DENVER-Giving chemotherapy concurrently with radiation therapy before surgery for T3-T4 rectal cancer improves the rate of local control, investigators reported at the 47th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (abstract 4).
"When we started this protocol in 1992, the local relapse rate was considered to be between 25% and 45%," said presenting author Pascale Romestaing, MD, a radiation oncologist at the Center Hospital of Lyon-South in France. "And remember that at this time, total mesorectal excision was not the usual protocol for surgery." Research to date had suggested an advantage of preoperative therapy over postoperative therapy, and had pointed to the benefits of combining chemotherapy and radiation therapy.
Patients were eligible for the trial (FFCD 9203) if they had rectal adenocarcinomas that were accessible by digital rectal exam and large (T3 or T4) but resectable, Dr. Romestaing said. In addition, patients had to be younger than 80 years, have a good performance status, and be free of metastases. After stratification, they were assigned in balanced fashion to 45 Gy of external-beam radiation therapy given over 5 weeks, either alone or with two cycles of concurrent chemotherapy (fluorouracil by bolus and folinic acid) given during week 1 and week 5 of radiation therapy. All patients were scheduled to undergo surgery (total mesorectal excision was recommended) between 3 and 10 weeks later and to receive adjuvant chemotherapy.
Analyses were based on 733 patients treated between 1992 and 2003. Tumors were located in the inferior part of the rectum in about 52% of patients, were T3 tumors in 89%, and involved lymph nodes, as assessed by ultrasound, in roughly 67%.
The compliance rate was 96% for radiotherapy, 84% for preoperative chemotherapy, about 98% for surgery, and about 50% for adjuvant chemotherapy, with roughly one-fourth of all patients not receiving any adjuvant chemotherapy, Dr. Romestaing noted. Patients who received preoperative chemotherapy had a significantly higher incidence of grade 3-4 toxicity relative to those who did not receive it (15% vs 3%).
Pathologic Complete Responses
The rate of pathologic complete response was significantly higher with preoperative chemotherapy than without it (12% vs 4%). Despite this, the rate of sphincter preservation was almost identical-about 52% in each group. The lack of change in this outcome suggests that "the surgeons decided at the beginning of the treatment what they were going to do, and they did not change their mind when they saw the patient," Dr. Romestaing commented. "So it could be important maybe to change their mind." The rate of postoperative death was 1% in each group.
At 5 years, patients who did and did not receive preoperative chemotherapy had similar rates of overall survival (67% and 66%, respectively) and disease-free survival (59% and 56%), Dr. Romestaing said. However, preoperative chemotherapy was associated with a one-half reduction in the rate of local failure (8% vs 16%); moreover, this benefit was similar in men and women, in patients with tumors in the middle rectum and the low rectum, for T3 and T4 tumors, and after abdominoperineal resection and anterior resection.
In addition, about midway through the trial, surgical practices changed to favor total mesorectal excision, Dr. Romestaing noted, but the addition of chemotherapy before surgery still conferred a benefit in terms of reduced local recurrence in the trial's second half, 1999 to 2003 (4% vs 13%).
The trial's results, when considered along with those from two randomized trials also looking at concurrent chemotherapy (EORTC 22921 and a Polish trial), Dr. Romestaing said, suggest that preoperative chemotherapy improves pathologic response and local control, with a moderate increase in acute toxicity, but does not improve sphincter preservation or survival, and leaves the issue of late toxicity unresolved.
"For us, after these three randomized trials, preoperative
radiotherapy with concurrent chemotherapy will be the standard treatment for
tumors T3 and T4, low and middle tumors," she concluded. "The next step will
chemotherapy will be the best, and we are going to start a new trial addressing different chemotherapy protocols with external radiation therapy."