In this article, Dr. Rich traces the evolution of chemoradiation in cancer of the rectum from its role as adjuvant therapy to its role in neoadjuvant therapy and its potential as definitive therapy. The efficacy of irradiation and fluorouracil(Drug information on fluorouracil) (5-FU)-based chemotherapy as adjuvant therapy for resected high-risk rectal cancer (stage II or III disease) was first established in a series of prospective randomized trials conducted in the 1980s and '90s in the United States.[1-4] These studies demonstrated that patients receiving postoperative irradiation with concurrent and maintenance 5-FU-based chemotherapy had improved local control and survival, as compared with patients receiving no adjuvant therapy, postoperative irradiation only, or chemotherapy only.
Recent phase III studies have documented the merits of 5-FU administered as a continuous peripheral venous infusion throughout the 5- to 6-week course of irradiation--an approach first pioneered by Dr. Rich and colleagues in the early 1980s. Current adjuvant trials in rectal cancer are investigating various combinations of 5-FU with leucovorin and levamisole(Drug information on levamisole) (Ergamisol), as well as different methods of 5-FU administration.
Because of the success of combined-modality treatment in the postoperative setting, there has been intense interest in utilizing this approach neoadjuvantly. Numerous phase II studies have demonstrated the safety of this program, and preliminary analyses indicate satisfactory local control and survival rates.
These studies also show higher rates of complete pathologic response following treatment with chemoradiation than after irradiation alone. Complete pathologic responses occur in only 6% to 12% of patients following moderate- to high-dose (45- to 50-Gy) preoperative irradiation (Table 1).[5-9] Continuous-infusion 5-FU programs or various 5-FU-based regimens with irradiation have increased these complete pathologic response rates to 20% to 29% (Table 1).
Although the primary goals of neoadjuvant therapy are improved local control and improved survival, there is an additional important benefit to this approach for tumors in the distal rectum--sphincter preservation. Chemoradiation programs have been utilized to promote tumor regression, thus facilitating a resection that spares the sphincter and insetting the left colon as a coloanal anastomosis. The sphincter is disturbed by this surgery, and many patients experience initial difficulty with control, a sense of urgency, and stool frequency, although most patients eventually have acceptable functional results. Table 2 summarizes the results of three studies utilizing this approach of neoadjuvant treatment and resection with coloanal anastomosis.[10-12]
The data demonstrate that approximately 80% of patients with distal rectal cancers can undergo a resection, with a coloanal anastomosis as an alternative to abdominoperineal resection with satisfactory results. Investigators from Thomas Jefferson University Hospital have used preoperative irradiation (45 to 55 Gy) and local excision as an alternative to a resection with coloanal anastomosis in 48 patients with distal rectal cancer. Of these patients, 30 were judged to have transmural tumors (T3) prior to irradiation.
The 5-year actuarial survival was 83.5% and the local recurrence rate was 10%. Surgical complications occurred in 10% of patients. Sphincter function was described as good to excellent in 88% of patients. As the data from this study and other investigations show, neoadjuvant chemoradiation promotes regression of rectal cancer and facilitates sphincter-sparing procedures. Preliminary local control and survival rates, as well as bowel function, appear to be encouraging.
Current Indications for Definitive Infusional Chemoradiation
The indications for infusional chemoradiation as definitive therapy of rectal cancer without surgical intervention are limited at present. With residual disease present in over 70% to 80% of resection specimens after standard neoadjuvant chemoradiation and surgery, it is unlikely that this approach, by itself, will offer satisfactory long-term local control and survival rates. As pointed out by Dr. Rich, efforts to select patients for definitive infusional chemoradiation according to kinetic and genetic markers, as well as further investigations of fractionation and new drugs, may make this a possibility in the future.