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      Neoadjuvant FOLFOX chemotherapy combined with radiotherapy followed by radical resection in patients with locally advanced colon cancer

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          Abstract

          Background

          Patients with locally advanced colon cancer (LACC) have a relatively poor prognosis despite radical resection and adjuvant chemotherapy. This study investigated the treatment efficacy and toxicity of neoadjuvant chemoradiotherapy in patients with LACC.

          Methods

          We retrospectively reviewed 36 patients with LACC preoperatively treated with chemotherapy and radiotherapy. Patients were administered chemoradiotherapy, which comprised radiotherapy and neoadjuvant chemotherapy involving a 5-fluorouracil, leucovorin, and oxaliplatin regimen every 2 weeks.

          Results

          Median age was 64 years (45–86 years) and median follow-up period was 23.5 months (5.0–49.1 months). Seven (19.4%) patients developed grade 3 or 4 adverse events during neoadjuvant concurrent chemoradiotherapy. Pathologic responses were not evaluated in two patients who did not undergo radical resection. Of the 34 patients who underwent surgery, nine (26.4%) achieved a pathologic complete response (pCR). The 2-year estimated overall survival and disease-free survival rates were 88.7% and 73.6%, respectively.

          Conclusions

          Our results demonstrated that neoadjuvant chemoradiotherapy is feasible and safe. A prominent pCR rate with an acceptable toxicity profile suggests that the multimodality therapy might be a treatment option for patients with LACC.

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          Most cited references23

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          Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03.

          Although chemoradiotherapy plus resection is considered standard treatment for operable rectal carcinoma, the optimal time to administer this therapy is not clear. The NSABP R-03 (National Surgical Adjuvant Breast and Bowel Project R-03) trial compared neoadjuvant versus adjuvant chemoradiotherapy in the treatment of locally advanced rectal carcinoma. Patients with clinical T3 or T4 or node-positive rectal cancer were randomly assigned to preoperative or postoperative chemoradiotherapy. Chemotherapy consisted of fluorouracil and leucovorin with 45 Gy in 25 fractions with a 5.40-Gy boost within the original margins of treatment. In the preoperative group, surgery was performed within 8 weeks after completion of radiotherapy. In the postoperative group, chemotherapy began after recovery from surgery but no later than 4 weeks after surgery. The primary end points were disease-free survival (DFS) and overall survival (OS). From August 1993 to June 1999, 267 patients were randomly assigned to NSABP R-03. The intended sample size was 900 patients. Excluding 11 ineligible and two eligible patients without follow-up data, the analysis used data on 123 patients randomly assigned to preoperative and 131 to postoperative chemoradiotherapy. Surviving patients were observed for a median of 8.4 years. The 5-year DFS for preoperative patients was 64.7% v 53.4% for postoperative patients (P = .011). The 5-year OS for preoperative patients was 74.5% v 65.6% for postoperative patients (P = .065). A complete pathologic response was achieved in 15% of preoperative patients. No preoperative patient with a complete pathologic response has had a recurrence. Preoperative chemoradiotherapy, compared with postoperative chemoradiotherapy, significantly improved DFS and showed a trend toward improved OS.
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            Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial.

            Patients with locally advanced rectal cancer who achieve a pathological complete response to neoadjuvant chemoradiation have an improved prognosis. The need for surgery in these patients has been questioned, but the proportion of patients achieving a pathological complete response is small. We aimed to assess whether adding cycles of mFOLFOX6 between chemoradiation and surgery increased the proportion of patients achieving a pathological complete response.
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              Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial.

              Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fluorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment. This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (1000 mg/m(2) days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) days 1-5 and 29; fluorouracil group); and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (250 mg/m(2) days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m(2) days 1 and 15), leucovorin (400 mg/m(2) days 1 and 15), and infusional fluorouracil (2400 mg/m(2) days 1-2 and 15-16; fluorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, efficacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076. Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil group). Preoperative grade 3-4 toxic effects occurred in 140 (23%) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fluorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fluorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fluorouracil group (odds ratio 1·40, 95% CI 1·02-1·92; p=0·038). In the fluorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fluorouracil group. Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS. German Cancer Aid (Deutsche Krebshilfe). Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                jimmyhuang0215@gmail.com
                miyihu@gmail.com.tw
                kmu880402@gmail.com
                920055@gmail.com
                chunpin870132@yahoo.com.tw
                baseball5824@yahoo.com.tw
                ccjjhh@kmu.edu.tw
                +886-7-3122805 , cy614112@ms14.hinet.net , jayuwa@cc.kmu.edu.tw
                Journal
                Radiat Oncol
                Radiat Oncol
                Radiation Oncology (London, England)
                BioMed Central (London )
                1748-717X
                7 March 2017
                7 March 2017
                2017
                : 12
                : 48
                Affiliations
                [1 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, Department of Radiation Oncology, Kaohsiung Medical University Hospital, , Kaohsiung Medical University, ; Kaohsiung, Taiwan
                [2 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, Graduate Institute of Medicine, College of Medicine, , Kaohsiung Medical University, ; Kaohsiung, Taiwan
                [3 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, Department of Radiation Oncology, Faculty of Medicine, College of Medicine, , Kaohsiung Medical University, ; Kaohsiung, Taiwan
                [4 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, Department of Surgery, Division of General and Digestive Surgery, Kaohsiung Medical University Hospital, , Kaohsiung Medical University, ; Kaohsiung, Taiwan
                [5 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, Department of Surgery, Division of Colorectal Surgery, Kaohsiung Medical University Hospital, , Kaohsiung Medical University, ; No. 100 Tzyou 1st Road, Kaohsiung, 807 Taiwan
                [6 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, Graduate Institute of Clinical Medicine, College of Medicine, , Kaohsiung Medical University, ; Kaohsiung, Taiwan
                [7 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, Department of Surgery, Division of Trauma and Critical Care, Kaohsiung Medical University Hospital, , Kaohsiung Medical University, ; Kaohsiung, Taiwan
                [8 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, Department of Emergency Medicine, Kaohsiung Medical University Hospital, , Kaohsiung Medical University, ; Kaohsiung, Taiwan
                [9 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, Department of Surgery, Faculty of Medicine, College of Medicine, , Kaohsiung Medical University, ; Kaohsiung, Taiwan
                [10 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, Center for Biomarkers and Biotech Drugs, , Kaohsiung Medical University, ; Kaohsiung, Taiwan
                [11 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, Research Center for Environmental Medicine, , Kaohsiung Medical University, ; Kaohsiung, Taiwan
                [12 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, Research Center for Natural Products & Drug Development, , Kaohsiung Medical University, ; Kaohsiung, Taiwan
                Author information
                http://orcid.org/0000-0002-7705-2621
                Article
                790
                10.1186/s13014-017-0790-3
                5341372
                28270172
                b007153d-aa17-4057-be81-2c71690af75e
                © 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. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 16 December 2016
                : 22 February 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;
                Award ID: MOST105-2325-B-037-001
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100008903, Ministry of Health and Welfare;
                Award ID: MOHW105-TDU-B-212-134007
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Oncology & Radiotherapy
                colon cancer,oxaliplatin,chemoradiotherapy,pathologic complete response

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