ArticlesFluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study
Introduction
In locally advanced rectal cancer, 5-year results of randomised clinical trials1, 2 have shown that adding fluorouracil-based chemotherapy concurrently to preoperative long-course radiotherapy (preoperative radiotherapy and chemotherapy) significantly increased local control compared with either postoperative radiotherapy and chemotherapy1 or preoperative radiotherapy alone.2, 3 However, no effect on overall survival was shown. Moreover, these trials did not question the benefit of adjuvant chemotherapy, since in both trials all patients received adjuvant chemotherapy. The European Organisation for Research and Treatment of Cancer (EORTC) 22921 trial3 was a 2 × 2 factorial design with four randomised groups that explored the value of adding chemotherapy to preoperative radiotherapy either concurrently, as adjuvant therapy, or both. After a median follow-up of 5·4 years, no significant effect of adjuvant chemotherapy on disease-free survival and overall survival could be shown: 5-year overall survival was 67·2% in the adjuvant chemotherapy groups and 63·2% in the surveillance groups (hazard ratio [HR] 0·85, 95% CI 0·68–1·04; p=0·12); likewise, 5-year disease-free survival was 58·2% in the adjuvant chemotherapy group and 52·2% in the surveillance groups (HR 0·87, 95% CI 0·72–1·04; p=0·13).3 However, a divergence between the disease-free survival and the overall survival Kaplan-Meier curves seemed to emerge after 2 years and 4 years, respectively, favouring the groups that received adjuvant chemotherapy and suggesting that a benefit of adjuvant chemotherapy might become evident with longer follow-up. An exploratory analysis of the M0 patients who had a R0 resection was therefore undertaken. The results suggested that adjuvant chemotherapy induced a significant increase in overall and disease-free survival only in the subgroup of patients who had a tumour downstaged by preoperative treatment.4
Local recurrences at 5 years were almost twice as common in patients who received preoperative radiotherapy alone compared with the groups who received chemotherapy, irrespective of timing (concomitant to radiotherapy, adjuvant, or both).
We report the results of the EORTC 22921 trial after a median follow-up of 10·4 years to assess a possible long-term benefit of adjuvant chemotherapy on disease-free and overall survival.
Section snippets
Patients
Full details of the patient eligibility criteria and procedures of this trial have been reported elsewhere.3, 5 Briefly, patients were included if they were aged 80 years or younger, had resectable T3 or T4 M0 adenocarcinoma of the rectum (according to the 1987 International Union Against Cancer staging system) located within 15 cm of the anal verge, and had a WHO performance status of 0 or 1. Disease staging was established by clinical examination, rigid proctoscopy, chest radiography, and
Results
1011 patients were randomly assigned to treatment between April, 1993, and March, 2003, from 40 sites in nine European countries and Israel: 252 to the preoperative radiotherapy group, 253 to the preoperative chemoradiotherapy group, 253 to the preoperative radiotherapy and adjuvant chemotherapy group, and 253 to the preoperative chemoradiotherapy and adjuvant chemotherapy group. Radiotherapy was delivered in 500 of 505 patients assigned to preoperative radiotherapy and in 505 of 506 patients
Discussion
After a median follow-up of 10·4 years, the long-term analysis of the EORTC 22921 trial showed that very few relapses occur beyond 5 years of follow-up, whereas deaths due to causes other than rectal cancer become more common. The updated analysis shows no significant improvement in disease-free survival or in overall survival. Therefore, the hypothesis of a delayed benefit provided by adjuvant chemotherapy generated by the initial analysis4 is not supported by the updated results (panel).
References (23)
- et al.
Preoperative chemoradiotherapy versus preoperative radiotherapy in rectal cancer patients: assessment of acute toxicity and treatment compliance. Report of the 22921 randomised trial conducted by the EORTC Radiotherapy Group
Eur J Cancer
(2004) - et al.
Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial
Lancet Oncol
(2012) - et al.
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
Lancet Oncol
(2012) - et al.
Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials
Ann Oncol
(2010) - et al.
Multidisciplinary rectal cancer management: 2nd European Rectal Cancer Consensus Conference (EURECA-CC2)
Radiother Oncol
(2009) - et al.
Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial
Lancet Oncol
(2010) - et al.
Preoperative versus postoperative chemoradiotherapy for rectal cancer
N Engl J Med
(2004) - et al.
Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203
J Clin Oncol
(2006) - et al.
Chemotherapy with preoperative radiotherapy with rectal cancer
N Engl J Med
(2006) - et al.
Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the EORTC Radiation Oncology Group
J Clin Oncol
(2007)