The local renin-angiotensin system promotes angiogenesis and vascular proliferation via expression of vascular endothelial growth factor or epidermal growth factor receptor. We hypothesized that angiotensin II type-1 receptor blockers (ARBs) in combination with bevacizumab (Bev) may improve clinical outcomes in patients with metastatic colorectal cancer (mCRC). A total of 181 patients with histopathologically confirmed mCRC treated with first-line oxaliplatin-based chemotherapy in combination with Bev were enrolled between June, 2007 and September, 2010. The patients were divided into two groups based on the presence or absence of treatment with ARBs prior to the initiation of second-line chemotherapy. Kaplan-Meier analysis and Cox proportional hazard modeling were used in the statistical analysis. The median progression-free survival (PFS) in patients undergoing second-line chemotherapy in combination with Bev and ARBs (n=56) vs. those treated in the absence of ARBs (n=33) was 8.3 vs. 5.7 months, respectively [hazard ratio (HR)=0.57, 95% confidence interval (CI): 0.35–0.94, P=0.028]. The median overall survival (OS) was 26.5 vs. 15.2 months, respectively (HR=0.47, 95% CI: 0.25–0.88, P=0.019). In the multivariate analysis, the use of ARBs was independently associated with prolongation of OS and PFS. In conclusion, the use of ARBs prolonged survival in mCRC patients.

Receptor tyrosine kinase (RTK)-related genes, including HER2, EGFR, MET, FGFR2 and KRAS, are target molecules that are clinically beneficial in gastric cancer (GC). We investigated the correlation between RTK-related genes and the curative effect of first-line S-1 plus cisplatin (SP) combination chemotherapy in metastatic and recurrent GC. We enrolled 150 patients with histopathologically confirmed metastatic and recurrent GC treated with SP. KRAS mutation was detected using direct sequencing. DNA copy number was measured by real-time PCR. Formalin-fixed paraffin-embedded specimens were examined immunohistochemically for HER2, EGFR, FGFR2 and MET. Among 144 patients, KRAS mutation was detected in five (3.5%) at codon 12 and one (0.7%) at codon 13. FGFR2, EGFR, HER2, MET and KRAS gene amplification was suggested in 4.4%, 5.9%, 9%, 3.7% and 10.3% of patients, respectively. KRAS mutation, but not KRAS amplification, was associated with significantly shorter overall and progression-free survival. MET membranous overexpression was associated with a significantly higher tumor response. MET amplification was associated with significantly shorter overall survival. We show for the first time that KRAS mutation and MET amplification are promising predictive markers in metastatic and recurrent GC patients treated with SP. KRAS status may be a useful prognostic marker in patients treated with SP.

Cetuximab could be more effective without prior bevacizumab treatment in metastatic colorectal cancer patients Yasuyoshi Sato, Satoshi Matsusaka, Mitsukuni Suenaga, Eiji Shinozaki, Nobuyuki Mizunuma Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan Background: Cetuximab and bevacizumab reportedly improve the survival of patients with metastatic colorectal cancer (mCRC), but their most effective sequence of administration is unknown. The aim of this study was to compare the survival of patients with mCRC treated with cetuximab after bevacizumab failure with that of patients with mCRC without previous bevacizumab therapy. Patients and methods: In total, 190 of 323 patients with mCRC treated with cetuximab from March 2006 to July 2013 were enrolled in our hospital for this retrospective study. Forty-seven patients were treated with cetuximab-based second-line therapy, 21 of whom had received prior bevacizumab; 143 patients were treated with cetuximab-based third-line therapy, 109 of whom had received prior bevacizumab. The Kaplan–Meier method with a log-rank test and Cox regression analysis were performed to evaluate the overall survival and progression-free survival (PFS) of each group of patients. Results: The median follow-up time was 11.8 months in patients who received second-line cetuximab-based chemotherapy and 13.7 months in those who received third-line cetuximab-based chemotherapy. Univariate analysis revealed that the median PFS was significantly longer in patients without prior bevacizumab therapy than in patients with prior bevacizumab therapy (second line, P=0.048; third line, P=0.0022). Multivariate analysis adjusted for baseline characteristics showed that third-line cetuximab-based chemotherapy with or without prior bevacizumab was significantly associated with PFS (P=0.014). Neither the presence nor the absence of prior bevacizumab administration was associated with overall survival. Conclusion: Cetuximab could be more effective without prior bevacizumab. Prior bevacizumab use may decrease the efficacy of cetuximab. Keywords: cetuximab, bevacizumab, EGFR, VEGF, metastatic colorectal cancer

The objective of this phase I study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of preoperative chemoradiotherapy (CRT) with S-1 plus oxaliplatin in patients with locally advanced rectal cancer. Patients received radiotherapy in a total dose of 50.4 Gy in 28 fractions. Concurrent chemotherapy consisted of a fixed oral dose of S-1 (80 mg/m2/day) on days 1–5, 8–12, 22–27, and 29–33, plus escalated doses of oxaliplatin as an intravenous infusion on days 1, 8, 22, and 29. Oxaliplatin was initially given in a dose of 40 mg/m2/week to three patients. The dose was then increased in a stepwise fashion to 50 mg/m2/week and the highest dose level of 60 mg/m2/week until the MTD was attained. Thirteen patients were enrolled, and 12 received CRT. Dose-limiting toxicity (DLT) occurred in two of six patients (persistent grade 2 neutropenia, delaying oxaliplatin treatment by more than 3 days) at dose level 3; there were no grade 3 or 4 adverse events defined as DLT. The RD was 60 mg/m2/week of oxaliplatin on days 1, 8, 22, and 29. Twelve patients underwent histologically confirmed R0 resections, and two out of six patients (33%) given dose level 3 had pathological complete responses. The RD for further studies is 80 mg/m2 of S-1 5 days per week plus 60 mg/m2 of oxaliplatin on days 1, 8, 22, and 29 and concurrent radiotherapy. Although our results are preliminary, this new regimen for neoadjuvant chemoradiotherapy is considered safe and active. This trial was registered with Clinicaltrials.gov (identifier: NCT01227239 ).