title: Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial.
abstract: BACKGROUND
  The role of adjuvant chemotherapy for patients with rectal cancer is controversial, especially when used after preoperative chemoradiotherapy. Fluoropyrimidine-based adjuvant chemotherapy, including fluorouracil and leucovorin, has been widely used; however, the addition of oxaliplatin to fluorouracil and leucovorin (FOLFOX), a standard adjuvant regimen for colon cancer, has not been tested in rectal cancer. We aimed to compare the efficacy and safety of adjuvant fluorouracil and leucovorin with that of FOLFOX in patients with locally advanced rectal cancer after preoperative chemoradiotherapy.
  
  
  METHODS
  In this open-label, multicentre, phase 2, randomised trial, patients with postoperative pathological stage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after preoperative fluoropyrimidine-based chemoradiotherapy and total mesorectal excision were recruited and randomly assigned (1:1) via a web-based software platform to receive adjuvant chemotherapy with either four cycles of fluorouracil and leucovorin (fluorouracil 380 mg/m(2) and leucovorin 20 mg/m(2) on days 1-5, every 4 weeks) or eight cycles of FOLFOX (oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil bolus 400 mg/m(2) on day 1, and fluorouracil infusion 2400 mg/m(2) for 46 h, every 2 weeks). Stratification factors were pathological stage (II vs III) and centre. Neither patients nor investigators were masked to group assignment. The primary endpoint was 3-year disease-free survival, analysed by intention to treat. This study is fully enrolled, is in long-term follow-up, and is registered with ClinicalTrials.gov, number NCT00807911.
  
  
  RESULTS
  Between Nov 19, 2008, and June 12, 2012, 321 patients were randomly assigned to fluorouracil and leucovorin (n=161) and FOLFOX (n=160). 141 (95%) of 149 patients in the fluorouracil plus leucovorin group and 141 (97%) of 146 in the FOLFOX group completed all planned cycles of adjuvant treatment. Median follow-up was 38·2 months (IQR 26·4-50·6). 3-year disease-free survival was 71·6% (95% CI 64·6-78·6) in the FOLFOX group and 62·9% (55·4-70·4) in the fluorouracil plus leucovorin group (hazard ratio 0·657, 95% CI 0·434-0·994; p=0·047). Any grade neutropenia, thrombocytopenia, fatigue, nausea, and sensory neuropathy were significantly more common in the FOLFOX group than in the fluorouracil plus leucovorin group; however, we noted no significant difference in the frequency of these events at grade 3 or 4. The most common grade 3 or worse adverse events were neutropenia (38 [26%] of 149 patients in the fluorouracil plus leucovorin group vs 52 [36%] of 146 patients in the FOLFOX group), leucopenia (eight [5%] vs 12 [8%]), febrile neutropenia (four [3%] vs one [<1%]), diarrhoea (four [3%] vs two [1%]), and nausea (one [<1%] vs two [1%]).
  
  
  CONCLUSIONS
  Adjuvant FOLFOX improves disease-free survival compared with fluorouracil plus leucovorin in patients with locally advanced rectal cancer after preoperative chemoradiotherapy and total mesorectal excision, and warrants further investigation.
  
  
  BACKGROUND
  Korea Healthcare Technology R&D Project (South Korean Ministry of Health and Welfare).
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Hong
authors.affiliation: Department of Cancer Control and Policy, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, South Korea.
authors.forename: Byung-Ho
authors.initials: BH
authors.lastname: Nam
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Kyu-Pyo
authors.initials: KP
authors.lastname: Kim
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Seong Joon
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Park
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Joon Oh
authors.initials: JO
authors.lastname: Park
authors.affiliation: Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, South Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Joong Bae
authors.initials: JB
authors.lastname: Ahn
authors.affiliation: Department of Colorectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Seok-Byung
authors.initials: SB
authors.lastname: Lim
authors.affiliation: Department of Colorectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Chang Sik
authors.initials: CS
authors.lastname: Yu
authors.affiliation: Department of Colorectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Jin Cheon
authors.initials: JC
authors.lastname: Kim
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Seong Hyeon
authors.initials: SH
authors.lastname: Yun
authors.affiliation: Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Jin-Hong
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Hee Chul
authors.initials: HC
authors.lastname: Park
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Kyung Hae
authors.initials: KH
authors.lastname: Jung
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. Electronic address: twkimmd@amc.seoul.kr.
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D059248:Chemoradiotherapy / Q000379:methods*; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000627:therapeutic use; D000077150:Oxaliplatin; D011300:Preoperative Care / Q000379:methods; D011379:Prognosis; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D016019:Survival Analysis; D013624:Taiwan; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil