Shuichi Hironaka

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.

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, Open-Label, Phase III Study Comparing Irinotecan With Paclitaxel in Patients With Advanced Gastric Cancer Without Severe Peritoneal Metastasis After Failure of Prior Combination Chemotherapy Using Fluoropyrimidine Plus Platinum: WJOG 4007 Trial

PURPOSE This phase III study compared treatment with weekly paclitaxel and biweekly irinotecan in patients with advanced gastric cancer refractory to treatment with fluoropyrimidine plus platinum. PATIENTS AND METHODS Patients were randomly assigned to receive either paclitaxel (80 mg/m(2) on days 1, 8, and 15, every 4 weeks) or irinotecan (150 mg/m(2) on days 1 and 15, every 4 weeks). Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, adverse events, and proportion of patients who received third-line chemotherapy. RESULTS Of 223 patients, 219 were eligible for analysis. Median OS was 9.5 months in 108 patients allocated to the paclitaxel group and 8.4 months in 111 patients allocated to the irinotecan group (hazard ratio [HR], 1.13; 95% CI, 0.86 to 1.49; P = .38). Median PFS was 3.6 months in the paclitaxel group and 2.3 months in the irinotecan group (HR, 1.14; 95% CI, 0.88 to 1.49; P = .33). Response rate was 20.9% in the paclitaxel group and 13.6% in the irinotecan group (P = .24). Common grade 3 to 4 adverse events were neutropenia (paclitaxel group, 28.7%; irinotecan group, 39.1%), anemia (21.3%; 30.0%), and anorexia (7.4%; 17.3%). Treatment-related deaths occurred in two patients (1.8%) in the irinotecan group. Third-line chemotherapy was administered in 97 patients (89.8%) after paclitaxel treatment and in 80 patients (72.1%) after irinotecan treatment (P = .001). CONCLUSION No statistically significant difference was observed between paclitaxel and irinotecan for OS. Both are reasonable second-line treatment options for advanced gastric cancer.

Nonrandomized comparison between definitive chemoradiotherapy and radical surgery in patients with T2–3Nany M0 squamous cell carcinoma of the esophagus

PURPOSE To compare the treatment results between radical surgery and definitive chemoradiotherapy for resectable squamous cell carcinoma of the esophagus and to identify useful clinicopathologic and biologic markers to select better treatment. METHODS AND MATERIALS Between August 1992 and April 1999, 98 consecutive patients were selected for this study; 53 were treated with chemoradiotherapy and 45 with surgery. The patients in the chemoradiotherapy group received 5-fluorouracil combined with cisplatin plus 60 Gy of radiation, and those in the surgery group received an esophagectomy with radical node dissection. Biologic markers were investigated immunohistochemically using pretreatment biopsy specimens. RESULTS The baseline clinical TNM stage was more advanced in the chemoradiotherapy group than in the surgery group. With a median follow-up period of 43 months, the 5-year survival rate was 46% in the chemoradiotherapy and 51% in the surgery group, without statistical significance (p = 0.47, log-rank test). Cox regression analysis for prognosis revealed that epidermal growth factor receptor positivity, high microvessel density, and cyclin D1 positivity yielded a low value for relative risk (0.66, 0.54, and 0.62, respectively), which favored chemoradiotherapy over surgery, without statistical significance. CONCLUSION This nonrandomized study showed a trend for the chemoradiotherapy in the treatment of esophageal carcinoma, but the results need to be confirmed by additional study.

Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer

BACKGROUND We evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC). PATIENTS AND METHODS In this randomized, open-label, multicenter phase III study, patients were randomly assigned to receive SOX (80-120mg/day S-1 for 2 weeks with 100mg/m2 oxaliplatin on day 1, every 3 weeks) or CS (S-1 for 3 weeks with 60mg/m2 cisplatin on day 8, every 5 weeks). The primary end points were noninferiority in progression-free survival (PFS) and relative efficacy in overall survival (OS) for SOX using adjusted hazard ratios (HRs) with stratification factors; performance status and unresectable or recurrent (+adjuvant chemotherapy) disease. RESULTS Overall, 685 patients were randomized from January 2010 to October 2011. In per-protocol population, SOX (n = 318) was noninferior to CS (n = 324) in PFS [median, 5.5 versus 5.4 months; HR 1.004, 95% confidence interval (CI) 0.840-1.199; predefined noninferiority margin 1.30]. The median OS for SOX and CS were 14.1 and 13.1 months, respectively (HR 0.958 with 95% CI 0.803-1.142). In the intention-to-treat population (SOX, n = 339; CS, n = 337), the HRs in PFS and OS were 0.979 (95% CI 0.821-1.167) and 0.934 (95% CI 0.786-1.108), respectively. The most common ≥grade 3 adverse events (SOX versus CS) were neutropenia (19.5% versus 41.8%), anemia (15.1% versus 32.5%), hyponatremia (4.4% versus 13.4%), febrile neutropenia (0.9% versus 6.9%), and sensory neuropathy (4.7% versus 0%). CONCLUSION SOX is as effective as CS for AGC with favorable safety profile, therefore SOX can replace CS. CLINICAL TRIAL NUMBER JapicCTI-101021.BACKGROUND We evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC). PATIENTS AND METHODS In this randomized, open-label, multicenter phase III study, patients were randomly assigned to receive SOX (80-120 mg/day S-1 for 2 weeks with 100 mg/m(2) oxaliplatin on day 1, every 3 weeks) or CS (S-1 for 3 weeks with 60 mg/m(2) cisplatin on day 8, every 5 weeks). The primary end points were noninferiority in progression-free survival (PFS) and relative efficacy in overall survival (OS) for SOX using adjusted hazard ratios (HRs) with stratification factors; performance status and unresectable or recurrent (+adjuvant chemotherapy) disease. RESULTS Overall, 685 patients were randomized from January 2010 to October 2011. In per-protocol population, SOX (n = 318) was noninferior to CS (n = 324) in PFS [median, 5.5 versus 5.4 months; HR 1.004, 95% confidence interval (CI) 0.840-1.199; predefined noninferiority margin 1.30]. The median OS for SOX and CS were 14.1 and 13.1 months, respectively (HR 0.958 with 95% CI 0.803-1.142). In the intention-to-treat population (SOX, n = 339; CS, n = 337), the HRs in PFS and OS were 0.979 (95% CI 0.821-1.167) and 0.934 (95% CI 0.786-1.108), respectively. The most common ≥grade 3 adverse events (SOX versus CS) were neutropenia (19.5% versus 41.8%), anemia (15.1% versus 32.5%), hyponatremia (4.4% versus 13.4%), febrile neutropenia (0.9% versus 6.9%), and sensory neuropathy (4.7% versus 0%). CONCLUSION SOX is as effective as CS for AGC with favorable safety profile, therefore SOX can replace CS. CLINICAL TRIAL NUMBER JapicCTI-101021.

Weekly paclitaxel as second-line chemotherapy for advanced or recurrent gastric cancer

BackgroundPaclitaxel scheduled every 3 weeks has shown a response rate of ∼20% for gastric cancer, with modest hematological toxicity. Weekly administration of paclitaxel in patients with breast or ovarian cancer has shown equivalent efficacy and milder toxicity compared with an every-3 week schedule. We investigated, retrospectively, the antitumor effects and toxicity profiles of weekly paclitaxel for patients with metastatic or recurrent gastric cancer in clinical practice.MethodsIn 38 patients who had metastatic or recurrent histologically confirmed gastric cancer and a history of one prior chemotherapy regimen, other than paclitaxel or docetaxel, paclitaxel (8mg/m2) was administered weekly, three times every 4 weeks, with short-term premedication.ResultsAll 38 patients had had prior chemotherapy that included 5-fluorouracil, the fluoropyrimidine anticancer drug S-1, or cisplatin. The median number of courses in the present regimen was 6 (range, 1–44+). Dose intensity was 5mg/m2 per week, corresponding to 92% of the planned dose (6mg/m2 per week). The overall response rate was 24% (6/25) in measurable lesions, and pleural effusion and ascites disappeared in 2 of 7 patients (29%) and in 3 of 21 patients (14%), respectively. Median survival time was 151 days from the commencement of this treatment, with a median follow-up period of 260 days. Grade 3 or 4 leukopenia and neutropenia were observed in 11 (29%) and 12 (32%) patients, respectively. Seven patients (18%) died within 30 days of the last administration of paclitaxel.ConclusionWeekly paclitaxel seems to be active as second-line chemotherapy against metastatic and recurrent gastric cancer. Further study is needed to confirm the efficacy and safety of weekly paclitaxel.

Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours

Background:TAS-102 consists of α, α, α-trifluorothymidine (TFT) and an inhibitor of thymidine phosphorylase (TPI). We conducted a dose-escalation phase I study in Japanese patients with advanced solid tumours.Methods:TAS-102 was administered twice daily on days 1–5 and days 8–12 in a 28-day cycle to patients with solid tumours refractory to standard chemotherapy, to determine its maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). MTD was evaluated in cycle 1.Results:Safety and PKs were evaluated in 21 patients treated with TAS-102 at 30, 40, 50, 60, or 70 mg m−2 per day. DLTs, such as grade 4 leucopenia, grade 4 neutropenia, and grade 4 thrombocytopenia, were observed in two patients at doses of 30 and 70 mg m−2. α, α, α-trifluorothymidine and TPI exposures increased dose dependently, and the percentage of decrease in neutrophil count and TFT exposure were significantly correlated. The disease control rate was 50.0% with a median progression-free survival of 2.4 months in 18 colorectal cancer patients. The dose of TAS-102 was not increased above 70 mg m−2 per day because of the increased tendency for grade 3 and 4 neutropenia, and 70 mg m−2 per day was the recommended dose for phase II studies.Conclusions:TAS-102 at 70 mg m−2 per day was tolerated in Japanese patients with advanced solid tumours. Phase II studies are ongoing in patients with colorectal cancer.

Three-arm Phase III Trial Comparing Cisplatin Plus 5-FU (CF) Versus Docetaxel, Cisplatin Plus 5-FU (DCF) Versus Radiotherapy with CF (CF-RT) as Preoperative Therapy for Locally Advanced Esophageal Cancer (JCOG1109, NExT Study)

A three-arm Phase III trial was started in November 2012. Preoperative chemotherapy with cisplatin plus 5-fluorouracil is the current standard treatment for locally advanced esophageal cancer in Japan, while preoperative chemoradiotherapy with cisplatin plus 5-fluorouracil is the standard in Western countries. Preoperative chemotherapy with docetaxel, cisplatin plus 5-fluorouracil is another promising regimen. The purpose of this study is to confirm the superiority of docetaxel, cisplatin plus 5-fluorouracil over cisplatin plus 5-fluorouracil and the superiority of cisplatin plus 5-fluorouracil with chemoradiotherapy over cisplatin plus 5-fluorouracil as preoperative therapy for squamous cell carcinoma of esophagus. A total of 501 patients will be accrued from 41 Japanese institutions within 6.25 years. The primary endpoint is overall survival and the secondary endpoints include progression-free survival, %R0 resection, response rate, pathologic complete response rate and adverse events.

Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial

BACKGROUND Nivolumab is a human monoclonal IgG4 antibody that inhibits programmed cell death protein 1 (PD-1) expressed on activated T cells. We investigated the safety and activity of nivolumab in patients with treatment-refractory oesophageal cancer. METHODS We did an open-label, single-arm, multicentre phase 2 study. Eligible patients had advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. Patients were treated with 3 mg/kg nivolumab given intravenously once every 2 weeks in 6-week cycles. The primary endpoint was centrally assessed objective response (the proportion of patients whose best response was complete or partial response), according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Adverse events and treatment-related adverse events (defined as events for which a causal relation to nivolumab could not be ruled out) were monitored throughout the study. The safety analysis was done in patients who received at least one dose of nivolumab, and drug activity was assessed in patients who received at least one dose of nivolumab and had at least one central assessment of tumour response. This study is registered with clinicaltrials.jp, number ONO-4538-07/JapicCTI-No.142422. Follow-up of patients is ongoing. FINDINGS Between Feb 25 and Nov 14, 2014, 65 patients were enrolled, all with squamous-cell carcinoma. 64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers; all patients were assessable for safety. Median follow-up was 10·8 months (IQR 4·9-14·3). 11 (17%, 95% CI 10-28) of 64 patients had a centrally assessed objective response. Of the 65 patients assessed for adverse events, the most common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one [2%) patient each), grade 3 lung infection (five [8%] patients), grade 3 decreased appetite (two [3%] patients), grade 3 increased blood creatinine phosphokinase (two [3%] patients), and grade 3 dehydration (two [3%] patients). Serious adverse events that occurred during the study were lung infection (four [6%] patients), dehydration (two [3%]), interstitial lung disease (two [3%]), and hyponatraemia, dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis, gastroenteritis, pneumonia, oedema, and back pain (one [2%] patient each). There were no treatment-related deaths. INTERPRETATION Nivolumab showed promising activity with a manageable safety profile. This drug could offer a potential new treatment approach for patients with treatment-refractory advanced squamous-cell carcinoma. FUNDING Ono Pharmaceutical, Bristol-Myers Squibb.

Analysis of dose-volume histogram parameters for radiation pneumonitis after definitive concurrent chemoradiotherapy for esophageal cancer

PURPOSE To evaluate dose-volume histogram (DVH) parameters as predictors of radiation pneumonitis (RP) in esophageal cancer patients treated with definitive concurrent chemoradiotherapy. PATIENTS AND METHODS Thirty-seven esophageal cancer patients treated with radiotherapy with concomitant chemotherapy consisting of 5-fluorouracil and cisplatin were reviewed. Radiotherapy was delivered at 2 Gy per fraction to a total of 60 Gy. For most of the patients, two weeks of interruption was scheduled after 30 Gy. The percentage of lung volume receiving more than 5-50 Gy in increments of 5 Gy (V5-V50, respectively), and the mean lung dose (MLD) were analyzed. RESULTS Ten (27%) patients developed RP of grade 2; 2 (5%), grade 3; 0 (0%), grade 4; and 1 (3%), grade 5. By univariate analysis, all DVH parameters (i.e., V5-V50 and MLD) were significantly associated with grade 2 RP (p < 0.01). The incidences of grade 2 RP were 13%, 33%, and 78% in patients with V20s of 24%, 25-36%, and 37%, respectively. The optimal V20 threshold to predict symptomatic RP was 30.5% according to the receiver operating characteristics curve analysis. CONCLUSION DVH parameters were predictors of symptomatic RP and should be considered in the evaluation of treatment planning for esophageal cancer.