Abstract
In addition to immunomodulatory and cytokine-modulatory properties, thalidomide has antiangiogenic activity. It has been investigated in a number of cancers including multiple myeloma, myelodysplastic syndromes, gliomas, Kaposi’s sarcoma, renal cell carcinoma, advanced breast cancer, and colon cancer. Its role has been best explored in myeloma, where, at daily doses of 100 to 800mg, it is remarkably active, causing clinically meaningful responses in one-third of extensively pretreated patients and in over half of patients treated early in the course of the disease. It also acts synergistically with corticosteroids and chemotherapy in myeloma. Thalidomide produces improvement of cytopenias characteristic of myelodysplastic syndrome, resulting in the reduction or elimination of transfusion dependence in some patients. Responses have also been seen in one-third of patients with Kaposi’s sarcoma, in a small proportion of patients with renal cell carcinoma and high grade glioma and, in combination with irinotecan, in some patients with colon cancer. Thalidomide is being investigated currently in a number of clinical trials for cancer. Drowsiness, constipation and fatigue are common adverse effects seen in 75% of patients. Symptoms of peripheral neuropathy and skin rash are seen in 30%. A minority of patients experience bradycardia and thrombotic phenomena. Despite the high frequency of adverse effects, those severe enough to necessitate cessation of therapy are seen in only 10 to 15% of patients. A therapeutic trial of thalidomide should be considered in all patients with myeloma who are unresponsive to or relapse after standard therapy. In other malignant diseases, the most appropriate way to use the drug is in the setting of well designed clinical trials. In the absence of access to such studies, thalidomide could be considered singly or in combination with standard therapy in patients with no meaningful therapeutic options.
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References
Annas GJ, Elias S. Thalidomide and the Titanic: reconstructing the technology tragedies of the twentieth century. Am J Public Health 1999; 89: 98–101
Koch HP. Thalidomide and congeners as anti-inflammatory agents. Prog Med Chem 1985; 22: 165–242
Zwingenberger K, Wnendt S. Immunomodulation by thalidomide: systematic review of the literature and of unpublished observations. J Inflamm 1995; 46: 177–211
Corral LG, Kaplan G. Immunomodulation by thalidomide and0 thalidomide analogues. Ann Rheum Dis 1999; 58Suppl. 1: 1107–13
Sheskin J. The treatment of lepra reaction in lepromatous leprosy. Fifteen years’ experience with thalidomide. Int J Dermatol 1980; 19:318–22
Vogelsang GB, Fanner ER, Hess AD, et al. Thalidomide forthe treatment of chronic graft-versus-host disease. N Engl J Med 1992; 326: 1055–8
Olson KB, Hall T, Horton J, et al. Thalidomide (N-phthaloylglutamide) in the treatment of advanced cancer. Clin Pharmacol Ther1965; 6: 292–7
Grabstad H, Golbey R. Clinical experiences with thalidomide in patients with cancer. Clin Pharmacol Ther 1965; 6: 298–302
Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–71
Bensaid P, Machet L, Vaillant L, et al. Langerhans-cell histiocytosis in the adult: regressive parotid involvement following thalidomide therapy. Ann Dermatol Venereol 1992; 119: 281–3
Thomas L, Ducros B, Secchi T, et al. Successful treatment of adult’s Langerhans cell histiocytosis with thalidomide. Report of two cases and literature review. Arch Dermatol 1993; 129: 1261–4
Dallafior S, Pugin P, Cerny T, et al. Successful treatment of a case of cutaneous Langerhans cell granulomatosis with 2-chlorodeoxyadenosine and thalidomide. Hautarzt 1995; 46: 553–60
Soler RA, Howard M, Brink NS, et al. Regression of AIDS-related Kaposi’s sarcoma during therapy with thalidomide. Clin Infect Dis 1996; 23: 501–3
Nguyen M, Tran C, Barsky S, et al. Thalidomide and chemotherapy combination: preliminary results of preclinical and clinical studies. Int J Oncol 1997; 10: 965–9
Fife K, Howard MR, Gracie F, et al. Activity of thalidomide in AIDS-related Kaposi’s sarcoma and correlation with HHV8 titre. Int J STD AIDS 1998; 9: 751–5
Lair G, Marie I, Cailleux N, et al. Langerhans histiocytosis in adults: cutaneous and mucous lesion regression after treatment with thalidomide. Rev Med Intern 1998; 19: 196–8
Figg WD, Raje S, Bauer KS, et al. Pharmacokinetics of thalidomide in an elderly prostate cancer population. J Pharm Sci 1999; 88: 121–5
Munshi N, Desikan R, Zangari M, et al. Chemoangiotherapy with DT-PACE for previously treated multiple myeloma (MM) [abstract]. Blood 1999; 94Suppl. 1: no. 540
Neben K, Hawighorst H, Moehler TM. Clinical response to thalidomide monotherapy correlates with improvement in dynamic magnetic resonance (d-MRI) angiogenesis parameters [abstract]. Blood 1999; 94Suppl. 1: no. 545
Moehler TM, Neben K, Egerer G, et al. Thalidomide plus CED-chemotherapy in patients with poor prognosis multiple myeloma [abstract]. Blood 1999; 94uppl. 1: no. 547
Sabir T, Raza S, Anderson L, et al. Thalidomide is effective in the treatment of recurrent, refractory multiple myeloma (MM) [abstract]. Blood 1999; 94Suppl. 1: no. 548
Cheng D, Kini AR, Rodriguez J, et al. Microvascular density and cytotoxic T cell activation correlate with response to thalidomide therapy in myeloma patients [abstract]. Blood 1999; 94Suppl. 1: no. 1408
Rajkumar SV, Fonseca R, Dispenzieri A, et al. Thalidomide in the treatment of relapsed and refractory myeloma [abstract]. Blood 1999; 94Suppl. 1: no. 1414
Munshi N, Desikan R, Anaissie E, et al. Peripheral blood stem cell collection (PBSC) after CAD + G-CSF as part of Total Therapy II in newly diagnosed multiple myeloma (MM): influence of thalidomide (THAL) administration [abstract]. Blood 1999; 94Suppl. 1: no. 2577
Desikan R, Munshi N, Zeldis J, et al. Activity of thalidomide (THAL) in multiple myeloma (MM) confirmed in 180 patients with advanced disease [abstract]. Blood 1999; 94Suppl. 1: no. 2685
Bruera E, Neumann CM, Pituskin E, et al. Thalidomide in patients with cachexia due to terminal cancer: preliminary report. Ann Oncol 1999; 10: 857–9
Weber DM, Gavino M, Delasalle K, et al. Thalidomide alone or with dexamethasone for multiple myeloma [abstract]. Blood 1999; 94Suppl. 1: no. 2686
Alexanian R, Weber D. Thalidomide for resistant and relapsing myeloma. Semin Hematol 2000; 37Suppl. 3: 22–5
Thomas DA. Pilot studies of thalidomide in acute myelogenous leukemia, myelodysplastic syndromes, and myeloproliferative disorders. Semin Hematol 2000; 37Suppl. 3: 26–34
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 2000; 82: 812–7
Fine HA, Figg WD, Jaeckle K, et al. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 2000; 18: 708–15
Kneller A, Raanani P, Hardan I, et al. Therapy with thalidomide in refractory multiple myeloma patients — the revival of an old drug. Br J Haematol 2000; 108: 391–3
Juliusson G, Celsing F, Turesson I, et al. Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma. Br J Haematol 2000; 109: 89–96
Patt YZ, Hassan MM, Lozano RD, et al. Durable clinical response of refractory hepatocellular carcinoma to orally administered thalidomide. Am J Clin Oncol 2000; 23: 319–21
Govindarajan R, Heaton KM, Broadwater R, et al. Effect of thalidomide on gastrointestinal toxic effects of irinotecan. Lancet 2000; 356: 566–7
Little RF, Wyvill KM, Pluda JM, et al. Activity of thalidomide in AIDS-related Kaposi’s sarcoma. J Clin Oncol 2000; 18: 2593–602
Baidas SM, Winer EP, Fleming GF, et al. Phase II evaluation of thalidomide in patients with metastatic breast cancer. J Clin Oncol 2000; 18: 2710–7
Raza A, Liask K, Andrews C, et al. Encouraging improvement in cytopenias of patients with myelodysplastic syndromes (MDS) with thalidomide [abstract]. Proc ASCO 2000; no. 111
Coleman M, Leonard JR BLT-D (biaxin, low-dose thalidomide and dexamethasone) produces consistent responses in myeloma and Waldenstrom’s macroglobulinemia [abstract]. Proc ASCO 2000; no. 27
Sampaio EP, Sarno EN, Galilly R, et al. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991; 173: 699–703
Moreira AL, Sampaio EP, Zmuidzinas A, et al. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing MRNA degradation. J Exp Med 1993; 177: 1675–80
Neubert R, Nogueira AC, Neubert D. Thalidomide derivatives and the immune system. I. Changes in the pattern of integrin receptors and other surface markers on T lymphocyte sub-populations of marmoset blood. Arch Toxicol 1993; 67: 1–17
D’Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994; 91: 4082–5
Nogueira AC, Neubert R, Helge H, et al. Thalidomide and the immune system. 3. Simultaneous up- and down-regulation of different integrin receptors on human white blood cells. Life Sci 1994; 55: 77–92
McHugh SM, Rifkin IR, Deighton J, et al. The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen- and antigen-stimulated human peripheral blood mononuclear cell cultures. Clin Exp Immunol 1995; 99: 160–7
Shannon EJ, Sandoval F. Thalidomide increases the synthesis of IL-2 in cultures of human mononuclear cells stimulated with concanavalin-A, staphylococcal enterotoxin A, and purified protein derivative. Immunopharmacology 1995; 31: 109–16
Geitz H, Handt S, Zwingenberger K. Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade. Immunopharmacology 1996; 31:213–21
Haslett P, Hempstead M, Seidman C, et al. The metabolic and immunologie effects of short-term thalidomide treatment of patients infected with the human immunodeficiency virus. AIDS Res Hum Retrovir 1997; 13: 1047–54
Kenyon BM, Browne F, D’Amato RJ. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res 1997; 64: 971–8
Moller DR, Wysocka M, Greenlee BM, et al. Inhibition of IL-12 production by thalidomide. J Immunol 1997; 159: 5157–61
Moreira AL, Tsenova-Berkova L, Wang J, et al. Effect of cytokine modulation by thalidomide on the granulomatous response in murine tuberculosis. Tuber Lung Dis 1997; 78: 47–55
Haslett PA, Corral LG, 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 1998; 187: 1885–92
Kruse FE, Joussen AM, Rohrschneider K, et al. Thalidomide inhibits corneal angiogenesis induced by vascular endothelial growth factor. Graefes Arch Clin Exp Ophthalmol 1998; 236: 461–6
Or R, Feferman R, Shoshan S. Thalidomide reduces vascular density in granulation tissue of subcutaneously implanted polyvinyl alcohol sponges in guinea pigs. Exp Hematol 1998; 26: 217–21
Partida-Sanchez S, Favila-Castillo L, Pedraza-Sanchez S, et al. IgG antibody subclasses, tumor necrosis factor and IFN-gamma levels in patients with type II lepra reaction on thalidomide treatment. Int Arch Allergy Immunol 1998; 116: 60–6
Rowland TL, McHugh SM, Deighton J, et al. Differential regulation by thalidomide and dexamethasone of cytokine expression in human peripheral blood mononuclear cells. Immunopharmacology 1998; 40: 11–20
Moreira AL, Friedlander DR, Shif B, et al. Thalidomide and a thalidomide analogue inhibit endothelial cell proliferation in vitro. J Neurooncol 1999; 43: 109–14
Rowland TL, McHugh SM, Deighton J, et al. Selective down-regulation of T cell- and non-T cell-derived tumour necrosis factor alpha by thalidomide: comparisons with dexamethasone. Immunol Lett 1999; 68: 325–32
Verheul HM, Panigrahy D, Yuan J, et al. Combination therapy with thalidomide and sulindac inhibits tumour growth in rabbits. Br J Cancer 1999; 79: 114–8
Walchner M, Meurer M, Plewig G, et al. Clinical and immunologic parameters during thalidomide treatment of lupus erythematosus. Int J Dermatol 2000; 39: 383–8
Battegay EJ. Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J Mol Med 1995; 73: 333–46
Folkman J. Angiogenesis in cancer, vascular, rheumatoid, and other disease. Nature Med 1995; 1: 27–31
Vacca A, Ribatti D, Roncali L, et al. Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol 1994; 87: 503–8
Mundle SD, Ali A, Cartlidge JD, et al. Evidence for involvement of tumor necrosis factor-alpha in apoptotic death of bone marrow cells in myelodysplastic syndromes. Am J Hematol 1999; 60: 36–47
Rettig MB, Ma HJ, Vescio RA, et al. Kaposi’s sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients. Science 1997; 276: 1851–4
Kulkarni S, Powles R, Mehta J, et al. Thalidomide in GVHD — is anti-GVHD effect separable from the antiangiogenesis? Blood 1998; 92Suppl. 1: 344b
Chao NJ, Parker PM, Niland JC, et al. Paradoxical effect of thalidomide prophylaxis on chronic graft-vs.-host disease. Biol Blood Marrow Transplant 1996; 2: 86–92
Zeldis JB, Williams BA, Thomas SD, et al. S.T.E.P.S.: a comprehensive program for controlling and monitoring access to thalidomide. Clin Ther 1999; 21: 319–30
Flageul B, Wallach D, Cavelier-Balloy B, et al. Thalidomide and thrombosis. Ann Dermatol Venereol 2000; 127: 171–4
Ochonisky S, Verroust J, Bastuji-Garin S, et al. Thalidomide neuropathy incidence and clinico-electrophysiologic findings in 42 patients. Arch Dermatol 1994; 130: 66–9
Harland CC, Steventon GB, Marsden JR. Thalidomide-induced neuropathy and genetic differences in drug metabolism. Eur J Clin Pharmacol 1995; 49: 1–6
Hess CW, Hunziker T, Kupfer A, et al. Thalidomide-induced peripheral neuropathy. A prospective clinical, neurophysiological and pharmacogenetic evaluation. JNeurol 1986; 233: 83–9
Rajkumar SV, Gertz MA, Witzig TE. Life-threatening toxic epidermal necrolysis with thalidomide therapy for myeloma. N Engl J Med 2000; 343: 972–3
Horowitz SB, Stirling AL. Thalidomide-induced toxic epidermal necrolysis. Pharmacotherapy 1999; 19: 1177–80
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Disclosure: Drs Singhal and Mehta own stock in Celgene Corporation, the company which manufactures and markets thalidomide in USA.
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Singhal, S., Mehta, J. Thalidomide in Cancer. BioDrugs 15, 163–172 (2001). https://doi.org/10.2165/00063030-200115030-00003
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DOI: https://doi.org/10.2165/00063030-200115030-00003