Thalidomide Diminishes Irinotecan Toxicity
ABSTRACT & COMMENTARY
Synopsis: Thalidomide is currently being actively investigated as cancer treatment because of its anti-angiogenic and immunomodulatory effects. However, an important observation was recently discovered in a series of patients with colorectal cancer receiving irinotecan. This commonly used chemotherapeutic has an associated incidence of diarrhea that at times has been prohibitive, but in this small series of patients receiving irinotecan and thalidomide, there was virtually no gastrointestinal toxicity, including diarrhea. Thus, thalidomide might be a useful adjunct to chemotherapy for reasons in addition to its anti-tumor effect.
Source: Govindarajan R, et al. Lancet 2000;356:566-567.
Irinotecan (cpt 11, camptosar) is the only approved second-line chemotherapy for colorectal cancer in the United States. However, overall response rates remain low (< 20%) and treatment is often limited by severe gastrointestinal toxicity, most prominent of which is diarrhea.1,2 Thalidomide, a glutamic acid derivitive, was originally introduced as a sedative but was removed after it was shown to be associated with severe teratogenicity. Recently, thalidomide has been shown to have antiangiogenesis and immunomodulatory properties, and its role in the treatment of cancer is currently being explored.3
In a pilot trial from the University of Arkansas for Medical Sciences, Govindarajan and colleagues treated nine patients with advanced colorectal cancer with thalidomide (400 mg, orally at bedtime) and irinotecan (325-350 mg/m2 q 21 days). They discovered that there was a striking absence of diarrhea and/or nausea in the treated patients. After 2-8 cycles of irinotecan, all patients but one were able to complete therapy at the prescribed dose (1 patient required a 50% dose reduction because of asthenia); and all but one patient tolerated the thalidomide (1 patient had the dose reduced by 75% because of somnolence). Of the seven assessable patients, one achieved a complete antitumor response and two had partial responses.
Compared to previously published data, there was significantly less than expected nausea, vomiting, and diarrhea in the treated patients. Whereas published series would predict greater than 85% incidence of diarrhea with 30% grade 3 or 4, only one patient in this series had mild diarrhea and none had grade 3 or 4. Similarly, the incidence of nausea and vomiting was dramatically reduced.
COMMENT by William B. Ershler, MD
This brief report is remarkable because it highlights a new and potentially very important observation from a clinical trial. Thalidomide was added to the established second-line drug for colorectal cancer with the hopeful expectation of observing enhanced clinical responses. The series is too small and of too small a duration to conclude any effect at this time. However, the striking disappearance of nausea, vomiting, and diarrhea from the treatment group is remarkable and, in itself, may be of sufficient importance to move thalidomide into the recommended treatment plan.
The finding needs to be confirmed and additional questions need to be addressed. What dose of thalidomide is required and will you get the same protective effect if administered just on the day of chemotherapy and perhaps a few days after? This question, of course, would be precluded if the larger investigation demonstrates an additive anti-cancer effect of thalidomide, in which case, continuous treatment might be required.
References
1. Cunningham D, et al. Lancet 1998;352:1413-1418.
2. Hecht JR. Oncology 1998;12:72-78.
3. Kerbel RS, et al. Eur J Cancer 2000;36:1248-1257.
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