Elsevier

The Lancet Oncology

Volume 15, Issue 2, February 2014, Pages 184-190
The Lancet Oncology

Articles
Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study

https://doi.org/10.1016/S1470-2045(13)70599-0Get rights and content

Summary

Background

EORTC trial 22921 examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. After a median follow-up of 5 years, chemotherapy—irrespective of timing—significantly improved local control. Adjuvant chemotherapy did not improve survival, but the Kaplan-Meier curves diverged, suggesting possible delayed benefit. Here, we report the updated long-term results.

Methods

We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy with or without concomitant chemotherapy before surgery followed by either adjuvant chemotherapy or surveillance. Randomisation was done using minimisation with factors of institution, sex, T stage, and distance from the tumour to the anal verge. Study coordinators, clinicians, and patients were aware of assignment. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m2 per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m2 per day intravenous bolus). For preoperative chemotherapy, two courses were given (during weeks 1 and 5 of radiotherapy). Adjuvant chemotherapy was given in four cycles, every 3 weeks. The primary endpoint was overall survival. This analysis was done by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00002523.

Findings

1011 patients were randomly assigned to treatment between April, 1993, and March, 2003 (252 to preoperative radiotherapy and 253 to each of the other three groups). After a median follow-up of 10·4 years (IQR 7·8–13·1), 10-year overall survival was 49·4% (95% CI 44·6–54·1) for the preoperative radiotherapy group and 50·7% (45·9–55·2) for the preoperative radiotherapy and chemotherapy group (HR 0·99, 95% CI 0·83–1·18; p=0·91). 10-year overall survival was 51·8% (95% CI 47·0–56·4) for the adjuvant chemotherapy group and 48·4% (43·6–53·0) for the surveillance group (HR 0·91, 95% CI 0·77–1·09, p=0·32). 10-year disease-free survival was 44·2% (95% CI 39·5–48·8) for the preoperative radiotherapy group and 46·4% (41·7–50·9) for the preoperative radiotherapy and chemotherapy group (HR 0·93, 95% CI 0·79–1·10; p=0·38). 10-year disease-free survival was 47·0% (95% CI 42·2–51·6) for the adjuvant chemotherapy group and 43·7% (39·1–48·2) for the surveillance group (HR 0·91, 95% CI 0·77–1·08, p=0·29). At 10 years, cumulative incidence of local relapse was 22·4% (95% CI 17·1–27·6) with radiotherapy alone, 11·8% (7·8–15·8) with neoadjuvant radiotherapy and chemotherapy, 14·5% (10·1–18·9) with radiotherapy and adjuvant chemotherapy and 11·7% (7·7–15·6) with both adjuvant and neoadjuvant chemotherapy (p=0·0017). There was no difference in cumulative incidence of distant metastases (p=0·52). The frequency of long-term side-effects did not differ between the four groups (p=0·22).

Interpretation

Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival. Our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy. New treatment strategies incorporating neoadjuvant chemotherapy are required.

Funding

EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comité du Doubs.

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).

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