Ichiro Iwanaga

Phase II Study of Combined Treatment with Irinotecan and S-1 (IRIS) in Patients with Inoperable or Recurrent Advanced Colorectal Cancer (HGCSG0302)

Objectives: This phase II study was designed to evaluate the efficacy and safety of oral fluoropyrimidine S-1 plus irinotecan (IRIS regimen) in patients with previously untreated metastatic colorectal cancer. Methods: The response rate was the primary endpoint. Safety, progression-free survival time, and median survival time were secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer. Irinotecan was administered at a dose of 100 mg/m2 (on days 1 and 15). S-1 (40 mg/m2) was administered for 2 weeks (on days 1 to 14) and followed by a 2-week rest. Results: Forty patients were enrolled. Four patients had grade 4 neutropenia, and six patients had grade 3 diarrhea. No other serious hematologic or nonhematologic adverse reactions occurred, and all patients received IRIS safely on an outpatient basis. The response rate was 52.5% (95% confidence interval [CI], 36.1–68.5%). Median progression-free survival was 8.6 months (95% CI, 5.3–11.9), and median survival time was 23.4 months (95% CI, 15.9–30.8). Conclusions: IRIS produced a high response rate and could be given safely. IRIS may become a first-line treatment for inoperable or recurrent advanced colorectal cancer.

Randomized controlled trial on the skin toxicity of panitumumab in Japanese patients with metastatic colorectal cancer: HGCSG1001 study; J-STEPP

AIM We planned a randomized, open-label trial to evaluate differences between pre-emptive and reactive skin treatment for panitumumab (Pmab)-associated skin toxicities in Japanese patients with metastatic colorectal cancer. PATIENTS & METHODS Patients receiving third-line Pmab-containing regimens were randomized to pre-emptive or reactive treatment. The primary end point was the cumulative incidence of ≥grade 2 skin toxicities during 6 weeks. Retrospectively, a dermatologist reviewed skin toxicities, in a blinded manner. RESULTS A total of 95 patients were enrolled (pre-emptive: 47, reactive: 48). The primary end point was achieved (21.3 and 62.5% [risk ratio: 0.34; p < 0.001], for pre-emptive and reactive treatment, respectively). A similar trend was observed in central review. CONCLUSION Pre-emptive skin treatment could reduce the severity of Pmab-associated skin toxicities in Japanese metastatic colorectal cancer patients.

Phase II study of combined chemotherapy with irinotecan and S-1 (IRIS) plus bevacizumab in patients with inoperable recurrent or advanced colorectal cancer

Abstract Background. In Japan, a study comparing the effectiveness and safety of irinotecan plus S-1 (IRIS) with those of a combination of 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as second-line treatment in patients with advanced or recurrent colorectal cancer demonstrated that IRIS was non-inferior to FOLFIRI. We previously reported that IRIS is also effective as first-line treatment. Patients and methods. Eligibility criteria included inoperable recurrent colorectal cancer with a confirmed diagnosis of adenocarcinoma, age ≥20 years, and no history of prior chemotherapy. S-1 (40–60 mg twice daily) was given orally on Days 1 to 14, and irinotecan (100 mg/m2) and bevacizumab (5 mg/kg) were given intravenously on Days 1 and 15 of a 28-day cycle. The primary endpoint was safety. The secondary endpoints included overall response (OR), progression-free survival (PFS), and overall survival (OS). Results. A total of 52 eligible patients were enrolled from October 2007 through March 2009. In safety analysis, the incidences of grade 3 or 4 adverse reactions were as follows: neutropenia, 27%; hypertension, 21%; and diarrhea, 17%. The overall response rate was 57.7%. Median progression-free survival was 16.7 months. Conclusion. IRIS plus bevacizumab is a well-tolerated, highly effective chemotherapeutic regimen that is easy to administer.

Open‐label, randomized, comparative, phase III study on effects of reducing steroid use in combination with Palonosetron

The purpose of this study is to compare the efficacy of a single administration of dexamethasone (DEX) on day 1 against DEX administration on days 1–3 in combination with palonosetron (PALO), a second‐generation 5‐HT3 receptor antagonist, for chemotherapy‐induced nausea and vomiting (CINV) in non‐anthracycline and cyclophosphamide (AC) moderately‐emetogenic chemotherapy (MEC). This phase III trial was conducted with a multi‐center, randomized, open‐label, non‐inferiority design. Patients who received non‐AC MEC as an initial chemotherapy were randomly assigned to either a group administered PALO (0.75 mg, i.v.) and DEX (9.9 mg, i.v.) prior to chemotherapy (study treatment group), or a group administered additional DEX (8 mg, i.v. or p.o.) on days 2–3 (control group). The primary endpoint was complete response (CR) rate. The CR rate difference was estimated by logistic regression with allocation factors as covariates. The non‐inferiority margin was set at −15% (study treatment group − control group). From April 2011 to March 2013, 305 patients who received non‐AC MEC were randomly allocated to one of two study groups. Overall, the CR rate was 66.2% in the study treatment group (N = 151) and 63.6% in the control group (N = 154). PALO plus DEX day 1 was non‐inferior to PALO plus DEX days 1–3 (difference, 2.5%; 95% confidence interval [CI]: −7.8%–12.8%; P‐value for non‐inferiority test = 0.0004). There were no differences between the two groups in terms of complete control rate (64.9 vs 61.7%) and total control rate (49.7% vs 47.4%). Anti‐emetic DEX administration on days 2–3 may be eliminated when used in combination with PALO in patients receiving non‐AC MEC.

Retrospective Cohort Study on the Safety and Efficacy of Bevacizumab with Chemotherapy for Metastatic Colorectal Cancer Patients: The HGCSG0801 Study

OBJECTIVE After approval of bevacizumab in Japan, post-marketing surveillance studies reported on safety. However, few reports have shown the efficacy of bevacizumab as used in daily practice. We evaluated the efficacy and safety of bevacizumab for metastatic colorectal cancer patients in daily practice. METHODS All unresectable metastatic colorectal cancer patients who began receiving bevacizumab in participating facilities from June 2007 to October 2008 were retrospectively analyzed for safety and efficacy. Adverse events were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events. Response Evaluation in Solid Tumors criteria, version 1.0, was used for the tumor response rate. RESULTS A total of 212 patients from 17 institutions were assessed. Grade 3 or higher adverse events related to bevacizumab included gastrointestinal perforation in 3, thrombosis in 7, hypertension in 30 and gastrointestinal bleeding in 2. Response rates were 62.5, 30.1 and 11.8% overall among patients receiving bevacizumab as first-, second- and third-line or greater therapy. Median progression-free survival was 14.4 [95% confidence interval (CI): 10.8-18.1], 7.8 (95% CI: 6.5-9.1) and 6.0 (95% CI: 4.6-7.3) months, and median overall survival was 32.5 (95% CI: 24.6-40.3), 16.4 (95% CI: 14.4-18.5) and 11.8 (95% CI: 8.6-15.0) months, respectively. CONCLUSIONS The general cohort of patients in HGCSG0801 showed a similar efficacy and safety profile of bevacizumab as seen in clinical trials. Although the sample size was small and there were several study limitations, these results suggest that colorectal cancer patients in Japan might safely receive and benefit from bevacizumab in combination with chemotherapy in daily practice, as is seen in patients in other countries.

Feasibility Study of Bolus 5-Fluorouracil+L-Leucovorin as Salvage Line Chemotherapy for Oral Fluorouracil-Resistant Unresectable Gastric Cancer: Hokkaido Gastrointestinal Cancer Study Group Study HGCSG1502

In November 2015 we began a feasibility study of salvage line chemotherapy with 5-fluorouracil and l-leucovorin given in an intravenous bolus once weekly followed by a 2-week rest period within a 8-week cycle in patients with gastric cancer resistant to other chemotherapies. This study aims to assess the safety and efficacy of this treatment and determine whether the treatment has an adverse effect on patients’ quality of life. In total, 38 patients with chemotherapy-resistant advanced or recurrent gastric cancer will be recruited to this study. The primary end point is 8-week progression-free survival after the date of first treatment; the major secondary end points are progressionfree survival, overall survival, and quality of life assessed by European Organization for Research and Treatment of Cancer QLQ-C30 (quality of life score-30) and QLQ-STO22 (quality of life for gastric cancer patients) questionnaires. Based on the results of the study, we will conduct further trials to compare this treatment with best supportive care only.

Rescue technique using a diathermic dilator for an unremovable stent in malignant perihilar biliary obstruction

Endoscopic biliary stenting is a useful and safe technique for malignant biliary obstructions. A plastic stent is frequently used because of its low cost and ease of deployment. However, it is occasionally difficult to remove a plastic stent because of severe stricture. We describe a rescue technique for immovable plastic stents, using a diathermic dilator in a case of perihilar biliary obstruction. A 63-year-old woman with jaundice due to hilar biliary obstruction was referred to our hospital. A diagnosis of gallbladder cancer was made from findings of a thickened gallbladder wall and massive ascites revealed by computed tomography (▶Fig. 1) and magnetic resonance cholangiopancreatography (▶Fig. 2). For biliary decompression and pathological confirmation, endoscopic retrograde cholangiography (ERC) was performed, and a 7-Fr plastic stent was placed (▶Fig. 3, ▶Video1). The patient underwent a second ERC 4 days later because of elevated biliary enzymes. The plastic stent could not be removed using forceps and snares, and the torn-off stent was left in place (▶Fig. 4). Although needle-knife sphincterotomy was performed to expose the residual plastic stent, the stent could not be grasped. A 0.025-inch guidewire could be advanced alongside the plastic stent, but a sphincterotome (CleverCut 3V; Olympus, Tokyo, Japan) could not. Successful dilation of the perihilar biliary stricture was achieved by advancing a 6-Fr wire-guided diathermic dilator (Cysto-Gastro-Set; Endo-Flex GmbH, Voerde, Germany) (▶Fig. 5). However, the remaining plastic stent also migrated. Thus, a 10-mm lumen partially covered, self-expandable, metallic stent (WallFlex biliary stent; Boston Scientific Japan, Tokyo, Japan) was deployed alongside the plastic stent (▶Fig. 6). In cases of malignant biliary stricture, removal of a plastic stent is time-consuming and might cause complications. The VIDEO 1

Observational cohort study of first-line bevacizumab with oxaliplatin or irinotecan and fluoropyrimidines in metastatic colorectal cancer: HGCSG0802—Analysis of early tumor shrinkage (ETS).

753 Background: It was reported that early tumor shrinkage (ETS) was associated with better overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) receiving first line chemotherapy. We investigated association of ETS with progression-free survival (PFS) and OS in pts with mCRC treated with first-line bevacizumab (BV)-based chemotherapy (HGCSG0802). Methods: The objective of HGCSG0802 was to evaluate PFS, OS, response rate (RR), safety and so on. The key eligibility criteria were evaluable lesions, older than 20 years old, ECOG PS 0-2. This analysis evaluated the association of ETS at 8 weeks from the start of chemotherapy with pts characteristics, PFS and OS. To identify factors associated with ETS, if there were clinical variables with p < 0.2 in univariate analysis, we planned a multivariate analysis using the logistic regression model. To identify predictive and prognostic factors, a multivariate analysis was performed using Cox proportional hazard model with backward eliminat...

Observational cohort study of 1st line bevacizumab combined with chemotherapy in metastatic colorectal cancer (HGCSG0802): Sub-group analysis by the GERCOR index.

743 Background: The GERCOR index based on performance status and serum LDH was reported to be useful to predict survival for patients with previously untreated mCRC. However, the validity of the GERCOR index has not been reported in patients treated with bevacizumab (Bev)-based first line chemotherapy. Methods: 115 patients with mCRC treated with Bev contained first line chemotherapy were registered from 15 centers in Japan. Univariate and multivariate analysis for overall survival (OS) were performed using patient characteristics. Survival analyses were performed with the Kaplan-Meier method, log-rank test and the Cox proportional hazards model. The analysis was also designed to determine whether the GERCOR index could be extended to progression-free survival (PFS). Results: All data were available for prognostic categorization in 108 patients. Patients with the GERCOR index of low, intermediate and high risk were 45, 57, and 6, respectively. The pts characteristics between low risk (L) and intermediate/...

Observational cohort study of first-line bevacizumab combined with chemotherapy in metastatic colorectal cancer (HGCSG0802): Sub-group analysis by KRAS Exon2 status.

782 Background: A few reports have shown the efficacy of bevacizumab (BV) independent of the KRAS Exon2 mutational status (KRAS). We performed a sub-group analysis by KRAS from the HGCSG0802 observ...