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© 2002 American Society for Clinical Oncology
Thalidomide in Solid MalignanciesRoyal Marsden Hospital, Sutton, Surrey, United Kingdom THALIDOMIDE IS a drug with a long and checkered history. Originally developed and marketed as a sedative in pregnancy, thalidomide produced disastrous teratogenic effects when taken by women in the first trimester of pregnancy.1,2 These effects were attributed to inhibition of blood vessel growth in the developing fetal limb bud.3
Thalidomide continued to be used in a number of nonmalignant conditions, including leprosy, graft-versus-host disease, and human immunodeficiency virus–associated oral aphthous ulceration. A common feature of these three conditions is that they are characterized by high levels of tumor necrosis factor alpha (TNF Thalidomide also downregulates several other angiogenic and growth-promoting factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and interleukin (IL)-6, which may be released locally by tumors.3 The finding that thalidomide has significant antiangiogenic activity in animal models, especially when administered for long periods,3 led to examination of its effects in malignancies. Its interference with a gamut of biochemical processes has certain theoretical advantages, at least until we can more clearly identify specific therapeutic targets in individual tumors. Encouraging results have already been obtained with single-agent thalidomide in hematologic conditions, with a reduction of the myeloma protein in serum or Bence-Jones protein in urine that lasted for at least 6 weeks in approximately 30% of myeloma patients and clinical improvement in up to 60% of patients with myelodysplasia.8-10 The results of phase II studies of thalidomide as a single agent in the treatment of certain solid tumors have been most encouraging in Kaposi’s sarcoma, in which response rates in excess of 40%11 have been reported. Other results in solid malignancies have been far less impressive, although investigators have found some evidence of activity in renal cell cancer and glioma,12-15 with low objective response rates but with suggestions that there may be a dose-dependent, disease-stabilizing effect. The side effects of thalidomide are significant, consisting mainly of lethargy, constipation, and peripheral neuropathy. These side effects may be alleviated by taking thalidomide in the evening, maintaining a good fluid intake, and following an aggressive laxative policy. Patients should be examined regularly for peripheral neuropathy, and the thalidomide dose should be reduced or interrupted as necessary. There is evidence that gradual increase of the dose improves tolerance of thalidomide and allows some patients to tolerate doses of thalidomide in excess of 1g daily. The next approach has been to combine thalidomide with other, more standard cytotoxic agents. Thalidomide combined with cyclophosphamide, etoposide, and dexamethasone chemotherapy resulted in a 68% response rate in 50 patients treated for poor-prognosis multiple myeloma.16 There are many ongoing studies in the treatment of solid malignancies combining thalidomide with standard chemotherapeutic agents17 and immunologic agents such as IL-2 or interferon alfa-2b, as in the current Eastern Cooperative Oncology Group study in renal cell carcinoma. However, caution must be exercised when combining thalidomide with other agents. For example, there have been reports of an increased incidence of thromboembolic disease when thalidomide is combined with chemotherapy.10 Neurologic and heart rhythm disturbances may be seen when thalidomide is combined with interferon.18 The effects of single-agent thalidomide at low dose (100 mg daily) and high dose (600 mg daily) in the treatment of melanoma were investigated in two phase II studies at the Royal Marsden Hospital12 (600-mg data are from Martin Gore, personal communication, January 2001) in which neither dose showed significant activity. In this issue, Hwu et al19 report a phase I trial of a 6-week regimen of temozolomide, 50 to 75 mg/m2/d,20 with thalidomide, starting at 200 mg daily and increasing in fortnightly increments of 100 mg to a planned target dose of 400 mg, in patients with metastatic melanoma. Hwu et al amended the protocol after a patient in cohort 1 developed toxicity related to thalidomide. It was thought that the age of the patient affected his ability to tolerate thalidomide, and the protocol was amended to reduce the thalidomide dose in patients over 70 years of age. Although a perfectly reasonable decision, this amendment damaged the design of the study by effectively doubling the number of cohorts, each with only one or two patients. It would have been preferable to perform two phase I studies, one in each age group. The results from the present design make it difficult to determine the true incidence of dose-limiting toxicities in this study. In addition to the expected toxicities, two patients had thromboembolic events and four patients developed neuropathy, despite the relatively brief duration of treatment, raising the concern that these toxicities may be related to an interaction between the two drugs. Although this was a phase I study, it is also worth noting that five of the 12 patients responded to treatment, which has led to a phase II study of temozolomide 75 mg/m2/d for 6 weeks and thalidomide up to 400 mg/d in an 8-week cycle. The dose of thalidomide is reduced for patients over 70 years of age. Where should we go now? Thalidomide is a tantalizing drug, but to have the best chance of establishing its value, it may be necessary to discover which of its many activities are important. Clearly, different activities may be of importance in different disease settings.
Four key groups of thalidomide activities have been identified. First, there is downregulation of peptide signals such as IL-6, bFGF, VEGF, and TNF Preclinical work to establish which of the above mechanisms of action are important in specific diseases may allow the development of more effective anticancer agents. For example, IL-6 is of particular importance in supporting growth and preventing apoptosis of myeloma cells and is therefore an attractive therapeutic target.24 In this regard, the most exciting aspect of this field is the development of a range of thalidomide analogs that are far more specific and powerful than the parent molecule. These analogs fall into two groups, the selective cytokine inhibitory drugs and the immunomodulatory drugs. These drugs are now in early clinical studies, and results are eagerly awaited. Early indications suggest that these analogs may also be better tolerated and hence better candidates for combination with other drugs. Clearly, the hope must be that the old rogue thalidomide really has found a new lease on life and will be the parent to a new range of well-tolerated and effective adjuncts to the current anticancer armamentarium. REFERENCES 1. McBride WG: Thalidomide and congenital abnormalities. Lancet 2: 1358, 1961 (letter) 2. Lenz W: Thalidomide and congenital abnormalities. Lancet 1: 45, 1962 (letter)[Medline]
3.
D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91: 4082-4085, 1994 4. Crawford CL: Use of thalidomide in leprosy. Adverse Drug React Toxicol Rev 13: 177-192, 1994[Medline] 5. Vogelsang GB, Farmer ER, Hess AD, et al: Thalidomide for the treatment of chronic graft-versus-host disease. N Engl J Med 326: 1055-1058, 1992[Abstract]
6.
Jacobson JM, Greenspan JS, Spritzler J, et al: Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 336: 1487-1493, 1997 7. Ching LM, Xu ZF, Gummer BH, et al: Effect of thalidomide on tumour necrosis factor production and anti-tumour activity induced by 5,6-dimethylxantheone-4-acetic acid. Br J Cancer 72: 339-343, 1995[Medline]
8.
Singhal S, Mehta J, Desikan R, et al: Antitumour activity of thalido-mide in refractory multiple myeloma. N Engl J Med 341: 1565-1571, 1999 9. Strupp C, Germing U, Aivado M, et al: Thalidomide for the treatment of patients with myelodysplastic syndromes. Leukemia 16: 1-16, 2002[CrossRef][Medline] 10. Singhal S, Mehta J: Thalidomide in cancer. Biomed Pharmacother 56: 4-12, 2002[CrossRef][Medline]
11.
Little R, Wyvill K, Pluda J, et al: Activity of thalidomide in AIDS-related Kaposi’s sarcoma. J Clin Oncol 18: 2593-2602, 2000 12. Eisen T, Boshoff C, Mak I, et al: Continuous low dose thalidomide: A phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br J Cancer 82: 812-817, 2000[CrossRef][Medline] 13. Stebbing J, Benson C, Eisen T, et al: The treatment of advanced renal cell cancer with high-dose oral thalidomide. Br J Cancer 85: 953-958, 2001[CrossRef][Medline]
14.
Motzer R, Berg W, Ginsberg M, et al: Phase II trial of thalidomide for patients with advanced renal cell carcinoma. J Clin Oncol 20: 302-306, 2002 15. Short S, Traish D, Dowe A, et al: Thalidomide as an anti-angiogenic agent in relapsed gliomas. J Neurooncol 51: 41-45, 2001[CrossRef][Medline]
16.
Moehler T, Neben K, Benner A, et al: Salvage therapy for multiple myeloma with thalidomide and CED chemotherapy. Blood 98: 3846-3848, 2001 17. Figg W, Arlen P, Gulley J, et al: A randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. Semin Oncol 28;62-66, 2001 (4 suppl 15)
18.
Nathan P, Gore M, Eisen T: Unexpected toxicity of combination thalidomide and interferon alfa-2a treatment in metastatic renal cell carcinoma. J Clin Oncol 20: 1429-1430, 2002 (letter)
19.
Hwu W-J, Krown SE, Panageas KS, et al: Temozolomide plus thalidomide in patients with advanced melanoma: Results of a dose-finding trial. J Clin Oncol 20: 2610-2615, 2002
20.
Brock C, Newlands E, Wedge S, et al: Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res 58: 4363-4367, 1998
21.
Haslett P, Corral L, Albert M, et al: Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production and cytotoxic responses in the CD8+ subset. J Exp Med 187: 1885-1892, 1998 22. Geitz H, Handt S, Zwingenberger K: Thalidomide selectively modulates the density of cell surface molecules involved in the cell adhesion cascade. Immunopharmacology 31: 213-221, 1996[CrossRef][Medline]
23.
Fujita J, Mestre J, Zeldis J, et al: Thalidomide and its analogues inhibit lipopolysaccharide-mediated induction of cyclooxgenase-2. Clin Cancer Res 7: 3349-3355, 2001 24. Anderson K: Multiple myeloma: Advances in disease biology—Therapeutic implications. Semin Hematol 38: 6-10, 2001 (2 suppl 3)[Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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