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      Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer

      research-article
      1 , , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 1 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 7 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 1 , 36 , 9 , 37 , Japanese Society for Cancer of the Colon and Rectum
      International Journal of Clinical Oncology
      Springer Japan
      Colorectal cancer, Guideline, Surgery, Chemotherapy, Endoscopy, Radiotherapy

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          Abstract

          Japanese mortality due to colorectal cancer is on the rise, surpassing 49,000 in 2015. Many new treatment methods have been developed during recent decades. The Japanese Society for Cancer of the Colon and Rectum Guidelines 2016 for the treatment of colorectal cancer (JSCCR Guidelines 2016) were prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines were prepared by consensus reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches, and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2016.

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          Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.

          Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.
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            Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.

            To evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC). Patients with MCRC were randomly assigned, in a 2 x 2 factorial design, to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point was progression-free survival (PFS). A total of 1,401 patients were randomly assigned in this 2 x 2 analysis. Median progression-free survival (PFS) was 9.4 months in the bevacizumab group and 8.0 months in the placebo group (hazard ratio [HR], 0.83; 97.5% CI, 0.72 to 0.95; P = .0023). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077). Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials. The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC. Overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.
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              Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.

              Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.
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                Author and article information

                Contributors
                +81-3-5800-8653 , toshwatanabe@yahoo.co.jp
                Journal
                Int J Clin Oncol
                Int. J. Clin. Oncol
                International Journal of Clinical Oncology
                Springer Japan (Tokyo )
                1341-9625
                1437-7772
                27 March 2017
                27 March 2017
                2018
                : 23
                : 1
                : 1-34
                Affiliations
                [1 ]ISNI 0000 0001 2151 536X, GRID grid.26999.3d, Department of Surgical Oncology, , The Graduate School of Medicine, The University of Tokyo, ; 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan
                [2 ]ISNI 0000 0001 0722 8444, GRID grid.410800.d, Department of Clinical Oncology, , Aichi Cancer Center Hospital, ; Nagoya, Japan
                [3 ]ISNI 0000 0001 0671 5144, GRID grid.260975.f, Division of Molecular and Diagnostic Pathology, , Graduate School of Medical and Dental Sciences, Niigata University, ; Niigata, Japan
                [4 ]ISNI 0000 0000 9239 9995, GRID grid.264706.1, Department of Surgery, , Teikyo University, ; Tokyo, Japan
                [5 ]ISNI 0000 0001 2168 5385, GRID grid.272242.3, Department of Radiation Oncology, , National Cancer Center Hospital, ; Tokyo, Japan
                [6 ]ISNI 0000 0001 2168 5385, GRID grid.272242.3, Endoscopy Division, , National Cancer Center Hospital, ; Tokyo, Japan
                [7 ]ISNI 0000 0001 2168 5385, GRID grid.272242.3, Division of Gastrointestinal Medical Oncology, , National Cancer Center Hospital, ; Tokyo, Japan
                [8 ]ISNI 0000 0004 0467 0255, GRID grid.415020.2, Department of Digestive Tract and General Surgery, , Saitama Medical Center, Saitama Medical University, ; Saitama, Japan
                [9 ]ISNI 0000 0001 1014 9130, GRID grid.265073.5, Department of Translational Oncology, , Tokyo Medical and Dental University Graduate School, ; Tokyo, Japan
                [10 ]ISNI 0000 0001 2168 5385, GRID grid.272242.3, Colorectal Surgery Division, , National Cancer Center Hospital, ; Tokyo, Japan
                [11 ]ISNI 0000 0004 0569 9156, GRID grid.416881.2, Department of Gastroenterology, , St. Mary’s Hospital, ; Fukuoka, Japan
                [12 ]ISNI 0000 0004 1774 9501, GRID grid.415797.9, Department of Colon and Rectal Surgery, , Shizuoka Cancer Center, ; Shizuoka, Japan
                [13 ]ISNI 0000 0001 2151 536X, GRID grid.26999.3d, Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, , Graduate School of Medicine, University of Tokyo, ; Tokyo, Japan
                [14 ]Radiation Oncology Department, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
                [15 ]ISNI 0000 0004 0372 3116, GRID grid.412764.2, Department of Clinical Oncology, , St. Marianna University School of Medicine, ; Kawasaki, Japan
                [16 ]ISNI 0000 0004 0618 7953, GRID grid.470097.d, Gastroenterology and Metabolism, , Hiroshima University Hospital, ; Hiroshima, Japan
                [17 ]ISNI 0000 0004 0372 2033, GRID grid.258799.8, Department of Surgery, , Kyoto University, ; Kyoto, Japan
                [18 ]ISNI 0000 0000 8662 309X, GRID grid.258331.e, Department of Clinical Oncology, Faculty of Medicine, , Kagawa University, ; Takamatsu, Japan
                [19 ]ISNI 0000 0001 0943 978X, GRID grid.27476.30, Division of Surgical Oncology, Department of Surgery, , Nagoya University Graduate School of Medicine, ; Nagoya, Japan
                [20 ]ISNI 0000 0004 0374 0880, GRID grid.416614.0, Department of Surgery, , National Defense Medical College, ; Saitama, Japan
                [21 ]ISNI 0000 0004 1774 9501, GRID grid.415797.9, Division of Gastrointestinal Oncology, , Shizuoka Cancer Center, ; Shizuoka, Japan
                [22 ]ISNI 0000 0004 0531 3030, GRID grid.411731.1, Department of Hemodialysis and Surgery, , Chemotherapy Research Institute, International University of Health and Welfare, ; Ichikawa, Japan
                [23 ]ISNI 0000 0001 2168 5385, GRID grid.272242.3, Department of Gastroenterology and Gastrointestinal Oncology, , National Cancer Center Hospital East, ; Chiba, Japan
                [24 ]ISNI 0000 0004 1771 8393, GRID grid.415766.7, Diagnostic Pathology Center, , Shinko Hospital, ; Kobe, Japan
                [25 ]ISNI 0000 0001 0720 6587, GRID grid.410818.4, Department of Surgery, , Institute of Gastroenterology, Tokyo Women’s Medical University, ; Tokyo, Japan
                [26 ]ISNI 0000 0001 2166 7427, GRID grid.412755.0, Department of Health Administration and Policy, , Tohoku Medical and Pharmaceutical University, ; Sendai, Japan
                [27 ]ISNI 0000 0004 0378 7152, GRID grid.413825.9, Department of Surgery, , Cancer Center, Aomori Prefectural Central Hospital, ; Aomori, Japan
                [28 ]ISNI 0000 0004 1771 7147, GRID grid.474805.a, Department of Surgery, , Japanese Red Cross Kanazawa Hospital, ; Ishikawa, Japan
                [29 ]ISNI 0000 0004 1764 7652, GRID grid.459767.e, CEO, , Misawa City Hospital, ; Misawa, Japan
                [30 ]Division of Clinical Oncolgy, Kochi Health Sciences Center, Kochi, Japan
                [31 ]GRID grid.415479.a, Department of Surgery, , Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, ; Tokyo, Japan
                [32 ]ISNI 0000 0004 0618 7953, GRID grid.470097.d, Department of Endoscopy, , Hiroshima University Hospital, ; Hiroshima, Japan
                [33 ]ISNI 0000 0001 0706 0776, GRID grid.410781.b, Division of GI Endoscopy, , Kurume University School of Medicine, ; Fukuoka, Japan
                [34 ]Department of Gastroenterological Surgery, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
                [35 ]GRID grid.440137.5, Library of SEIREI SAKURA Citizen Hospital, ; Sakura, Japan
                [36 ]ISNI 0000 0004 0378 8729, GRID grid.420115.3, Department of Surgery, , Tochigi Cancer Center, ; Utsunomiya, Japan
                [37 ]Koujinkai Daiichi Hospital, Tokyo, Japan
                Article
                1101
                10.1007/s10147-017-1101-6
                5809573
                28349281
                552e4455-9c37-414e-91aa-d3a4d4b0f9cb
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 7 February 2017
                : 8 February 2017
                Categories
                Special Article
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                © Japan Society of Clinical Oncology 2018

                colorectal cancer,guideline,surgery,chemotherapy,endoscopy,radiotherapy

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