Irinotecan/Thalidomide in Metastatic Colorectal Cancer

Irinotecan/Thalidomide in Metastatic Colorectal Cancer

ABSTRACT: The prognosis for patients with metastatic colorectal cancer is poor. Use of irinotecan (CPT-11, Camptosar) results in modest response rates of approximately 20% in refractory patients diagnosed with this advanced stage of disease and offers a side-effect profile that improves on that of previous standard treatments. Thalidomide (Thalomid) has antiangiogenic properties, and angiogenesis has been shown to influence the outcome of colon cancer patients. A good response rate and acceptable tolerability regarding gastrointestinal effects were demonstrated in a pilot study of the irinotecan/thalidomide combination in patients with metastatic colorectal cancer. This combination is being assessed at the University of Arkansas for Medical Sciences as second-line therapy in a phase II trial. Patients with metastatic colorectal cancer are receiving 350 mg/m² of irinotecan every 3 weeks plus 400 mg/m²/d of thalidomide. Preliminary response and safety data are presented for 18 enrolled patients. [ONCOLOGY 16(Suppl 3):23-26, 2002]

Patients with metastatic colorectal cancer have a poor prognosis—median 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 (5-FU) has been the only
agent that has produced a response rate of approximately 20% in patients with
metastatic colorectal cancer.[1] 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 (Ergamisole),
an anthelminthic with immunomodulatory properties. 5-FU can be administered in
various ways—on 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.[2] 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,[3] 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 in Metastatic Colorectal Cancer

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 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 as an Antiangiogenic Agent
in Colorectal Cancer

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 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.[12] More recently, the antiangiogenic properties
of thalidomide were recognized initially by D’Amato and colleagues.[13]
Angiogenesis plays a major role in malignant disorders, and the influence of
angiogenesis in colorectal cancer was demonstrated by Takahashi and
colleagues.[14] Thalidomide was used successfully to treat patients with
refractory multiple myeloma.[15] 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.[16] 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.


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