A phase II study of combination therapy with oral S-1 and cisplatin in elderly patients with advanced gastric cancer.

BACKGROUND: A combination of S-1 and cisplatin is recognized as one of the standard first-line chemotherapy regimens for patients with advanced gastric cancer. However, demographic analyses of pivotal phase III studies have showed that only a minority of treated patients were aged 76 years or older. The purpose of this phase II study was to evaluate the safety and efficacy of combination therapy with S-1 and cisplatin in elderly patients with chemotherapy-naive advanced gastric cancer. METHODS: Patients aged 76 years or older received S-1 40 mg/m2 orally twice daily for 21 days and cisplatin 60 mg/m2 intravenously infused at day 8 of each 35-day cycle. Dose modification was performed according to creatinine clearance. The primary endpoint was overall survival (OS). Secondary endpoints included response rate, progression-free survival (PFS), time to treatment failure (TTF), and adverse events. RESULTS: A total of 40 patients were enrolled. Median OS was 12.3 months, PFS was 7.8 months, and TTF was 4.3 months. The response rate was 54%. The most common grade 3-4 adverse events were anorexia (25%), neutropenia (23%), hyponatremia (20%), anemia (18%), and febrile neutropenia (8%). No treatment-related death occurred. CONCLUSIONS: Combination chemotherapy with S-1 and cisplatin is an effective and well-tolerated regimen for elderly patients with advanced gastric cancer when the dose is adjusted according to renal function.

Phase II study of chemoselection with docetaxel plus cisplatin and 5-fluorouracil induction chemotherapy and subsequent conversion surgery for locally advanced unresectable oesophageal cancer.

BACKGROUND: The standard treatment for locally advanced unresectable squamous cell carcinoma (SCC) of the oesophagus is chemoradiation with cisplatin and 5-fluorouracil (CF-RT). This multicentre phase II trial assessed the safety and efficacy of chemoselection with docetaxel plus cisplatin and 5-fluorouracil (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for initially unresectable locally advanced SCC of the oesophagus. METHODS: Patients with clinical T4 and/or unresectable supraclavicular lymph node metastasis were eligible. Treatment started with three cycles of DCF-ICT, followed by CS if resectable, or by CF-RT if unresectable. The resectability was re-evaluated at 30-40 Gy of CF-RT, followed by CS if resectable, or by completion of 60 Gy of CF-RT. If resectable after CF-RT, CS was performed. The primary end point was 1-year overall survival (OS). RESULTS: From April 2013 to July 2014, 48 patients were enrolled. CS was performed in 41.7% (n=20), including DCF-CS (n=18), DCF-CF-RT40Gy-CS (n=1), and DCF-CF-RT60Gy-CS (n=1). R0 resection was confirmed in 19 patients (39.6%). Grade ⩾3 postoperative complications included one event each of recurrent laryngeal nerve palsy, lung infection, wound infection, pulmonary fistula, and dysphagia; but no serious postoperative complications were observed in patients undergoing CS. Clinical complete response after CF-RT was confirmed in 4 patients (8.3%). The estimated 1-year OS was 67.9% and lower limit of 80% confidence interval was 59.7%. There was one treatment-related death in patient receiving DCF-CF-RT60Gy. CONCLUSIONS: Chemoselection with DCF-ICT followed by CS as a multidisciplinary treatment strategy showed promising signs of tolerability and efficacy in patients with locally advanced unresectable SCC of the oesophagus.

Phase II study of bolus 5-fluorouracil and leucovorin combined with weekly paclitaxel as first-line therapy for advanced gastric cancer.

OBJECTIVE: We evaluated the efficacy and safety of bolus 5-fluorouracil (5-FU) and leucovorin combined with weekly paclitaxel (FLTAX) in advanced gastric cancer (GC) patients. METHODS: Patients with untreated stage IV GC received paclitaxel 80 mg/m(2) as a 1-hour infusion, followed by 5-FU 600 mg/m(2) as a bolus infusion and L-leucovorin 250 mg/m(2) as a 2-hour infusion on days 1, 8 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was response rate. RESULTS: Thirty-five patients were enrolled. The median age was 62 years (range 34-75). Twenty-one patients (60%) had diffuse-type cancer and 11 had peritoneal metastasis. The confirmed response rate was 43% (95% CI 26-61) with 15 partial responses. Stable disease was observed in 16 (46%) patients. Median progression-free survival and overall survival were 6.8 months (95% CI 5.8-7.4) and 16.2 months (95% CI 10.0-22.8), respectively. Grade 3-4 adverse events were: neutropenia (54%), febrile neutropenia (3%), diarrhea (6%) and sensory neuropathy (11%). CONCLUSION: FLTAX showed a desirable safety profile, and the efficacy against advanced GC was encouraging. FLTAX may be a good option for GC patients with deteriorated general condition, and a randomized clinical trial in such patients is currently underway.

Middle-term prognosis in patients with ulcerative colitis who achieved clinical and endoscopic remission by budesonide rectal foam.

BACKGROUND: Budesonide foam is effective in inducing clinical remission in ulcerative colitis (UC) patients with active proctosigmoiditis. The aim of this study was to evaluate the duration of remission and predictors of relapse in UC patients who achieved clinical remission and mucosal healing by 6-week treatment with topical budesonide. METHODS: This is a retrospective, observational, multicenter study with a 2-year follow-up period. UC patients who were treated with budesonide foam in phase 2 or phase 3 clinical trials and achieved both clinical remission and mucosal healing were enrolled. RESULTS: Among 84 patients who met the eligibility criteria, 60 participated in the study. Eighteen of the 60 patients (30.0%; 95% confidence interval [CI]: 18.9-43.2) experienced no relapse (i.e., maintenance of remission) during the 2-year follow-up period. The median relapse-free survival time was 0.82 years (95% CI: 0.51-1.52). Of 37 patients with a Mayo endoscopic subscore of 0 after inducing remission with budesonide foam, 25 (67.6%) relapsed within 2 years. Patients with a disease duration of <1 year experienced a worse clinical outcome than patients with a disease duration of >5 years, and the hazard ratio was 2.38 (95% CI: 1.04-5.45). CONCLUSION: This is the first study to evaluate the short- to middle-term prognosis in UC patients who achieved mucosal healing with topical preparations. After inducing remission by budesonide foam, treatment for maintaining remissions and strict follow-up may be needed for patients with shorter disease duration.

A Prospective, Multicenter Phase II Study of the Efficacy and Feasibility of 15-minute Panitumumab Infusion Plus Irinotecan for Oxaliplatin- and Irinotecan-refractory, KRAS Wild-type Metastatic Colorectal Cancer (Short Infusion of Panitumumab Trial).

BACKGROUND: In some recently updated clinical guidelines, the fully humanized monoclonal antibody panitumumab, combined with irinotecan, has been recommended as an optional third-line chemotherapy for KRAS wild-type metastatic colorectal cancer (mCRC). The present prospective, multicenter phase II study evaluated the effectiveness and safety of short 15-minute panitumumab infusions. PATIENTS AND METHODS: From January 2011 to December 2011, patients with KRAS wild-type mCRC were enrolled at 8 centers. The key eligibility criteria were age ≥ 20 years and resistance or intolerance to irinotecan, fluoropyrimidine, and oxaliplatin. All patients received 6 mg/kg of panitumumab and 150 mg/m2 or the previous tolerated dose of irinotecan, biweekly, until disease progression or unacceptable toxicity. The initial panitumumab infusion was 60 minutes, followed by a 30-minute infusion and then 15-minute infusions. The primary endpoint was the confirmed response rate using Response Evaluation Criteria In Solid Tumors, version 1.0. The secondary endpoints were progression-free survival, overall survival, and toxicity. The trial is registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN no. 000004647). RESULTS: Of the 43 patients, the median age was 62 years (range, 32-75 years), 58% were male, and the Eastern Cooperative Oncology Group performance status was 0 to 1. The total response rate was 37.2% (95% confidence interval [CI], 23.0-53.3), and the confirmed response rate was 18.6% (95% CI, 8.4-33.4). The median progression-free and overall survival were 5.8 months (95% CI, 3.3-8.4 months) and 13.6 months (95% CI, 10.8-16.5 months), respectively. The most frequent grade 3/4 toxicities were anorexia (12%), leukopenia (9%), and neutropenia (9%). Nine patients did not reach the 15-minute infusion, primarily because of disease progression. No infusion-related reactions were observed. CONCLUSION: The short 15-minute panitumumab infusion regimen was well tolerated, without compromising safety or efficacy in patients with KRAS wild-type, oxaliplatin- and irinotecan-refractory mCRC.

Value of KRAS, BRAF, and PIK3CA Mutations and Survival Benefit from Systemic Chemotherapy in Colorectal Peritoneal Carcinomatosis.

BACKGROUND: It is well known that peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is associated with a poor prognosis. However, data on the prognostic significance of modern chemotherapy containing bevacizumab, cetuximab or panitumumab are not available. MATERIALS AND METHODS: This retrospective review concerned 526 patients with metastatic CRC who were classified into two groups according to the presence or absence of PC, and were treated with systemic chemotherapy, with or without bevacizumab or anti-EGFR antibodies. The genetic background, in particular KRAS, BRAF, and PIK3CA gene mutations, and overall survival (OS) were compared between the two groups. RESULTS: The median OS values were 23.3 and 29.1 months for PC and non-PC patients, respectively (hazard ratio [HR]=1.20; p=0.17). Among all patients, tumor location, number of metastatic sites and BRAF mutation status were significant prognostic factors, whereas the presence of PC was not. In the PC group, chemotherapy with bevacizumab resulted in a significantly longer OS than forchemotherapy without bevacizumab (HR=0.38, p<0.01), but this was not the case in the non-PC group (HR=0.80, p=0.10). Furthermore, the incidence of the BRAF V600E mutation was significantly higher in PC than in non-PC patients (27.7% versus 7.3%, p<0.01). BRAF mutations displayed a strong correlation with shorter OS in non-PC (HR=2.26), but not PC patients (HR=1.04). CONCLUSIONS: Systemic chemotherapy, especially when combined with bevacizumab, improved survival in patients with PC from CRC as well as non-PC patients. While BRAF mutation demonstrated a high frequency in PC patients, but it was not associated with prognosis.