No Survival Benefit of Adjuvant 5-FU–Based Chemotherapy After Neoadjuvant Radiotherapy or Chemoradiation for Resectable Rectal Cancer
As reported in The Lancet Oncology by Bosset et al, long-term results of the European Organisaton for Research and Treatment of Cancer (EORTC) trial 22921 indicate that adjuvant fluorouracil (5-FU)-based chemotherapy after preoperative radiotherapy with or without chemotherapy does not affect disease-free survival or overall survival in patients with rectal cancer.
Study Details
In the trial, 1,011 patients with clinical stage T3 or T4 resectable rectal cancer were randomly assigned between April 1993 and March 2003 to receive preoperative radiotherapy with (n = 253) or without (surveillance, n = 252) adjuvant chemotherapy or preoperative chemoradiation with (n = 253) or without (surveillance, n = 253) adjuvant chemotherapy.
Radiotherapy consisted of 45 Gy in 25 fractions of 1.8 Gy over 5 weeks. Chemotherapy consisted of 5-FU (350 mg/m2 per day) and leucovorin (20 mg/m2 per day). Preoperative courses were given during weeks 1 and 5 of radiotherapy. Adjuvant chemotherapy was given in four cycles every 3 weeks. Radiotherapy was delivered in 500 patients randomly assigned to preoperative radiotherapy and in 505 randomly assigned to preoperative chemoradiation; concurrent chemotherapy was delivered in 501 patients randomly assigned to preoperative chemoradiation.
Only 43% of patients randomly assigned to receive adjuvant chemotherapy received the planned dose within the scheduled time interval, with more than one-quarter not starting adjuvant chemotherapy due to postoperative complications, absence of tumor resection, disease progression, or patient refusal.
The primary endpoint was overall survival. After a median follow-up of 5 years, chemotherapy significantly improved local disease control irrespective of whether it was given in the neoadjuvant or adjuvant setting. Adjuvant chemotherapy did not improve survival, but a divergence in Kaplan-Meier survival curves suggested the possibility of delayed benefit.
Long-Term Results
After median follow-up of 10.4 years, the effects of postoperative treatment on overall survival and disease-free survival did not differ significantly according to neoadjuvant treatment (P for interaction = .47 for overall survival and .66 for progression-free survival). Ten-year overall survival was 49.4% in the preoperative radiotherapy group vs 50.7% in the preoperative chemoradiation group (hazard ratio [HR] = 0.99, P = .91) and 51.8% in the adjuvant chemotherapy group vs 48.4% in the surveillance group (HR = 0.91, P = .32).
Ten-year disease-free survival was 44.2% in the preoperative radiotherapy group vs 46.4% in the preoperative chemoradiation group (HR = 0.93, P = .38) and 47.0% in the adjuvant chemotherapy group vs 43.7% in the surveillance group (HR = 0.91, P = .29).
At 10 years, the incidence of local relapse was 22.4% with radiotherapy alone compared with 11.8% with preoperative chemoradiation, 14.5% with radiotherapy and adjuvant chemotherapy, and 11.7% with preoperative chemoradiation and adjuvant chemotherapy (P = .0017). There was no difference among treatments in cumulative incidence of distant metastases, with 77% of distant metastases being observed at the time of the first trial report in 2006.
The frequency of long-term side effects did not differ among the four groups (P = .22).
Conclusions
The investigators concluded, “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.”
They further noted that the long-term analysis showed a “persistent significant improvement of local control” after adding 5-FU–based chemotherapy to preoperative radiotherapy, and distant metastases were two and a half times more common than local relapses at 10 years. Approximately 90% of distant metastases occurred before 3 years, they reported, and adjuvant chemotherapy was unable to prevent their occurrence.
“[T]he control of occult distant disease is becoming a major objective in treatment strategies. Upfront chemotherapy before chemoradiotherapy is a relevant option and should be investigated…. [A] phase 3 trial (PRODIGE 23) is currently ongoing to compare preoperative chemoradiotherapy alone with neoadjuvant chemotherapy followed by preoperative chemoradiotherapy for patients with resectable locally advanced rectal cancer,” the authors wrote.
Jean-François Bosset, MD, of Besançon University Hospital J Minjoz, France, is the corresponding author for the Lancet Oncology article.
The study was funded by EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, and Ligue contre le Cancer Comité du Doubs.
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