Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study.
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/m(2) per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m(2) 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.


RESULTS
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).


CONCLUSIONS
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.


BACKGROUND
EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comité du Doubs.
Department of Radiation Oncology, Besançon University Hospital J Minjoz, Besançon, France. Electronic address: jean-francois.bosset@univ-fcomte.fr.
Jean-François
JF
Bosset
Department of Radiation Therapy, University François Rabelais, Tours, France.
Gilles
G
Calais
Department of Radiation Therapy, Clinique Sainte-Catherine, Avignon, France.
Laurent
L
Mineur
Department of Radiation Oncology, Centre Georges-François Leclerc, Dijon, France.
Philippe
P
Maingon
Institute for Oncology and Radiology, Belgrade, Serbia.
Suzana
S
Stojanovic-Rundic
Department of Radiation Oncology, Centre Hospitalier Universitaire of Poitiers, Poitiers, France.
René-Jean
RJ
Bensadoun
Department of Radiation Therapy, Cancer Centre Nantes, Nantes, France.
Etienne
E
Bardet
Department of Radiation Therapy, Rambam Medical Centre, Haifa, Israel.
Alexander
A
Beny
Department of Surgery, Cancer Centre Strasbourg, Strasbourg, France.
Jean-Claude
JC
Ollier
Department of Radiation Oncology, Centre Hospitalier Universitaire A Michallon, Grenoble, France.
Michel
M
Bolla
Department of Radiation Therapy, Centre Hospitalier Universitaire de Charleroi, Charleroi, Belgium.
Dominique
D
Marchal
Department of Gastroenterology, Hopitaux Universitaires Bordet-Erasme, Brussels, Belgium.
Jean-Luc
JL
Van Laethem
Department of Radiation Therapy, Centre Saint Yves, Vannes, France.
Vincent
V
Klein
Department of Radiation Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
Jordi
J
Giralt
Department of Radiotherapy, Centre Hospitalier Universitaire de Limoges, Limoges, France.
Pierre
P
Clavère
Department of Radiation Oncology, Universität Spital Zürich, Zürich, Switzerland.
Christoph
C
Glanzmann
Department of Radiation Therapy, Institut de Cancérologie de l'Ouest-Centre Paul Papin, Angers, France.
Patrice
P
Cellier
Department of Statistics, European Organisation for Research and Treatment of Cancer, Brussels, Belgium.
Laurence
L
Collette
D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D059186:Chemoradiotherapy, Adjuvant / Q000009:adverse effects / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D013505:Digestive System Surgical Procedures / Q000009:adverse effects / Q000401:mortality; D018450:Disease Progression; D018572:Disease-Free Survival; D005060:Europe; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D057194:Intention to Treat Analysis; D007557:Israel; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000009:adverse effects / Q000401:mortality; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D012004:Rectal Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D002955:Leucovorin; D005472:Fluorouracil