Current Status of Thalidomide in the Treatment of Cancer

In his comprehensive review, Dr.Rajkumar provides a summary ofthe current status of thalidomide (Thalomid) therapy in cancer. As discussed inthe article, it was the teratogenic effects, particularly phocomelia, thatprompted researchers to examine thalidomide’s antitumor activity in the 1960s.Although, the results of early phase I trials of thalidomide as an anticanceragent were disappointing, they clearly demonstrated that thalidomide is neithera cytotoxic agent nor a mutagen. The mystery of its teratogenic effect began tounfold after D’Amato et al observed that thalidomide is an inhibitor ofangiogenesis.[1] This finding renewed enthusiasm for studying thalidomide as ananticancer agent in the last several years.

The Potential ofCombination Therapy

Dr. Rajkumar reviews the clinical trials that establishedthalidomide as an effective anticancer agent in relapsed or previously untreatedmultiple myeloma, either as a single agent or in combination therapy. However,contrary to its success in myeloma, single-agent thalidomide has very limitedantitumor activity in most solid tumors (see Dr. Rajkumar’s Table 3). Inanimal models, the combination of an antiangiogenic agent and cytotoxic therapycan be curative, whereas either agent alone is only inhibitory.[2] These datasuggested that therapy directed against both the endothelial cell and tumor cellcomponents of a tumor is more effective than therapy targeting tumor cellsalone.

Weber et al conducted a study of the combination ofdexamethasone and thalidomide in patients with refractory myeloma.[3] Assingle-agent therapy, dexamethasone or thalidomide had failed in approximatelyhalf of the 47 previously treated patients; 24 patients had responded. Theimproved activity of the combination suggests that the synergistic activity ofthese agents can overcome drug resistance in myeloma patients. Using the samescenario, the combination of standard chemotherapy and the antiangiogenic agentthalidomide may be more effective in chemoresistant solid tumors.

Preliminary results of several phase II studies have shownthat thalidomide is safe and well tolerated when combined withchemotherapy.[4-6]. Numerous trials have been initiated to study thalidomide incombination with standard chemotherapy in various solid tumors, and onlypreliminary results are currently available. Govindarajan and colleaguesconducted a pilot study of thalidomide in combination with irinotecan(Camptosar) for metastatic colorectal cancer.[7] They were encouraged by theobservation that thalidomide had almost eliminated the dose-limitinggastrointestinal toxicities associated with irinotecan, especially diarrhea andvomiting. Thus, eight of nine treated patients were able to complete thetherapeutic course without a dose reduction.

Responses Seen in Brain Metastases

The prognosis of patients with cerebral metastases remains poor,and the median survival from diagnosis of central nervous system involvement isno more than 4 months, as reported in many series.[8] Chemotherapy is generallyineffective for brain metastases from melanoma, partly because mostchemotherapeutic agents do not penetrate the blood-brain barrier.

Recently, at Memorial Sloan-Kettering Cancer Center, we used thecombination of temozolomide (Temodar) and thalidomide to treat melanoma that hasmetastasized to the brain. When thalidomide was administered 30 to60 minutes before temozolomide, it eliminated nausea and vomiting but alsoincreased constipation. Although either drug alone shows limited activityagainst metastatic melanoma in the brain, 6 of the 16 treated patients respondedto the combination.

All patients who achieved systemic responses also had cerebralresponses. Furthermore, responses were seen in patients who received priortherapy with temozolomide or dacarbazine (DTIC-Dome), an intravenous analog oftemozolomide. At a median follow-up of 8 months, the median survival of the 16patients is 9 months; 9 patients are alive and 2 show no evidence of metastaticdisease. These preliminary results strongly support the hypothesis that thecombination of cytotoxic and antiangiogenic agents provides more effectivetreatment for chemoresistant tumors.

Investigators from the University of Pittsburgh have reportedthat in animal models, the combination of an antiangiogenic compound andimmunotherapy has a more potent antitumor effect than either modality alone.[8]In addition, the angiogenesis inhibitors had a stronger impact on immunogenictumors than on nonimmunogenic tumors. This may provide the scientific basis forthe encouraging preliminary results of the combination of thalidomide andinterferon-alpha in metastatic renal cell carcinoma.[T.G. Eisen, personalcommunication, 2000.]

Conclusions

Dr. Rajkumar summarizes the clinical trials that establishedthalidomide as an effective antitumor agent in the treatment of myeloma.Preliminary results have suggested promising activity in other hematologicmalignancies. However, except for Kaposi’s sarcoma, brain tumors, and renalcancer, thalidomide has little anticancer activity as a single agent in solidtumors. Many studies have demonstrated that thalidomide can be administered withstandard antitumor agents. Both experimental and clinical data confirm thesynergistic activity of thalidomide when combined with other antitumor agents.The combined use of thalidomide with standard anticancer therapy, such aschemotherapy, hormonal therapy, or immunotherapy, holds promise for moreeffective treatment of chemoresistant tumors.

References:

1. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is aninhibitor of angiogenesis. Proc Natl Acad Sci USA 91:4082-4085, 1994.

2. Teicher BA, Sotomayor EA, Huang ZD: Antiangiogenic agentspotentiate cytotoxic cancer therapies against primary and metastatic disease.Cancer Res 52:6702-6704, 1992.

3. Weber DM, Rankin K, Gavino M, et al: Thalidomide withdexamethasone for resistant multiple myeloma. Blood 96:167a, 2000.

4. Merchant JJ, Hammes LC, Larson ML, et al: Pilot and safetytrial of carboplatin, paclitaxel, and thalidomide in advanced non-small-celllung cancer (abstract 2130). Proc Am Soc Clin Oncol 19:541a, 2000.

5. Barlogie B, Desikan R, Munshi N, et al: Single-course D.T.PACE anti-angiochemotherapy effects CR in plasma cell leukemia and fulminantmultiple myeloma (MM). Blood 92(suppl 1):273b, 1998.

6. Arance A, Middleton M, Lorigan PC, et al: Three-arm phase IIstudy of temozolomide in metastatic melanoma: Preliminary results (abstract2257). Proc Am Soc Clin Oncol 19:573a, 2000.

7. Govindarajan R, Heaton KM, Broadwater R, et al: Effect ofthalidomide on gastrointestinal toxic effects of irinotecan. Lancet 356:566-567,2000.

8. Gorelik E, Zhu ZY, Huang X, et al: Increased efficacy ofangiostatin and endostatin therapy by stimulation of antitumor immunity.Presented at the "Era of Hope" Department of Defense Breast CancerResearch Program meeting, Atlanta, June 11, 2000.