Switching from FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab based on early tumor shrinkage in RAS wild-type metastatic colorectal cancer: A phase II trial (HYBRID).

BACKGROUND: Long-term anti-EGFR antibody treatment increases the risk of severe dermatologic toxicities. This single-arm, phase II trial aimed to investigate the strategy of switching from cetuximab to bevacizumab in combination with FOLFIRI based on early tumor shrinkage (ETS) in patients with RAS wild-type metastatic colorectal cancer (mCRC). METHODS: Radiologic assessment was performed to evaluate ETS, defined as ≥20% reduction in the sum of the largest diameters of target lesions 8 weeks after the introduction of FOLFIRI plus cetuximab. ETS-negative patients switched to FOLFIRI plus bevacizumab, whereas ETS-positive patients continued FOLFIRI plus cetuximab for eight more weeks, with a switch to FOLFIRI plus bevacizumab thereafter. The primary endpoint was progression-free survival. RESULTS: This trial was prematurely terminated due to poor accrual after a total enrollment of 30 patients. In 29 eligible patients, 7 were ETS-negative and 22 were ETS-positive. Two ETS-negative patients and 17 ETS-positive patients switched to FOLFIRI plus bevacizumab 8 weeks and 16 weeks after initial FOLFIRI plus cetuximab, respectively. Median progression-free and overall survival durations were 13.4 and 34.7 months, respectively. Six (20%) patients experienced grade ≥3 paronychia, which improved to grade ≤2 by 18 weeks. Grade ≥3 acneiform rash, dry skin, and pruritus were not observed in any patients. CONCLUSIONS: Our novel treatment strategy delivered acceptable survival outcomes and reduced severe dermatologic toxicities.

Risk of colonoscopic post-polypectomy bleeding in patients after the discontinuation of antithrombotic therapy.

BACKGROUND/AIMS: Few studies have examined the incidence of post-polypectomy bleeding (PPB) after discontinuation of antithrombotic therapies. Therefore, this study aimed to evaluate the incidence of PPB and thromboembolic events in patients whose antithrombotic agents were discontinued before colonoscopy. MATERIALS AND METHODS: We retrospectively selected all patients who underwent colon polypectomy at a community hospital. A total of 282 patients (540 polypectomies) discontinued antithrombotic agents (group 1), and 1,648 patients (2,827 polypectomies) did not take antithrombotic agents (group 2). The cessation periods before and after polypectomies were 4 and 3 days for warfarin, 5 and 3 days for anti-platelet agents, and 7 and 5 days of combination therapy, respectively. Main outcome measurements were the incidence of PPB and thromboembolic events. RESULTS: Immediate PPB rates were 3.9% (11/282) in group 1 and 4.6% (76/1648) in group 2 (adjusted odds ratio [OR], 0.85; 95% confidence interval [CI], 0.42-1.72; p=0.65). Delayed PPB rates were 1.4% (4/282) in group 1 and 1.1% (18/1648) in group 2 (adjusted OR, 1.24; 95% CI, 0.36-4.24; p=0.732). No thromboembolic events were observed in either group. CONCLUSION: Our cessation periods were appropriate, and further shortening of these periods is possible.

A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2).

BACKGROUND: Nivolumab, an anti-programmed death-1 agent, showed survival benefits in Asian patients, including Japanese, with gastric/gastro-esophageal junction (G/GEJ) cancer. We report the analysis of the Japanese subpopulation from ATTRACTION-2 that evaluated nivolumab versus placebo in unresectable advanced or recurrent G/GEJ cancer after ≥ 2 chemotherapy regimens. METHODS: Data from the Japanese subpopulation in the randomized, double-blind, placebo-controlled, phase 3 trial were analyzed (data cutoff, February 25, 2017). Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). RESULTS: Among the overall study population of 493 patients, 226 (nivolumab 152; placebo 74) were enrolled from 28 sites in Japan. In the Japanese subset, median OS was longer with nivolumab versus placebo (5.4 months, 95% CI 4.6-7.4 versus 3.6 months, 95% CI 2.8-5.0). The risk of death was lower in the nivolumab versus placebo group (hazard ratio 0.58, 95% CI 0.42-0.78; p = 0.0002). Incidences of serious adverse events were 23% (35/152) and 25% (18/72) in the nivolumab and placebo groups, respectively. In the Japanese ITT population, 22% of nivolumab-treated and 28% of placebo-treated patients received prior ramucirumab treatment. Overall, clinical activity of nivolumab was observed regardless of prior ramucirumab use. In the nivolumab group, ORR and PFS were numerically higher in patients with prior ramucirumab use than in those without. CONCLUSIONS: In the Japanese subpopulation, patients receiving nivolumab had longer OS, similar to the overall population, with a manageable safety profile. The interaction between nivolumab and ramucirumab will be clarified in ongoing clinical trials.

Phase II study of S-1 plus oxaliplatin 130 mg/m2 in Japanese patients with advanced gastric cancer.

PURPOSE: Although oxaliplatin 130 mg/m2 every 3 weeks was approved for advanced gastric cancer in Japan, data regarding S-1 plus oxaliplatin 130 mg/m2 (SOX130) are limited in Japanese patients with advanced gastric cancer. We investigated the feasibility and safety of SOX130 in Japanese patients with advanced gastric cancer. METHODS: Patients with unresectable or recurrent gastric adenocarcinoma, no previous chemotherapy, and Eastern Cooperative Oncology Group Performance Status of 0-1 were treated with SOX130. The primary endpoint was the 3-cycle completion rate, defined as the proportion of patients who completed the first three cycles with ≥ 80% relative dose intensity of oxaliplatin. RESULTS: Twenty-five patients were enrolled from April 2015 to 2016. The 3-cycle completion rate was 72.0% (90% confidence interval: 53.8-86.1), which was higher than the predetermined threshold rate of 50%. With the median number of cycles being 6 (range, 1-19+), grade 3 or 4 adverse events occurred in 10 patients (40%). Major grade 3 adverse events were anorexia (24%), thrombocytopenia (16%), and neutropenia (12%). No febrile neutropenia or treatment-related deaths occurred. Among 12 patients with measurable lesions, the overall response rate was 58.3%. Median progression-free and overall survival were 5.7 months (95% confidence interval 2.9-8.5) and 13.1 months (95% confidence interval 7.4-19.0), respectively. CONCLUSION: Results indicated that SOX130 was feasible in Japanese patients with advanced gastric cancer.

Antimicrobial stewardship without infectious disease physician for patients with candidemia: A before and after study.

BACKGROUND: Little is known about the effects of antimicrobial stewardship team (AST) without infectious disease physician (IDP) on clinical outcome in patients with candidemia. METHODS: We conducted a before and after study involving patients with hospital-acquired candidemia at a tertiary hospital without IDPs. The AST consisted of physicians, pharmacists, nurse, microbiologist, and administrative staff. A candidemia care bundle was developed based on the Infectious Disease Society of America (IDSA) guideline. The non-IDP AST provided recommendations to the attending physicians whose patients developed candidemia during hospitalization. The primary outcome was 30-day all-cause mortality, while the secondary outcomes were adherence to the IDSA guidelines regarding the management of candidemia. Data of up to 3 years of preintervention and 3 years of intervention period were analyzed. RESULTS: By 30 days, 11 of 46 patients (23.9%) in the intervention group and 7 of 30 patients (23.3%) in the preintervention group died (adjusted hazard ratio for the intervention group: 0.68 [95% CI 0.24-1.91]). The non-IDP AST was associated with appropriate empirical antifungal therapy (100% vs 60.0%; proportion ratio 1.67 [95% CI 1.24-2.23]), appropriate duration of treatment (84.7% vs 43.3%; 1.96 [1.28-3.00]), removal of central venous catheters (94.4% vs 70.8%; 1.33 [1.02-1.74]), and ophthalmological examination (93.5% vs 63.3%; 1.48 [1.12-1.96]). CONCLUSIONS: Although we found no significant difference in 30-day mortality, the non-IDP AST was associated with improved adherence to guidelines for management of candidemia.

First-line chemotherapy with S-1 alone or S-1 plus cisplatin for elderly patients with advanced gastric cancer: a multicenter propensity score matched study.

BACKGROUND: Fluoropyrimidine and platinum combination is the standard treatment for advanced or recurrent gastric cancer (AGC). However, fluoropyrimidine monotherapy is commonly used for elderly patients with AGC because of its good tolerability. METHODS: In this multicenter retrospective study, we collected clinical data of AGC patients aged 70 years or older, treated with S-1 alone or S-1 plus cisplatin (SP) as the first-line treatment between January 2009 and December 2011. Propensity score matched cohorts (PSMC) were used for reducing the confounding effects to compare efficacy and safety between the two treatment groups. Cox regression analysis was performed to clarify the prognostic factors. RESULTS: PSMC (n = 109 in each group) were selected from among 444 eligible patients (S-1 group, 210; SP group, 234); the S-1 group included more patients deemed unfit for intensive chemotherapy than the SP group (e.g., higher age, poorer PS, poor renal function). In the PSMC, patients' characteristics were comparable between groups, except the male ratio (S-1 group, 64.2%; SP group, 77.1%; p = 0.04). No significant differences were observed in either overall survival [hazard ratio (HR) 0.93, p = 0.63] or progression-free survival (HR 1.09, p = 0.61). Severe adverse events (AEs) and hospitalization due to AEs were more frequent in the SP group than in the S-1 group (p < 0.001 each). CONCLUSION: Our findings do not support the survival benefit of SP over S-1 in elderly patients with AGC. We are now conducting a prospective comparative study to optimize treatment strategy and explore applicability of the geriatric assessment for these patients.