Thalidomide May Enhance Response Rate of Metastatic Colorectal Cancer to Irinotecan

LITTLE ROCK, Arkansas—The antiangiogenic properties of thalidomide (Thalomid) as well as its ability to inhibit tumor necrosis factor-alpha (TNF-alpha) suggest that thalidomide might be a useful addition to regimens for treating advanced cancers. Rangaswamy Govindarajan, MD, said that thalidomide may enhance the response rate of metastatic colorectal cancer to irinotecan (Camptosar) while also reducing irinotecan-related gastrointestinal toxicities. Dr. Govindarajan is assistant professor of medicine at the University of Arkansas for Medical Science in Little Rock, Arkansas.

In stage 2 colorectal cancer, recurrence risk is correlated to angiogenesis. This has been demonstrated both with microvessel counts and with expression of vascular endothelial growth factor (VEGF). Thalidomide also has a number of effects on immune function, including inhibiting TNF-alpha and stimulating CD8+ T-lymphocytes. "Thalidomide’s immune modulating properties may be more important than its antiangiogenic effects in cancer treatment," Dr. Govindarajan said.

Experimental Use

Dr. Govindarajan discussed experimental use of thalidomide to treat a patient with stage IV colon cancer who had developed liver metastases after resection and adjuvant therapy with the Mayo Clinic 5-fluorouracil/leucovorin regimen. After radiofrequency ablation of liver metastases and three cycles of floxuridine, the patient developed lung metastases and worsening of liver metastases. He was then treated with irinotecan (325 mg/m² IV q 21 d) and thalidomide (400 mg/d PO) for three cycles with marked resolution of pulmonary metastasis and a decrease in the size of liver metastases.

Three more cycles of treatment were given and produced remission with no evidence of disease on CT scan. This patient remained in remission for 6 months on thalidomide maintenance treatment (400 mg/d) then relapsed with brain metastases.

This experience inspired a pilot study of thalidomide and irinotecan in 11 patients. Dr. Govindarajan said that treatment produced 3 complete remissions (CR) lasting 6 to 15 months and one partial remission (PR) lasting 20 months. "Nausea, vomiting, and diarrhea were all significantly less than would be expected with irinotecan alone," he said.

GI Toxicities Reduced

This promising result was follow by a study of 18 patients with metastatic colon cancer who had disease progression on 5-FU-based regimens. Dr. Govindarajan said that patients are treated with irinotecan on the European infusion schedule of 350 mg/m² IV over 90 minutes q 21 d and thalidomide 400 mg/d at bedtime. Response was assessed after every third cycle with imaging and carcinoembryonic antigen (CEA) assay. Patients with CR receive two more cycles of irinotecan/thalidomide and continue thalidomide for 1 year.

Fourteen of 18 patients were evaluable at the time of this report. "There has been one complete remission, in addition to three partial remissions, six patients with stable disease, and four with disease progression," Dr. Govindarajan said.

Late grade-3 diarrhea occurred in two patients, including one who had stopped thalidomide for other reasons. Grade 3/4 nausea and vomiting were rare.

"The reduction in the GI toxicities compared to historical data is extremely impressive," Dr. Govindarajan said. "Thalidomide appears to decrease the gastrointestinal toxicities of irinotecan. It is well tolerated at 400 mg/d, and the response rate of metastatic colorectal cancer to irinotecan appears to be enhanced by thalidomide."