282 results on '"Daisuke Takahari"'
Search Results
252. Randomized phase II study comparing dose-escalated weekly paclitaxel versus standard dose weekly paclitaxel for patients with previously treated advanced gastric cancer
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Chihiro Kondo, Shuichi Hironaka, Yasushi Tsuji, Ayumu Hosokawa, Setsuo Utsunomiya, Takashi Tsuda, Atsushi Ishiguro, Kohei Shitara, Michio Nakamura, Kei Muro, Daisuke Sakai, Keitaro Matsuo, Daisuke Ichikawa, Takayuki Kii, Daisuke Takahari, Satoshi Yuki, and Isao Oze
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Weekly paclitaxel ,Phases of clinical research ,Neutropenia ,Advanced gastric cancer ,medicine.disease ,Surgery ,Internal medicine ,medicine ,Overall survival ,business ,Previously treated - Abstract
4076 Background: Retrospective analyses of neutropenia during chemotherapy of weekly paclitaxel (wPTX) suggested better overall survival (OS) among patients with neutropenia. We conducted a randomized phase II trial comparing dose-escalated wPTX with dose adjustments determined by degree of neutropenia versus standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC). Methods: Ninety-patients with AGC that progressed during one or more previous chemotherapy regimens were randomized to a standard dose of wPTX (80 mg/m2, standard dose arm) or an escalated dose of wPTX (80 mg/m2 on day 1, 100 mg/m2 on day 8, and 120 mg/m2 on day 15 unless severe toxicity nor neutropenia9/L is observed, escalated dose arm) to assess superiority with a one-sided alpha of 0.3 and a power of 0.8. Results: The primary endpoint of median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs. 9.6 months; hazard ratio [HR], 0.75; 95% CI, 0.45-1.22; one-sided P=0.12). Median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs. 2.5 months, HR, 0.55; 95% CI, 0.34-0.90; P=0.017). Objective response rate was 30.3% with dose-escalation and 17.1% with standard dose (P=0.2). The disease control rate (DCR) was significantly higher with dose-escalation (78.8% vs. 48.6%, P=0.009). Subset-analysis according to stratification factors including ECOG PS, presence of measurable lesions and lines of previous chemotherapy indicated that OS benefit of the dose escalation is more prominent in PS 0-1 patients (N=81, median 13.6 vs. 9.8 months, HR 0.68, 95% CI 0.41-1.11) than PS2 patients with significant interaction (p=0.01) Conclusions: Dose escalated wPTX was associated with sufficiently longer OS in patients with pretreated AGC. In addition, significant longer PFS and higher DCR associated with dose-escalation and subset analysis according PS warrant further investigations in phase III trials, especially in patients with favorable PS patients. Clinical trial information: UMIN000004055.
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- 2013
253. A randomized phase III trial of S-1/oxaliplatin (SOX) plus bevacizumab versus 5-FU/l-LV/oxaliplatin (mFOLFOX6) plus bevacizmab in patients with metastatic colorectal cancer: The SOFT study
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Yasutsuna Sasaki, Hiroshi Matsumoto, Yasuhiro Shimada, Motoki Yoshida, Daisuke Takahari, Satoshi Morita, Kei Muro, Keiichi Takahashi, Masato Nakamura, Masahiko Watanabe, Kenichi Sugihara, Shigeyoshi Iwamoto, Kazuhiro Yoshida, Yasuhide Yamada, Yasutaka Takinishi, Taroh Satoh, Hideyuki Mishima, Yuh Sakata, Yoshito Komatsu, and Hideo Baba
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Oncology ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,Combination therapy ,business.industry ,Colorectal cancer ,medicine.disease ,Gastroenterology ,Oxaliplatin ,Bolus (medicine) ,Internal medicine ,Clinical endpoint ,Medicine ,In patient ,business ,medicine.drug - Abstract
3519 Background: Several studies of oxaliplatin plus S-1 combination therapy (SOX) conducted in Asia have shown promising efficacy and safety for metastatic colorectal cancer (mCRC), suggesting the potential to replace mFOLFOX6. We performed a randomized phase III trial to determine whether SOX plus bevacizmab (SOX+Bev) is non-inferior to mFOLFOX6 plus bevacizmab (mFOLFOX6+Bev) in terms of progression-free survival (PFS). Methods: The SOFT study was a randomized, open-label, phase III trial. Chemotherapy-naïve patients (pts) with mCRC, an ECOG PS of 0-1, and adequate organ functions were randomized to receive either mFOLFOX6+Bev (5 mg/kg of bevacizumab, followed by 200 mg/m2 of l-leucovorin given simultaneously with 85 mg/m2 of oxaliplatin, followed by a 400 mg/m2 bolus of 5-FU on day 1 and then 2,400 mg/m2 of 5-FU over 46 h, every 2 weeks) or SOX+Bev (7.5 mg/kg of bevacizumab, 130 mg/m2 of oxaliplatin on day 1, and 40−60 mg of S-1 twice daily for 2 weeks, followed by a 1-week rest). The primary endpoint was PFS. A sample size of 225 pts per group was estimated to be necessary based on a median PFS of 10.0 months in each group and an 80% power to demonstrate non-inferiority of SOX+Bev with a 2.5-month margin (hazard ratio, HR = 1.33) and a 2-sided alpha of 0.05. Results: A total of 512 pts were enrolled from February 2009 to March 2011. Data were analyzed after confirming >388 events as planned. Demographic factors were well balanced. Pts received a median of 12 cycles (1 cycle = 2 weeks) of mFOLFOX6+Bev and 8 cycles (1 cycle = 3 weeks) of SOX+Bev (range: 1−16). Median PFS was 11.5 months (95% CI: 10.7−13.2) with mFOLFOX6+Bev and 11.7 months (95% CI: 10.7−12.9) with SOX+Bev. The adjusted HR for PFS was 1.043 (95% CI: 0.860−1.266), and the p value for non-inferiority was 0.0139. Response rate was 62.7% with mFOLFOX6+Bev and 61.5% with SOX+Bev. Grade 3/4 toxicities (%) with mFOLFOX6+Bev/SOX+Bev were leukopenia 8.4/2.4, neutropenia 33.7/8.8, anorexia 1.2/5.2, and diarrhea 2.8/9.2. Conclusions: SOX+Bev is non-inferior to mFOLFOX6+Bev with respect to PFS as 1st-line treatment for mCRC and thus can replace mFOLFOX6+Bev. Clinical trial information: JapicCTI-090699.
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- 2013
254. Prognostic and predictive value of CA19-9 in metastatic colorectal cancer
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Daisuke Takahari, Azusa Komori, Sohhei Nitta, Shigenori Kadowaki, Kazuhisa Yamaguchi, Kei Muro, Takashi Ura, Hiroya Taniguchi, Masashi Andoh, Chihiro Kondoh, and Yukiya Narita
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,endocrine system diseases ,Bevacizumab ,Colorectal cancer ,business.industry ,medicine.medical_treatment ,medicine.disease ,medicine.disease_cause ,digestive system diseases ,Oxaliplatin ,Internal medicine ,Pancreatic cancer ,medicine ,CA19-9 ,KRAS ,business ,medicine.drug ,Tumor marker - Abstract
354 Background: CA19-9 has been approved by FDA as a tumor marker in pancreatic cancer. The prognostic and predictive value of CA19-9 in metastatic colorectal cancer (mCRC) is still unclear. Moreover, CA19-9, a sialyl Lewis A antigen, acts as an adhesion factor of cells lining the blood vessels, but the association between the CA19-9 value and the effect of bevacizumab (BV) has not been reported. Methods: We conducted a retrospective review of 239 patients undergoing first-line chemotherapy by oxaliplatin-based regimens at a single institution from April 2005 to December 2009. The relationship between the CA19-9 value at baseline and the various clinicopathological factors and survival data was analyzed. Results: Median age was 62 years (range 23–83 years). 133 patients had a baseline CA19-9 value above the normal upper limit (>50 U/ml, high group), 86 had ULN (
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- 2013
255. Preliminary Safety Data from Randomized Phase II Study Comparing Dose-Escalated Weekly Paclitaxel Versus Standard-Dose Weekly Paclitaxel for Patients with Previously Treated Advanced Gastric Cancer
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Daisuke Takahari, Ayumu Hosokawa, Setsuo Utsunomiya, Yasushi Tsuji, Takayuki Kii, Satoshi Yuki, K. Muro, Masafumi Nakamura, C. Kondo, Daisuke Ichikawa, Takashi Tsuda, Atsushi Ishiguro, Isao Oze, and K. Shitara
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Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Phases of clinical research ,Weekly paclitaxel ,Hematology ,Neutropenia ,medicine.disease ,chemistry.chemical_compound ,Oncology ,Paclitaxel ,chemistry ,Internal medicine ,medicine ,Clinical endpoint ,Adverse effect ,business ,Febrile neutropenia - Abstract
Background Recently, we studied the effects of neutropenia occurring during second-line chemotherapy with weekly paclitaxel in a retrospective analysis of 242 patients with advanced gastric cancer, and observed better survival among patients with neutropenia compared to patients without neutropenia (Shitara K, et al. Annals of Oncol. 2011). Therefore, we conducted a multi-institutional, open-label, randomized phase II trial comparing dose-escalated weekly paclitaxel with dose adjustments determined by degree of neutropenia versus standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer (protocol ID UMIN000004055). Patients and methods Patients with advanced or recurrent gastric cancer that progressed during one or more previous chemotherapy regimens were included. Ninety patients were randomized to a standard dose of weekly paclitaxel (80 mg/m2, Arm A) or an escalated dose of weekly paclitaxel (80 mg/m2 on day 1, 100 mg/m2 on day 8, and 120 mg/m2 on day 15 unless severe toxicity is observed, Arm B). The primary endpoint was overall survival. Secondary endpoints included objective response rate, disease control rate, progression-free survival, and adverse events. We present the preliminary safety data from the first 8 weeks. Results From September 2010 to November 2011, a total of 90 patients were enrolled at 13 institutions. One patient in Arm B did not receive paclitaxel. The dose of paclitaxel was escalated to 100 mg/m2 in 41 patients (91.1%) and then to 120 mg/m2 in 29 patients (64.4%) in Arm B. In the first 8 weeks, 25 (55.5%) patients in Arm A patients and 20 (46.7%) patients in Arm B required dose reduction or treatment delay. Frequencies of grade 1 or more neutropenia were 66.7% in Arm A and 86.4% in Arm B, and grade 3 or more neutropenia frequencies were 31.1% in Arm A and 38.6% in Arm B. Grade 1 or more sensory neuropathy frequencies were 55.6% in Arm A and 68.1% in Arm B. Two patients in Arm A and one patient in Arm B experienced febrile neutropenia. No treatment-related deaths occurred. Conclusions Preliminary safety data during the first 8 weeks of treatment indicate comparable compliance between the two arms, despite the substantial number of patients who underwent dose escalation. Disclosure All authors have declared no conflicts of interest.
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- 2012
256. Recursive partitioning for new classification of patients with esophageal cancer treated by chemoradiotherapy
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M. Nomura, Chihiro Kondoh, Hiroyuki Kojima, Takeshi Kodaira, Satoshi Sawada, Kohei Shitara, Minoru Kamata, Takashi Ura, Daisuke Takahari, and Kei Muro
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Oncology ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,business.industry ,Univariate ,Recursive partitioning ,Hematology ,Definitive chemoradiotherapy ,Esophageal cancer ,medicine.disease ,Object (computer science) ,Surgery ,medicine.anatomical_structure ,Internal medicine ,Medicine ,business ,Lymph node ,Chemoradiotherapy ,Cancer staging - Abstract
e14500 Background: The 7th edition of the American Joint Committee on Cancerstaging system does not include lymph node size in the guidelines for staging patients with esophageal cancer. The objectives of this study were to determine the prognostic impact of the largest lymph node diameter (ND) on survival and to develop and validate a new staging system for patients with esophageal squamous cell cancer who were treated with definitive chemoradiotherapy (CRT). Methods: Information on 402 patients with esophageal cancer undergoing CRT at 2 institutions was reviewed. Univariate and multivariate analyses of data from 1 institution were used to assess the impact of clinical factors on survival, and recursive partitioning analysis was performed to develop the new staging classification. To assess its clinical utility, the new classification was validated using data from the second institution. Results: According to RPA, ND stages were best when classified as ND0 (the absence of lymph node metastases), ND1 (< 2.8 cm), and ND2 (≥ 2.8 cm). By multivariate analysis, gender, T, N, and ND stages were independently and significantly associated with survival (p
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- 2012
257. Survival analysis of adjuvant chemotherapy with S-1 plus cisplatin for stage III gastric cancer
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Hirofumi Yasui, Daisuke Takahari, Hitoshi Katai, Tetsuya Hamaguchi, Seiji Ito, Taira Kinoshita, Masanori Terashima, Kenichi Yoshimura, Masahiro Gotoh, and Nozomu Fuse
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Cisplatin ,Cancer Research ,medicine.medical_specialty ,Adjuvant chemotherapy ,business.industry ,D2 gastrectomy ,Stage III Gastric Cancer ,Cancer ,medicine.disease ,Gastroenterology ,Oncology ,Recurrence free survival ,Internal medicine ,medicine ,Stage (cooking) ,business ,Survival analysis ,medicine.drug - Abstract
107 Background: The efficacy of S-1 for stage II-III gastric cancer has been shown. However, the survival of stage III remains unsatisfactory (the 3-year recurrence free survival rates in stage IIIA and IIIB receiving S-1 were 68.0% and 49.8%, respectively). We already reported the feasibility of S-1 plus cisplatin as adjuvant chemotherapy for Stage III gastric cancer after curative resection (ASCO-GI 2009, Cancer Chemother Pharmacol 2011). Here we evaluate the recurrence and survival as secondary endpoints. Methods: Japanese patients with stage III gastric cancer who underwent D2 gastrectomy were enrolled. Treatment consisted of 3 cycles of S-1 (40 mg/m2 po) twice daily on days 1-21 and CDDP (60 mg/m2 iv) on day 8 and S-1 monotherapy was given on days 1-28 every 6 weeks until 1 year post surgery. Results: From August 2007 to September 2009, 63 patients were accrued. 35 patients were stage IIIA, the rest 28 patients were IIIB. After a median follow-up 2.9 years, 15 patients experienced recurrence, and 12 patients died. The 3-year recurrence free survival rate was 76.4% (95%CI:63.0-85.4%, IIIA 88.8%, IIIB 60.1%). The 3-year overall survival rate was 78.5% (95%CI:63.4-87.9%, IIIA 85.0%, IIIB 71.9%). The site of recurrence was mainly peritoneum (n=10), liver (n=3), and lymph node (n=3). Conclusions: Our results indicated that adjuvant therapy with S-1 plus 3 cycles of cisplatin may reduce recurrence and improve survival of stage III gastric cancer. This treatment should be considered as an experimental arm comparing with S-1 monotherapy for the next postoperative adjuvant phase III trial.
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- 2012
258. Survival of patients with HER2-positive gastric cancer with introduction of trastuzumab
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Daisuke Takahari, Kohei Shitara, Masato Sugano, Kei Muro, Keitaro Matsuo, Masahiro Tajika, Takashi Ura, Chihiro Kondo, and Yasushi Yatabe
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Oncology ,Cisplatin ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,Systemic chemotherapy ,medicine.medical_treatment ,Treatment outcome ,Cancer ,medicine.disease ,Trastuzumab ,Internal medicine ,medicine ,Immunohistochemistry ,skin and connective tissue diseases ,business ,neoplasms ,Median survival ,medicine.drug - Abstract
128 Background: ToGA study showed that trastuzumab given in combination with first-line chemotherapy (fluoropyrimidine plus cisplatin) improved the overall survival of HER2-positive patients with advanced gastric cancer (AGC). Meanwhile, the prognostic value of HER2 or the efficacy of trastuzumab in second- or further-line chemotherapy remains controversial. Methods: We retrospectively analyzed 567 patients with AGC who initiated systemic chemotherapy before March 2011. Among them, 287 were evaluated for their HER2 status. HER2 positivity was defined as IHC 3+ or IHC 2+ with amplification by FISH. Treatment outcomes were compared between patients with HER2-positive and HER2-negative AGC. To evaluate the impact of exposure to trastuzumab in any line of chemotherapy, we applied time-varying covariates (TVC) analysis to avoid possible lead-time bias. Results: The median survival time (MST) of HER2-evaluated patients (n=287) tended to be better than that of HER2-non-evaluated patients (n=280, 14.5 vs. 13.2 months; P=0.03). Among the HER2-evaluated patients, 47 (16.3%) were HER2-positive and had longer survival than HER2-negative patients (24.1 vs. 13.4 months; P=0.05). Among the HER2-positive patients, 35 received trastuzumab; 15 patients received it as first-line therapy and 20 received it as second- or further-line therapy. The MST of HER2-positive patients with trastuzumab treatment was significantly longer than that of HER2-positive patients without trastuzumab (26.6 vs. 13.5 months; P=0.015). HER2-negative patients and HER2-positive patients without trastuzumab had similar survival durations. According to multivariate analysis with TVCs, exposure to trastuzumab was independently associated with better prognosis (HR 0.54, P=0.04). Conclusions: Although the retrospective nature and small sample size are major limitations of this study, recent HER2-positive AGC patients showed a better prognosis than HER2-negative patients, especially with the introduction of trastuzumab.
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- 2012
259. 6513 POSTER Reporting Patient Characteristics and Stratification Factors in Randomized Trials of Systemic Chemotherapy for Advanced Gastric Cancer
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K. Muro, Keitaro Matsuo, C. Kondo, Kohei Shitara, Junichi Ikeda, and Daisuke Takahari
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Oncology ,Cancer Research ,medicine.medical_specialty ,Prognostic factor ,Chemotherapy ,Systemic chemotherapy ,business.industry ,medicine.medical_treatment ,Patient characteristics ,Advanced gastric cancer ,law.invention ,Surgery ,Clinical trial ,stomatognathic diseases ,Stratification Factor ,Randomized controlled trial ,law ,Internal medicine ,medicine ,business - Abstract
Background There is no consensus on which patient characteristics are the most suitable to report or to be used as stratification factors in clinical trials for advanced gastric cancer (AGC), to our knowledge.
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- 2011
260. Prognostic effect of the sixth and seventh American Joint Committee on Cancer TNM staging systems on esophageal cancer patients treated with chemoradiotherapy
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Shunzo Hatooka, Kei Muro, Takashi Ura, M. Nomura, Daisuke Takahari, Chihiro Kondoh, Takeshi Kodaira, Tomoya Yokota, K. Shitara, and Ayako Mizota
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Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Esophageal cancer ,TNM staging system ,medicine.disease ,Oncology ,parasitic diseases ,Medicine ,TNM Staging ,Radiology ,business ,Chemoradiotherapy - Abstract
e14659 Background: The new seventh edition of the American Joint Committee on Cancer TNM staging system is based on pathologic data from esophageal cancers treated by surgery alone. There is no inf...
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- 2011
261. Multicenter feasibility study of 5-FU, leucovorin, plus paclitaxel (FLTAX) for peritoneal disseminated gastric cancer with massive ascites or inadequate oral intake
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Hiroya Takiuchi, Koichi Taira, Norisuke Nakayama, Tomohiro Nishina, Shuichi Hironaka, Takako Eguchi Nakajima, Hisateru Yasui, Daisuke Takahari, Hitoshi Kusaba, and Nozomu Fuse
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Cancer Research ,medicine.medical_specialty ,business.industry ,Standard treatment ,Inadequate oral intake ,medicine.disease ,Gastroenterology ,Surgery ,Regimen ,Bolus (medicine) ,Oncology ,Gastrointestinal perforation ,Fluorouracil ,Internal medicine ,Ascites ,medicine ,medicine.symptom ,business ,Febrile neutropenia ,medicine.drug - Abstract
119 Background: Oral fluoropyrimidine plus cisplatin is widely used as a standard treatment for advanced gastric cancer, but patients (pts) with severe peritoneal metastasis often cannot tolerate this regimen. The aim of this study was to assess the feasibility of fluorouracil (5-FU), leucovorin (LV), plus paclitaxel (PTX) for peritoneal disseminated gastric cancer with massive ascites or inadequate oral intake. Methods: Peritoneal disseminated gastric cancer with massive ascites or inadequate oral intake were enrolled in Part I (Level 1 (n=6): 5-FU bolus/l- LV div 2hr/PTX div 1hr = 500/250/60, Level 2 (n=6): 600/250/80 mg/m2 (day1, 8, 15, q4w) to determine dose-limiting toxicity (DLT) and recommended dose (RD). In Part II (n=19), primary endpoint was completion rate of 2 cycles to evaluate the feasibility of this regimen at RD level. Results: One of Level 1 pts had DLT with grade 4 gastrointestinal perforation. Two of Level 2 pts had DLT (grade 3 febrile neutropenia and grade 3 infection with normal neutrophils) and treatment-related death (TRD) was observed in one patient due to pneumonia with grade 4 neutropenia. The RD was determined to be Level 1. Twenty-five patients were enrolled at RD level: first-line/second-line=18/7, performance status 0/1/2=1/19/5. The completion rate of 2 cycles was 92% and objective response rate of ascites was 45%. Grade 3 or 4 neutropenia was observed in 12% (febrile neutropenia in 8%). Five patients out of 7 second-line patients died within 30 days after last administration of FLTAX (TRD: 1 and disease progression: 4). Conclusions: RD of FLTAX regimen was 5-FU/l-LV/PTX=500/250/60 mg/m2. This regimen was feasible as the first-line treatment against peritoneal disseminated gastric cancer patients with massive ascites or inadequate oral intake. [Table: see text]
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- 2011
262. Progression-free survival and time to progression as surrogate markers of overall survival in patients with advanced gastric cancer: Literature-based analysis of 36 randomized trials
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Takashi Ura, M. Nomura, Tomoya Yokota, K. Shitara, Ayako Mizota, Kei Muro, Keitaro Matsuo, Chihiro Kondo, Daisuke Takahari, and Junichi Ikeda
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Hazard ratio ,Advanced gastric cancer ,Spearman's rank correlation coefficient ,Surgery ,law.invention ,Clinical trial ,Randomized controlled trial ,law ,Internal medicine ,Overall survival ,Medicine ,In patient ,Progression-free survival ,business - Abstract
103 Background: We evaluated the potential of progression-free survival (PFS) and time to progression (TTP) to act as surrogates of overall survival (OS) in clinical trial settings by a comprehensive literature-based analysis. Methods: Randomized trials of systemic chemotherapy for advanced gastric cancer were identified by comprehensive electronic and manual search. Correlations between PFS/TTP and OS were evaluated. Results: Thirty-six trials with a total of 83 treatment arms and 10,484 patients were selected for analysis. The nonparametric Spearman rank correlation coefficient (p) between median PFS/TTP and OS was 0.70 (95% CI, 0.59 to 0.82) and the correlation coefficient between hazard ratios in PFS/TTP and OS was 0.80 (95% CI, 0.68 to 0.92). Correlation tended to be higher in non-Asian (p = 0.80; 0.61-0.98) than Asian trials (p = 0.67; 0.39-0.94), higher in trials reporting PFS (p = 0.85; 0.72-0.97) than in those reporting TTP (p = 0.60; 0.24-0.97), and higher in trials in patients with measurable lesions only (p = 0.91; 0.77-1.00) than in those including non-measurable lesions (p = 0.71; 0.50-0.93), albeit that none of these differences was significant. Conclusions: Our results indicate that improvements in PFS/TTP in advanced gastric cancer strongly correlate with improvements in OS. PFS/TTP may be an appropriate surrogate for OS in clinical trials for advanced gastric cancer. No significant financial relationships to disclose.
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- 2011
263. Phase I study of cediranib in combination with cisplatin plus fluoropyrimidine (S-1 or capecitabine) in Japanese patients (pts) with untreated advanced gastric cancer (AGC)
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Kei Muro, Yuki Yamada, Daisuke Takahari, Hidetoshi Hayashi, Keisei Taku, X. Shi, Taroh Satoh, Yoshihisa Shimada, Takako Eguchi Nakajima, and N. Boku
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Oncology ,Cisplatin ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Combination therapy ,business.industry ,medicine.medical_treatment ,Pharmacology ,Capecitabine ,Cediranib ,Tolerability ,Pharmacokinetics ,Internal medicine ,medicine ,Adverse effect ,business ,medicine.drug - Abstract
111 Background: Cediranib (AZD2171) is an oral, highly potent inhibitor of VEGF signalling with activity versus all three VEGFRs and c-Kit. Combination therapy with cisplatin + oral fluoropyrimidine is commonly used as first-line treatment for AGC. This phase I study assessed cediranib in combination with cisplatin/S-1 or cisplatin/capecitabine in Japanese pts with previously untreated AGC. Methods: Eligible pts received cediranib 20 mg/day and either cisplatin 60 mg/m2 iv, day 1 + S-1 40–60 mg bd, days 1–21, q5w (Arm A) or cisplatin 80 mg/m2 iv, day 1 + capecitabine 1000 mg/m2 bd, days 1–14, q3w (Arm B). The primary endpoint was safety and tolerability. Secondary endpoints included assessment of steady-state pharmacokinetics (PK) of cediranib and chemotherapy alone and in combination. Preliminary efficacy was an exploratory objective. Adverse events (AEs) were evaluated according to CTCAE v3.0. Results: Between Aug–Dec 2009, 14 pts (median age, 60.5 [27–72] years; male, n = 9; PS 0/1, n = 7/7) were recruited to Arm A (n = 6) or Arm B (n = 8). The safety profile in both arms was consistent with that of the individual agents. There were no unexpected toxicities. All pts experienced ≥1 AE. Dose-limiting toxicities were reported in 1 pt in Arm A (decreased appetite) and 1 pt in Arm B (decreased appetite, fatigue, hyponatremia). The most common AEs in Arm A were decreased appetite, fatigue, nausea, diarrhoea, decreased weight and neutropenia (all n = 5; 83%), and decreased appetite, fatigue, nausea (all n = 8; 100%) and constipation (n = 7; 88%) in Arm B. Five (83%) pts in Arm A and 6 (75%) in Arm B experienced grade ≥ 3 AEs. Grade 3 AEs in > 1 pt were neutropenia (n = 3) in Arm A and hypokalaemia (n = 3), neutropenia, hyponatraemia and fatigue (all n = 2) in Arm B. Grade 4 syncope was reported in 1 pt in Arm A; this resolved on the same day it was observed. Preliminary efficacy and PK data will be presented. Conclusions: Cediranib 20 mg plus cisplatin/S-1 or cisplatin/capecitabine was generally well tolerated and considered suitable for further evaluation in pts with AGC. The safety profile of each regimen was comparable with the individual agents. No new toxicities were identified. [Table: see text]
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- 2011
264. Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines
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Satoshi Yuki, Kei Muro, Masahiro Tajika, Yasushi Sato, Tomoya Yokota, K. Shitara, Setsuo Utsunomiya, Daisuke Takahari, and Motoki Yoshida
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Oncology ,Cancer Research ,medicine.medical_specialty ,Cetuximab ,business.industry ,Colorectal cancer ,Phases of clinical research ,Combination chemotherapy ,medicine.disease ,medicine.disease_cause ,digestive system diseases ,Irinotecan ,Regimen ,Refractory ,Internal medicine ,Medicine ,KRAS ,business ,neoplasms ,medicine.drug - Abstract
561 Background: Weekly cetuximab and irinotecan is a standard regimen in heavily pretreated patients with metastatic colorectal cancer (MCRC). The aim of this study was to prospectively evaluate the efficacy of combination chemotherapy with biweekly cetuximab and irinotecan in patients with pretreated MCRC harboring wild-type KRAS. Methods: Patients with wild- type KRAS MCRC that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included in this study. Cetuximab was administered at 500 mg/m2 biweekly with irinotecan. The primary endpoint was response rate. The secondary endpoints included adverse events, progression-free survival, and overall survival. The pharmacokinetics of cetuximab was also evaluated in five patients. Results: From May, 2009 to February, 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 assessable patients, ECOG PS was 0 in 12, 1 in 16, and 2 in two patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7-49.4), and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95%CI, 61.4-92.3). The median progression-free survival was 5.3 months (95%CI, 3.4-7.3). Grade 3 skin toxicity was observed in 3 patients (10%), and treatment related death due to pneumonia occurred in one patient. Conclusions: The efficacy data are similar to those of standard dose of cetuximab plus irinotecan. Combination chemotherapy with biweekly cetuximab and irinotecan is effective for pretreated metastatic wild-type KRAS MCRC. No significant financial relationships to disclose.
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- 2011
265. Evaluation of the seventh TNM classification system in patients with esophageal cancer receiving chemoradiotherapy
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Daisuke Takahari, Tomoya Yokota, Takashi Ura, Takeshi Kodaira, K. Shitara, Ayako Mizota, M. Nomura, Chihiro Kondoh, Kei Muro, and Shunzo Hatooka
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,In patient ,Esophageal cancer ,medicine.disease ,business ,Chemoradiotherapy - Abstract
83 Background: The new 7th edition of the TNM classification system is based on pathologic data of esophageal cancer underwent surgery alone. No report is available on the prognostic evaluation of the new staging system in patients treated with chemoradiotherapy (CRT). The objective of this study was to evaluate the prognostic impact of the 7th edition of the TNM staging system in esophageal cancer patients treated with CRT. Methods: A retrospective review was performed of 301 consecutive patients who met the following inclusion criteria: (1) squamous cell carcinoma of thoracic esophagus; (2) total radiation dose ≥ 50 Gy; (3) concomitant chemotherapy consisting of 5-fluolouracil and platinum; (4) no previous thoracic radiotherapy or surgery. We compared the prognostic impact of the 6th and 7th editions of the TNM staging systems. Also, we compared the prognostic impact of stage group and prognostic group, which was newly defined in the 7th edition. Survival analysis was performed by using log-rank and Cox regression testing. Results: Patients with stage I/II/III/IV were 52/42/54/153 and 57/46/128/70 according to 6th and 7th edition, respectively. Eighty-four patients were shifted to a lower stage in 7th edition compared with 6th edition, and most of these were from stage IV to III (n = 74). There were significant differences among stages I to III (p < 0.01, respectively) according to each edition. However, 7th edition poorly distinguishes between stages III and IV (p = 0.43). The survival curve of stage IV (lymph) almost completely overlapped with stage III (p = 0.69), although there were significant differences between stages IV (lymph) and IV (organ) (p = 0.04). Among the factors included in prognostic group in 7th edition, the histological grade and cancer site had no significant influence on patient survival, and T factor was only independent prognostic factors in multivariate analysis (p < 0.01). Conclusions: Our study suggested several pitfalls in 7th TNM classification as prognostic factor in patients who received CRT. No significant financial relationships to disclose.
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- 2011
266. Evaluation of BRAF mutation as a powerful prognostic factor in advanced and recurrent colorectal cancer
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Tomoya Yokota, Chihiro Kondo, Ayako Mizota, Daisuke Takahari, K. Shitara, N. Shibata, Yasushi Yatabe, Takashi Ura, Kei Muro, and M. Nomura
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Cancer Research ,Prognostic factor ,endocrine system diseases ,Colorectal cancer ,business.industry ,Erk signaling ,medicine.disease_cause ,medicine.disease ,digestive system diseases ,Oncology ,Mutation (genetic algorithm) ,medicine ,Cancer research ,Recurrent Colorectal Cancer ,KRAS ,business ,neoplasms - Abstract
413 Background: Alterations in the RAS/RAF/ERK signaling pathways frequently occur in colorectal cancer (CRC). KRAS mutations preclude responsiveness to EGFR-targeted therapies for CRC patients. However, prognostic significance of KRAS mutation is still controversial. The aim of this study is to investigate clinicopathological features of KRAS mutation in codon 12 and 13 as well as of BRAF mutation, and to validate prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC. Methods: The population consisted of 230 unselected patients who had undergone first-line chemotherapy for advanced and recurrent CRC between November 2002 and June 2010. Cycleave PCR was performed to detect a point mutation at codon 12, 13 or 61 in KRAS, and the V600E mutation in BRAF. Prognostic factors associated with survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. Results: KRAS mutations were present in 34.8% (n= 80) of patients, including 23.5% (n = 54) in codon 12, 11.3% (n = 26) in codon 13, and 0% in codon 61. 6.5% (n = 15) of patients had BRAF mutation. None of the CRC patients carried both KRAS and BRAF mutations. The primary tumor lesions were located on the right side of the colon in 60% of the BRAF mutant patients (p=0.0371). Furthermore, BRAF mutant was significantly associated with the pathological subtypes of poorly differentiated adenocarcinoma/mucinous carcinoma (p Conclusions: This retrospective analysis shows that clinicopathological features of CRC patients with BRAF mutations seem to be distinct from those with wild type BRAF. BRAF mutation is one of the most powerful prognostic factors in advanced and recurrent CRC. No significant financial relationships to disclose.
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- 2011
267. PTEN/p-AKT expression as predictive markers for cetuximab in colorectal cancer
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Daisuke Takahari, N. Shibata, K. Shitara, Tomoya Yokota, Kei Muro, T. Shibata, Yasushi Yatabe, and Takashi Ura
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MAPK/ERK pathway ,Oncology ,Cancer Research ,medicine.medical_specialty ,endocrine system diseases ,biology ,Cetuximab ,business.industry ,Colorectal cancer ,medicine.disease_cause ,medicine.disease ,digestive system diseases ,Internal medicine ,medicine ,biology.protein ,PTEN ,KRAS ,Signal transduction ,business ,neoplasms ,Protein kinase B ,PI3K/AKT/mTOR pathway ,medicine.drug - Abstract
e14031 Background: Alterations in the Ras/Raf/ERK and PTEN/PI3K/AKT signaling pathways frequently occur in colorectal cancer (CRC). KRAS or BRAF mutations preclude responsiveness to EGFR-targeted t...
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- 2010
268. Association of folate intake and outcome of patients with advanced gastric cancer treated with first-line fluorouracil-based chemotherapy
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Daisuke Takahari, Hiroki Kawai, Tomoya Yokota, Akira Sawaki, K. Shitara, Keitaro Matsuo, Seiji Ito, Takashi Ura, Kei Muro, and T. Shibata
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,First line ,Advanced gastric cancer ,Preclinical data ,Fluorouracil ,Dietary folate ,Internal medicine ,medicine ,Folate intake ,business ,medicine.drug - Abstract
e14518 Background: A relationship between dietary folate intake and efficacy of fluorouracil (FU) is supported by preclinical data. We already reported that dietary folate intake and genetic polymo...
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- 2010
269. Neutropenia as a prognostic factor in metastatic colorectal cancer patients undergoing chemotherapy with first-line FOLFOX
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Keitaro Matsuo, Kei Muro, Takashi Ura, Daisuke Takahari, Tomoya Yokota, and K. Shitara
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Oncology ,Cancer Research ,medicine.medical_specialty ,Prognostic factor ,Chemotherapy ,Bevacizumab ,business.industry ,Colorectal cancer ,First line ,medicine.medical_treatment ,Neutropenia ,medicine.disease ,digestive system diseases ,FOLFOX ,hemic and lymphatic diseases ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
4115 Background: FOLFOX combined with bevacizumab is established as standard first-line chemotherapy for metastatic colorectal cancer (MCRC), and neutropenia is one of the most common of its side effects. Neutropenia during chemotherapy has been reported to be a predictor of better survival in patients with several type of cancers, although there are no reports in MCRC. We aimed to assess whether neutropenia during chemotherapy could be a marker of improved survival of patients with MCRC. Methods: Patients with MCRC who received FOLFOX with or without bevacizumab as first-line chemotherapy were retrospectively analyzed to assess whether neutropenia during chemotherapy is associated with improved survival. Several background characteristics and chemotherapy features (grade of neutropenia, use of bevacizumab, use of irinotecan, reintroduction of oxaliplatin, and tumor progression) as time-varying covariates (TVCs) were analyzed as potential prognostic factors. Results: Of 153 patients, mild neutropenia (grade 1–2) occurred in 60 patients (39%) and severe neutropenia (grade 3–4) occurred in 46 patients (30%). The other 47 patients (31%) did not experience neutropenia. In 106 patients experiencing neutropenia, 66% of patients experienced their highest grade within 4 cycles. According to a multivariate Cox model with TVCs, hazard ratios of death were 0.55 (95% CI, 0.31–0.98; P = 0.044) for patients with mild neutropenia and 0.35 (95% CI, 0.18–0.66; P = 0.002) for those with severe neutropenia. If the analysis of neutropenia was limited to 4 cycles of FOLFOX, mild or severe neutropenia remained a significant prognostic factor according to survival analysis with TVCs. Conclusions: Both mild and severe neutropenia during chemotherapy are associated with improved survival in patients with MCRC. Prospective trials are required to assess whether dosing adjustments based on neutropenia may improve chemotherapy efficacy. No significant financial relationships to disclose.
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- 2009
270. Development of an assay for KRAS mutation as a predictive marker for cetuximab in colorectal cancer
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K. Shitara, Kei Muro, Tomoya Yokota, Daisuke Takahari, N. Shibata, Takashi Ura, and Yasushi Yatabe
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Cancer Research ,Predictive marker ,Cetuximab ,Colorectal cancer ,business.industry ,medicine.disease ,digestive system diseases ,Oncology ,medicine ,Cancer research ,business ,neoplasms ,Pathological ,Kras mutation ,medicine.drug - Abstract
e15048 Background: The activating KRAS mutation is an important predictive marker for anti-EGFR therapy against colorectal cancer (CRC), although valid assays using pathological specimens have not been yet established. We present a rapid, sensitive assay for KRAS genotyping using small biopsy specimens. Methods: We used Cycleave PCR to detect the KRAS mutation in CRC with a chimeric DNA-RNA-DNA probe labeled with fluorescent dye and quencher, with results obtained within 4 hours. Template DNA was extracted from formalin-fixed, paraffin-embedded specimens, which are surgically resected or biopsied in clinical practice. Results: To evaluate Cycleave PCR accuracy for detecting the KRAS mutation, we compared with results of reverse transcriptase-PCR-coupled direct sequencing (RT-PCR-DS) of metastatic lung tumor specimens from CRC patients. KRAS mutations were present in 40 (43%) of 94 patients, including 28 (30%) and 8 (9%) in codon 12 and codon 13 mutations, respectively. Concordant results between Cycleave PCR and RT-PCR-DS in KRAS codon 12 and 13 were found in 35/36 (97%) and 23/23 (100%), respectively. We also applied this method to surgical specimens in clinical practice. Although 8 from 73 patients (11%) could not be evaluated with Cycleave PCR, corresponding biopsy specimens could be used alternatively. Because biopsy specimens were fixed by formalin for a shorter period, fixation of surgical specimens for longer time may have contributed to PCR failure. Indeed, over- fixation by formalin impaired PCR amplification of KRAS in time-dependently. Furthermore, results of 4 randomly selected biopsy specimens using Cycleave PCR were consistent with those of surgical specimens. Conclusions: Cycleave PCR even using biopsy specimens is accurate, rapid, and useful to detect KRAS mutations in CRC patients. This study also called attention to specimen selection, as over-fixation by formalin may lead to failure of the gene examination due to template DNA fragmentation. This method can be applied to examine BRAF genotyping as well as KRAS. KRAS/BRAF genotyping by Cycleave PCR leads to individualized therapy using cetuximab for CRC patients. No significant financial relationships to disclose.
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- 2009
271. Chemotherapy for patients with advanced gastric cancer with performance status 2
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Kei Muro, Yuh Sakata, Daisuke Takahari, K. Shitara, Takashi Ura, Masaki Munakata, Hiroki Kawai, Tomoya Yokota, and Akira Sawaki
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Cisplatin ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Phase iii trials ,Performance status ,business.industry ,Standard treatment ,medicine.medical_treatment ,Advanced gastric cancer ,Treatment results ,Gastroenterology ,Surgery ,Oncology ,Internal medicine ,medicine ,Poor performance status ,skin and connective tissue diseases ,business ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
e15627 Background: S-1 plus cisplatin is considered to be the standard chemotherapy for Japanese patients with advanced gastric cancer (AGC) according to the results of three phase III trials (JCOG9912/SPIRITS/TOP-002). However, since few patients with poor performance status (PS2) were included in these phase III trials (27 of 1317; 2%), the standard treatment of patients with PS2 has not been established yet. In also, the characteristics and prognosis of AGC patients with PS2 has not been reported in detail. Methods: We retrospectively analyzed 545 patients with AGC treated by chemotherapy during the period from January 2003 to June 2008. Patients characteristic and treatment results were compared between PS0–1 and PS2. Results: At the beginning of 1st-line chemotherapy, PS0–1/2/3–4 was 454/69/22 cases respectively. Patients with peritoneal/pleural dissemination was more common in PS2 than PS0–1 (75% vs. 43%, p No significant financial relationships to disclose.
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- 2009
272. Efficacy of palliative radiotherapy for gastric bleeding in patients with unresectable advanced gastric cancer: a retrospective cohort study.
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Chihiro Kondoh, Kohei Shitara, Motoo Nomura, Daisuke Takahari, Takashi Ura, Hiroyuki Tachibana, Natsuo Tomita, Takeshi Kodaira, and Kei Muro
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HEMOGLOBINS ,HEMORRHAGE ,HEMOSTASIS ,LONGITUDINAL method ,PALLIATIVE treatment ,RADIOTHERAPY ,STOMACH tumors ,RETROSPECTIVE studies ,DATA analysis software ,DESCRIPTIVE statistics ,KAPLAN-Meier estimator ,DISEASE complications - Abstract
Background: Bleeding negatively impacts quality of life in patients with unresectable advanced gastric cancer and has the potential to be lethal. When blood transfusion and endoscopic hemostasis are unsuccessful to stop bleeding, radiation to stomach is selected in patients with unsuitable condition for surgery. We performed a retrospective cohort study to clarify the utility of radiotherapy in treating gastric bleeding, particularly for patients with limited life expectancy. Methods: We evaluated the efficacy and safety of palliative radiotherapy in patients with advanced gastric cancer between January 2007 and December 2012 in Aichi Cancer Center Hospital. All patients had gastric bleeding requiring blood transfusion. We defined hemostasis as an increase in hemoglobin level to more than 7.0 g/dL together with the cessation of melena or hematemesis for at least 1 week. Results: During the study period, 313 advanced gastric cancer patients treated in our institution. Of these 17 patients received gastric radiotherapy to stop bleeding. Two patients were excluded from analysis due to combined treatment of intravascular embolization. Eleven out of 15 patients (73 %) had undergone two or more previous chemotherapy regimens. Ten patients (67 %) had an Eastern Cooperative Oncology Group performance status of 3 and 14 patients (93 %) were in palliative prognostic index group B or C. The median total planned radiation dose was 30 Gy in 10 fractions. At a median interval of 2 days after initiation of radiotherapy, 11 patients (73 %) achieved hemostasis; rebleeding was observed in four patients (36 %). The median hemoglobin level before radiotherapy was significantly increased from 6.0 to 9.0 g/dL (p < 0.0001). The median volume of red blood cell transfusion was significantly decreased from 1120 to 280 mL (p = 0.007). The median rebleeding-free survival interval was 27 days, with a median overall survival of 63 days. The cause of death was bleeding in 1 patient (7 %) and cancer progression without bleeding in 12 patients (80 %). There were no severe adverse events attributable to radiotherapy. Conclusions: Palliative radiotherapy for gastric bleeding achieves hemostasis within a short time frame. This appears to be a useful treatment option, especially for patients with end-stage, unresectable advanced gastric cancer. [ABSTRACT FROM AUTHOR]
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- 2015
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273. A single-arm phase II trial of combined chemotherapy with S-1, oral leucovorin, and bevacizumab in heavily pre-treated patients with metastatic colorectal cancer.
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Kazuhisa Yamaguchi, Hiroya Taniguchi, Azusa Komori, Yukiya Narita, Sohei Nitta, Motoo Nomura, Shigenori Kadowaki, Daisuke Takahari, Takashi Ura, Masashi Andoh, Kei Muro, Keita Mori, and Yoshinori Igarashi
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CANCER chemotherapy ,FOLINIC acid ,BEVACIZUMAB ,CLINICAL trials ,COLON cancer patients ,COLON cancer treatment ,THERAPEUTICS - Abstract
Background: The mean 5-6-month survival after failed standard chemotherapy for metastatic colorectal cancer (mCRC) necessitates more effective treatments for refractory mCRC. For untreated mCRC, S-1 + oral leucovorin (SL) therapy offers promising results without severe toxicity. The ML18147 trial demonstrated that bevacizumab (Bev) prolongs overall survival after mCRC progression. We conducted a single-centre phase-II trial to evaluate the safety and efficacy of SL/Bev combination chemotherapy as mCRC salvage therapy. Methods: Major eligibility criteria were confirmed adenocarcinoma diagnosis; age >20 years; Eastern Cooperative Oncology Group performance status, 0-2; and progression after administration/intolerance of/to approved drugs for mCRC. (5-FU, oxaliplatin, irinotecan, Bev, and anti-EGFR antibody, if KRAS wild-type). S-1 (80-120 mg/body) and leucovorin (25 mg) were orally administered in a 1-week-on/1-week-off schedule. Bev (5 mg/kg) was administered on day 1 of every 2-week cycle. The primary endpoint was disease control rate (DCR). Results: A total of 31 patients were enrolled. DCR was 65% [95% confidence interval (CI), 48-100%] and the response rate was 7% (95% CI, 0.7-22%). One patient showing partial response to SL/Bev had a BRAF-mutant tumor. Median progression-free survival and overall survivals were 5.3 [95% CI, 2.1-9.3] and 9.9 [95% CI, 7.4-NA] months, respectively. The most-frequent grade-3/4 adverse events were mucositis (26%) and diarrhea (11%), which were manageable by dose reduction/interruption. Conclusions: SL/Bev showed impressive activity in refractory mCRC and was tolerable, suggesting its potential as an alternative chemotherapy for refractory mCRC. [ABSTRACT FROM AUTHOR]
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- 2015
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274. Relationship of insulin-like growth factor-1 receptor and epidermal growth factor receptor expression to clinical outcomes in patients with colorectal cancer
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Yuki Yamada, Yoshihisa Shimada, Daisuke Takahari, Kuniaki Shirao, Junichi Matsubara, A. Takashima, Natsuko Okita, Tetsuya Hamaguchi, Yoshinori Hirashima, Kyoko Kato, and Tadakazu Shimoda
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Cancer Research ,biology ,business.industry ,Colorectal cancer ,medicine.medical_treatment ,Cell ,medicine.disease ,Insulin-like growth factor ,medicine.anatomical_structure ,Oncology ,Apoptosis ,Cancer research ,biology.protein ,Medicine ,Growth factor receptor inhibitor ,In patient ,Epidermal growth factor receptor ,business ,Receptor - Abstract
4117 Background: Insulin-like growth factor-1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), and HER2 have been reported to regulate tumor growth by interfering with apoptosis, cell proliferation, angiogenesis, and metastasis. However, the clinical significance of these molecules in colorectal cancer (CRC) remains undetermined. To gain further insight, we evaluated the prognostic implications of these biomarkers in patients with CRC treated with fluoropyrimidines or irinotecan. Methods: The study group comprised 91 patients who underwent surgery at National Cancer Center Hospital and subsequently received fluoropyrimidines as 1st-line chemotherapy for recurrent or residual tumors. The expressions of IGF-1R, EGFR, and HER2 in surgically removed specimens of primary lesions were analyzed immunohistochemically to determine the prognostic significance of these biomarkers. Results: IGF-1R expression (defined as >10% membranous staining) was found in 81 tumors (89%), EGFR in 77 (85%), and HER2 in 3 (3%). IGF-1R expression significantly correlated with EGFR expression (P=0.038). Overexpression (defined as >50% membranous staining) of IGF-1R was found in 48 tumors (53%), EGFR in 57 (63%), and HER2 in 2 (2%). Overexpression of IGF-1R significantly correlated with shorter survival from the start of 1st-line chemotherapy (P=0.032). Overexpression of EGFR was a significant predictive factor for a clinical response to fluoropyrimidines (P=0.037) and tended to correlate with TTP in patients given irinotecan as 2nd-line therapy (P=0.087). A multivariate analysis of potential prognostic factors showed that IGF-1R expression and worse performance status were independent predictors of poor outcomes ( Table ). Conclusions: IGF-1R and EGFR were highly positive in patients with CRC. Overexpression of IGF-1R predicts a poor outcome, and overexpression of EGFR predicts a good clinical response to fluoropyrimidines. [Table: see text] No significant financial relationships to disclose.
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- 2007
275. Impact of insulin-like growth factor-1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), and HER2 expressions on outcomes of patients with gastric cancer
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Kuniaki Shirao, Junichi Matsubara, Yoshinori Hirashima, N. Tsuda, Yoshihisa Shimada, Yuki Yamada, Daisuke Takahari, Kyoko Kato, Tadakazu Shimoda, and Tetsuya Hamaguchi
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Cancer Research ,biology ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Insulin-like growth factor ,Oncology ,medicine ,Cancer research ,biology.protein ,Growth factor receptor inhibitor ,Epidermal growth factor receptor ,business ,Receptor - Abstract
4539 Background: Insulin-like growth factor-1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), and HER2 expressions have been reported to correlate with clinical outcomes in several solid tumors. However, the clinical significance of these biomarkers in gastric cancer (GC) remains unclear. Detailed exploratory evaluations are required to better understand their clinical implications. Methods: The study group comprised 87 patients who underwent gastrectomy at National Cancer Center Hospital and subsequently received chemotherapy for recurrent or residual tumor. Using immunohistochemical techniques, we analyzed the expressions of IGF-1R, EGFR, and HER2 in surgically removed tumor specimens to determine the prognostic significance of these biomarkers. Results: IGF-1R expression (defined as >10% membranous staining) was found in 67 tumors (77%), EGFR in 55 tumors (63%), and HER2 in 16 tumors (18%). IGF-1R expression correlated with EGFR expression (P=0.019) as well as with HER2 expression (P=0.001). A univariate analysis revealed that IGF-1R expression correlated with shorter survival (P=0.030). A multivariate analysis of potential prognostic factors showed that IGF-1R expression, worse performance status and pathological stage, and diffuse type tumor were independent predictors of poor outcomes ( Table ). Conclusions: IGF-1R expression in surgical GC specimens may be a predictor of poor outcomes in postoperative patients with GC. Our data suggest that anti-IGF-1R strategies may prove valuable in such patients. [Table: see text] No significant financial relationships to disclose.
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- 2007
276. TGFβ Activates p53 Via PP2A in Hematopoietic Cells
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Yoshiro Niitsu, Koichi Takada, Daisuke Takahari, Junji Kato, and Rishu Takimoto
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Cell cycle checkpoint ,Cell growth ,Immunology ,Cell Biology ,Hematology ,Protein phosphatase 2 ,SMAD ,Biology ,Biochemistry ,Cell biology ,Haematopoiesis ,Cytosol ,Cell culture ,Signal transduction - Abstract
Dysfunction of TGFβ signal transduction has been shown to result in leukemogenesis. It has been generally accepted that Smads mediate the TGFβ signaling to inhibit cell proliferation, while several Smad4-impaired cell lines retain certain levels of responsiveness to TGFβ, suggesting an additional TGFβ signaling pathway for cell cycle arrest. Here we demonstrate evidence for a novel signal pathway for G1 arrest linking TGFβ and p53/Protein phosphatase 2A (PP2A) in CD4+ T lymphocyte and megakaryocytes. TGFβ induced growth suppression, associated with increment of PP2A activity was clearly observed in cells with impaired Smad signal. In these cells, upon TGFβ stimulation, PP2A was transiently recruited by heteromeric complex of TGFβ receptors (TβRs), released into cytosol, and activated. Subsequently, PP2A dephosphorylated p53 to import it into nucleus by interacting with importin-α/β followed by p21Waf1 induction. The recruitment of PP2A by TβRs and TGFβ-induced growth suppression as well as nuclear import of p53 were inhibited by introduction of siRNA for PP2A-Bα. Based on these preliminary observation, we next used human peripheral CD4+ T lymphocytes, which are reportedly impaired in Smad signaling, but sensitive to TGFβ when stimulated with PHA and IL-2. Growth suppression induced by TGFβ was almost completely abolished by siRNA for p53 (siRNA-p53), but not by siRNA for Smad4 (siRNA-Smad4). Further, nuclear translocation of p53 was inhibited by siRNA for PP2A-Bα(siRNA-Bα). These results suggest that growth suppressive activity of TGFβ in certain immunological responses could be ascribed to PP2A/p53 signal transduction. Thus these results define a novel pathway of TGFβ-induced growth suppression linking p53-PP2A, and suggest that loss of function of p53 which is frequently observed in hematological malignancies may result in the escape from growth inhibitory signal of TGFβ.
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- 2006
277. A Novel p53-PP2A Signaling Pathway Is Responsible for Regulation of Hematopoiesis Induced by TGFß
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Yoshiro Niitsu, Rishu Takimoto, Daisuke Takahari, Koichi Takada, and Junji Kato
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Cell cycle checkpoint ,Cell growth ,Immunology ,Stimulation ,Cell Biology ,Hematology ,Protein phosphatase 2 ,Biology ,Biochemistry ,Cell biology ,Cell nucleus ,Cytosol ,medicine.anatomical_structure ,Cell culture ,medicine ,Signal transduction - Abstract
TGFβ has been reported to play an important role in regulating the proliferation of hematopoietic cells. Dysfunction of signal transduction pathway of TGFβ may result in leukemogenesis. It has been generally accepted that Smads mediate the TGFβ signaling to inhibit cell proliferation, while several Smad4-defective cell lines have been shown to retain certain levels of responsiveness to TGFβ, suggesting an additional TGFβ signaling pathway for cell cycle arrest. We previously demonstrated the evidence for a novel signal pathway for G1 arrest linking TGFβ and p53/Protein phosphatase 2A (PP2A) in CD4+ T lymphocyte and megakaryocytes (ASH, San Diego, 2003). We also showed that, upon TGFβ stimulation, PP2A was transiently recruited by heteromeric complex of TGFβ receptors (TβRs), released into cytosol, and activated. Subsequently, PP2A dephosphorylated p53 to import it into nucleus by interacting with importin-α/β, followed by p21Waf1 induction. In this study, we extended our observation to explore TGFβ-induced growth suppression is required for increment of PP2A activity by using SiRNA against PP2A. When PP2A of CD4+ lymphocytes was knocked-down by specific SiRNA for PP2A, the recruitment of PP2A by TβRs and TGFβ-induced growth suppression as well as nuclear import of p53 were inhibited. As a result, TGFβ stimulation induces PP2A activation and subsequently dephosphorylated-p53 was translocated into nucleus. Thus these results further define a novel pathway of TGFβ-induced growth suppression linking p53-PP2A, and suggest that dysfunction of p53 may result in the escape from growth inhibitory signal of TGFβ in hematological malignancies.
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- 2004
278. Combination chemotherapy with bevacizumab and S-1 for elderly patients with metastatic colorectal cancer (BASIC trial)
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Takao Takahashi, Kazuhiro Yoshida, Motoki Yoshida, A. Ohtsu, Kei Muro, Yoshinori Miyata, Yasuo Hamamoto, Akihito Tsuji, Kuniaki Shirao, Daisuke Takahari, and Takayuki Yoshino
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Oncology ,Male ,medicine.medical_specialty ,Cancer Research ,Bevacizumab ,Colorectal cancer ,Phases of clinical research ,Neutropenia ,Antibodies, Monoclonal, Humanized ,Elderly ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Neoplasm Metastasis ,Adverse effect ,Aged ,Tegafur ,Aged, 80 and over ,Dose-Response Relationship, Drug ,business.industry ,Carcinoma ,Combination chemotherapy ,S-1 ,medicine.disease ,Survival Analysis ,digestive system diseases ,Oxaliplatin ,Irinotecan ,Drug Combinations ,Oxonic Acid ,Treatment Outcome ,Female ,business ,Colorectal Neoplasms ,medicine.drug - Abstract
Background Chemotherapeutic regimens for elderly patients with metastatic colorectal cancer (mCRC), such as bevacizumab combined with 5-fluorouracil (5-FU) and leucovorin, often exclude oxaliplatin and irinotecan owing to the risk of toxicity. However, treatment with infusional 5-fluorouracil and leucovorin requires percutaneous port-catheter placement and other precautions, causing unnecessary stress for patients as well as healthcare workers. Methods We conducted a phase II study to evaluate the efficacy and safety of bevacizumab plus S-1 in elderly patients with previously untreated mCRC. Bevacizumab was given intravenously every two weeks, and S-1 was administered orally on days 1–28 of a 42-day cycle. The primary end-point was progression-free survival (PFS). The secondary end-points were time to treatment failure, response rate (RR), overall survival (OS), treatment completion status and safety. Results From October 2007 through March 2010, 56 patients were enroled. The median PFS was 9.9 months, the median OS was 25.0 months, and the RR was 57%. The main adverse events of grade 3 or higher were hypertension (11%), diarrhoea (9%) and neutropenia (7%). Conclusion Our results suggest that combination chemotherapy with S-1 and bevacizumab can be administered safely and continuously on an outpatient basis and is therapeutically effective in elderly patients with mCRC.
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279. A single-arm phase II trial of combined chemotherapy with S-1, oral leucovorin, and bevacizumab in heavily pre-treated patients with metastatic colorectal cancer
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Kazuhisa Yamaguchi, Masashi Andoh, Keita Mori, Takashi Ura, Kei Muro, Daisuke Takahari, Hiroya Taniguchi, Shigenori Kadowaki, Motoo Nomura, Yukiya Narita, Azusa Komori, Sohei Nitta, and Yoshinori Igarashi
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Male ,Oncology ,medicine.medical_specialty ,Cancer Research ,Bevacizumab ,Leucovorin ,Administration, Oral ,Salvage therapy ,BRAF ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,KRAS ,medicine ,Mucositis ,Clinical endpoint ,Genetics ,Humans ,Chemotherapy ,Neoplasm Metastasis ,Aged ,Tegafur ,Salvage Therapy ,Metastatic colorectal cancer ,business.industry ,Combination chemotherapy ,S-1 ,Middle Aged ,medicine.disease ,digestive system diseases ,Oxaliplatin ,Irinotecan ,Clinical trial ,Drug Combinations ,Oxonic Acid ,Treatment Outcome ,Female ,Colorectal Neoplasms ,business ,Research Article ,medicine.drug - Abstract
Background The mean 5–6-month survival after failed standard chemotherapy for metastatic colorectal cancer (mCRC) necessitates more effective treatments for refractory mCRC. For untreated mCRC, S-1 + oral leucovorin (SL) therapy offers promising results without severe toxicity. The ML18147 trial demonstrated that bevacizumab (Bev) prolongs overall survival after mCRC progression. We conducted a single-centre phase-II trial to evaluate the safety and efficacy of SL/Bev combination chemotherapy as mCRC salvage therapy. Methods Major eligibility criteria were confirmed adenocarcinoma diagnosis; age >20 years; Eastern Cooperative Oncology Group performance status, 0–2; and progression after administration/intolerance of/to approved drugs for mCRC. (5-FU, oxaliplatin, irinotecan, Bev, and anti-EGFR antibody, if KRAS wild-type). S-1 (80–120 mg/body) and leucovorin (25 mg) were orally administered in a 1-week-on/1-week-off schedule. Bev (5 mg/kg) was administered on day 1 of every 2-week cycle. The primary endpoint was disease control rate (DCR). Results A total of 31 patients were enrolled. DCR was 65 % [95 % confidence interval (CI), 48–100 %] and the response rate was 7 % (95 % CI, 0.7–22 %). One patient showing partial response to SL/Bev had a BRAF-mutant tumor. Median progression-free survival and overall survivals were 5.3 [95 % CI, 2.1–9.3] and 9.9 [95 % CI, 7.4–NA] months, respectively. The most-frequent grade-3/4 adverse events were mucositis (26 %) and diarrhea (11 %), which were manageable by dose reduction/interruption. Conclusions SL/Bev showed impressive activity in refractory mCRC and was tolerable, suggesting its potential as an alternative chemotherapy for refractory mCRC. Trial registration This study has been registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry (IDUMIN000009083) on 11 October 2012. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1606-1) contains supplementary material, which is available to authorized users.
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280. Retrospective study of RAS/PIK3CA/BRAF tumor mutations as predictors of response to first-line chemotherapy with bevacizumab in metastatic colorectal cancer patients
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Izuma Nakayama, Kensei Yamaguchi, Takeru Wakatsuki, Tomohiro Matsushima, Takashi Ichimura, Nobuyuki Mizunuma, Keisho Chin, Mariko Ogura, Daisuke Takahari, Mitsukuni Suenaga, Masato Ozaka, and Eiji Shinozaki
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Male ,0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,Oncology ,Cancer Research ,Colorectal cancer ,Angiogenesis Inhibitors ,PIK3CA mutation ,medicine.disease_cause ,Metastasis ,0302 clinical medicine ,Surgical oncology ,Predictive marker ,Liver Neoplasms ,Combination chemotherapy ,Middle Aged ,Prognosis ,Survival Rate ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Female ,KRAS ,Colorectal Neoplasms ,Research Article ,medicine.drug ,Adult ,Proto-Oncogene Proteins B-raf ,medicine.medical_specialty ,Bevacizumab ,Class I Phosphatidylinositol 3-Kinases ,bevacizumab ,RAS mutation ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,medicine ,Genetics ,Humans ,neoplasms ,Aged ,Neoplasm Staging ,Retrospective Studies ,business.industry ,medicine.disease ,BRAF mutation ,030104 developmental biology ,Mutation ,ras Proteins ,Cancer research ,business ,Follow-Up Studies - Abstract
Background After analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies. However, it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first-line treatment for metastatic colorectal cancer. Methods Of the 1001 consecutive colorectal cancer patients examined for RAS, PIK3CA, and BRAF tumor mutations using a multiplex kit (Luminex®), we studied 90 patients who received combination chemotherapy with bevacizumab as first-line treatment for metastatic colorectal cancer. The objective response rate (ORR) and progression-free survival (PFS) were evaluated according to mutational status. Results The ORR was higher among patients with wild-type tumors (64.3%) compared to those with tumors that were only wild type with respect to KRAS exon 2 (54.8%), and the differences in ORR between patients with wild-type and mutant-type tumors were greater when considering only KRAS exon 2 mutations (6.8%) rather than RAS/PIK3CA/BRAF mutations (18.4%). There were no statistically significant differences in ORR or PFS between all wild-type tumors and tumors carrying any of the mutations. Multivariate analysis revealed that liver metastasis and RAS and BRAF mutations were independent negative factors for disease progression after first-line treatment with bevacizumab. Conclusions Patient selection according to RAS/PIK3CA/BRAF mutations could help select patients who will achieve a better response to bevacizumab treatment. We found no clinical benefit of restricting combination therapy with bevacizumab for metastatic colorectal cancer patients with EGFR-wild type tumors. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2994-6) contains supplementary material, which is available to authorized users.
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281. Clinical administration of oxaliplatin for patients previously treated for refractory advanced or recurrent colorectal cancer
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Daisuke Takahari, Tsuji, Y., Sagawa, T., Honda, K., Sumiyoshi, T., Yoshizaki, N., Kuroiwa, G., and Kondo, H.
282. Efficacy of palliative radiotherapy for gastric bleeding in patients with unresectable advanced gastric cancer: a retrospective cohort study
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Daisuke Takahari, Natsuo Tomita, Motoo Nomura, Takeshi Kodaira, Kohei Shitara, Hiroyuki Tachibana, Kei Muro, Chihiro Kondoh, and Takashi Ura
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Adult ,Male ,medicine.medical_specialty ,Blood transfusion ,Palliative care ,medicine.medical_treatment ,Severity of Illness Index ,Hemoglobins ,Quality of life ,Stomach Neoplasms ,Severity of illness ,medicine ,Humans ,Aged ,Retrospective Studies ,Aged, 80 and over ,Medicine(all) ,Hemostasis ,Radiotherapy ,business.industry ,Stomach ,Bleeding ,Palliative Care ,Radiotherapy Dosage ,Retrospective cohort study ,General Medicine ,Middle Aged ,Surgery ,Radiation therapy ,medicine.anatomical_structure ,Quality of Life ,Female ,Gastric cancer ,Gastrointestinal Hemorrhage ,business ,Research Article - Abstract
Background Bleeding negatively impacts quality of life in patients with unresectable advanced gastric cancer and has the potential to be lethal. When blood transfusion and endoscopic hemostasis are unsuccessful to stop bleeding, radiation to stomach is selected in patients with unsuitable condition for surgery. We performed a retrospective cohort study to clarify the utility of radiotherapy in treating gastric bleeding, particularly for patients with limited life expectancy. Methods We evaluated the efficacy and safety of palliative radiotherapy in patients with advanced gastric cancer between January 2007 and December 2012 in Aichi Cancer Center Hospital. All patients had gastric bleeding requiring blood transfusion. We defined hemostasis as an increase in hemoglobin level to more than 7.0 g/dL together with the cessation of melena or hematemesis for at least 1 week. Results During the study period, 313 advanced gastric cancer patients treated in our institution. Of these 17 patients received gastric radiotherapy to stop bleeding. Two patients were excluded from analysis due to combined treatment of intravascular embolization. Eleven out of 15 patients (73 %) had undergone two or more previous chemotherapy regimens. Ten patients (67 %) had an Eastern Cooperative Oncology Group performance status of 3 and 14 patients (93 %) were in palliative prognostic index group B or C. The median total planned radiation dose was 30 Gy in 10 fractions. At a median interval of 2 days after initiation of radiotherapy, 11 patients (73 %) achieved hemostasis; rebleeding was observed in four patients (36 %). The median hemoglobin level before radiotherapy was significantly increased from 6.0 to 9.0 g/dL (p
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