Irinotecan/Thalidomide in Metastatic Colorectal Cancer

ABSTRACT: The prognosis for patients with metastatic colorectal cancer is poor. Use ofirinotecan (CPT-11, Camptosar) results in modest response rates of approximately20% in refractory patients diagnosed with this advanced stage of disease andoffers a side-effect profile that improves on that of previous standardtreatments. Thalidomide (Thalomid) has antiangiogenic properties, andangiogenesis has been shown to influence the outcome of colon cancer patients. Agood response rate and acceptable tolerability regarding gastrointestinaleffects were demonstrated in a pilot study of the irinotecan/thalidomidecombination in patients with metastatic colorectal cancer. This combination isbeing assessed at the University of Arkansas for Medical Sciences as second-linetherapy in a phase II trial. Patients with metastatic colorectal cancer arereceiving 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 definitivetherapy for colorectal cancer is surgery, which can be curative for diseasestages I, II, and III. Chemotherapy or radiation therapy has a limited role,providing survival benefit in the adjuvant setting and palliation in themetastatic setting. For nearly 40 years, fluorouracil (5-FU) has been the onlyagent that has produced a response rate of approximately 20% in patients withmetastatic colorectal cancer.[1] However, complete responses with 5-FU are rare.

5-FU is associated with a modest survival benefit in metastatic colorectalcancer patients in the adjuvant and metastatic settings. Various agents havebeen combined with 5-FU in attempts to improve response rates. Such agentsinclude leucovorin, which binds to the ternary complex of 5-FU, and levamisole (Ergamisole),an anthelminthic with immunomodulatory properties. 5-FU can be administered invarious ways—on a weekly schedule, via continuous infusion, on a high-doseweekly schedule, and as outlined by the popular Mayo Clinic regimen. Eachregimen induces different response rates, but none has demonstrated a survivalbenefit over another.

Patients presenting with isolated hepatic metastases can be treated withsurgery. Surgical resection is appropriate only in selected cases and improves5-year survival from 10% to 35%. Recently, an improvement in hepaticdisease-free survival and, possibly, overall survival time was demonstrated whenKemeny and colleagues administered hepatic arterial floxuridine (FUDR) withsystemic 5-FU following resection of hepatic metastases.[2] Long-term benefitsof this therapy are not known. Furthermore, while patients with hepaticmetastases who are treated with chemotherapy consisting of hepatic arterialinfusion of FUDR have higher response rates than do those receiving systemic5-FU,[3] no survival advantage of hepatic arterial FUDR over 5-FU infusion hasbeen demonstrated. Novel therapeutic approaches for unresectable hepaticmetastases include radiofrequency ablation and cryotherapy.

Irinotecan in Metastatic Colorectal Cancer

Irinotecan, a semisynthetic derivative of camptothecin, is a topoisomerase Iinhibitor associated with modest response rates of approximately 20% inrefractory metastatic colorectal cancer and rare complete responses (Table 1and Table 2).[4-11] Irinotecan is a prodrug that is converted to SN-38, the primarymetabolite responsible for drug efficacy and toxicity. Irinotecan usually isadministered in one of two schedules. According to the European schedule, thedrug is given as 300 to 350 mg/m² every 3 weeks. The North American schedule is125 mg/m² IV on a weekly basis × 4 followed by a 2-week rest. Response ratesand toxicities are comparable for both schedules. Diarrhea can be thedose-limiting toxicity (Table 3).

Thalidomide as an Antiangiogenic Agentin Colorectal Cancer

Thalidomide is a glutamic acid derivative, which initially was sold inGermany as an over-the-counter sedative. The drug was withdrawn nearly half acentury ago due to effects including teratogenicity and peripheral neuropathy.Subsequently, thalidomide was shown to be effective for the treatment oferythema nodosum leprosum and chronic graft-vs-host disease. Furthermore, basedon its potent TNF-alpha inhibition, thalidomide has been useful in treatingrefractory Crohn’s disease.[12] More recently, the antiangiogenic propertiesof thalidomide were recognized initially by D’Amato and colleagues.[13]Angiogenesis plays a major role in malignant disorders, and the influence ofangiogenesis in colorectal cancer was demonstrated by Takahashi andcolleagues.[14] Thalidomide was used successfully to treat patients withrefractory multiple myeloma.[15] The mechanism of action of thalidomide inmultiple myeloma is not understood, although it may be based on immunomodulatoryrather than antiangiogenic properties.

Combined Thalidomide/Irinotecan Therapy

The efficacy of combined thalidomide and irinotecan therapy for metastaticcolorectal cancer was demonstrated in a pilot study conducted at the Universityof Arkansas for Medical Sciences.[16] The data demonstrated good response rateswith fewer gastrointestinal side effects than seen with use of irinotecan alone,which is associated with late-onset diarrhea as a dose-limiting toxicity. Aphase II study combining thalidomide and irinotecan as second-line therapy forpatients with metastatic colorectal cancer is being conducted at the sameinstitution; a preliminary report follows.

Phase II Study of Second-Line Thalidomide/Irinotecan in Metastatic ColorectalCancer

Patients with metastatic colorectal cancer with bidimensional measurabledisease are being enrolled in a phase II study at the University of Arkansas forMedical Sciences.[17] All patients progressed on previous 5-FU-based therapyreceived in either the adjuvant or metastatic setting. The team is administering350 mg/m² of irinotecan IV every 3 weeks (300 mg/m² for patients over 70 years of age); 400 mg of thalidomide is beinggiven orally at bedtime.

At the time of the interim analysis, 18 patients had received thethalidomide/irinotecan combination. Fourteen of the 18 patients were evaluablefor response. The median patient age was 64 years (range: 29-76 years). A total of 77 irinotecan treatment cycles were delivered, with eachpatient given a median of three treatment cycles (range: 1-13 cycles). Themedian thalidomide dose was 400 mg/d (range: 100-400 mg/d), and the durationof thalidomide treatment ranged from 1 week to 40 weeks. Preliminary resultsshowed that four patients responded (one complete response, three partialresponses), six had stable disease, and four had progressive disease.Preliminary safety analysis in all 18 patients showed a marked decrease ingastrointestinal effects as compared with that expected with irinotecanmonotherapy (Table 4). Final results of this ongoing phase II study areforthcoming.

Conclusions

Previous data from a pilot study of irinotecan and thalidomide in patientswith refractory metastatic colorectal cancer have demonstrated a good responserate and acceptable tolerability regarding gastrointestinal effects. Thiscombination now is being assessed as first- and second-line therapy in phase IItrials, and preliminary results are encouraging.

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