Patients with metastatic colorectal cancer have a poor prognosismedian survival time is described as being 12 to 18 months. The definitive therapy for colorectal cancer is surgery, which can be curative for disease stages I, II, and III. Chemotherapy or radiation therapy has a limited role, providing survival benefit in the adjuvant setting and palliation in the metastatic setting. For nearly 40 years, fluorouracil(Drug information on fluorouracil) (5-FU) has been the only agent that has produced a response rate of approximately 20% in patients with metastatic colorectal cancer. However, complete responses with 5-FU are rare.
5-FU is associated with a modest survival benefit in metastatic colorectal cancer patients in the adjuvant and metastatic settings. Various agents have been combined with 5-FU in attempts to improve response rates. Such agents include leucovorin, which binds to the ternary complex of 5-FU, and levamisole(Drug information on levamisole) (Ergamisole), an anthelminthic with immunomodulatory properties. 5-FU can be administered in various wayson a weekly schedule, via continuous infusion, on a high-dose weekly schedule, and as outlined by the popular Mayo Clinic regimen. Each regimen induces different response rates, but none has demonstrated a survival benefit over another.
Patients presenting with isolated hepatic metastases can be treated with surgery. Surgical resection is appropriate only in selected cases and improves 5-year survival from 10% to 35%. Recently, an improvement in hepatic disease-free survival and, possibly, overall survival time was demonstrated when Kemeny and colleagues administered hepatic arterial floxuridine (FUDR) with systemic 5-FU following resection of hepatic metastases. Long-term benefits of this therapy are not known. Furthermore, while patients with hepatic metastases who are treated with chemotherapy consisting of hepatic arterial infusion of FUDR have higher response rates than do those receiving systemic 5-FU, no survival advantage of hepatic arterial FUDR over 5-FU infusion has been demonstrated. Novel therapeutic approaches for unresectable hepatic metastases include radiofrequency ablation and cryotherapy.
Irinotecan, a semisynthetic derivative of camptothecin, is a topoisomerase I inhibitor associated with modest response rates of approximately 20% in refractory metastatic colorectal cancer and rare complete responses (Table 1 and Table 2).[4-11] Irinotecan(Drug information on irinotecan) is a prodrug that is converted to SN-38, the primary metabolite responsible for drug efficacy and toxicity. Irinotecan usually is administered in one of two schedules. According to the European schedule, the drug is given as 300 to 350 mg/m² every 3 weeks. The North American schedule is 125 mg/m² IV on a weekly basis × 4 followed by a 2-week rest. Response rates and toxicities are comparable for both schedules. Diarrhea can be the dose-limiting toxicity (Table 3).
Thalidomide is a glutamic acid derivative, which initially was sold in Germany as an over-the-counter sedative. The drug was withdrawn nearly half a century ago due to effects including teratogenicity and peripheral neuropathy. Subsequently, thalidomide(Drug information on thalidomide) was shown to be effective for the treatment of erythema nodosum leprosum and chronic graft-vs-host disease. Furthermore, based on its potent TNF-alpha inhibition, thalidomide has been useful in treating refractory Crohn’s disease. More recently, the antiangiogenic properties of thalidomide were recognized initially by D’Amato and colleagues. Angiogenesis plays a major role in malignant disorders, and the influence of angiogenesis in colorectal cancer was demonstrated by Takahashi and colleagues. Thalidomide was used successfully to treat patients with refractory multiple myeloma. The mechanism of action of thalidomide in multiple myeloma is not understood, although it may be based on immunomodulatory rather than antiangiogenic properties.
Combined Thalidomide/Irinotecan Therapy
The efficacy of combined thalidomide and irinotecan therapy for metastatic colorectal cancer was demonstrated in a pilot study conducted at the University of Arkansas for Medical Sciences. The data demonstrated good response rates with fewer gastrointestinal side effects than seen with use of irinotecan alone, which is associated with late-onset diarrhea as a dose-limiting toxicity. A phase II study combining thalidomide and irinotecan as second-line therapy for patients with metastatic colorectal cancer is being conducted at the same institution; a preliminary report follows.