Postoperative radiation and concomitant bolus fluorouracil with or withoutadditional chemotherapy with fluorouracil and high-dose leucovorin in patients with high-risk rectal cancer: A randomized phase III study conducted by the Hellenic Cooperative Oncology Group

Background: Randomized studies have shown that postoperative chemotherapy w ith or without radiation therapy (RT) improved local control and survival o f patients with stages II or III rectal cancer. However, the optimal sequen ce of treatments and the optimal chemotherapeutic regimen have not been def ined. Modulation of fluorouracil (FU) by leucovorin (LV) has yielded a high ly significant difference in response rate from that of FU monotherapy, as suggested by an overview of randomized trials in patients with advanced col orectal cancer. However, this difference in response rate did not translate into a survival benefit. Purpose: To evaluate the impact on the disease-free survival (DFS) and over all survival (OS) of patients with stages II or III rectal cancer of postop erative RT and concomitant bolus FU administration alone or with additional chemotherapy using FU and high-dose LV. Patients and methods: From October 1989 until February 1997, 220 patients w ere randomized postoperatively to receive either one cycle of chemotherapy with FU (600 mg/m(2)/week x 6 followed by a two-week rest) and leucovorin ( LV, 500 mg/m(2)/week x 6 as a two-hour infusion) followed by pelvic RT with concomitant FU (400 mg/m(2)) as a rapid intravenous injection during the f irst three and last three days of RT, and three more cycles of the same che motherapy with FU and LV (standard, group A, 111 patients) or pelvic RT wit h concomitant FU only (experimental, group B, 109 patients). Results: As of August 1998, after a median follow-up of 4.9 years, there wa s no significant difference in either three-year DFS (Group A, 70.3%; group B, 68.2%, P = 0.53) or OS (group A, 77%; group B, 73.3%, P = 0.75). Cox mu ltivariate analysis revealed stage of disease, number of infiltrated nodes, tumor grade, presence of regional implants and perforation to be significa nt prognostic factors. The incidence of severe side effects was significant ly higher in the patients in group A than in those in group B (32.4% vs. 4. 6%, P < 0.0001). Conclusions: The incorporation of additional chemotherapy with FU and LV in to postoperative concomitant RT and bolus infusion of FU does not offer a g reater than or equal to 10% three-year survival benefit over that of concom itant RT and bolus infusion of FU, and significantly increases toxicity in patients with stages II or III rectal cancer.