Ten years of preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation in three consecutive studies

Abstract

Purpose: To compare acute toxicity, tumor response, and sphincter preservation in three schedules of concurrent chemoradiation in resectable transmural and/or node-positive extraperitoneal rectal cancer.Patients and Methods: Between 1990 and 1999, 163 consecutive patients were treated according to the following combined modalities: FUMIR: between 1990 and 1995, 83 patients were treated with bolus i.v. mitomycin C (MMC), 10 mg/m2 day 1, plus 24-h continuous infusion i.v. 5-fluorouracil (5-FU) 1,000 mg/m2 days 1–4, and concurrent external beam radiotherapy (37.8 Gy). PLAFUR-4: between 1995 and 1998, 40 patients were treated with cisplatin (c-DDP) 60 mg/m2 given as slow infusion (1–4 h) on days 1 and 29, plus 24-h continuous infusion i.v. 5-FU 1,000 mg/m2, days 1–4 and 29–32 with concurrent external-beam radiotherapy (50.4 Gy). PLAFUR-5: between 1998 and 1999, 40 patients were treated with c-DDP 60 mg/m2 given as slow infusion (during 1–4 h) on days 1 and 29, plus 24-h continuous infusion i.v. 5-FU 1,000 mg/m2, days 1–5 and 29–33 with concurrent external-beam radiotherapy (50.4 Gy).Results: Grade ≥ 3 acute toxicity occurred in 14%, 5%, and 17% of patients treated in the FUMIR, PLAFUR-4, and PLAFUR-5 studies, respectively (p = 0.201). In the FUMIR, PLAFUR-4, and PLAFUR-5 studies, clinical response rate was 77%, 70%, and 83%, respectively. Tumor downstaging occurred in 57%, 68%, and 58% of patients, respectively. Pathologic complete response was recorded in 9% (FUMIR), 23% (PLAFUR-4), and 20% (PLAFUR-5) of patients. Sphincter-preserving surgery was feasible in 44% (FUMIR), 40% (PLAFUR-4), and 61% (PLAFUR-5) of patients having a distance between the anal-rectal ring and the lower pole of the tumor of 0–30 mm, and in 95%, 100%, and 100%, respectively, in those having a distance of 31–50 mm. Comparing FUMIR vs. PLAFUR, the clinical response rate was similar in the two series: a partial response was observed in 62/81 (77%) patients with FUMIR treatment, and in 61/80 (76%) patients with PLAFUR treatment. Tumor downstaging was observed in 46/81 (57%) patients and in 50/80 (68%) patients, respectively. The pathologic complete response rate was statistically higher in the PLAFUR series: 7/81 (9%) patients with FUMIR treatment and 17/80 (21%) patients with PLAFUR treatment (p = 0.04). Major downstaging (pT0+ pTmic+ pT1) in the FUMIR group was reported in 12/81 (15%) patients versus 31/80 (39%) patients in the PLAFUR group (p = 0.0006). The anal sphincter was preserved in 63/81 (78%) patients with FUMIR treatment and in 69/80 (86%) patients with PLAFUR treatment. The perioperative morbidity was statistically lower with PLAFUR: a perioperative morbidity was experienced by 20/81 (25%) patients with FUMIR treatment and by 9/80 (11%) patients with PLAFUR treatment (p = 0.042).Conclusion: In our experience, higher radiation dose (50.4 Gy vs. 37.8 Gy), a second course of concurrent 5-FU, and the use of c-DDP instead of MMC improved the pathologic response rate without increasing acute toxicity and perioperative morbidity. The use of 5-FU 5-day infusion (PLAFUR-5) resulted in higher toxicity with a similar response rate compared to 4-day infusion (PLAFUR-4).