Kenji Ina

Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study)

BACKGROUNDnFluorouracil and folinic acid with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are widely used as first-line or second-line chemotherapy for metastatic colorectal cancer. However, infusional fluorouracil-based regimens, requiring continuous infusion and implantation of an intravenous port system, are inconvenient. We therefore planned an open-label randomised controlled trial to verify the non-inferiority of irinotecan plus oral S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate; IRIS) to FOLFIRI as second-line chemotherapy for metastatic colorectal cancer.nnnMETHODSnBetween Jan 30, 2006, and Jan 29, 2008, 426 patients with metastatic colorectal cancer needing second-line chemotherapy from 40 institutions in Japan were randomly assigned by a computer-based minimisation method to receive either FOLFIRI (n=213) or IRIS (n=213). In the FOLFIRI group, patients received folinic acid (200 mg/m(2)) and irinotecan (150 mg/m(2)) and then a bolus injection of fluorouracil (400 mg/m(2)) on day 1 and a continuous infusion of fluorouracil (2400 mg/m(2)) over 46 h, repeated every 2 weeks. In the IRIS group, patients received irinotecan (125 mg/m(2)) on days 1 and 15 and S-1 (40-60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was progression-free survival, with a non-inferiority margin of 1.333. Statistical analysis was on the basis of initially randomised participants. This study is registered with ClinicalTrials.gov, number NCT00284258.nnnFINDINGSnAll randomised patients were included in the primary analysis. After a median follow-up of 12.9 months (IQR 11.5-18.2), median progression-free survival was 5.1 months in the FOLFIRI group and 5.8 months in the IRIS group (hazard ratio 1.077, 95% CI 0.879-1.319, non-inferiority test p=0.039). The most common grade three or four adverse drug reactions were neutropenia (110 [52.1%] of 211 patients in the FOLFIRI group and 76 [36.2%] of 210 patients in the IRIS group; p=0.0012), leucopenia (33 [15.6%] in the FOLFIRI group and 38 [18.1%] in the IRIS group; p=0.5178), and diarrhoea (ten [4.7%] in the FOLFIRI group and 43 [20.5%] in the IRIS group; p<0.0001). One treatment-related death from hypotension due to shock was reported in the FOLFIRI group within 28 days after the end of treatment; no treatment-related deaths were reported in the IRIS group.nnnINTERPRETATIONnProgression-free survival with IRIS is not inferior to that with FOLFIRI in patients receiving second-line chemotherapy for metastatic colorectal cancer. Treatment with IRIS could be an additional therapeutic option for second-line chemotherapy in metastatic colorectal cancer.nnnFUNDINGnTaiho Pharmaceutical Co Ltd and Daiichi Sankyo Co Ltd.

Rebamipide enema therapy as a treatment for patients with active distal ulcerative colitis

Background:u2002 The clinical efficacy of corticosteroids in the treatment of ulcerative colitis (UC) is well‐established. However, prolonged usage of these drugs can result in serious complications. Rebamipide {2‐(4‐chlorobenzoylamino)‐3[2‐(1H)‐quinolinon‐4‐yl] propionic acid}, a cytoprotective agent, has been reported to have anti‐inflammatory activity and to repair mucosal injury in animal colitis models. The aim of the present study was to assess the clinical efficacy and safety of a novel Rebamipide enema therapy in UC patients.

A phase 3 non-inferiority study of 5-FU/l-leucovorin/irinotecan (FOLFIRI) versus irinotecan/S-1 (IRIS) as second-line chemotherapy for metastatic colorectal cancer: updated results of the FIRIS study.

PurposeThe FIRIS study previously demonstrated non-inferiority of IRIS (irinotecan plus S-1) to FOLFIRI (5-fluorouracil/leucovorin with irinotecan) for progression-free survival as the second-line chemotherapy for metastatic colorectal cancer (mCRC) as the primary endpoint. The overall survival (OS) data were immature at the time of the primary analysis.MethodsBetween 30 January 2006 and 29 January 2008, 426 patients with mCRC who failed in first-line chemotherapy were randomly assigned to receive either FOLFIRI or IRIS. After the primary analysis, the follow-up survey was cut off on 29 July 2010, and the final OS data were analysed.ResultsWith a median follow-up of 39.2xa0months, the median OS was 17.4xa0months in the FOLFIRI group and 17.8xa0months in the IRIS group [hazard ratio (HR) 0.900; 95xa0% confidence interval (CI) 0.728–1.112]. In the pre-planned subgroup of patients who received prior chemotherapy containing oxaliplatin, the median OS was 12.7xa0months in the FOLFIRI group and 15.3xa0months in the IRIS group (HR 0.755; 95xa0% CI 0.580–0.983).ConclusionsIRIS is non-inferior to FOLFIRI for OS as second-line chemotherapy for mCRC. IRIS can be an option for second-line chemotherapy of mCRC. (ClinicalTrials.gov Number: NCT00284258).

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study

EAGLE was a randomized, multicenter phase III study which evaluated the superiority of bevacizumab 10 mg/kg plus FOLFIRI compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC previously treated with first-line bevacizumab plus an oxaliplatin-based regimen. The results suggest that the higher 10 mg/kg dose offers no clear clinical benefit compared with bevacizumab 5 mg/kg in this setting.

Importance of appropriate pharmaceutical management in pregnant women with ulcerative colitis

BackgroundUlcerative colitis (UC) often occurs in women of childbearing age. Compared to Western countries, however, few studies have investigated the impact of UC on the progress of pregnancy in Asian populations.MethodsWe retrospectively examined 91 pregnancies in 64 patients with UC experienced at our hospital and related institutions from 1991 to 2011, focusing on the relationship between the progression of UC during pregnancy, progress of the pregnancy itself, and the treatment of UC.ResultsIn 80 of 91 pregnancies the patient had already been diagnosed with UC at the time she became pregnant, of whom 31 (38.8%) experienced exacerbation during pregnancy. Regarding severity, moderate or severe active-stage disease during pregnancy was seen in 13.7% of those who had been in remission at the onset of pregnancy versus 58.6% of those who had been in the active stage at onset (OR 8.9: 95%CI 3.0~26.4; P<0.01). The incidence of miscarriage or abortion was 9.8% in pregnancies in which UC was in remission at onset versus 31% in those in which it was in the active stage at onset (OR 4.1: 95%CI 1.2~13.9; P=0.02). Among patients, 62.5% were receiving pharmaceutical treatment at onset of pregnancy. Exacerbation during pregnancy occurred in 26.5% of the group who continued to receive the same treatment during pregnancy versus 56.3% of those with a dose decrease or discontinuation after onset (OR 3.6: 95%CI 1.0~12.4; P=0.04).ConclusionsUC patients wishing to conceive should do so when in remission and continue appropriate pharmaceutical treatment during pregnancy.

Coloduodenal Fistula in Crohn’s Disease

1 34-year-old man was hospitalized with complaints of right upperquadrant pain and melena with no fecal vomiting. The patient ad a history of Crohn’s disease at age 24 years, but was not followed p over the past several years. During this admission, he initially nderwent an abdominal computerized tomographic scan and a oloduodenal fistula was suspected (Figure A). Upper-gastrointestinal ndoscopy revealed the end of the fistula on the posterior duodenal wall Figure B). Colonoscopy revealed several geographic ulcerations in the ransverse colon with severe stenosis that could not be passed by olonoscope. Colonography was followed by colonoscopy. A fistula was onfirmed just above the ileocecal valve in the ascending colon and the econd portion of the duodenum could be visualized (Figure C). Crohn’s disease is one of the chronic inflammatory diseases that nvolves any part of the gastrointestinal tract and mainly affects young dults. The major symptoms of this disorder are abdominal pain, iarrhea, and weight loss. Crohn’s disease is a possible cause of internal stula and diagnosis of coloduodenal fistula usually is made by conrast radiography.1 It is extremely rare to document a clear endoscopic iew of the duodenal end of a coloduodenal fistula; only 2 cases have een reported thus far.2,3

A retrospective analysis of chemotherapy for gastric cancer in later-stage elderly patients

AIMnDespite the significant advances in chemotherapy, the prognosis of unresectable or recurrent gastric cancer is still very poor. Given that older adults are likely to have a number of concomitant diseases and an impaired major organ function, cancer chemotherapy in elderly patients requires particular caution. We examined what factors are associated with the overall survival of gastric cancer patients undergoing chemotherapy.nnnMETHODSnA retrospective chart review of gastric cancer patients receiving oral fluoropyrimidines (N=130) was performed at Nagoya Memorial Hospital over 9 years. The overall survival was calculated from the beginning of chemotherapy until death or the most recent date of follow-up. The Kaplan-Meier method was used to plot survival curves, which were compared using the log-rank test. A multivariate analysis was performed using stepwise Cox proportional hazards models. A comprehensive geriatric assessment was conducted for the elderly patients. The chart review was approved by the ethics committee of Nagoya Memorial Hospital.nnnRESULTSnThe objective response rate and overall survival did not differ markedly between the patients < 75 years (N=64) and those ≥ 75 years of age (N=28). The addition of lentinan significantly prolonged the survival of the stage 4 gastric cancer patients. In a multivariate analysis of those ≥ 75 years of age, the only independent prognostic factor for the survival was the functional capacity, as measured by the TMIG Index of Competence.nnnCONCLUSIONSnThis comprehensive geriatric assessment was useful for predicting the longevity of patients with stage 4 gastric cancer ≥ 75 years of age.

Bladder squamous cell cancer accompanied by Trousseau's syndrome: a case report

The association between thrombosis and cancer has been recognized since Trousseaus report in 1865. We present a case of bladder squamous cell carcinoma associated with multiple cerebral infarctions. This patient was diagnosed as having Trousseaus syndrome and received radiotherapy for bladder cancer treatment, along with anticoagulation therapy.

The efficacy and safety of docetaxel-based chemotherapy combined with dexamethasone 1 mg daily oral administration: JMTO Pca 10-01 phase II trial

ObjectivesnPreviously, one randomized control trial (TAX327) revealed the efficacy of docetaxel-based chemotherapy combined with prednisone. On the other hand, several studies showed a high prostate specific antigen (PSA) response with low-dose dexamethasone in castration-resistant prostate cancer (CRPC) patients. The objective of this study was to evaluate the efficacy and safety of docetaxel-based chemotherapy combined with dexamethasone in CRPC patients.nnnMaterials and methodsnThis study was a single-arm multi-institutional phase II trial. Patients received 75 mg/m2 of docetaxel, and 0.5 mg of dexamethasone orally twice a day continuing throughout the treatment period. Treatment was planned for 10 cycles, and continued for at least four cycles depending on the observation of PSA flare. The primary endpoint was PSA response defined as a reduction from baseline of at least 50% that continued for at least 3 weeks. Secondary endpoints were safety, PSA flare, time to PSA failure and adherence rate to protocol treatment (10 cycles).nnnResultsnBetween January 2011 and February 2014, a total of 76 chemotherapy-naïve CRPC patients were enrolled. Seventy-five patients received docetaxel-based chemotherapy combined with dexamethasone. The median age and PSA level at enrollment were 71 years (53-85) and 23.2 ng/mL (2.9-852), respectively. PSA response rate was 76.8% (90% confidence interval (CI): 66.9-84.9). Of all patients, 30 patients completed 10 cycles of chemotherapy (40%). The incidence rate of PSA flare was 10.7% (eight patients). The median time to PSA failure was 369 days (95% CI: 245-369). The most frequently observed adverse event was hematotoxicity (neutropenia of G2 or greater: 100%).nnnConclusionsnThe present study showed a significantly high PSA response compared with previous reports. Most patients tolerated the protocol treatment well, whereas hematotoxicity was often observed.

Adverse Effects of Bevacizumab During Treatment for Metastatic Colorectal Cancer

Objective : Bevacizumab has been increasingly used in combination chemotherapy for the treatment of metastatic or recurrent colorectal cancer. The aim of this report is to underline the possible risks associated with bevacizumab use. Methods : Between July 2005 and March 2013, a total of 130 patients with metastatic colorectal cancer who received oxaliplatin as first-line chemotherapy were divided into 2 groups those treated with bevacizumab (group A) and those without (group B), and compared. The primary endpoint was to clarify the profile of bevacizumab - induced adverse effects. Secondary endpoints examined therapeutic effects, including overall survival (OS). Results : The incidence of major side effects was almost equivalent, except for bleeding, between the 2 groups. With regard to the therapeutic effects, 1 patient in group A showed complete disappearance of multiple lung metastases without any evidence of recurrence. The median OS was 926 days (95% confidence interval [CI], 756 - 1257) in group A and 534 days (95% CI, 421 – 621) in group B ( p < 0.01). Conclusion : The results demonstrate that bevacizumab prolonged survival in these patients although there was an increased risk of clinically significant bleeding.