PHILADELPHIAPreoperative chemoradiotherapy with irinotecan(Drug information on irinotecan) (CPT-11, Camptosar), fluorouracil(Drug information on fluorouracil) (5-FU), and radiation showed a significant ability to downsize rectal adenocarcinomas and is being studied further in clinical trials, Edith P. Mitchell, MD, reported. Due to problems associated with the central venous access required for continuous infusion 5-FU, capecitabine(Drug information on capecitabine) (Xeloda) is being substituted for 5-FU in ongoing studies. Dr. Mitchell is clinical professor of medicine at Thomas Jefferson University in Philadelphia.
The risk of recurrence after surgery rises rapidly with stage of rectal cancer: 5% to 10% for stage I, 25% to 30% for stage II, and more than 50% for stage III. "This is an important point because there are few diagnostic tests that enable us to accurately stage rectal cancer prior to surgery," Dr. Mitchell said.
Surgical considerations include the size of the tumor, of the prostate or uterus, and of the patient, the extent of local invasion, tumor stage, co-existent disease, and the biological behavior of the tumor such as poor differentiation, vascularity, or lymphatic invasion.
Dr. Mitchell said that lower risk of local recurrence is associated with lower tumor stage, smaller tumor size, fewer nodal metastases, metastases that do not extend past the nodal capsule, and absence of perivascular or intravascular tumor invasion. Other favorable factors are more proximal tumor, female gender, removal of a larger number of nodes, and mesorectal excision of the tumor.
Dr. Mitchell said that analysis of rectal cancer treatment from 1988 through 1995 revealed the following patterns:
Stage I disease is being diagnosed less frequently.
Chemoradiotherapy is being used more often for stage II or stage III disease.
Chemoradiotherapy downstaged many patients with locally advanced or unresectable disease and made them candidates for resection.
Mesorectal excision followed by radiation therapy is more effective at preventing local recurrence than surgery alone.
"Radiotherapy reduces local-regional recurrence rates but has little effect on disease-free survival or on overall survival," she said.
Dr. Mitchell and colleagues conducted a phase I/II trial of weekly irinotecan and continuous 5-FU with concomitant preoperative radiation therapy in previously untreated patients with T3 or T4 rectal adenocarcinomas. Eligibility criteria included adenocarcinomas below 15 cm above the anal verge, distal border of the tumor below the peritoneal reflection, and clinical stage of II or III.
Chemotherapy included irinotecan in escalating doses from 30 mg/m2 to 60 mg/m2 IV over 60 minutes, given weekly on days 1, 8, 15, and 22. The researchers attempted to continue irinotecan throughout radiation therapy but the combination was too toxic, Dr. Mitchell noted. 5-FU was given by continuous infusion at 300 mg/m2/day for 5 days during radiation therapy. Radiation was given at 1.8 Gy/day to a total of 45 Gy.
Of the 67 patients enrolled in the study, 51 had undergone surgery and were evaluable for response. The most common grade 3 or 4 toxicities were diarrhea and catheter infections or clots (see Table 1).
High Response Rates
Dr. Mitchell reported that 100% of tumors were downsized following preoperative chemoradiotherapy. Clinical complete responses occurred in 24 (47%), and pathologic complete responses in 13 (25%). Clinical partial responses occurred in 27 (53%) and pathologic partial responses in 32 (63%). "In an additional six patients (12%), there was only minimal residual disease, which was defined as even a single tumor cell seen on pathologic examination of the tumor specimen," Dr. Mitchell said.
Patients with high levels of microsatellite instability (MSI) had the highest complete response rates. "We currently have an ongoing phase I study of irinotecan, capecitabine, and radiation therapy with capecitabine substituted for continuous infusion 5-FU because of the catheter problems," Dr. Mitchell said.
"Our conclusions thus far are that this preoperative chemoradiotherapy approach is feasible and well tolerated. The maximum tolerated chemotherapy doses are 50 mg/m2 for irinotecan with 225 mg/m2 of continuous infusion 5-FU and radiotherapy."