Abstract
Thalidomide is reported to suppress levels of several cytokines, angiogenic and growth factors including TNF-α, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). The resulting anti-angiogenic, immunomodulatory and growth suppressive effects form the rationale for investigating thalidomide in the treatment of malignancies. We have evaluated the use of high-dose oral thalidomide (600 mg daily) in patients with renal carcinoma. 25 patients (all men; median age, 51 years; range 34–76 years) with advanced measurable renal carcinoma, who had either progressed on or were not suitable for immunotherapy, received thalidomide in an escalating schedule up to a maximum dose of 600 mg daily. Treatment continued until disease progression or unacceptable toxicity were encountered. 22 patients were assessable for response. 2 patients showed partial responses (9%; 95% CI: 1–29), 7 (32%; 95% CI: 14–55) had stable disease for more than 6 months and a further 5 (23%; 95% CI: 8–45) had stable disease for between 3 and 6 months. We also measured levels of TNF-α, bFGF, VEGF, IL-6 and IL-12 before and during treatment. In patients with SD ≥ 3 months or an objective response, a statistically significant decrease in serum TNF-α levels was demonstrated (P = 0.05). The commonest toxicities were lethargy (≥ grade II, 10 patients), constipation (≥ grade II, 11 patients) and neuropathy (≥ grade II, 5 patients). Toxicities were of sufficient clinical significance for use of a lower and well tolerated dose of 400 mg in currently accruing studies. © 2001 Cancer Research Campaign http://www.bjcancer.com
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References
Atzpodien J, Kirchner H and Franzke A (1997) Results of a randomised clinical trial comparing SC interleukin-2, SC alpha-2A-interferon and iv bolus 5-fluorouracil against oral tamoxifen in progressive metastatic renal cell carcinoma patients. Proc ASCO 16: 326a
Berger TG, Hoffman C and Thierberg MD (1995) Prurigo nodularis and photosensitivity and AIDS: treatment with thalidomide. J Am Acad Dermatol 33: 837–838
Ching LM, Xu ZF and Gummer BH (1995) 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
D'Amato RJ, Loughnan MS, Flynn E and Folkman J (1994) Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 91: 4082–4085
Eisen T, Boshoff C, Mak I, Sapunar F, Vaughan MM, Pyle L, Johnston SRD, Ahern R, Smith IE and Gore ME (2000) Continuous low dose thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br J Cancer 82: 812–817
Elsasser-Beile U and Grussenmeyer T (1999) Semiquantitative analysis of Th1 and Th2 cytokine expression in CD3+, CD4+ and CD8+ renal-cell carcinoma-infiltrating lymphocytes. Cancer Immunol Immunother 48: 204–208
Fine HA and Figg WD (2000) Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 18: 708–715
Folkman J (1971) Tumour angiogenesis: therapeutic implications. N Engl J Med 285: 1182–1186
Folkman J (1995) Clinical applications of research on angiogenesis. N Engl J Med 333: 1757–1763
Fortier AH, Nelson BJ, Grella DK and Holaday JW (1999) Antiangiogenic activity of prostate-specific antigen. J Natl Cancer Inst 91: 1635–1640
Fullerton PM and Kremer M (1961) Neuropathy after intake of thalidomide (Distaval). BMJ 2: 853–858
Haslett PA (1998) Anticytokine approaches to the treatment of anorexia and cachexia. Semin Oncol 25: 53–57
Jacobson JM and Greenspan JS (1997) Thalidomide for the treatment of oral apthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 336: 1487–1493
Koo Beldegrum A (1992) Interleukin-6 and renal cell cancer: production, regulation and growth effects. Cancer Immunol Immunother 35: 97–105
Konig B and Steinbach F (1999) The differential expression of proinflammatory cytokines IL-6, IL-8 and TNF-alpha in renal cell carcinoma. Anticancer Res 19: 1519–1524
La Maestra L, Zaninoni A and Marriott JB (2000) The thalidomide analogue CC-3052 inhibits HIV-1 and tumour necrosis factor-alpha expression in acutely and chronically infected cells in vitro. Clin Exp Immunol 119: 123–129
Lopez-Hanninen E, Kirchner H and Atzpodien J (1996) Interleukin-2 based home therapy of metastatic renal cell carcinoma: risks and benefits in 215 consecutive single institution patients. J Urol 155: 19–25
Medical Research Council Renal Cancer Collaborators (1999) Interferon-α and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet 353: 14–17
Mitsuyasu RT (2000) Update on the pathogenesis and treatment of Kaposi's sarcoma. Curr Opin Oncol 12: 174–180
O'Reilly MS, Holmgren L and Shing Y (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis Lung carcinoma. Cell 79: 315–328
O'Reilly MS, Boehm T and Shing Y (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumour growth. Cell 88: 277–285
Raje N and Anderson K (1999) Thalidomide – a revival story. N Engl J Med 341: 1606–1608
Rak J, Filmus J and Kerbel RS (1996) Reciprocal paracrine interactions between tumour cells and endothelial cells: the angiogenic progression' hypothesis. Eur J Cancer 32A: 2438–2450
Rhodes J, Thomas G and Evans BK (1997) Inflammatory bowel disease management. Some thoughts on future drug developments. Drugs 53: 189–194
Sampaio EP and Kaplan G (1993) The influence of thalidomide on the clinical and immunologic manifestation of erythema nodosum leprosum. J Infect Dis 168: 408–414
Sands BE and Podolsky DK (1999) New life in a sleeper: thalidomide and Crohn's disease. Gastroenterology 117: 1485–1488
Sauer H and Gunther J (2000) Thalidomide inhibits angiogenesis in embryoid bodies by the generation of hydroxyl radicals. Am J Pathol 156: 151
Singhal S (1999) Antitumour activity of thalidomide in refractory multiple myeloma. N Engl J Med 341: 1565–1571
Stephens TD and Filmore BJ (2000) Hypothesis: thalidomide embryopathy-proposed mechanism of action. Teratology 61: 189–195
Tavares JL, Wangoo A and Dilworth P (1997) Thalidomide reduces tumour necrosis factor-alpha production by human alveolar macrophages. Respir Med 91: 31–39
Teicher BA, Sotomayor EA and Huang ZD (1992) Antiangiogenic agents potentiate cytotoxic cancer therapies against primary and metastatic disease. Cancer Res 52: 6702–6704
Teicher BA, Holder SA and Ara G (1994) Potentiation of cytotoxic cancer therapies by TNP-40 alone and with other anti-angiogenic agents. Cancer 57: 1–6
Teicher BA, Holder SA and Ara G (1996) Comparison of several antiangiogenic regimens alone and with cytotoxic therapies in the Lewis lung carcinoma. Cancer Chemother Pharmacol 38: 169–177
Thiel R, Kastner U and Neubert R (2000) Expression of adhesion receptors on rat limb bud cells and results of treatment with a thalidomide derivative. Life Sci 66: 133–141
Vogelsang GB, Farmer ER and Hess AD (1992) Thalidomide for the treatment of chronic graft-versus-host disease. N Engl J Med 326: 1055–1058
Weidmann E, Bergmann L and Stock J (1992) Rapid cytokine release in cancer patients treated with interleukin-2. J Immunother 12: 123–131
Yoneda T (1991) Evidence that tumour necrosis factor plays a pathogenetic role in the paraneoplastic syndromes of cachexia, hypercalcemia, and leukocytosis in a human tumour nude mice. J Clin Invest 87: 977–985
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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). https://doi.org/10.1054/bjoc.2001.2025
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DOI: https://doi.org/10.1054/bjoc.2001.2025
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