title: Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial.
abstract: BACKGROUND
  Patients with poor-risk rectal cancer defined by MRI can be at high risk of disease recurrence despite standard chemoradiotherapy and optimum surgery. We aimed to assess the safety and long-term efficacy of neoadjuvant chemotherapy with capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision, a treatment strategy developed to enhance the outcome of this population.
  
  
  METHODS
  Between November, 2001, and August, 2005, we enrolled eligible patients with poor-risk rectal cancer defined by high-resolution MRI and without metastatic disease. The protocol was amended in January, 2004, following clinically significant cardiotoxic events (nine events in eight of 77 patients), to exclude patients with a recent history of clinically significant cardiac problems. Patients received 12 weeks of neoadjuvant capecitabine and oxaliplatin (oxaliplatin 130 mg/m2 on day 1 with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks) followed by chemoradiotherapy (54 Gy over 6 weeks) with capecitabine (825 mg/m2 twice daily), total mesorectal excision, and 12 weeks of postoperative adjuvant capecitabine (1250 mg/m2 twice daily for 14 days every 3 weeks). The primary endpoint was pathological complete response rate. We followed up patients for a median of 55 months (IQR 47-67). Efficacy analyses were undertaken for the intention-to-treat population, unless otherwise specified. This study is registered with ClinicalTrials.gov, number NCT00220051.
  
  
  RESULTS
  105 eligible patients were enrolled. Radiological response rates after neoadjuvant chemotherapy and chemoradiotherapy were 74% (78/105) and 89% (93/105), respectively. 97 patients underwent surgery, of whom 95 underwent total mesorectal excision, of whom 93 had microscopically clear resection margins and 21 had pathological complete response (21/105 [20%]). 3-year progression-free and overall survival were 68% (95% CI 59-77) and 83% (76-91), respectively. 3-year relapse-free survival for patients who had complete resection was 74% (65-83). Following the protocol amendment for cardiovascular safety, only one further thromboembolic event was reported (fatal pulmonary embolism).
  
  
  CONCLUSIONS
  Intensification of systemic therapy with neoadjuvant combination chemotherapy before standard treatment is feasible in poor-risk potentially operable rectal cancer, with acceptable safety and promising long-term outcomes. Future development of this multidisciplinary treatment strategy in randomised trials is warranted.
  
  
  BACKGROUND
  UK National Health Service, Sanofi-Aventis.
authors.affiliation: Department of Medicine, Royal Marsden Hospital, Sutton, Surrey, UK.
authors.forename: Yu Jo
authors.initials: YJ
authors.lastname: Chua
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Barbachano
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.forename: Jacqui R
authors.initials: JR
authors.lastname: Oates
authors.forename: Gina
authors.initials: G
authors.lastname: Brown
authors.forename: Andrew
authors.initials: A
authors.lastname: Wotherspoon
authors.forename: Diana
authors.initials: D
authors.lastname: Tait
authors.forename: Alison
authors.initials: A
authors.lastname: Massey
authors.forename: Niall C
authors.initials: NC
authors.lastname: Tebbutt
authors.forename: Ian
authors.initials: I
authors.lastname: Chau
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D012004:Rectal Neoplasms / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil