Atsushi Ohtsu

Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial

BACKGROUND Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. METHODS ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. FINDINGS 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18.6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and 17.1 months (9-25) in the chemotherapy alone group. Median overall survival was 13.8 months (95% CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups. INTERPRETATION Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. FUNDING F Hoffmann-La Roche.

Bevacizumab in Combination With Chemotherapy As First-Line Therapy in Advanced Gastric Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase III Study

PURPOSE The Avastin in Gastric Cancer (AVAGAST) trial was a multinational, randomized, placebo-controlled trial designed to evaluate the efficacy of adding bevacizumab to capecitabine-cisplatin in the first-line treatment of advanced gastric cancer. PATIENTS AND METHODS Patients received bevacizumab 7.5 mg/kg or placebo followed by cisplatin 80 mg/m(2) on day 1 plus capecitabine 1,000 mg/m(2) twice daily for 14 days every 3 weeks. Fluorouracil was permitted in patients unable to take oral medications. Cisplatin was given for six cycles; capecitabine and bevacizumab were administered until disease progression or unacceptable toxicity. The primary end point was overall survival (OS). Log-rank test was used to test the OS difference. RESULTS In all, 774 patients were enrolled; 387 were assigned to each treatment group (intention-to-treat population), and 517 deaths were observed. Median OS was 12.1 months with bevacizumab plus fluoropyrimidine-cisplatin and 10.1 months with placebo plus fluoropyrimidine-cisplatin (hazard ratio 0.87; 95% CI, 0.73 to 1.03; P = .1002). Both median progression-free survival (6.7 v 5.3 months; hazard ratio, 0.80; 95% CI, 0.68 to 0.93; P = .0037) and overall response rate (46.0% v 37.4%; P = .0315) were significantly improved with bevacizumab versus placebo. Preplanned subgroup analyses revealed regional differences in efficacy outcomes. The most common grade 3 to 5 adverse events were neutropenia (35%, bevacizumab plus fluoropyrimidine-cisplatin; 37%, placebo plus fluoropyrimidine-cisplatin), anemia (10% v 14%), and decreased appetite (8% v 11%). No new bevacizumab-related safety signals were identified. CONCLUSION Although AVAGAST did not reach its primary objective, adding bevacizumab to chemotherapy was associated with significant increases in progression-free survival and overall response rate in the first-line treatment of advanced gastric cancer.

Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial

BACKGROUND VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel. METHODS This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase. FINDINGS Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment-330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 months [95% CI 8·5-10·8] vs 7·4 months [95% CI 6·3-8·4], hazard ratio 0·807 [95% CI 0·678-0·962]; p=0·017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%]). INTERPRETATION The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer. FUNDING Eli Lilly and Company.

Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study

BACKGROUND The best chemotherapy regimen for metastatic gastric cancer is uncertain, but promising findings have been reported with irinotecan plus cisplatin and S-1 (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate). We aimed to investigate the superiority of irinotecan plus cisplatin and non-inferiority of S-1 compared with fluorouracil, with respect to overall survival, in patients with metastatic gastric cancer. METHODS We undertook a phase 3 open label randomised trial in 34 institutions in Japan. We enrolled patients aged 20-75 years or younger, who had histologically proven gastric adenocarcinoma, and randomly assigned them by minimisation to receive either: a continuous infusion of fluorouracil (800 mg/m(2) per day, on days 1-5) every 4 weeks (n=234); intravenous irinotecan (70 mg/m(2), on days 1 and 15) and cisplatin (80 mg/m(2), on day 1) every 4 weeks (n=236); or oral S-1 (40 mg/m(2), twice a day, on days 1-28) every 6 weeks (n=234). The primary endpoint was overall survival. Analyses were done by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00142350, and with UMIN-CTR, number C000000062. FINDINGS All randomised patients were included in the primary analysis. Median overall survival was 10.8 months (IQR 5.7-17.8) for individuals assigned fluorouracil, 12.3 months (8.1-19.5) for those allocated irinotecan plus cisplatin (hazard ratio 0.85 [95% CI 0.70-1.04]; p=0.0552), and 11.4 months (6.4-21.3) for those assigned S-1 (0.83 [0.68-1.01]; p=0.0005 for non-inferiority). Three treatment-related deaths occurred in the irinotecan plus cisplatin group and one was recorded in the S-1 group. INTERPRETATION S-1 is non-inferior to fluorouracil and, in view of the convenience of an oral administration, could replace intravenous fluorouracil for treatment of unresectable or recurrent gastric cancer, at least in Asia. Irinotecan plus cisplatin is not superior to fluorouracil in this setting.

Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer : The Japan Clinical Oncology Group Study (JCOG9205)

PURPOSE To compare fluorouracil (FU) alone with FU plus cisplatin (FP) and with uracil and tegafur plus mitomycin (UFTM) for patients with advanced gastric cancer in a prospective, randomized, controlled trial. PATIENTS AND METHODS A total of 280 patients with advanced gastric cancer were randomly allocated and analyzed for survival, response, and toxicity. The survival curves were compared between groups by log-rank test on an intent-to-treat basis. RESULTS At the interim analysis, the UFTM arm showed a significantly inferior survival with higher incidences of hematologic toxic effects than did control arm FU alone, and the registration to UFTM was terminated. Both investigational regimens, FP and UFTM, had a significantly higher incidence of hematologic toxic effects than FU alone, although the effects were manageable. The overall response rates of the FU-alone, FP, and UFTM arms were 11%, 34%, and 9%, respectively. The median progression-free survival was 1.9 months with FU alone, 3.9 months with FP, and 2.4 months with UFTM, respectively. Although FP demonstrated a higher response rate (P <.001) and longer progression-free survival than did FU alone (P <.001), no differences in overall survival were observed between the arms. The median survival times and 1-year survival rates were 7.1 months and 28% with FU, 7.3 months and 29% with FP, and 6.0 months and 16% with UFTM, respectively. CONCLUSION Neither investigational regimen, FP nor UFTM, showed a survival advantage as compared with FU alone. FU alone will remain a reference arm in our future trial for advanced gastric cancer.

Bevacizumab in Combination With Chemotherapy as First-Line Therapy in Advanced Gastric Cancer: A Biomarker Evaluation From the AVAGAST Randomized Phase III Trial

PURPOSE The AVAGAST study showed that adding bevacizumab to chemotherapy in patients with advanced gastric cancer improves progression-free survival and tumor response rate but not overall survival. To examine the hypothesis that angiogenic markers may have predictive value for bevacizumab efficacy in gastric cancer, AVAGAST included a prospective, mandatory biomarker program. PATIENTS AND METHODS Patients with previously untreated, locally advanced or metastatic gastric cancer were randomly assigned to bevacizumab (n = 387) or placebo (n = 387) in combination with chemotherapy. Blood and tumor tissue samples were collected at baseline. Prespecified biomarkers included plasma vascular endothelial growth factor-A (VEGF-A), protein expression of neuropilin-1, and VEGF receptors-1 and -2 (VEGFR-1 and VEGFR-2). Correlations between biomarkers and clinical outcomes were assessed by using a Cox proportional hazards model. RESULTS Plasma was available from 712 patients (92%), and tumor samples were available from 727 patients (94%). Baseline plasma VEGF-A levels and tumor neuropilin-1 expression were identified as potential predictors of bevacizumab efficacy. Patients with high baseline plasma VEGF-A levels showed a trend toward improved overall survival (hazard ratio [HR], 0.72; 95% CI, 0.57 to 0.93) versus patients with low VEGF-A levels (HR, 1.01; 95% CI, 0.77 to 1.31; interaction P = .07). Patients with low baseline expression of neuropilin-1 also showed a trend toward improved overall survival (HR, 0.75; 95% CI, 0.59 to 0.97) versus patients with high neuropilin-1 expression (HR, 1.07; 95% CI, 0.81 to 1.40; interaction P = .06). For both biomarkers, subgroup analyses demonstrated significance only in patients from non-Asian regions. CONCLUSION Plasma VEGF-A and tumor neuropilin-1 are strong biomarker candidates for predicting clinical outcome in patients with advanced gastric cancer treated with bevacizumab.

Definitive chemoradiotherapy for T4 and/or M1 lymph node squamous cell carcinoma of the esophagus.

PURPOSE To investigate the efficacy and feasibility of concurrent chemoradiotherapy for locally advanced carcinoma of the esophagus. PATIENTS AND METHODS Fifty-four patients with clinically T4 and/or M1 lymph node (LYM) squamous cell carcinoma of the esophagus were enrolled. Patients received protracted infusion of fluorouracil 400 mg/m(2)/24 hours on days 1 to 5 and 8 to 12, 2-hour infusion of cisplatin 40 mg/m(2) on days 1 and 8, and concurrent radiation therapy at a dose of 30 Gy in 15 fractions over 3 weeks. Filgrastim was prophylactically administered to 35 patients. This schedule was repeated twice every 5 weeks, for a total radiation dose of 60 Gy, followed by two courses of fluorouracil (800 mg/m(2)/24 hours for 5 days) and cisplatin (80 mg/m(2) on day 1). RESULTS There were 21 patients with T4M0 disease, one with T2M1 LYM, 17 with T3M1 LYM, and 15 withT4M1 LYM. Forty-nine patients (91%) completed at least the chemoradiotherapy segment. The 18 patients (33%) who achieved a complete response included nine (25%) of the 36 with T4 disease and nine (50%) of the 18 with non-T4 disease. Major toxicities were leukocytopenia and esophagitis; there were four (7%) treatment-related deaths. Prophylactic filgrastim reduced the incidence of grade 3 or worse leukopenia without improving dose-intensity or response. With a median follow-up duration of 43 months, median survival time was 9 months. The 3-year survival rate was 23%. CONCLUSION Despite its significant toxicity, this combined modality seemed to have curative potential even in cases of locally advanced carcinoma of the esophagus.

Long-Term Toxicity After Definitive Chemoradiotherapy for Squamous Cell Carcinoma of the Thoracic Esophagus

PURPOSE To assess the long-term toxicity after definitive chemoradiotherapy (CRT) for squamous cell carcinoma (SCC) of the esophagus. PATIENTS AND METHODS Patients newly diagnosed with SCC of the esophagus and treated with definitive CRT between 1992 and 1999 in our institution were recruited from our database on the basis of the following criteria: age </= 75 years, performance status (PS; based on the Eastern Cooperative Oncology Group scale) 0 to 2, and clinical tumor-node-metastasis system stage I to IVA. The CRT consisted of two cycles of cisplatin 40 mg/m2 on days 1 and 8, and continuous infusion of fluorouracil 400 mg/m2/d on days 1 to 5 and 8 to 12, repeated every 5 weeks with concurrent radiotherapy of 60 Gy in 30 fractions. For the assessment of toxicity, the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme was adopted. RESULTS A total of 139 patients were recruited, and their characteristics were as follows: median age, 62 years (range, 38 to 75 years); 121 males and 18 females; 96 patients PS 0, 42 patients PS 1, and one patient PS 2; 15 patients T1, 11 patients T2, 60 patients T3, and 53 patients T4; and 101 patients M0, 38 patients M1a. With a median follow-up of 53 months, the median survival time and 5-year survival rate were 21 months and 29%, respectively. Of 78 patients with complete remission, two patients died as a result of acute myocardial infarction. Grade 2, 3, and 4 late toxicities occurred with the following incidences: pericarditis in eight patients, seven patients, and one patient, respectively; heart failure in zero, zero, and two patients; pleural effusion in seven, eight, and zero patients; and radiation pneumonitis in one patient, three patients, and zero patients, respectively. CONCLUSION Definitive CRT for SCC of the esophagus is effective with substantial toxicities. Additional investigation to minimize the normal tissue toxicities is warranted.

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

BACKGROUND Early clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the treatment of refractory colorectal cancer. We conducted a phase 3 trial to further assess the efficacy and safety of TAS-102 in a global population of such patients. METHODS In this double-blind study, we randomly assigned 800 patients, in a 2:1 ratio, to receive TAS-102 or placebo. The primary end point was overall survival. RESULTS The median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the hazard ratio for death in the TAS-102 group versus the placebo group was 0.68 (95% confidence interval [CI], 0.58 to 0.81; P<0.001). The most frequently observed clinically significant adverse events associated with TAS-102 were neutropenia, which occurred in 38% of those treated, and leukopenia, which occurred in 21%; 4% of the patients who received TAS-102 had febrile neutropenia, and one death related to TAS-102 was reported. The median time to worsening performance status (a change in Eastern Cooperative Oncology Group performance status [on a scale of 0 to 5, with 0 indicating no symptoms and higher numbers indicating increasing degrees of disability] from 0 or 1 to 2 or more) was 5.7 months with TAS-102 versus 4.0 months with placebo (hazard ratio, 0.66; 95% CI, 0.56 to 0.78; P<0.001). CONCLUSIONS In patients with refractory colorectal cancer, TAS-102, as compared with placebo, was associated with a significant improvement in overall survival. (Funded by Taiho Oncology-Taiho Pharmaceutical; RECOURSE ClinicalTrials.gov number, NCT01607957.).

Phase II Study of a Combination of Irinotecan and Cisplatin Against Metastatic Gastric Cancer

PURPOSE A phase II study of a combination chemotherapy regimen of cisplatin (CDDP) and irinotecan (CPT-11) was conducted to assess its efficacy and feasibility in patients with metastatic gastric cancer. PATIENTS AND METHODS Eligibility criteria included the following: (1) histologically proven gastric cancer with measurable metastatic lesions, (2) performance status of 2 or less, (3) age of 75 years or younger, (4) one or no prior chemotherapy regimens, (5) adequate bone marrow, liver, renal, and cardiac functions, and (6) written informed consent. The treatment consisted of CPT-11 (70 mg/m2) on day 1 and day 15 and CDDP (80 mg/m2) on day 1, repeated every 4 weeks. RESULTS Forty-four patients were entered onto the study. The overall response rate was 48% (21 of 44 patients, 95% confidence interval [CI], 33% to 63%) and included one complete remission (2%). The response rate of the patients who had not received prior chemotherapy was 59% (17 of 29 patients, 95% CI, 39% to 77%). The median survival time was 272 days for all patients and 322 days for the 29 patients who had not received prior chemotherapy. Grade 4 neutropenia was observed in 25 patients (57%), and grade 3 or 4 diarrhea was observed in nine patients (20%). Other adverse reactions were mild. No treatment-related deaths occurred. CONCLUSION This combination chemotherapy regimen is active and well tolerated. It may be an appropriate regimen for future phase III trials.