery warrant further investigation of a taxane-based regimen in the preoperative setting PURPOSE Surgical resection of gastric cancer has produced suboptimal survival despite multiple r and omized trials that used postoperative chemotherapy or more aggressive surgical procedures . We performed a r and omized phase III trial of postoperative radiochemotherapy in those at moderate risk of locoregional failure ( LRF ) following surgery . We originally reported results with 4-year median follow-up . This up date , with a more than 10-year median follow-up , presents data on failure patterns and second malignancies and explores selected subset analyses . PATIENTS AND METHODS In all , 559 patients with primaries ≥ T3 and /or node-positive gastric cancer were r and omly assigned to observation versus radiochemotherapy after R0 resection . Fluorouracil and leucovorin were administered before , during , and after radiotherapy . Radiotherapy was given to all LRF sites to a dose of 45 Gy . RESULTS Overall survival ( OS ) and relapse-free survival ( RFS ) data demonstrate continued strong benefit from postoperative radiochemotherapy . The hazard ratio ( HR ) for OS is 1.32 ( 95 % CI , 1.10 to 1.60 ; P = .0046 ) . The HR for RFS is 1.51 ( 95 % CI , 1.25 to 1.83 ; P < .001 ) . Adjuvant radiochemotherapy produced substantial reduction in both overall relapse and locoregional relapse . Second malignancies were observed in 21 patients with radiotherapy versus eight with observation ( P = .21 ) . Subset analyses show robust treatment benefit in most subsets , with the exception of patients with diffuse histology who exhibited minimal nonsignificant treatment effect . CONCLUSION Intergroup 0116 ( INT-0116 ) demonstrates strong persistent benefit from adjuvant radiochemotherapy . Toxicities , including second malignancies , appear acceptable , given the magnitude of RFS and OS improvement . LRF reduction may account for the majority of overall relapse reduction . Adjuvant radiochemotherapy remains a rational st and ard therapy for curatively resected gastric cancer with primaries T3 or greater and /or positive nodes Abstract Purpose : To evaluate FAM [ 5-FU ( 5-fluorouracil ) , doxorubicin , mitomycin C ] chemotherapy as adjuvant therapy for patients with resected TNM stage I , II , or III gastric carcinoma . Patients and Methods : One hundred ninety-three eligible patients were accrued from 1978 to 1991 in a phase III trial comparing six cycles ( 1 year ) of postoperative FAM chemotherapy with observation only . Results : The median follow-up on this study was 9.5 years . For all patients , no differences ( log-rank analysis ) in disease-free survival ( p=0.45 ) and overall survival ( p=0.57 ) between FAM therapy ( 93 cases ) and surgery ( 100 cases ) were observed . Quality of surgical resection affected survival irrespective of FAM use . Cases with curative resection , defined in a retrospective review of pathology and surgical reports as cases having no evidence of residual disease in the abdomen and tumor-free margins > 1 cm , had superior survival compared to cases not meeting these requirements ( p<0.001 ) . FAM was well tolerated with 6 % ( five of 90 ) of cases demonstrating grade IV hematologic toxicity . There were two drug-related fatalities ( one cardiomyopathy , one hematolytic uremic syndrome ) . Conclusion : FAM is not effective adjuvant therapy for TNM stage I , II , and III patients with resected gastric cancer . Future adjuvant studies must emphasize prospect i ve surgical quality control to assure enrollment of appropriately staged and resected cases and wide participation to assure adequate case accrual over a reasonable period A group of 243 patients with gastric cancer was subjected to a prospect i ve r and omized trial of adjuvant chemotherapy after curative gastrectomy . One of the three arms ( regimen A ) is induction therapy with a three-drug combination of mitomycin C ( MMC ) , 5-fluorouracil ( 5-FU ) , and cytosine arabinoside ( ara-C ) followed by intermittent oral administration of 5-FU for two years ( MFC + F ) . In regimen B , 5-FU in regimen A is replaced by ftorafur , administered on the same schedule as regimen A ( MF'C + F ' ) . Regimen C is the control , in which patients are treated by surgery alone . Regimen A was proven effective for the suppression of relapse in the limited groups of moderately locally advanced cancer ; five-year survival rates of the subset of stages I , II , and III were 72.1 % with regimen A and 53.1 % with regimen C ( P less than .05 ) . Regimen B yielded a better survival than the control , although the difference did not reach statistical significance . The results seem to favor 5-FU as adjuvant chemotherapy for gastric cancer BACKGROUND Surgical resection of adenocarcinoma of the stomach is curative in less than 40 percent of cases . We investigated the effect of surgery plus postoperative ( adjuvant ) chemoradiotherapy on the survival of patients with resectable adenocarcinoma of the stomach or gastroesophageal junction . METHODS A total of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction were r and omly assigned to surgery plus postoperative chemoradiotherapy or surgery alone . The adjuvant treatment consisted of 425 mg of fluorouracil per square meter of body-surface area per day , plus 20 mg of leucovorin per square meter per day , for five days , followed by 4500 cGy of radiation at 180 cGy per day , given five days per week for five weeks , with modified doses of fluorouracil and leucovorin on the first four and the last three days of radiotherapy . One month after the completion of radiotherapy , two five-day cycles of fluorouracil ( 425 mg per square meter per day ) plus leucovorin ( 20 mg per square meter per day ) were given one month apart . RESULTS The median overall survival in the surgery-only group was 27 months , as compared with 36 months in the chemoradiotherapy group ; the hazard ratio for death was 1.35 ( 95 percent confidence interval , 1.09 to 1.66 ; P=0.005 ) . The hazard ratio for relapse was 1.52 ( 95 percent confidence interval , 1.23 to 1.86 ; P<0.001 ) . Three patients ( 1 percent ) died from toxic effects of the chemoradiotherapy ; grade 3 toxic effects occurred in 41 percent of the patients in the chemoradiotherapy group , and grade 4 toxic effects occurred in 32 percent . CONCLUSIONS Postoperative chemoradiotherapy should be considered for all patients at high risk for recurrence of adenocarcinoma of the stomach or gastroesophageal junction who have undergone curative resection Following curative resection for gastric adenocarcinoma , 142 patients were r and omized to receive adjuvant chemotherapy of methyl‐CCNU and 5‐FU or to be  closely followed without chemotherapy . The median patient has been followed for four years . At the present time , there have been 38 recurrences and 40 deaths among the 71 patients in the control arm and 28 recurrences with 29 deaths in the group of patients r and omized to chemotherapy .  Median survival for control patients is 33 months whereas it is estimated to be in excess of four years for the adjuvant therapy group . A survival advantage appears to be associated with adjuvant treatment , a test for treatment difference being significant ( P < 0.03 ) after adjustment for important covariates . Survival and disease‐free intervals are longer in the chemotherapy arm for patients in all prospect i ve stratification subgroups ( proximal and total vs distal subtotal gastrectomy , presence or absence of lymph node metastases , invasion of adjacent organs vs confined to stomach wall and location of tumor within the stomach ) . A final assessment of this surgical adjuvant approach must await complete results of this trial , as well as of others currently in progress evaluating this same concept Background : Neoadjuvant chemotherapy for resectable advanced esophageal squamous cell carcinoma ( ESCC ) requires re assessment . We have conducted a trial aim ing at the comparison between DCF and ACF concerning perioperative adverse events . Methods : Patients were r and omly assigned to receive either DCF [ docetaxel 70 mg/m2 , cisplatin 70 mg/m2 on day 1 , and 5-fluorouracil ( 5-FU ) 700 mg/m2 for 5 days ] every 3 weeks or ACF ( adriamycin 35 mg/m2 , cisplatin 70 mg/m2 on day 1 , and 5-FU 700 mg/m2 for 7 days ) every 4 weeks . Each group consisted of 81 patients . Two cycles of preoperative chemotherapy were planned , after which patients underwent subtotal esophagectomy via a right thoracotomy with lymphadenectomy . Chemotherapy- and surgery-related adverse effects were assessed . Results : Grade 3 - 4 neutropenia and febrile neutropenia occurred in 90 and 39 % of patients , respectively , in the DCF group compared with 69 and 17 % of patients , respectively , in the ACF group ( p < 0.01 ) . Perioperative complications did not differ significantly between the groups . The overall response rates of DCF and ACF were 61 and 40 % , respectively , while the histopathological complete responses were 15 and 3 % , respectively ( p < 0.01 ) . Conclusion : The DCF and ACF regimens were found to be equally feasible in patients with resectable advanced ESCC ; however , DCF delivered an antitumor effect and therefore potentially improved the long-term outcomes PURPOSE Toxicity , pathologic complete response , and long-term outcomes are reported for the neoadjuvant therapies assessed in a r and omized phase 2 Eastern Cooperative Oncology Group and American College of Radiology Imaging Network trial for operable esophageal adenocarcinoma , staged as II-IVa by endoscopy/ultrasonography ( EUS ) . METHODS AND MATERIAL S A total of 86 eligible patients began treatment . For arm A , preoperative chemotherapy was cisplatin , 30 mg/m(2 ) , and irinotecan , 50 mg/m(2 ) , on day 1 , 8 , 22 , 29 during 45 Gy radiation therapy ( RT ) , 1.8 Gy per day over 5 weeks . Adjuvant therapy was cisplatin , 30 mg/m(2 ) , and irinotecan , 65 mg/m(2 ) day 1 , 8 every 21 days for 3 cycles . Arm B therapy was cisplatin , 30 mg/m(2 ) , and paclitaxel , 50 mg/m(2 ) , day 1 , 8 , 15 , 22 , 29 with RT , followed by adjuvant cisplatin , 75 mg/m(2 ) , and paclitaxel , 175 mg/m(2 ) , day 1 every 21 days for 3 cycles . Stratification included EUS stage and performance status . RESULTS In arm A , median overall survival was 35 months , and 5- , 6- , and 7-year survival rates were 46 % , 39 % , and 35 % , respectively , whereas for arm B , they were 21 months and 27 % , 27 % , and 23 % , respectively . Median progression- or recurrence-free survival ( PFS ) was 39.8 months with a 3-year PFS of 50 % for arm A and 12.4 months ( P=.046 ) with 3-year PFS of 28 % for arm B. Eighty percent of the observed incidents of progression occurred within 19 months . Survival did not differ significantly by EUS and performance status strata . CONCLUSIONS Long-term survival was similar for both arms and did not appear superior to results achieved with other st and ard regimens Adjuvant chemotherapy of gastric cancer after curative resection is still subject to discussion . In this study 137 patients with gastric adenocarcinoma , all with positive nodes , were r and omized after curative resection so that 69 received epidoxorubicin ( EPI ) , leucovorin ( LV ) and 5-fluorouracil ( 5-FU ) on days 1–3 every 3 weeks for 7 months , whereas the remaining 68 did not . After a follow-up period of 5 years , 21 of the 69 treated patients ( 30 % ) and nine controls ( 13 % ) were still alive ; median survival time was 18 months for the controls and 31 months for the patients treated with adjuvant chemotherapy ( P < 0.01 ) . © 2001 Cancer Research The aim of this trial was to investigate whether pre-operative chemotherapy leads to a 15 % higher curative resectability rate in patients with operable gastric cancer . In this r and omised trial , patients were allocated to receive either four courses of chemotherapy using 5-fluorouracil , doxorubicin and methotrexate ( FAMTX ) prior to surgery or to undergo surgery only .  Patients younger than 75 years of age with a good physical and mental condition and a histologically proven adenocarcinoma of the stomach without clinical or radiographic ( computed tomography scan ) evidence of distant metastases were eligible for this trial . Early gastric cancer or cardia carcinoma were excluded . The response to chemotherapy was evaluated after two and four courses . In case of progressive disease ( PD ) after two courses , patients were operated upon as soon as possible . Otherwise complete response ( CR ) partial response ( PR ) or stable disease ( SD ) , two more courses were scheduled . The st and ard surgical procedure was a limited lymphadenectomy ( D1 ) with staging biopsy of the para-aortic lymph nodes . Between September 1993 and February 1996 , 56 eligible and evaluable patients were entered : 27 were r and omised to receive FAMTX before surgery and 29 to undergo surgery only . In the FAMTX + surgery treatment group , 15/27 ( 56 % ) had curative resections versus 18/29 ( 62 % ) in the surgery only arm . There was no difference in the frequency of TNM stages I + II in both treatment arms : 15/27 versus 15/29 . Due to PD and /or toxicity , 12 patients ( 44 % ) could not complete the planned four courses of FAMTX . Response evaluation after chemotherapy was possible in 25 patients : 2 CR , 6 PR , 8 SD and 9 PD . The difference in curative resectability rate was 6.5 % ( 95 % confidence interval -32 to + 19 % ) in favour of surgery only . Downstaging for stages I + II did not occur . PD was more often the reason for not completing the planned four courses than toxicity . More active regimens than FAMTX are required for future r and omised trials BACKGROUND The outlook for patients with oesophageal cancer undergoing surgical resection with curative intent is poor . We aim ed to assess the effects of preoperative chemotherapy on survival , dysphagia , and performance status in this group of patients . METHODS 802 previously untreated patients with resectable oesophageal cancer of any cell type were r and omly allocated either two 4-day cycles , 3 weeks apart , of cisplatin 80 mg/m(2 ) by infusion over 4 h plus fluorouracil 1000 mg/m(2 ) daily by continuous infusion for 4 days followed by surgical resection ( CS group , n=400 ) , or resection alone ( S group , 402 ) . Clinicians could choose to give preoperative radiotherapy to all their patients irrespective of r and omisation . Primary outcome measure was survival time . Analysis was by intention to treat . FINDINGS No patients dropped out of the study . Resection was microscopically complete in 233 ( 60 % ) of 390 assessable CS patients and 215 ( 54 % ) of 397 S patients ( p<0.0001 ) . Postoperative complications were reported in 146 ( 41 % ) CS and 161 ( 42 % ) S patients . Overall survival was better in the CS group ( hazard ratio 0.79 ; 95 % CI 0.67 - 0.93 ; p=0.004 ) . Median survival was 512 days ( 16.8 months ) in the CS group compared with 405 days ( 13.3 months ) in the S group ( difference 107 days ; 95 % CI 30 - 196 ) , and 2-year survival rates were 43 % and 34 % ( difference 9 % ; 3 - 14 ) . INTERPRETATION Two cycles of preoperative cisplatin and fluorouracil improve survival without additional serious adverse events in the treatment of patients with resectable oesophageal cancer The overall survival in patients with gastric cancer is low , even among those undergoing resection . It has been hoped that the development of adjuvant therapy might improve survival in patients following surgery when tumour burden was minimal and both chemotherapy and radiotherapy have been proposed as suitable for use in gastric cancer . Their value has been evaluated by the British Stomach Cancer Group Second adjuvant therapy trial . 436 patients entered a prospect i ve , r and omised , controlled trial of adjuvant radiotherapy or cytotoxic chemotherapy with mitomycin , doxorubicin , and fluorouracil  after gastrectomy for adenocarcinoma . After at least 5 years , there have been 372 deaths of which 7 were due to surgical complications and 327 from recurrent cancer . Following stratified r and omisation , 145 patients were allocated to  surgery alone  , 153 to receive adjuvant radiotherapy , and 138 to adjuvant combination chemotherapy . The overall 2-year and 5-year survival were 33 % ( 95 % confidence interval 31 - 35 % ) and 17 % ( 13 - 21 % ) . No survival advantage has been shown for those patients receiving either adjuvant therapy compared to those undergoing surgery alone . The 5-year survival for surgery alone was 20 % , for surgery plus radiotherapy 12 % , and for surgery plus chemotherapy 19 % . Surgery , therefore , remains the st and ard treatment for this condition and the use of adjuvant treatments should be restricted to controlled trials PURPOSE The primary treatment modality for patients with carcinoma of the esophagus or gastroesophageal junction has been surgery , although primary radiation therapy with concurrent chemotherapy produces similar results . As both have curative potential , there has been great interest in the use of trimodality therapy . To this end , we compared survival , response , and patterns of failure of trimodality therapy to esophagectomy alone in patients with nonmetastatic esophageal cancer . PATIENTS AND METHODS Four hundred seventy-five eligible patients were planned for enrollment . Patients were r and omly assigned to either esophagectomy with node dissection alone or cisplatin 100 mg/m(2 ) and fluorouracil 1,000 mg/m(2)/d for 4 days on weeks 1 and 5 concurrent with radiation therapy ( 50.4 Gy total : 1.8 Gy/fraction over 5.6 weeks ) followed by esophagectomy with node dissection . RESULTS Fifty-six patients were enrolled between October 1997 and March 2000 , when the trial was closed due to poor accrual . Thirty patients were r and omly assigned to trimodality therapy and 26 were assigned to surgery alone . Patient and tumor characteristics were similar between groups . Treatment was generally well tolerated . Median follow-up was 6 years . An intent-to-treat analysis showed a median survival of 4.48 v 1.79 years in favor of trimodality therapy ( exact stratified log-rank , P = .002 ) . Five-year survival was 39 % ( 95 % CI , 21 % to 57 % ) v 16 % ( 95 % CI , 5 % to 33 % ) in favor of trimodality therapy . CONCLUSION The results from this trial reflect a long-term survival advantage with the use of chemoradiotherapy followed by surgery in the treatment of esophageal cancer , and support trimodality therapy as a st and ard of care for patients with this disease Purpose We conducted a r and omized , multicenter , phase III trial to compare S-1 plus docetaxel ( DS ) with S-1 plus cisplatin ( SP ) as adjuvant chemotherapy for stage III gastric cancer patients . Material s and Methods Stage III gastric cancer patients who had received curative gastrectomy with D2 lymphadenectomy were r and omized into equal groups to receive adjuvant chemotherapy of eight cycles of DS ( S-1 70 mg/m2/day on days 1 - 14 plus docetaxel 35 mg/m2on days 1 and 8) every 3 weeks or SP ( S-1 70 mg/m2/day on days 1 - 14 plus cisplatin 60 mg/m2on day 1 ) every 3 weeks . The primary endpoint was 3-year disease-free survival ( DFS ) rate . Results Between November 2010 and July 2013 , 153 patients ( 75 patients to DS and 78 patients to SP ) were enrolled from 8 institutions in Korea . After the capecitabine plus oxaliplatin was approved based on the CLASSIC study , itwas decided to close the study early . With a median follow-up duration of 56.9 months , the 3-year DFS rate between two groups was not significantly different ( 49.14 % in DS group vs. 52.5 % in SP group ) . The most common grade 3 - 4 adverse event was neutropenia ( 42.7 % in DS and 38.5 % in SP , p=0.351 ) . SP group had more grade 3 - 4 anemia ( 1.3 % vs. 11.5 % , p=0.037 ) , whereas grade 3 - 4 h and -foot syndrome ( 4.1 % vs. 0 % , p=0.025 ) and mucositis ( 10.7 % vs. 2.6 % , p=0.001 ) were more common in DS group . Fifty-one patients ( 68 % ) in DS group and 52 ( 66.7 % ) in SP group finished planned treatment . Conclusion Our findings suggest that SP or DS is an effective and tolerable option for patients with curatively resected stage III gastric cancer BACKGROUND Uncontrolled studies suggest that a combination of chemotherapy and radiotherapy improves the survival of patients with esophageal adenocarcinoma . We conducted a prospect i ve , r and omized trial comparing surgery alone with combined chemotherapy , radiotherapy , and surgery . METHODS Patients assigned to multimodal therapy received two courses of chemotherapy in weeks 1 and 6 ( fluorouracil , 15 mg per kilogram of body weight daily for five days , and cisplatin , 75 mg per square meter of body-surface area on day 7 ) and a course of radiotherapy ( 40 Gy , administered in 15 fractions over a three-week period , beginning concurrently with the first course of chemotherapy ) , followed by surgery . The patients assigned to surgery had no preoperative therapy . RESULTS Of the 58 patients assigned to multimodal therapy and the 55 assigned to surgery  , 10 and 1 , respectively , were withdrawn for protocol violations . At the time of surgery , 23 of 55 patients ( 42 percent ) treated with preoperative multimodal therapy who could be evaluated had positive nodes or metastases , as compared with 45 of the 55 patients ( 82 percent ) who underwent surgery alone ( P<0.001 ) . Thirteen of the 52 patients ( 25 percent ) who underwent surgery after multimodal therapy had complete responses as determined pathologically . The median survival of patients assigned to multimodal therapy was 16 months , as compared with 11 months for those assigned to surgery alone ( P=0.01 ) . At one , two , and three years , 52 , 37 , and 32 percent , respectively , of patients assigned to multimodal therapy were alive , as compared with 44 , 26 , and 6 percent of those assigned to surgery , with the survival advantage favoring multimodal therapy reaching significance at three years ( P=0.01 ) . CONCLUSIONS Multimodal treatment is superior to surgery alone for patients with resectable adenocarcinoma of the esophagus BACKGROUND A phase III single-center r and omized trial was performed in order to determine whether the addition of mitomycin C ( MMC ) and /or doxorubicin to 5-fluorouracil ( 5-FU ) as adjuvant chemotherapy could influence survival in patients with curatively resected gastric cancer . PATIENTS AND METHODS A total of 416 patients who had undergone curative resection for stage IB-IIIB gastric adenocarcinoma were stratified according to the stage and type of surgery , and then r and omized to receive one of the three chemotherapy regimens , 5-FU alone ( F ) or 5-FU and MMC ( FM ) or 5-FU , doxorubicin and MMC ( FAM ) within 5 weeks after surgery . RESULTS Of 416 patients registered , 395 ( 133 in F , 131 in FM and 131 in FAM ) were assessable . Median follow-up duration was 91 months . Five-year overall survival rates were 67.2 % for F , 67.0 % for FM and 66.7 % for FAM ( P = 0.97 ) . Five-year disease-free survival rates were 62.1 % for F , 63.3 % for FM and 62.5 % for FAM ( P = 0.83 ) . Hematological toxicities were more frequent in the FM and FAM groups , whereas stomatitis was more common in the F group . CONCLUSIONS Compared with adjuvant 5-FU alone , the addition of MMC and /or doxorubicin to 5-FU did not influence survival in patients with resected gastric cancer BACKGROUND This r and omized , multicenter , phase III trial evaluated the efficacy and safety of the combination of epirubicin , leucovorin , 5-fluorouracil and etoposide ( ELFE regimen ) as adjuvant therapy for radically resected gastric cancer patients . PATIENTS AND METHODS From June 1996 to June 2001 , 228 stage IB-IIIB gastric cancer patients were enrolled . All patients received a total or subtotal gastrectomy with at least a D1 lymphoadenectomy  and were r and omly assigned to receive surgery alone or surgery followed by chemotherapy . RESULTS A total number of 630 cycles was delivered with a median number of 5 . With a median follow-up of 60 months , the 5-year overall survival ( OS ) was 48 % in the treatment arm and 43.5 % in the control arm [ hazard ratio ( HR ) 0.91 ; 95 % confidence interval ( CI ) 0.69 - 1.21 ; P = 0.610 ) ; the 5-year disease-free survival ( DFS ) was 44 % in the treatment arm and 39 % in the control arm ( HR 0.88 ; 95 % CI 0.78 - 0.91 ; P = 0.305 ) . In node-positive patients , the 5-year OS was 41 % in the treatment arm and 34 % in the control arm ( HR 0.84 ; 95 % CI 0.69 - 1.01 ; P = 0.068 ) , while the 5-year DFS was 39 % in the treatment arm and 31 % in the control arm ( HR 0.88 ; 95 % CI 0.78 - 0.91 ; P = 0.051 ) . The most common grade 3 - 4 toxic effects according to World Health Organization criteria were hematological and gastrointestinal . CONCLUSIONS In radically resected gastric cancer patients , adjuvant chemotherapy with ELFE regimen does not improve OS over surgery alone Objective : Combination therapies of fluorouracil ( FU ) with irinotecan ( CPT-11 ) and docetaxel plus cisplatin have been proven to be active in metastatic gastric cancer . In this paper , we present the results of a phase III trial in which these two combinations given sequentially were compared to mitomycin C ( MMC ) monochemotherapy in an adjuvant setting . Methods : 169 patients with radically resected gastric cancer were r and omized to receive CPT-11 ( 180 mg/m2 day 1 ) , leucovorin ( 100 mg/m2 days 1–2 ) , FU ( 400–600 mg/m2 days 1–2 , q 14 ; for four cycles ; FOLFIRI regimen ) , followed by docetaxel ( 85 mg/m2 day 1 ) , cisplatin ( 75 mg/m2 day 1 , q 21 ; for three cycles ; arm A ) , or MMC ( 8 mg/m2 days 1–2 as 2-hour infusion , q 42 ; for four cycles ; arm B ) . All patients had histologically confirmed gastric carcinoma with nodal positivity or pT3/4 . A total of 166 patients ( 85 in arm A and 81 in arm B ) were treated . Adjuvant treatment was completed in 76 % of the patients in arm A and in 70 % of the patients in arm B. The main grade 3/4 side effects recorded were neutropenia in 35 % , with only 1 febrile patient , and diarrhea in 11 % in arm A , and thrombocytopenia in 10 % and neutropenia in 7 % in arm B. The FOLFIRI regimen and docetaxel/cisplatin given in sequence was well tolerated and feasible in adjuvant setting . This sequence treatment currently represents the experimental arm of an ongoing multicenter trial BACKGROUND Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone . ITACA-S study was design ed to evaluate whether a sequential treatment of FOLFIRI [ irinotecan plus 5-fluorouracil/folinic acid ( 5-FU/LV ) ] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer . PATIENTS AND METHODS Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were r and omly assigned to either FOLFIRI ( irinotecan 180 mg/m(2 ) day 1 , LV 100 mg/m(2 ) as 2 h infusion and 5-FU 400 mg/m(2 ) as bolus , days 1 and 2 followed by 600 mg/m(2)/day as 22 h continuous infusion , q14 for four cycles ) followed by docetaxel 75 mg/m(2 ) day 1 , cisplatin 75 mg/m(2 ) day 1 , q21 for three cycles ( sequential arm ) or De Gramont regimen ( 5-FU/LV arm ) . RESULTS From February 2005 to August 2009 , 1106 patients were enrolled , and 1100 included in the analysis : 562 in the sequential arm and 538 in the 5-FU/LV arm . With a median follow-up of 57.4 months , 581 patients recurred or died ( 297 sequential arm and 284 5-FU/LV arm ) , and 483 died ( 243 and 240 , respectively ) . No statistically significant difference was detected for both disease-free [ hazard ratio ( HR ) 1.00 ; 95 % confidence interval ( CI ) : 0.85 - 1.17 ; P = 0.974 ] and overall survival ( OS ) ( HR 0.98 ; 95 % CI : 0.82 - 1.18 ; P = 0.865 ) . Five-year disease-free and OS rates were 44.6 % and 44.6 % , 51.0 % and 50.6 % in the sequential and 5-FU/LV arm , respectively . CONCLUSIONS A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy . CLINICAL TRIAL REGISTRATION Clinical Trials.gov Identifier : NCT01640782 Objective : The aim of this study was to evaluate the efficacy of adjuvant chemotherapy with etoposide , Adriamycin and cisplatin ( EAP ) after potentially curative resections for gastric cancer . Methods : After surgery , patients were r and omly assigned to the EAP or control arm .  Chemotherapy included 3 courses , administered every 28 days . Each cycle consisted of doxorubicin ( 20 mg/m2 ) on days 1 and 7 , cisplatin ( 40 mg/m2 ) on days 2 and 8 , and etoposide ( 120 mg/m2 ) on days 4 , 5 , and 6 . Results : Of 309 eligible patients , 141 were allocated to chemotherapy and 154 to the supportive care group .  Four ( 2.8 % ) treatment-related deaths were recorded , including 3 due to septic complications of myelosuppression and 1 due to cardiocirculatory failure . Grade 3 or 4 toxicities were found in 17 ( 22 % ) patients . According to the intention-to-treat analysis , the median survival was 41.3 months ( 95 % confidence interval , 24.5–58.2 ) and 35.9 months ( 95 % confidence interval , 25.5–46.3 ) in the chemotherapy and control group , respectively ( p = 0.398 ) . Subgroup analysis revealed survival benefit from chemotherapy in patients with tumors infiltrating the serosa and in those with 7–15 metastatic lymph nodes . Conclusion : Three cycles of EAP regimen postoperatively offer no survival advantage in gastric cancer patients Ninety-six patients with operable epidermoid cancer of the esophagus were entered into a phase III , r and om assignment study design ed to compare the efficacy of two preoperative approaches ( chemotherapy [ CT ] or radiation therapy [ RT ] ) . Major study end points were objective response rates , surgical outcome , and recurrence pattern . Patients were r and omly assigned to receive either two cycles of cisplatin , vindesine , and bleomycin or 55 Gy of radiation before a planned surgical procedure . Postoperative crossover therapy ( radiation to those receiving preoperative CT and vice versa ) was given to patients with T3Nany or unresectable tumors .  Objective response rates of the primary tumor to preoperative therapy were similar ( RT 64 % , CT 55 % ) , as were operability rates ( RT 77 % , CT 75 % ) , resection rates ( RT 65 % , CT 58 % ) , and operative mortality ( RT 13.5 % , CT 11.1 % ) . Significantly higher doses of CT could be administered when CT was given as initial therapy , rather than after RT/surgery . Local failure or persistence occurred in 33 % of operable patients . The median survival for all patients was 11 months ; 20 % remain alive without disease ( median follow-up , 34 months ) . Because of the crossover design , it was not possible to analyze survival according to the preoperative therapy arm alone . This study suggests that since CT is as effective in treating local tumor as RT , but can also potentially treat systemic disease , investigational programs using CT before surgery as part of initial treatment for localized esophageal cancer should continue . However , if a significant impact on overall survival is to be achieved , more effective chemotherapy regimens or schedules need to be identified . Outside of carefully design ed clinical trials , surgery alone or radiation alone remain st and ard therapy Three hundred fifteen patients with operable gastric cancer were r and omized to receive fluorouracil , Adriamycin ( doxorubicin ; Adria Laboratories , Columbus , OH ) , and mitomycin ( FAM ) or no adjuvant treatment between September 1981 and July 1984 . After excluding ineligible patients , 281 patients are included in this analysis . Treatment was moderately well tolerated by the majority of patients , the common side effects being nausea and vomiting ( 58 % ) and alopecia ( 57 % ) . Three possible treatment-related deaths were seen , all due to cardiac failure . At median follow-up of 68 months , 164 patients have died , 73 in the treated arm and 91 in the control arm . There was no significant difference in disease-free or overall survival between the two arms of the study ( P = 0.21 ) . There is some evidence that patients with more advanced carcinoma ( T3-T4 ) derived some benefit from treatment ( P = 0.04 ) . The interpretation of this finding must take into account that all subgroups were defined retrospectively , and this could , therefore , be a chance finding . We conclude that adjuvant chemotherapy as given in this trial is not indicated as routine treatment in operable gastric cancer , but that further evaluation in stage T3-T4 patients is warranted Sophisticated surgical approaches have a definite but limited role in esophageal cancer . The majority have systemic disease at presentation , minimal residual disease following resection or co-morbid conditions that preclude extensive surgery . This paper examines whether neoadjuvant therapy is effective in advanced-stage disease . A r and omized trial , closing September 1995 , was followed up to determine results at 5 years . All patients were followed up for more than 5 years .  Median survival , based on intention-to-treat , was 17 months for multimodal therapy vs. 12 months for surgery alone ( P=0.002 ) . Survival based on treatment received was 27 months vs. 14 months ( P=0.0006 ) . Multimodal therapy  enhances survival for patients with minimal residual disease . This is consistent with the literature . Under-powered trials can not prove a real difference to be significant . Future trials should target patients with minimal residual disease PURPOSE Patients with locally advanced gastric cancer benefit from combined pre- and postoperative chemotherapy , although fewer than 50 % could receive postoperative chemotherapy . We examined the value of purely preoperative chemotherapy in a phase III trial with strict preoperative staging and surgical resection guidelines . PATIENTS AND METHODS Patients with locally advanced adenocarcinoma of the stomach or esophagogastric junction ( AEG II and III ) were r and omly assigned to  preoperative chemotherapy followed by surgery or to surgery alone . To detect with 80 % power an improvement in median survival from 17 months with surgery alone to 24 months with neoadjuvant , 282 events were required . RESULTS This trial was stopped for poor accrual after 144 patients were r and omly assigned ( 72:72 ) ; 52.8 % patients had tumors located in the proximal third of the stomach , including AEG type II and III . The International Union Against Cancer R0 resection rate was 81.9 % after neoadjuvant chemotherapy as compared with 66.7 % with surgery alone ( P = .036 ) . The surgery-only group had more lymph node metastases than the neoadjuvant group ( 76.5 % v 61.4 % ; P = .018 ) . Postoperative complications were more frequent in the neoadjuvant arm ( 27.1 % v 16.2 % ; P = .09 ) . After a median follow-up of 4.4 years and 67 deaths , a survival benefit could not be shown ( hazard ratio , 0.84 ; 95 % CI , 0.52 to 1.35 ; P = .466 ) . CONCLUSION This trial showed a significantly increased R0 resection rate but failed to demonstrate a survival benefit . Possible explanations are low statistical power , a high rate of proximal gastric cancer including AEG and /or a better outcome than expected after radical surgery alone due to the high quality of surgery with resections of regional lymph nodes outside the perigastic area ( celiac trunc , hepatic ligament , lymph node at a. lienalis ; D2 ) BACKGROUND Neoadjuvant therapy improves long-term survival after oesophagectomy , treating oesophageal cancer , but the evidence to date is insufficient to determine which of the two main neoadjuvant therapy types , chemotherapy ( nCT ) or chemoradiotherapy ( nCRT ) , is more beneficial . We aim ed to compare the effects of nCT with those of nCRT . PATIENTS AND METHODS This multicentre trial , which was conducted in Sweden and Norway , recruited 181 patients with carcinoma of the oesophagus or the gastro-oesophageal junction who were c and i date s for curative-intended treatment . The primary end point was histological complete response after neoadjuvant treatment , which has been shown to be correlated with increased long-term survival . Study participants were r and omized to nCT or nCRT  , followed by surgery with two-field lymphadenectomy . Three cycles of platin/5-fluorouracil were administered in both arms , whereas 40 Gy of concomitant radiotherapy was added in the nCRT arm . RESULTS The trial met the primary end point , histological complete response being achieved in 28 % after nCRT versus 9 % after nCT ( P = 0.002 ) . Lymph-node metastases were observed in 62 % in the nCT group versus 35 % in the nCRT group ( P = 0.001 ) . The R0 resection rate was 87 % after nCRT and 74 % after nCT ( P = 0.04 ) . There was no difference in overall survival between the treatment arms . CONCLUSION The addition of radiotherapy to neoadjuvant chemotherapy results in higher histological complete response rate , higher R0 resection rate , and a lower frequency of lymph-node metastases , without significantly affecting survival . CLINICAL TRIALSGOV NCT01362127 ( https:// clinical trials.gov ; The full study protocol was registered in the Clinical Trials Data base ) This study evaluated combined 5‐fluorouracil ( 5FU ) and doxorubicin as postoperative adjuvant chemotherapy for patients who had undergone potentially curative resection of a primary gastric adenocarcinoma . One hundred twenty‐five eligible and evaluable patients were stratified according to extent of surgical resection , location of the primary tumor within the stomach , and lymph node status . They were then r and omized to either receive three cycles of chemotherapy or be observed . The median time from patient entry was 7 years . Results showed no significant difference in time to recurrence . The 5‐year survival rate was 33 % for the observation arm and 32 % for the adjuvant therapy arm . The data excluded a 16 % improvement in the 5‐year survival rate for patients receiving chemotherapy with a P value less than 0.05 . There were two drug‐related fatalities due to sepsis . These results demonstrate no substantive benefit for this chemotherapy regimen as postoperative adjuvant treatment of resected gastric cancer BACKGROUND Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study ( CROSS ) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months ' follow-up . In this Article , we report the long-term results after a minimum follow-up of 5 years . METHODS Patients with clinical ly resectable , locally advanced cancer of the oesophagus or oesophagogastric junction ( clinical stage T1N1M0 or T2 - 3N0 - 1M0 , according to the TNM cancer staging system , sixth edition ) were r and omly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy ( intravenous carboplatin [ AUC 2 mg/mL per min ] and intravenous paclitaxel [ 50 mg/m(2 ) of body-surface area ] for 23 days ) with concurrent radiotherapy ( 41·4 Gy , given in 23 fractions of 1·8 Gy on 5 days per week ) followed by surgery , or surgery alone . The primary endpoint was overall survival , analysed by intention-to-treat . No adverse event data were collected beyond those noted in the initial report of the trial . This trial is registered with the Netherl and s Trial Register , number NTR487 , and has been completed . FINDINGS Between March 30 , 2004 , and Dec 2 , 2008 , 368 patients from eight participating centres ( five academic centres and three large non-academic teaching hospitals ) in the Netherl and s were enrolled into this study and r and omly assigned to the two treatment groups : 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone . Two patients in the neoadjuvant chemoradiotherapy group withdrew consent , so a total of 366 patients were analysed ( 178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group ) . Of 171 patients who received any neoadjuvant chemoradiotherapy  in this group , 162 ( 95 % ) were able to complete the entire neoadjuvant chemoradiotherapy regimen . After a median follow-up for surviving patients of 84·1 months ( range 61·1 - 116·8 , IQR 70·7 - 96·6 ) , median overall survival was 48·6 months ( 95 % CI 32·1 - 65·1 ) in the neoadjuvant chemoradiotherapy plus surgery group and 24·0 months ( 14·2 - 33·7 ) in the surgery alone group ( HR 0·68 [ 95 % CI 0·53 - 0·88 ] ; log-rank p=0·003 ) . Median overall survival for patients with squamous cell carcinomas was 81·6 months ( 95 % CI 47·2 - 116·0 ) in the neoadjuvant chemoradiotherapy plus surgery group and 21·1 months ( 15·4 - 26·7 ) in the surgery alone group ( HR 0·48 [ 95 % CI 0·28 - 0·83 ] ; log-rank p=0·008 ) ; for patients with adenocarcinomas , it was 43·2 months ( 24·9 - 61·4 ) in the neoadjuvant chemoradiotherapy plus surgery group and 27·1 months ( 13·0 - 41·2 ) in the surgery alone group ( HR 0·73 [ 95 % CI 0·55 - 0·98 ] ; log-rank p=0·038 ) . INTERPRETATION Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer . This improvement is clinical ly relevant for both squamous cell carcinoma and adenocarcinoma subtypes . Therefore , neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a st and ard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer . FUNDING Dutch Cancer Foundation ( KWF Kankerbestrijding ) AIMS Gastric cancer in Western countries is often diagnosed in an advanced stage and prognosis is poor . We performed a r and omised trial with pre-operative FAMTX vs. surgery alone in order to evaluate the effect of pre-operative chemotherapy on resectability and survival . METHODS Patients with proven adenocarcinoma of the stomach were r and omised to receive four courses of  chemotherapy using 5-Fluorouracil , doxorubicin and methotrexate ( FAMTX ) prior to surgery or to undergo surgery alone . RESULTS Fifty-nine patients were r and omised ; 29 patients were allocated to the FAMTX regimen prior to surgery and 30 patients had surgery alone . Resectability rates were equal for both groups . Complete or partial response was registered in 32 % of the FAMTX group . With a median follow-up of 83 months the median survival since r and omisation is 18 months in the FAMTX group vs. 30 months in the surgery alone group ( p=0.17 ) . CONCLUSIONS This trial could not show a beneficial effect of pre-operative FAMTX . Until large r and omised studies prove otherwise , adequate surgery without delay is the best treatment for operable gastric cancer One hundred and fifteen patients with curative and palliative surgery for gastric cancer were r and omized to receive radiotherapy alone ( 1 ) or in combination with short-term ( ST ) 5-FU ( 2 ) , long-term ( LT ) 5-FU ( 3 ) , ST and LT 5-FU ( 4 ) . The ST 5-FU was given at a daily dose of 575 mg/m2 , every 4 - 6 h during the first 4 days of treatment before starting irradiation . The LT 5-FU was given at a dosage of 750 mg/m2 every 2 weeks for 18 months or until progression . The median survival times for treatment 1 to 4 was respectively 12 , 10 , 15 and 18 months . There was a statistically significant overall difference between the four treatments ( P = 0.041 ) . However , when the comparisons were adjusted for the most significant prognostic factors , the difference in survival disappeared . Moreover , no difference was found between treatments in terms of time progression . Nevertheless , among 22 patients with residual tumour , the three who were still alive without disease progression ( with survivals of 19 + , 49 + and 90 + months at the time of this analysis ) had been treated with radiotherapy combined with ST and LT 5-FU Purpose To improve the efficacy of adjuvant chemotherapy with mitomycin-C and fluoropyrimidine ( Mf ) in gastric cancer , we design ed a new regimen ( iceMFP ) and investigated in a phase III study . Methods We r and omly assigned 640 patients with resectable and macroscopically recognizable serosa-invading gastric cancer to Mf or iceMFP group during operation . The Mf consisted of intravenous mitomycin-C ( 20 mg/m2 ) at 3–6 weeks after surgery and oral doxifluridine ( 460–600 mg/m2/day ) starting 4 weeks after the administration of mitomycin-C and continuing for 3 months . The iceMFP consisted of intraoperative intraperitoneal cisplatin ( 100 mg ) , intravenous mitomycin-C ( 15 mg/m2 ) on postoperative day 1 , followed by oral doxifluridine for 12 months , and six monthly intravenous cisplatin ( 60 mg/m2 ) . The primary endpoint was 3-year recurrence-free survival ( RFS ) . Results A total of 521 patients ( 258 in Mf , 263 in iceMFP ) were eligible for analysis after excluding patients with stage I disease , distant metastasis , or R1 resection . With a median follow-up of 3.5 years , the iceMFP group had a higher RFS ( hazard ratio [ HR ] 0.70 ; 95 % confidence interval [ CI ] 0.54–0.90 ; p = 0.006 ; 3-year RFS 60 % vs. 50 % ) and overall survival ( HR 0.71 ; 95 % CI 0.53–0.95 ; p = 0.02 ; 3-year overall survival , 71 vs. 60 % ) compared with the Mf group . This was confirmed at extension analysis after a median 6.6 years of follow-up . Both regimens were well tolerated with no differences in surgical complications . Conclusion The efficacy of adjuvant Mf was significantly improved by the additional therapeutic strategies of iceMFP . Considering negative results of AMC0201 , these suggest that early initiation of chemotherapy and /or intraperitoneal cisplatin played a distinct role in the improved efficacy BACKGROUND To study the survival benefit of adjuvant chemotherapy in gastric cancer , seven cancer centres in Japan carried out a phase III clinical trial of adjuvant chemotherapy after curative gastrectomy for macroscopically serosa-negative gastric cancer . METHODS 579 patients were enrolled in the study , stratified by disease stage ( T1 , n=188 ; T2 , n=323 ) , and allocated r and omly adjuvant chemotherapy or no further treatment .  285 of 288 cases in the treatment group and 288 of 291 in the control group were eligible . Six cases were excluded because they did not fulfill the entry criteria . The treatment group had intravenous mitomycin ( 1.4 mg/m2 ) and fluorouracil ( 166.7 mg/m2 ) twice weekly for 3 weeks after surgery , and oral UFT ( uracil plus tegafur , 300 mg daily ) for 18 months . Analyses were by intention to treat . FINDINGS No serious toxic effects were observed in the treatment group . At median follow-up of 72 months , 59 patients in the control group and 47 in the treatment group had died . There was no significant difference in survival between the groups ( 5-year survival 82.9 % control vs 85.8 % treated ; hazard ratio 0.738 [ 95 % CI 0.498 - 1.093 ] ) . 5-year survival of patients with T1 ( mucosal or submucosal ) cancer in the control and treatment groups was 94.9 % versus 92.0 % , and that of patients with T2 ( muscularis propria or subserosa ) cancer was 76.9 % versus 83.0 % . However , a test for heterogeneity and interaction over T1 and T2 subgroups revealed no significant difference in terms of drug response . INTERPRETATION There was no survival benefit with this adjuvant therapy regimen for patients with macroscopically serosa-negative gastric cancer ( T1 and T2 ) after curative gastrectomy . Patients with T1 cancer can be excluded from future trials , because curative surgery alone yielded a very good survival rate and there seemed no need for adjuvant therapy BACKGROUND A regimen of epirubicin , cisplatin , and infused fluorouracil ( ECF ) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma . We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer . METHODS We r and omly assigned patients with resectable adenocarcinoma of the stomach , esophagogastric junction , or lower esophagus to either perioperative chemotherapy and surgery ( 250 patients ) or surgery alone ( 253 patients ) . Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin ( 50 mg per square meter of body-surface area ) and cisplatin ( 60 mg per square meter ) on day 1 , and a continuous intravenous infusion of fluorouracil ( 200 mg per square meter per day ) for 21 days . The primary end point was overall survival . RESULTS  ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer .  Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group ( 46 percent and 45 percent , respectively ) , as were the numbers of deaths within 30 days after surgery . The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group . With a median follow-up of four years , 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died . As compared with the surgery group , the perioperative-chemotherapy group had a higher likelihood of overall survival ( hazard ratio for death , 0.75 ; 95 percent confidence interval , 0.60 to 0.93 ; P=0.009 ; five-year survival rate , 36 percent vs. 23 percent ) and of progression-free survival ( hazard ratio for progression , 0.66 ; 95 percent confidence interval , 0.53 to 0.81 ; P<0.001 ) . CONCLUSIONS In patients with operable gastric or lower esophageal adenocarcinomas , a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival . ( Current Controlled Trials number , IS RCT N93793971 [ controlled-trials.com ] . ) PURPOSE A pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin , fluorouracil , and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution . We design ed a r and omized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone . MATERIAL S AND METHODS One hundred patients with esophageal carcinoma were r and omized to receive either surgery alone ( arm I ) or preoperative chemoradiation ( arm II ) with cisplatin 20 mg/m2/d on days 1 through 5 and 17 through 21 , fluorouracil 300 mg/m2/d on days 1 through 21 , and vinblastine 1 mg/m2/d on days 1 through 4 and 17 through 20 . Radiotherapy consisted of 1.5-Gy fractions twice daily , Monday through Friday over 21 days , to a total dose of 45 Gy . Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42 . RESULTS At median follow-up of 8.2 years , there is no significant difference in survival between the treatment arms . Median survival is 17.6 months in arm I and 16.9 months in arm II . Survival at 3 years was 16 % in arm I and 30 % in arm II ( P = .15 ) . This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years , with at least 80 % power . CONCLUSION This r and omized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference PURPOSE The ARTIST ( Adjuvant Chemoradiation Therapy in Stomach Cancer ) trial was the first study to our knowledge to investigate the role of postoperative chemoradiotherapy therapy in patients with curatively resected gastric cancer with D2 lymph node dissection . This trial was design ed to compare postoperative treatment with capecitabine plus cisplatin ( XP ) versus XP plus radiotherapy with capecitabine ( XP/XRT/XP ) . PATIENTS AND METHODS The XP arm received six cycles of XP ( capecitabine 2,000 mg/m2 per day on days 1 to 14 and cisplatin 60 mg/m2 on day 1 , repeated every 3 weeks ) chemotherapy . The XP/XRT/XP arm received two cycles of XP followed by 45-Gy XRT ( capecitabine 1,650 mg/m2 per day for 5 weeks ) and two cycles of XP . RESULTS Of 458 patients , 228 were r and omly assigned to the XP arm and 230 to the XP/XRT/XP arm . Treatment was completed as planned by 75.4 % of patients ( 172 of 228 ) in the XP arm and 81.7 % ( 188 of 230 ) in the XP/XRT/XP arm . Overall , the addition of XRT to XP chemotherapy did not significantly prolong disease-free survival ( DFS ; P = .0862 ) . However , in the subgroup of patients with pathologic lymph node metastasis at the time of surgery ( n = 396 ) , patients r and omly assigned to the XP/XRT/XP arm experienced superior DFS when compared with those who received XP alone ( P = .0365 ) , and the statistical significance was retained at multivariate analysis ( estimated hazard ratio , 0.6865 ; 95 % CI , 0.4735 to 0.9952 ; P = .0471 ) . CONCLUSION The addition of XRT to XP chemotherapy did not significantly reduce recurrence after curative resection and D2 lymph node dissection in gastric cancer . A subsequent trial ( ARTIST-II ) in patients with lymph node-positive gastric cancer is planned BACKGROUND We performed a multi-institutional r and omized trial comparing preoperative chemotherapy followed by surgery with surgery alone for patients with local and operable esophageal cancer . METHODS Preoperative chemotherapy for patients r and omly assigned to the chemotherapy group included three cycles of cisplatin and fluorouracil . Surgery was performed two to four weeks after the completion of the third cycle ; patients also received two additional cycles of chemotherapy after the operation . Patients r and omly assigned to the immediate-surgery group underwent the same surgical procedure . The main end point was overall survival . RESULTS Of the 440 eligible patients with adequate data , 213 were assigned to receive preoperative chemotherapy and 227 to undergo immediate surgery .  After a median possible study time of 55.4 months , there were no significant differences between the two groups in median survival : 14.9 months for the patients who received preoperative chemotherapy and 16.1 months for those who underwent immediate surgery ( P=0.53 ) . At one year , the survival rate was 59 percent for those who received chemotherapy and 60 percent for those who had surgery alone ; at two years , survival was 35 percent and 37 percent , respectively . The toxic effects of chemotherapy were tolerable , and the addition of chemotherapy did not appear to increase the morbidity or mortality associated with surgery . There were no differences in survival between patients with squamous-cell carcinoma and those with adenocarcinoma .  Weight loss was a significant predictor of poor outcome ( P=0.03 ) . With the addition of chemotherapy , there was no change in the rate of recurrence at locoregional or distant sites . CONCLUSIONS Preoperative chemotherapy with a combination of cisplatin and fluorouracil did not improve overall survival among patients with epidermoid cancer or adenocarcinoma of the esophagus BACKGROUND Resection remains the best treatment for carcinoma of the oesophagus in terms of local control , but local recurrence and distant metastasis remain an issue after surgery . We aim ed to assess whether a short preoperative chemoradiotherapy regimen improves outcomes for patients with resectable oesophageal cancer . METHODS 128 patients were r and omly assigned to surgery alone and 128 patients to surgery  after 80 mg/m(2 ) cisplatin on day 1 , 800 mg/m(2 ) fluorouracil on days 1 - 4 , with concurrent radiotherapy of 35 Gy given in 15 fractions . The primary endpoint was progression-free survival . Secondary endpoints were overall survival , tumour response , toxic effects , patterns of failure , and quality of life . Analysis was done by intention to treat . FINDINGS Neither progression-free survival nor overall survival differed between groups ( hazard ratio [ HR ] 0.82 [ 95 % CI 0.61 - 1.10 ] and 0.89 [ 0.67 - 1.19 ] , respectively ) . The chemoradiotherapy- and -surgery group had more complete resections with clear margins than did the surgery-alone group ( 103 of 128 [ 80 % ] vs 76 of 128 [ 59 % ] , p=0.0002 ) , and had fewer positive lymph nodes ( 44 of 103 [ 43 % ] vs 69 of 103 [ 67 % ] , p=0.003 ) . Subgroup analysis showed that patients with squamous-cell tumours had better progression-free survival with chemoradiotherapy than did those with non-squamous tumours ( HR 0.47 [ 0.25 - 0.86 ] vs 1.02 [ 0.72 - 1.44 ] ) . However , the trial was underpowered to determine the real magnitude of benefit in this subgroup . INTERPRETATION Preoperative chemoradiotherapy with cisplatin and fluorouracil does not significantly improve progression-free or overall survival for patients with resectable oesophageal cancer compared with surgery alone . However , further assessment is warranted of the role of chemoradiotherapy in patients with squamous-cell tumours PURPOSE In a r and omized clinical trial ( European Organization for the Research and Treatment of Cancer [ EORTC ] no. 40813 ) on adjuvant chemotherapy in gastric cancer , results obtained after administration of the FAM2 regimen ( fluorouracil [ 5-FU ] , doxorubicin , and mitomycin ) were compared with results obtained after surgery alone to assess the effect of this regimen on overall survival , time to progression , and disease-free interval . PATIENTS AND METHODS Three hundred fourteen patients who had undergone curative resection for stage II or stage III ( International Union Against Cancer [ UICC ] 1978 ) gastric adenocarcinoma were r and omized to receive chemotherapy ( treatment arm ) or no further treatment ( control arm ) . The chemotherapy schedule was repeated every 43 days for seven cycles . The log-rank test and the Cox model were used for statistical analysis . RESULTS Of 314 patients , 159 comprised the control group and 155 the FAM2 group . Nineteen FAM2 patients never received chemotherapy . The median number of cycles was five . Of the patients started on adjuvant treatment , severe hematologic and nonhematologic toxicity ( grade s 3 or 4 , World Health Organization [ WHO ] scale ) occurred , respectively , in 6 % to 9 % and in 1 % to 29 % of cases . The overall 5-year survival rate was 70 % for stage II and 32 % for stage III patients . No statistically significant difference was found between overall survival of the two treatment arms ( P = .295 ) . However , time to progression was significantly delayed in the FAM2 arm ( P = .020 ) and disease-free survival showed borderline significance ( P = .068 ) . CONCLUSION FAM2 , in view of its high toxicity , can not be advocated as st and ard adjuvant treatment for gastric cancer . Large-scale clinical trials using more active , less toxic regimens are required to demonstrate whether adjuvant chemotherapy provides any real benefit PURPOSE To compare the efficacy and toxicity between 2 regimens [ 5 fluorouracil ( 5-FU ) , leucovorin and etoposide ( ELF ) and 5-FU , leucovorin , cisplatin and epirubicin ( PELF ) ] administered as postoperative adjuvant chemotherapy to patients with completely resected advanced gastric cancer . PATIENTS AND METHODS Between 1998 - 2002 , 78 patients with advanced gastric cancer were r and omly assigned to receive 6 cycles of adjuvant ELF or PELF combination chemotherapy after complete surgical tumor resection . Endpoints were disease-free survival ( DFS ) , overall survival and treatment toxicity . RESULTS ELF was administered to 37 and PELF to 41 patients . Median overall survival was 12.3 months in the ELF group and 17.2 months in the PELF group ( p=0.01 ) , respectively . For the ELF group the median DFS was 17 weeks ( range 7 - 160 weeks ) , while for the PELF group it was 35 weeks ( range 12 - 172 weeks ) ( p=0.0004 ) . Two-year overall survival was 8 % ( 3 patients ) in the ELF group and 24 % ( 10 patients ) in the PELF group ( p=0.03 ) . Grade 2 hematologic toxicity occurred in 21 % ( 8 patients ) in the ELF group and in 22 % ( 9 patients ) in the PELF group ( p=0.5 ) and grade 3 in 29 % ( 11 patients ) in the ELF group and in 24 % ( 10 patients ) in the PELF group ( p=0.2 ) . Grade 2 non-hematologic toxicity was seen in 8 % ( 3 patients ) in the ELF group and in 17 % ( 7 patients ) in the PELF group ( p=0.2 ) . Grade 3 non-hematologic toxicity occurred in 29 % ( 11 patients ) in the ELF group and in 26.8 % ( 11 patients in the PELF group ) ( p=0.2 ) . CONCLUSION PELF combination chemotherapy result ed in DFS and overall survival advantage compared with ELF . No significant differences in hematologic or non-hematologic toxicities between the two groups were registered . PELF is superior to ELF and represents a valid option for the treatment of gastric cancer PURPOSE After curative resection , the prognosis of gastroesophageal adenocarcinoma is poor . This phase III trial was design ed to evaluate the benefit in overall survival ( OS ) of perioperative fluorouracil plus cisplatin in resectable gastroesophageal adenocarcinoma . PATIENTS AND METHODS Overall , 224 patients with resectable adenocarcinoma of the lower esophagus , gastroesophageal junction ( GEJ ) , or stomach were r and omly assigned to either  perioperative chemotherapy and surgery ( CS group ; n = 113 ) or surgery alone ( S group ; n = 111 ) . Chemotherapy consisted of two or three preoperative cycles of intravenous cisplatin ( 100 mg/m(2 ) ) on day 1 , and a continuous intravenous infusion of fluorouracil ( 800 mg/m(2)/d ) for 5 consecutive days ( days 1 to 5 ) every 28 days and three or four postoperative cycles of the same regimen . The primary end point was OS . RESULTS Compared with the S group , the CS group had a better OS ( 5-year rate 38 % v 24 % ; hazard ratio [ HR ] for death : 0.69 ; 95 % CI , 0.50 to 0.95 ; P = .02 ) ; and a better disease-free survival ( 5-year rate : 34 % v 19 % ; HR , 0.65 ; 95 % CI , 0.48 to 0.89 ; P = .003 ) . In the multivariable analysis , the favorable prognostic factors for survival were perioperative chemotherapy ( P = .01 ) and stomach tumor localization ( P < .01 ) . Perioperative chemotherapy significantly improved the curative resection rate ( 84 % v 73 % ; P = .04 ) . Grade 3 to 4 toxicity occurred in 38 % of CS patients ( mainly neutropenia ) but postoperative morbidity was similar in the two groups . CONCLUSION In patients with resectable adenocarcinoma of the lower esophagus , GEJ , or stomach , perioperative chemotherapy using fluorouracil plus cisplatin significantly increased the curative resection rate , disease-free survival , and OS PURPOSE The efficacy of adjuvant chemotherapy in gastric cancer is controversial . We conducted a phase III , r and omized , multicentric clinical trial with the goal of assessing the efficacy of the combination of mitomycin plus tegafur in prolonging the disease-free survival and overall survival of patients with resected stage III gastric cancer . PATIENTS AND METHODS Patients with resected stage III gastric adenocarcinoma were r and omly assigned , using sealed envelopes , to receive either chemotherapy or no further treatment . Chemotherapy was started within 28 days after surgery according to the following schedule : mitomycin 20 mg/m(2 ) intravenously ( bolus ) at day 1 of chemotherapy ; 30 days later , oral tegafur at 400 mg bid daily for 3 months . Disease-free survival and overall survival were estimated using the Kaplan-Meier analysis and the Cox proportional hazards model . RESULTS Between January 1988 and September 1994 , 148 patients from 10 hospitals in Catalonia , Spain , were included in the study . The median follow-up period was 37 months . The tolerability of the treatment was excellent . The overall survival and disease-free survival were higher in the group of patients treated with chemotherapy ( P = .04 for survival and P = .01 for disease-free survival in the log-rank test ) . The overall 5-year survival rate and the 5-year disease-free survival rate were , respectively , 56 % and 51 % in the treatment group and 36 % and 31 % in the control group . CONCLUSION Our positive results are consistent with the results of recent studies ; which conclude that there is a potential benefit from adjuvant chemotherapy in resected gastric cancer To investigate the usefulness of oral doxifluridine ( 5'-DFUR ) , an active intermediate metabolite of capecitabine ( XELODA ) , in gastric cancer patients after curative resection , we conducted a phase III r and omized controlled study to compare oral 5'-DFUR and oral 5-fluorouracil ( 5-FU ) .  485 gastric cancer patients with Stage II or III operative findings at curative resection were registered and administered 5'-DFUR ( 460 mg/m2/day , daily , for two years ) or 5-FU ( 115 mg/m2/day , daily , for the same period ) . Although no differences in overall survival or disease-free survival were detected , subset analysis showed 5'-DFUR was more effective in reducing peritoneal recurrence than 5-FU ( p = 0.047 ) , and in patients with Stage III or stage IIIb ( histologic findings ) in the 5'-DFUR group had more favorable disease-free survival curves and survival curves than the 5-FU group with similar stages PURPOSE The Adjuvant Chemoradiotherapy in Stomach Tumors ( ARTIST ) trial tested whether the addition of radiotherapy to adjuvant chemotherapy improved disease-free survival ( DFS ) in patients with D2-resected gastric cancer ( GC ) . PATIENTS AND METHODS Between November 2004 and April 2008 , 458 patients with GC who received gastrectomy with D2 lymph node dissection were r and omly assigned to either six cycles of adjuvant chemotherapy with capecitabine and cisplatin ( XP ) or to two cycles of XP followed by chemoradiotherapy and then two additional cycles of XP ( XPRT ) . This final up date contains the first publication of overall survival ( OS ) , together with up date d DFS and subset analyses . RESULTS With 7 years of follow-up , DFS remained similar between treatment arms ( hazard ratio [ HR ] , 0.740 ; 95 % CI , 0.520 to 1.050 ; P=.0922 ) . OS also was similar ( HR , 1.130 ; 95 % CI , 0.775 to 1.647 ; P=.5272 ) . The effect of the addition of radiotherapy  on DFS and OS differed by Lauren classification ( interaction P=.04 for DFS ; interaction P=.03 for OS ) and lymph node ratio ( interaction P<.01 for DFS ; interaction P<.01 for OS ) . Subgroup analyses also showed that chemoradiotherapy significantly improved DFS in patients with node-positive disease and with intestinal-type GC . There was a similar trend for DFS and OS by stage of disease . CONCLUSION In D2-resected GC , both adjuvant chemotherapy and chemoradiotherapy are tolerated and equally beneficial in preventing relapse . Because results suggest a significant DFS effect of chemoradiotherapy in subsets of patients , the ARTIST 2 trial evaluating adjuvant chemotherapy and chemoradiotherapy in patients with node-positive , D2-resected GC is under way 411 patients were entered into a prospect i ve , r and omised controlled trial of adjuvant chemotherapy after gastrectomy for adenocarcinoma . After a follow-up of at least 5 1/2 years there has been no survival advantage for those receiving adjuvant 5-fluorouracil and mitomycin C with or without an induction course of 5-fluorouracil , vincristine , cyclophosphamide , and methotrexate compared with those undergoing surgery only . There have been 366  deaths , including 22 from treatment-related conditions . A multivariate analysis of prognostic factors demonstrated that stage of disease , nodal and resection margin involvement , and the presence of residual disease are significant determinants of survival . Weight loss before surgery had a significant independent influence on survival . The combination of preoperative symptoms and intraoperative findings may be used to select patients for radical or palliative procedures OBJECTIVE To evaluate the efficacy of r oxaliplatin plus 5-fluorouracil/leucovorin calcium ( LV ) combined with concurrent radiotherapy in the treatment of local advanced gastric cancer . METHODS 83 patients with local advanced gastric cancer were r and omized into 2 groups . Group I ( n = 40 ) underwent irradiation at the dose of 40 - 45 Gy 5 times a week on the primary tumor and the lymph nodes with the size > or = 10 mm in short axis , and receiving intravenous drip of OXA 85 mg/m2 for 2 h , intravenous injection of LV 200 mg/m2 , and then intravenous injection of 5-fu 300 mg/m2 , followed by continuous intravenous infusion of 5-fu 500 mg/m2 , for 22 h , with 2 weeks as a cycle . Three cycles of chemotherapy were given during the radiotherapy . Then operative evaluation was conducted . Those resectable underwent operation and then 3 cycles of adjuvant chemotherapy . Those un-resectable underwent continuous 3 cycles of chemotherapy . Group II ( n = 43 ) received only chemotherapy . The treatment was repeated until disease progression or prohibitive toxicity . RESULTS 38 patients were evaluated in Group I , the result showed complete remission ( CR ) in 4 patients ( 10.5 % ) , partial remission ( PR ) in 23(60.5 % ) , no-change ( NC ) in 7(18.4 % ) , progressive disease ( PD ) in 5(13.2 % ) , with the remission rate ( RR ) of 71 % ( 27/40 ) . 42 patients were evaluated in Group II , the result showed CR in 3 patients ( 7.14 % ) , PR in 16(14.3 % ) , NC in 13(30.9 % ) , and PD in 9(26.2%)with the RR of 45 % ( 19/43 ) . The resection rates of Groups I and II were 32.5 % and 27.9 % respectively ( P = 0.649 ) . The R0 resection rates of Groups I and II were 77.8 % and 57.1 % respectively ( P = 0.161 ) . The mean survival times of the resectable patients in Groups I and II were 45 months and 28 months respectively , and the 2-year overall survival ( OS ) of the resectable patients in Groups I and II were 65.8 % and 56.3 % respectively ( P = 0.371 ) . The mean survival times of the un-resectable patients in Groups I and II were 14 months and 9 months respectively , and the 2-year OS rates of the un-resectable patients in Groups I and II were 28.3 % and 20.7 % respectively ( P = 0.017 ) . The toxic and adverse effects included gastrointestinal and hematological toxicity . There was no treatment-related death .  CONCLUSION Radiotherapy combined with concurrent chemotherapy may be an effective and well-tolerated regimen in patients with advanced and metastatic gastric cancer BACKGROUND Advanced gastric cancer can respond to S-1 , an oral fluoropyrimidine . We tested S-1 as adjuvant chemotherapy in patients with curatively resected gastric cancer . METHODS Patients in Japan with stage II or III gastric cancer who underwent gastrectomy with extended ( D2 ) lymph-node dissection were r and omly assigned to undergo surgery followed by adjuvant therapy with S-1 or to undergo surgery only . In the S-1 group , administration of S-1 was started within 6 weeks after surgery and continued for 1 year . The treatment regimen consisted of 6-week cycles in which , in principle , 80 mg of oral S-1 per square meter of body-surface area per day was given for 4 weeks and no chemotherapy was given for the following 2 weeks . The primary end point was overall survival . RESULTS We r and omly assigned 529 patients to the S-1 group and 530 patients to the surgery-only group between October 2001 and December 2004 . The trial was stopped on the recommendation of the independent data and safety monitoring committee , because the first interim analysis , performed 1 year after enrollment was completed , showed that the S-1 group had a higher rate of overall survival than the surgery-only group ( P=0.002 ) . Analysis of follow-up data showed that the 3-year overall survival rate was 80.1 % in the S-1 group and 70.1 % in the surgery-only group . The hazard ratio for death in the S-1 group , as compared with the surgery-only group , was 0.68 ( 95 % confidence interval , 0.52 to 0.87 ; P=0.003 ) . Adverse events of grade 3 or grade 4 ( defined according to the Common Toxicity Criteria of the National Cancer Institute ) that were relatively common in the S-1 group were anorexia ( 6.0 % ) , nausea ( 3.7 % ) , and diarrhea ( 3.1 % ) . CONCLUSIONS S-1 is an effective adjuvant treatment for East Asian patients who have undergone a D2 dissection for locally advanced gastric cancer . ( Clinical Trials.gov number , NCT00152217 [ Clinical Trials.gov ] . ) A cooperative , prospect i ve , r and omized study to evaluate the effectiveness of preoperative irradiation in curatively resected esophageal carcinoma was performed in 364 cases in eight institutions from August 1982 to November , 1983 . Based on the survival curves , postoperative irradiation alone was superior to preoperative plus postoperative irradiation . Because of the progression of the disease and complications after operation , there were many inevaluable cases in this study . However , analysis revealed there was no bias caused by a greater number of unfavorable patients being selectively included in inevaluable cases in the postoperative irradiation only group . Our data question the value of preoperative irradiation being performed in addition to resection plus postoperative irradiation METHODS A prospect i ve , r and omized controlled study of radiotherapy  after resection of esophageal carcinoma was carried out in 130 patients . Patients were stratified according to whether the resection was curative or palliative and were then r and omized to receive postoperative radiotherapy or no additional treatment .  Sixty patients underwent curative resection ;  30 each were r and omized into the radiotherapy group ( CR + R ) and the control group ( CR ) . Seventy patients underwent palliative resection ; 35 each were r and omized into the radiotherapy group ( PR + R ) and the control group ( PR ) . RESULTS No complications occurred while the patients were undergoing radiotherapy treatment . On follow-up , complications in the intrathoracic stomach occurred in 24 patients ( 37 % ) who underwent radiotherapy compared with four patients ( 6 % ) in the control group ( p < 0.0001 ) . Seventeen of these 24 patients in the radiotherapy group had gastric ulceration and there were five deaths as a result of bleeding . Local recurrence developed significantly less frequently in the PR + R group compared with the PR group ( seven patients [ 20 % ] vs 16 patients [ 46 % ] ; p = 0.04 ) ; no difference was observed between CR + R and CR groups ( 10 % and 13 % , respectively ) . Intrathoracic recurrence occurred in fewer patients in the radiotherapy groups ( CR + R and PR + R ) compared with the control groups ( CR and PR ) ( four patients vs 15 patients ; p = 0.01 ) . In patients with residual tumor in the mediastinum after resection , two ( 7 % ) of 29 patients who underwent radiotherapy  died of tracheobronchial obstruction , compared with nine ( 33 % ) of 27 patients in the control groups ( p = 0.03 ) . No difference in local recurrence was observed for extrathoracic or anastomotic recurrence . Distant metastasis developed in 12 patients ( 40 % ) in the CR + R group , nine patients ( 30 % ) in the CR group ( p = 0.59 ) , 24 patients ( 69 % ) in the PR + R group , and 18 patients ( 51 % ) in the PR group ( p = 0.22 ) . The time of onset of metastasis was 5.1 months for the PR + R group , which was shorter than the 8.5 months for the PR group ( p = 0.05 ) . The time of onset of metastasis was similar for the CR + R and CR groups ( 9.9 months and 11.0 months , respectively ; p = 0.76 ) . The overall median survival of patients after postoperative radiotherapy ( CR + R and PR + R ) was 8.7 months , which was shorter than the 15.2 months for the control groups ( CR and PR ) ( p = 0.02 ) . CONCLUSIONS The shorter survival of patients who underwent postoperative radiotherapy was the result of irradiation-related death and the early appearance of metastatic diseases . The role of postoperative radiotherapy is therefore limited to a specific group of patients with residual tumor in the mediastinum after operation , for whom radiotherapy can significantly reduce the incidence of local recurrence obstructing the tracheobronchial tree NeoRes I is a r and omized phase II trial comparing neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy in the treatment of resectable cancer of the esophagus or gastroesophageal junction . Patients with biopsy-proven adenocarcinoma or squamous cell carcinoma , T1N1 or T2 - 3N0 - 1 and M0-M1a ( AJCC 6th ed . ) , were r and omized to receive three 3-weekly cycles of cisplatin 100 mg/m2 day 1 and fluorouracil 750 mg/m2/24 hours , days 1 - 5 with or without the addition of concurrent radiotherapy 40 Gy , 2 Gy/fraction , 5 days a week , followed by esophageal resection with two-field lymphadenectomy . Primary endpoint was complete histopathological response rate in the primary tumor . Survival and recurrence patterns were evaluated as secondary endpoints . Between 2006 and 2013 , 181 patients were enrolled in Sweden and Norway . All three chemotherapy cycles were delivered to 73 % of the patients allocated to chemoradiotherapy and to 86 % of the patients allocated to chemotherapy . 87 % of those allocated to chemoradiotherapy received full dose radiotherapy . 87 % in the chemoradiotherapy group and 86 % in the chemotherapy group underwent tumor resection . Initial results showed that patients allocated to chemoradiotherapy more often responded with complete histopathological response in the primary tumor ( 28 % vs. 9 % ) . Treatment-related complications were similar between the groups although postoperative complications were more severe in the chemoradiotherapy group . This article reports the long-term results . Five-year progression-free survival was 38.9 % ( 95 % CI 28.9%-48.8 % ) in the chemoradiotherapy group versus 33.0 % ( 95 % CI 23.6%-42.7 % ) in the chemotherapy group , P = 0.82 . Five-year overall survival was 42.2 % ( 95 % CI 31.9%-52.1 % ) versus 39.6 % ( 95 % CI 29.5%-49.4 % ) , P = 0.60 . There were no differences in recurrence patterns between the treatment groups . This is to our knowledge that the largest completed r and omized trial comparing neoadjuvant chemotherapy with neoadjuvant chemoradiotherapy followed by esophageal resection in patients with cancer in the esophagus or gastroesophageal junction . Despite a higher tumor tissue response in those who received neoadjuvant chemoradiotherapy , no survival advantages were seen . Consequently , the results do not support unselected addition of radiotherapy to neoadjuvant chemotherapy as a st and ard of care in patients with resectable esophageal cancer Objective : To determine the relation between time to surgery ( TTS ) after neoadjuvant chemoradiotherapy ( nCRT ) and pathologically complete response ( pCR ) , surgical outcome , and survival in patients with esophageal cancer . Background : St and ard treatment for potentially curable esophageal cancer is nCRT plus surgery after 4 to 6 weeks . In rectal cancer patients , evidence suggests that prolonged TTS is associated with a higher pCR rate and possibly with better survival . Methods : We identified patients treated with nCRT plus surgery for esophageal cancer between 2001 and 2011 . TTS ( last day of radiotherapy to day of surgery ) varied mainly for logistical reasons . Minimal follow-up was 24 months . The effect of TTS on pCR rate , postoperative complications , and survival was determined with ( ordinal ) logistic , linear , and Cox regression , respectively . Results : In total , 325 patients were included .  Median TTS was 48 days ( p25–p75 = 40–60 ) . After 45 days , TTS was associated with an increased probability of pCR [ odds ratio ( OR ) = 1.35 per additional week of TSS , P = 0.0004 ] and a small increased risk of postoperative complications ( OR = 1.20 , P < 0.001 ) . Prolonged TTS had no effect on disease-free and overall survivals ( HR = 1.00 and HR = 1.06 per additional week of TSS , P = 0.976 and P = 0.139 , respectively ) . Conclusions : Prolonged TTS after nCRT  increases the probability of pCR and is associated with a slightly increased probability of postoperative complications , without affecting disease-free and overall survivals . We conclude that TTS can be safely prolonged from the usual 4 to 6 weeks up to at least 12 weeks , which facilitates a more conservative wait- and -see strategy after neoadjuvant chemoradiotherapy to be tested BACKGROUND Definitive chemoradiotherapy is a curative treatment option for oesophageal carcinoma , especially in patients unsuitable for surgery . The PRODIGE5/ACCORD17 trial aim ed to assess the efficacy and safety of the FOLFOX treatment regimen ( fluorouracil plus leucovorin and oxaliplatin ) versus fluorouracil and cisplatin as part of chemoradiotherapy in patients with localised oesophageal cancer . METHODS We did a multicentre , r and omised , open-label , parallel-group , phase 2/3 trial of patients aged 18 years or older enrolled from 24 centres in France between Oct 15 , 2004 , and Aug 25 , 2011 . Eligible participants had confirmed stage I-IVA oesophageal carcinoma ( adenocarcinoma , squamous-cell , or adenosquamous ) , Eastern Cooperative Oncology Group ( ECOG ) status 0 - 2 , sufficient caloric intake , adequate haematological , renal , and hepatic function , and had been selected to receive definitive chemoradiotherapy . Patients were r and omly assigned ( 1:1 ) to receive either six cycles ( three concomitant to radiotherapy ) of oxaliplatin 85 mg/m(2 ) , leucovorin 200 mg/m(2 ) , bolus fluorouracil 400 mg/m(2 ) , and infusional fluorouracil 1600 mg/m(2 ) ( FOLFOX ) over 46 h , or four cycles ( two concomitant to radiotherapy ) of fluorouracil 1000 mg/m(2 ) per day for 4 days and cisplatin 75 mg/m(2 ) on day 1 . Both groups also received 50 Gy radiotherapy in 25 fractions ( five fractions per week ) . R and om allocation to treatment groups was done by a central computerised r and omisation procedure by minimisation , stratified by centre , histology , weight loss , and ECOG status , and was achieved independently from the study investigators . The primary endpoint was progression-free survival . Data analysis was primarily done by intention to treat . This study is registered with Clinical Trials.gov , number NCT00861094 . FINDINGS 134 participants were r and omly allocated to the FOLFOX group and 133 to the fluorouracil and cisplatin group ( intention-to-treat population ) , and 131 patients in the FOLFOX group and 128 in the fluorouracil and cisplatin group actually received the study drugs ( safety population ) . Median follow-up was 25·3 months ( IQR 15·9 - 36·4 ) . Median progression-free survival was 9·7 months ( 95 % CI 8·1 - 14·5 ) in the FOLFOX group and 9·4 months ( 8·1 - 10·6 ) in the fluorouracil and cisplatin group ( HR 0·93 , 95 % CI 0·70 - 1·24 ; p=0·64 ) . One toxic death occurred in the FOLFOX group and six in the fluorouracil-cisplatin group ( p=0·066 ) . No significant differences were recorded in the rates of most frequent grade 3 or 4 adverse events between the treatment groups . Of all- grade adverse events that occurred in 5 % or more of patients , paraesthesia ( 61 [ 47 % ] events in 131 patients in the FOLFOX group vs three [ 2 % ] in 128 patients in the cisplatin-fluorouracil  group , p<0·0001 ) , sensory neuropathy ( 24 [ 18 % ] vs one [ 1 % ] , p<0·0001 ) , increases in aspartate aminotransferase concentrations ( 14 [ 11 % ] vs two [ 2 % ] , p=0·002 ) , and increases in alanine aminotransferase concentrations ( 11 [ 8 % ] vs two [ 2 % ] , p=0·012 ) were more common in the FOLFOX group , whereas serum creatinine increases ( four [ 3 % ] vs 15 [ 12 % ] , p=0·007 ) , mucositis ( 35 [ 27 % ] vs 41 [ 32 % ] , p=0·011 ) , and alopecia ( two [ 2 % ] vs 12 [ 9 % ] , p=0·005 ) were more common in the fluorouracil and cisplatin group . INTERPRETATION Although chemoradiotherapy with FOLFOX did not increase progression-free survival compared with chemoradiotherapy with fluorouracil and cisplatin , FOLFOX might be a more convenient option for patients with localised oesophageal cancer unsuitable for surgery . FUNDING UNICANCER , French Health Ministry , Sanofi-Aventis , and National League Against Cancer PURPOSE Although often investigated in locally advanced esophageal cancer ( EC ) , the impact of neoadjuvant chemoradiotherapy ( NCRT ) in early stages is unknown . The aim of this multicenter r and omized phase III trial was to assess whether NCRT  improves outcomes for patients with stage I or II EC . METHODS The primary end point was overall survival . Secondary end points were disease-free survival , postoperative morbidity , in-hospital mortality , R0 resection rate , and prognostic factor identification .  From June 2000 to June 2009 , 195 patients in 30 centers were r and omly assigned to surgery alone ( group S ; n = 97 ) or NCRT followed by surgery ( group CRT ; n = 98 ) . CRT protocol was 45 Gy in 25 fractions over 5 weeks with two courses of concomitant chemotherapy composed of fluorouracil 800 mg/m(2 ) and cisplatin 75 mg/m(2 ) . We report the long-term results of the final analysis , after a median follow-up of 93.6 months . RESULTS Pretreatment disease was stage I in 19.0 % , IIA in 53.3 % , and IIB in 27.7 % of patients . For group CRT compared with group S , R0 resection rate was 93.8 % versus 92.1 % ( P = .749 ) , with 3-year overall survival rate of 47.5 % versus 53.0 % ( hazard ratio [ HR ] , 0.99 ; 95 % CI , 0.69 to 1.40 ; P = .94 ) and postoperative mortality rate of 11.1 % versus 3.4 % ( P = .049 ) , respectively . Because interim analysis of the primary end point revealed an improbability of demonstrating the superiority of either treatment arm ( HR , 1.09 ; 95 % CI , 0.75 to 1.59 ; P = .66 ) , the trial was stopped for anticipated futility . CONCLUSION Compared with surgery alone , NCRT with cisplatin plus fluorouracil does not improve R0 resection rate or survival but enhances postoperative mortality in patients with stage I or II EC BACKGROUND The prognosis for stage III gastric cancer is unsatisfactory by D2 gastrectomy and S-1 adjuvant chemotherapy . Both S-1 plus cisplatin ( SC ) and paclitaxel plus cisplatin ( PC ) are promising regimens as neoadjuvant chemotherapy ; however , the optimal duration remains unclear . PATIENTS AND METHODS In this 2 × 2 r and omised phase II trial , stage III gastric cancer patients , those with a prognosis corresponding to stage III , and macroscopically resectable stage IV cases were r and omised to two or four courses of  S-1 ( 80 mg/m(2 ) for 21 d with 1 week rest)/cisplatin ( 60 mg/m(2 ) at day 8) or PC ( 80 and 25 mg/m(2 ) , respectively , on days 1 , 8 , and 15 with 1 week rest ) as neoadjuvant chemotherapy . The primary end-point was the 3-year overall survival ( OS ) . RESULTS Between October 2009 and July 2011 , 83 patients received 2 courses of SC ( n=21 ) , 4 courses of SC ( n=20 ) , 2 courses of PC  ( n=21 ) and 4 courses of PC ( n=21 ) . The 3-year OS was 60.9 % for SC and 64.3 % for PC and 64.3 % for the two courses and 61.0 % for the four courses . Subset analyses demonstrated no subgroup which showed any potential survival benefit  by PC in comparison to SC or by four courses as in comparison to two courses . CONCLUSIONS Two courses of SC as neoadjuvant chemotherapy are recommended as a test arm of a future phase III study for patients with locally advanced gastric cancer . CLINICAL TRIAL NUMBER UMIN-000002595
Background : Currently , preoperative chemoradiotherapy , perioperative chemotherapy and preoperative chemotherapy are recommended by NCCN , ESMO and Japanese guidelines respectively for resectable esophageal and junctional cancer .
However , these recommendations are mainly based on esophageal cancer research .
Therefore , specific for esophagogastric junction cancer , we conducted the first systematic review and network meta- analysis to rank all potential treatments simultaneously and hierarchically .