The Role of Radiation in the Management of Rectal Cancer - (page 1 of 2)
By Stephen M. Karlovits, M.D., and Tom Colonias, M.D.
Department of Radiation Oncology

Introduction
The treatment of rectal carcinoma has evolved over the past few decades to encompass a multidisciplinary approach of surgery, radiation and chemotherapy in an effort to improve outcomes in terms of survival and preservation of function. Historically, major surgical resection (usually in the form of an abdominal perineal resection with colostomy) was a mainstay in the treatment of rectal carcinoma. More recently, there has been a paradigm change toward maintaining the functional integrity of the rectum along with improving survival via neoadjuvant approaches, improved surgical techniques and emerging radiation technologies and chemotherapeutic agents.

Adjuvant Chemoradiation
Classically, the primary treatment for rectal cancer has been, and continues to be, surgical resection. Results of national cooperative group studies have shown an improvement in survival with combined adjuvant chemotherapy (CT) and radiotherapy (RT). Postoperative or adjuvant CRT has therefore been the standard of care in resected T3, T4 and/or node positive rectal carcinomas.

The rationale for using RT to sterilize potential microscopic residual disease following surgical resection in any disease is based on the pattern of local recurrence. In a review from Massachusetts General Hospital regarding patients treated with surgery alone, patients with T3N0, T3N1, T4N0 and T4N1 disease had local recurrence rates of 17, 36, 54 and 67 percent, respectively. This is primarily based on a tendency of these tumors to extend into the perirectal fat where the surgical margins may be limited. There can also be residual nodal disease, generally in the perirectal and pelvic lymphatics. Of importance is that the local recurrences are usually symptomatic and adversely impact quality of life.

Most of the large adjuvant therapy trials in the U.S. have been based on the treatment of patients with disease either extending through the bowel wall (T3) and/or with node positivity. Protocol R-01 in the AGHbased National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized patients into three arms: adjuvant MOF (methyl-CCNU, vincristine, fluorouracil), adjuvant RT and surgery alone. There was a statistically significant improvement in five-year disease free and overall survival in the adjuvant CT group but local control improvement only approached significance in the adjuvant RT group. NSABP R-02 randomized patients to adjuvant MOF with or without RT or adjuvant 5-FU/leucovorin with or without RT. This trial showed that combined modality therapy resulted in a significant decrease in locoregional failure. The Gastrointestinal Study Group performed a randomized trial in which a significant improvement in survival was observed with postoperative CRT for stage II and III rectal cancer as compared to surgery alone (54 percent versus 25 percent, p=0.005). The North Central Cancer Treatment Group (NCCTG) performed a randomized trial that compared postoperative CRT to postoperative RT alone and indicated an overall survival of 57 percent for adjuvant CRT versus 48 percent for adjuvant RT (p=0.025). Patients receiving adjuvant CRT also had a significantly lower incidence of both local recurrence (14 percent versus 25 percent; p=0.036) and distant metastasis (29 percent versus 46 percent; p=0.011) than patients treated with adjuvant RT alone. However, much of the improvement was observed in patients undergoing anterior resections (proximal rectal tumors) and not in patients undergoing abdominal-perineal resections (distal rectal tumors). A second NCCTG trial showed that continuous infusion 5-FU was significantly superior to bolus 5-FU in reducing the rate of overall failure (37 percent versus 47 percent; p=0.01) and distant metastasis (31 percent versus 40 percent; p=0.03). Four-year survival was also improved (70 percent versus 60 percent; p=0.005) with continuous infusion 5-FU.

The mechanism of enhanced local control with RT and 5-FU is unclear but may be related to 5-FU inhibiting DNA damage repair induced by the RT. There are also data that suggest that radiation enhances the effect of 5-FU induced cytotoxicity by decreasing the clearance of 5-FU from the tumor.