Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial

Lancet Oncol. 2010 Mar;11(3):241-8. doi: 10.1016/S1470-2045(09)70381-X. Epub 2010 Jan 25.


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, number NCT00220051.

Findings: 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).

Interpretation: 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.

Funding: UK National Health Service, Sanofi-Aventis.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Capecitabine
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Drug Administration Schedule
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / analogs & derivatives
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Neoadjuvant Therapy / methods*
  • Neoplasm Recurrence, Local / prevention & control*
  • Neoplasm Staging
  • Organoplatinum Compounds / administration & dosage
  • Oxaliplatin
  • Rectal Neoplasms / pathology
  • Rectal Neoplasms / therapy*
  • Survival Analysis


  • Organoplatinum Compounds
  • Oxaliplatin
  • Deoxycytidine
  • Capecitabine
  • Fluorouracil

Associated data