Thalidomide Appears to Enhance Activity of Irinotecan

LITTLE ROCK, Arkansas—Thalidomide appears to enhance the response rate produced by irinotecan (Camptosar) in metastatic colorectal cancer, while decreasing the drug’s gastrointestinal toxicities, reported Rangaswamy Govindarajan, MD. In addition, thalidomide is well tolerated at 400 mg/d, inhibits tumor necrosis factor-alpha, has antiangiogenic properties, and costimulates CD8+ T-cells, Dr. Govindarajan noted. He is assistant professor of medicine in the Division of Hematology/Oncology at the University of Arkansas for Medical Sciences, Little Rock, Arkansas.

"The search for better colorectal cancer therapy is urgent," Dr. Govindarajan stated. "Fluorouracil (5-FU)has been the single most effective agent for more than 30 years, and results are disappointing. The partial response rate is less than 25%, and complete responses are rare. Phase II studies of irinotecan in 5-FU-refractory colorectal cancer were encouraging, with response rates ranging from 13% to 22% (Figure 1)," he continued.

Thalidomide Case Report

Dr. Govindarajan described a case in which thalidomide produced significant results. "We were amazed at the response, and we also noted no toxicity."

The patient was a 48-year-old white male who had a hemicolectomy and stage III colon cancer. He had been treated with 6 cycles of the Mayo Clinic regimen of 5-FU at 425 mg/m² plus leucovorin at 20 mg/m² x 5 days, with dose reductions for mucositis. Liver metastases subsequently detected on CT scan were treated with radiofrequency ablation in December 1998 and the patient was treated with 3 cycles of fludarabine (Fludara) at 0.2 mg/kg/d. Disease progression (lung metastases and worsening liver metastases) was noted in April 1999, at which point the patient requested treatment with an antiangiogenic agent.

Dr. Govindarajan has a compassionate use IND for thalidomide, so the patient was treated with irinotecan (325 mg/m² IV q 21 days) and thalidomide (400 mg/day PO). In June 1999, after 3 cycles of therapy, there was "marked resolution of the pulmonary metastases and a decrease in the size of liver metastases." The patient was given three more cycles of treatment and in August 1999 had no evidence of disease on CT scan.

There was no toxicity observed, and the patient was given two additional cycles of irinotecan/thalidomide. In November 1999 the patient still had no evidence of disease on CT scan and was continued on maintenance therapy of thalidomide 400 mg/day. He relapsed the following February with brain, lung, and liver metastases.

Ongoing Clinical Trial

Following this encouraging experience, Dr. Govindarajan designed a phase II clinical trial, which is ongoing. The irinotecan dosage schedule is 350 mg/m² IV q 3 weeks or 300mg/m² IV q 3 weeks for patients older than 70 years of age. The thalidomide dose is 400 mg/d. The study is open to patients with histologically confirmed colon/rectal carcinoma and measurable metastatic disease. Prior therapy with a 5-FU-based regimen is permitted, either for adjuvant therapy within the past 6 months or for metastatic disease. Prior irinotecan and/or prior thalidomide are not permitted. Patients must adhere to birth control as prescribed by the S.T.E.P.S. program.

"Seventeen patients have been treated so far, and 13 are evaluable. Median age is 61 years (range 29 to 76). The median number of irinotecan cycles given is 3 (range 1 to 9). The median thalidomide dose is 400 mg/d (range 100 to 400), and the duration of thalidomide so far is 1 week to 36 weeks," Dr. Govindarajan explained.

"We have seen one complete response, two possible partial responses, six patients with disease stabilization, and four with disease progression," Dr. Govindarajan said. GI toxicities have been notably mild and diarrhea has been "significantly less than expected."