Hiroshi Nakatsumi

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.

Comparison of efficacy and toxicity of FOLFIRINOX and gemcitabine with nab-paclitaxel in unresectable pancreatic cancer

BACKGROUND Irinotecan, oxaliplatin and leucovorin-modulated fluorouracil (FOLFIRINOX) and the combination regimen of gemcitabine and nanoparticle albumin-bound paclitaxel (GnP) (nab-PTX) improve the prognosis of patients with metastatic pancreatic cancer. However, no study has compared the efficacy of the two regimens. We compared retrospectively the efficacy and safety of the two regimens in patients with unresectable pancreatic cancer. METHODS Thirty-eight patients with unresectable locally advanced or metastatic pancreatic cancer received FOLFIRINOX or GnP as first-line chemotherapy between December 2013 and September 2015. In the FOLFIRINOX group, patients received 85 mg/m2 oxaliplatin followed by 180 mg/m2 irinotecan and 200 mg/m2 L-leucovorin, and by 400 mg/m2 fluorouracil as a bolus and 2,400 mg/m2 fluorouracil as a 46-h continuous infusion every 14 days. In the GnP group, patients received 125 mg/m2 nab-PTX followed by 1 g/m2, and gemcitabine on days 1, 8 and 15, repeated every 28 days. RESULTS Response rate was 6.3% in the FOLFIRINOX group and 40.9% in the GnP group (P=0.025). Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 3.0-4.5] in the FOLFIRINOX group and 6.5 months (95% CI, 6.2-6.9 months) in the GnP group (P=0.031). Drug toxicity in the GnP group was less than in the FOLFIRINOX group. CONCLUSIONS Efficacy and safety of GnP compare favorably to those of FOLFIRINOX in patients with pancreatic cancer. Additional prospective trials are warranted.

Optimal Dose Period for Indisetron Tablets for Preventing Chemotherapy-Induced Nausea and Vomiting with Modified FOLFOX6: A Randomized Pilot Study

Background: Indisetron is a serotonin (5-hydroxytryptamine type 3) receptor antagonist that also antagonizes 5-hydroxytryptamine type 4 receptors. We designed a pilot study in order to explore the optimal dosing period for indisetron during modified FOLFOX6 (mFOLFOX6). Patients and Methods: Forty-two chemotherapy-naive patients with advanced colorectal cancer scheduled to receive mFOLFOX6 were randomly assigned to either a 1- or 3-day indisetron regimen arm. The primary endpoint was complete protection from vomiting. Results: Proportions of patients with complete protection from vomiting were 85.7% [95% confidence interval (CI) 63.7–97.0] with the 3-day regimen and 81.0% (95% CI 58.1–94.6) with the 1-day regimen. Proportions of patients with complete protection from nausea were 47.6% in each arm (95% CI 25.7–70.2). No rescue therapy rates were 66.7% (95% CI 43.0–85.4) versus 57.1% (95% CI 34.0–78.2). No severe adverse events were observed in either arm. Conclusion: Both 1- and 3-day indisetron regimens were feasible for preventing nausea and vomiting induced by mFOLFOX6.

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.

Efficacy and Safety of Bolus 5-Fluorouracil and L-Leucovorin as Salvage Chemotherapy for Oral Fluoropyrimidine-Resistant Unresectable or Recurrent Gastric Cancer: A Single Center Experience

Purpose The International Organization for Standardization-5fluorouracil (FU) 10 trial found that bolus 5-FU and l-leucovorin was not inferior to S-1 in the treatment of gastric cancer (GC). Continuous 5-FU and the rapid injection of 5-FU have different anti-cancer effects. Thus, bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. Materials and Methods We retrospectively analyzed the medical records of all patients with S-1 or capecitabine-resistant, unresectable, or recurrent GC treated with bolus 5-FU and l-leucovorin between January 2010 and December 2015 at Hokkaido University Hospital. The bolus 5-FU and l-leucovorin regimen consisted of intravenous l-leucovorin (250 mg/m2/2 h) and bolus 5-FU (600 mg/m2) administered once weekly followed by a 2-week rest period; each cycle was repeated every 8 weeks. Results A total of 14 patients were identified. The disease control rate was 35.7%. The median progression-free survival was 1.6 months (95% confidence interval [CI], 1.3~2.0 months), and the median overall survival was 6.3 months (95% CI, 4.7~7.9 months). No patient died from treatment-related causes. The most common severe adverse event associated with bolus 5-FU and l-leucovorin was neutropenia, which occurred in 21.4% of patients. Conclusions Bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. We are planning a multi-center prospective phase II trial to evaluate the efficacy and safety of bolus 5-FU and l-leucovorin treatment for pre-treated unresectable or recurrent GC to confirm the results of this limited, retrospective study.

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 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...

552PRANDOMIZED CONTROLLED TRIAL ON THE SKIN TOXICITY OF PANITUMUMAB IN THIRD LINE TREATMENT OF KRAS WILD-TYPE METASTATIC COLORECTAL CANCER: HGCSG1001 (JAPANESE SKIN TOXICITY EVALUATION PROTOCOL WITH PANITUMUMAB: J-STEPP): ADDITIONAL ANALYSIS OF QOL AND SKIN TOXICITY

ABSTRACT Aim: Panitumumab (Pmab) has demonstrated efficacy in patients with KRAS wild-type metastatic colorectal cancer (mCRC). Although the STEPP study (Lacouture M. E. et al. J Clin Oncol. 2010; 28: 1351-7.) showed that pre-emptive skin treatment reduced skin toxicities compared with reactive treatment among patients receiving Pmab, data for Asians has not been reported. We planned a randomized, open-label trial to verify the differences between pre-emptive and reactive treatment for skin toxicities in Japanese patients. Methods: Patients receiving third-line Pmab-containing regimens for mCRC were randomly assigned 1:1 to pre-emptive (skin moisturizers, sunscreen, topical steroid, and minocycline) or reactive (only skin moisturizers) skin treatment. The primary endpoint was the cumulative incidence of ≥grade 2 skin toxicities during the 6-week treatment period. Retrospectively, a dermatologist reviewed skin toxicities, in a blinded manner, using photographs. Results: Of 95 enrolled patients, 47 were assigned to pre-emptive, and 48 to reactive treatment. The incidence of ≥grade 2 skin toxicities during the 6-week treatment period (investigators’ assessment) was 21.3% and 62.5% (risk ratio [RR], 0.34; 95% CI, 0.19 to 0.62; P Conclusions: Although pre-emptive skin treatment could not be affected with QOL, it could reduce the severity of skin toxicities during Pmab treatment. Our data clearly validate that pre-emptive treatment can also be recommended in Japanese patients. Disclosure: M. Nakamura: Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Yakuhin; S. Yuki: Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Merck Serono, Takeda Pharmaceutical, Yakult Honsha; Y. Sakata: Taiho Pharmaceutical, Daiichi Sankyo, Yakult Honsha, Otsuka Pharmaceutical, Merck Serono, Bristol-Myers Squibb, Synergy International; Y. Komatsu: Yakult Honsha, Taiho Pharmaceutical, Chugai Pharmaceutical, Merck Serono, Pfizer Japan, Novartis Pharma, Sawai Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Takeda Pharmaceutical, Eli Lilly Japan, Kureha Corporation. All other authors have declared no conflicts of interest.

The optimal dose period of indisetron tablets for preventing chemotherapy-induced nausea and vomiting (CINV) induced by mFOLFOX6: An exploratory trial HGCSG0703.

589 Background: Indisetron is a 5-HT3 receptor antagonist which shows also 5-HT4 antagonistic activity, that had approved in 2004 by Japans PMDA. There are no recommendations of prophylactic regimens for preventing nausea and vomiting induced by FOLFOX therapy. To explore the optimal dose period of indisetron tablets during mFOLFOX6, we designed the study to compare the antiemetic efficacy and safety of 3-day regimen of indisetron with a single dose regimen. METHODS Advanced colorectal cancer patients who were treated with mFOLFOX6 (+/- bevacizumab) as first-line chemotherapy were enrolled in this study. They were randomly assigned to Group A (3-day of indisetron) or Group B (a single dose of indisetron). Dexamethazone (8mg) was also administered intravenously in both groups before administering of oxaliplatin. The follow-up period was 5 days from the start of chemotherapy. The primary endpoint was complete protection from vomiting, and secondary endpoints were complete protection from nausea, no use of rescue therapy, and severe adverse events. RESULTS Of 45 patients enrolled in this trial, 42 (93.3%) were assessable. The proportions of patients with complete protection from vomiting were 85.7% in Group A, and 81.0% in Group B (p=1.000; Fishers exact test). The proportions of patients with complete protection from nausea were 47.6% in each group (p=1.000; chi-square test). The no rescue therapy rates were 66.7% in Group A, and 57.1% in Group B (p=0.525; chi-square test). No severe adverse events were observed in both groups. CONCLUSIONS We suggested that the efficacy of a single dose of indisetron might be equivalent of 3-day regimen for preventing from nausea and vomiting induced by mFOLFOX6. [Table: see text].