LITTLE ROCK, ArkansasThalidomide 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
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
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."