Preoperative Chemoradiation using Capecitabine in Locally Advanced Rectal Cancer

Heather Jones, MD
University of Pennsylvania Cancer Center
Last Modified: November 4, 2001

Presenter: J.S. Kim
Affiliation: Department of Therapeutic Radiology, Chungnam National University, Taejon, South Korea

Background
Studies indicate that preoperative chemoradiation can result in tumor downstaging with increase resectability and sphincter preservation in locally advanced rectal lesions. Capecitabine is a new fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug consisting of 5'-deoxy-5-fluorouridine (5'-dFUrd), which is converted to 5-fluorouracil (5-FU) by thymidine phosphorylase (dThdPase). dThdPase activity is from 3 to10 times higher in tumor tissue than in normal tissue and is up-regulated in human cancer xenografts after irradiation. Capecitabine orally also mimics the continuous infusion of 5 FU, the preferred administration of the drug. This study, evaluated the efficacy and toxicity of preoperative chemoradiation using capecitabine in locally advanced adenocarcinoma of the rectum.

Materials and Methods

45 patients with locally advanced rectal cancer clinically staged (T3/T4 or N+) were treated with preoperative chemoradiation.

Patient TN characteristics were as follows T2N2M0 in 2%, T3N1-2M0 in 90%, and T4N1-2M0 in 8%.

Forty-five Gy of radiation was delivered to the pelvis in daily 1.8 Gy fractions; this was followed by a 5.4 Gy boost to the primary tumor site.

Oral chemotherapy consisted of 2 cycles of capecitabine (1650 mg/m2/day) and leucovorin (20 mg/ m2/day) during radiotherapy. Chemotherapy was given for 14 days followed by 7 days of rest.

Definitive surgery was performed six weeks after the completion of preoperative chemoradiation by a single surgeon.

Results

Thirty-eight patients received definitive surgery with a negative resection margin. Five patients refused surgery, and 2 of them showed a clinical complete response. Two patients only underwent endoanal full-thickness excision, and had a pathologic complete response.

The type of surgical resection in the 38 patients was low anterior resection in 69%, colo-anal resection in 19%, and abdominoperineal resection in 13%.

The pathologic stages were T0N0-1M0 in 37%, T2N0-1M0 in 19%, T3N0-1M0 in 37%, T4N2M0 in 3%, and T3N1M1 in 3%.

A pathologic complete response was achieved in 31% (10/32). Pathologic lymph node metastasis was seen in 25% of patients with definitive surgery.

Tumor down staging by T Stage was achieved in 63% of the patients.

Capecitabine was stopped due to suspected toxic hepatitis in one patient

Of the 19 patients with tumors located 5 cm or less from the anal verge, 67% received sphincter-preserving surgery.

Grade 3 hematologic toxicity according to the common toxicity criteria did not occur. The signs of Grade 3 toxicity were as follows: fatigue (3%), diarrhea (3%), radiation dermatitis (3%), hand-foot reaction (8%). Perioperative complications were neurogenic bladder (6%), pelvic abscess (3%), colitis (3%), and rectovaginal fistula (3%). There was no postoperative mortality.

Author's Conclusions
Preoperative chemoradiation with capecitabine seems to be a safe, well-tolerated, effective neoadjuvant treatment modality. It does not increase perioperative complications. This preoperative treatment produces a considerable down-staging effect, and increases the possibility of sphincter-preserving surgery in distal rectal cancer.

Clinical/Scientific Implications
In IV infusion studies there is a good record of how much drug is administrated and the compliance with administration schedule and dose intensity of the drug in question. The ability to record the amount of drug administered when using oral agents is more challenging. It would have been interesting to include in the presentation how compliance was assessed (ie pill count, pill diary or monitored administration). Nonetheless, these new oral chemotherapy agents continue to show promise in both the adjuvant setting and in the treatment of metastatic rectal disease.