By Edward Chu, MD
Professor of Medicine and Pharmacology
Chief, Section of Medical Oncology
Deputy Director, Yale Cancer Center
Yale University School of Medicine
New Haven, Connecticut

Adjuvant Chemoradiation
Several randomized phase III trials showed that chemotherapy when administered with concurrent radiation therapy after curative resection of rectal cancer decreased locoregional recurrence and improved survival. In the mid-1980s, the Gastrointestinal Study Group (GITSG) conducted GITSG 7175, which was a pivotal trial showing that adjuvant concurrent chemoradiation improved both local control and overall survival for patients with locally advanced rectal cancer, when compared with surgery alone or radiotherapy alone.[1] After curative surgical resection of rectal cancer, patients (n = 202) were randomized to one of four treatment arms:

(1) no postoperative therapy;
(2) postoperative radiotherapy alone;
(3) postoperative chemotherapy alone with 5-fluorouracil (5-FU) and methyl-CCNU; or
(4) concurrent chemoradiation with 5-FU and methyl-CCNU.

Patients treated with concurrent chemoradiation had a much lower risk of recurrence (33%) compared to those who did not receive postoperative therapy (55%). Time to tumor recurrence was also significantly prolonged in the concurrent chemoradiation arm (P < .009). Overall survival (OS) did not differ significantly among the treatment groups. This study supported the incorporation of adjuvant chemoradiation as the standard of care for patients with Dukes stage B2 and C rectal cancer.

The National Surgical Adjuvant Breast and Bowel Project trial R-01 (NSABP R-01) investigated the role of adjuvant therapy in the management of Dukes B and C rectal cancer after curative surgical resection.[2] Patients were randomized to one of three arms:

(1) no further treatment (n = 184);
(2) adjuvant MOF (methyl-CCNU, vincristine [Oncovin], 5-FU) chemotherapy (n = 187); or
(3) adjuvant radiation therapy alone (n = 184).

Patients treated with adjuvant chemotherapy experienced a significant increase in disease-free survival (DFS) (P = .006) and OS (P = .05) when compared to surgery alone. The use of adjuvant radiation therapy resulted in a reduction in locoregional recurrence in comparison to surgery alone (25% vs 16%, P = 0.6). Of note, no significant difference in DFS and OS was observed between radiation therapy and observation following surgical resection.

The North Central Cancer Treatment Group (NCCTG) trial 79-47-51 evaluated the role of adjuvant chemoradiation in the management of high-risk rectal cancer.[3] A total of 2,004 patients were randomized to receive either adjuvant radiation alone or adjuvant radiation with concurrent 5-FU/methyl-CCNU combination chemotherapy. Patients receiving concurrent chemoradiation experienced significant reductions in disease recurrence (34% reduction, P = .0016), cancer-related deaths (36% reduction, P = .0071), and overall deaths (29% reduction, P = 0.025). This trial documented the clear superiority of concurrent chemoradiation over radiation alone in the adjuvant therapy of rectal cancer.

NSABP R-02 evaluated the role of radiation in addition to chemotherapy in the adjuvant setting.[4] In this phase III randomized trial, 741 patients with Dukes B and C rectal cancer were randomized to receive adjuvant chemotherapy alone or adjuvant chemoradiation. Patients were stratified according to sex, number of positive lymph nodes, age, and institution. Male patients were randomized to one of four treatment arms:

(1) 5-FU/leucovorin weekly for 6 weeks followed by a 2-week rest period, given on an every 8-week cycle;
(2) infusional 5-FU/leucovorin plus radiotherapy;
(3) MOF (methyl-CCNU, vincristine [Oncovin], 5-FU at 325 mg/m²) on a 10-week cycle; or
(4) MOF plus radiotherapy given on a 10-week cycle.

Female patients were randomized to 5-FU/leucovorin alone or 5-FU/leucovorin plus radiotherapy. Patients treated with chemoradiation experienced a significant reduction in the cumulative incidence of locoregional relapse, from 13% to 8% at 5-year follow-up (P = .02). No differences in 5-year OS were observed between the MOF and 5-FU/leucovorin systemic chemotherapy arms in male patients (62% vs 65%, P = .17). This study confirmed that use of chemoradiotherapy in the adjuvant setting plays a key role in reducing the incidence of locoregional recurrence.