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. 2001 Sep;85(7):953–958. doi: 10.1054/bjoc.2001.2025

The treatment of advanced renal cell cancer with high-dose oral thalidomide

J Stebbing 1, C Benson 1, T Eisen 1, L Pyle 1, K Smalley 1, H Bridle 2, I Mak 3, F Sapunar 1, R Ahern 1, M E Gore 1
PMCID: PMC2375104  PMID: 11592764

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 Campaignhttp://www.bjcancer.com

Keywords: thalidomide, renal cell carcinoma

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Selected References

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  1. Berger T. G., Hoffman C., Thieberg M. D. Prurigo nodularis and photosensitivity in AIDS: treatment with thalidomide. J Am Acad Dermatol. 1995 Nov;33(5 Pt 1):837–838. doi: 10.1016/0190-9622(95)91846-9. [DOI] [PubMed] [Google Scholar]
  2. Ching L. M., Xu Z. F., Gummer B. H., Palmer B. D., Joseph W. R., Baguley B. C. Effect of thalidomide on tumour necrosis factor production and anti-tumour activity induced by 5,6-dimethylxanthenone-4-acetic acid. Br J Cancer. 1995 Aug;72(2):339–343. doi: 10.1038/bjc.1995.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. D'Amato R. J., Loughnan M. S., Flynn E., Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):4082–4085. doi: 10.1073/pnas.91.9.4082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Eisen T., Boshoff C., Mak I., Sapunar F., Vaughan M. M., Pyle L., Johnston S. R., Ahern R., Smith I. E., Gore M. E. Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br J Cancer. 2000 Feb;82(4):812–817. doi: 10.1054/bjoc.1999.1004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Elsässer-Beile U., Grussenmeyer T., Gierschner D., Schmoll B., Schultze-Seemann W., Wetterauer U., Schulte Mönting J. Semiquantitative analysis of Th1 and Th2 cytokine expression in CD3+, CD4+, and CD8+ renal-cell-carcinoma-infiltrating lymphocytes. Cancer Immunol Immunother. 1999 Jul;48(4):204–208. doi: 10.1007/s002620050566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. FULLERTON P. M., KREMER M. Neuropathy after intake of thalidomide (distaval). Br Med J. 1961 Sep 30;2(5256):855–858. doi: 10.1136/bmj.2.5256.855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fine H. A., Figg W. D., Jaeckle K., Wen P. Y., Kyritsis A. P., Loeffler J. S., Levin V. A., Black P. M., Kaplan R., Pluda J. M. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol. 2000 Feb;18(4):708–715. doi: 10.1200/JCO.2000.18.4.708. [DOI] [PubMed] [Google Scholar]
  8. Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med. 1995 Dec 28;333(26):1757–1763. doi: 10.1056/NEJM199512283332608. [DOI] [PubMed] [Google Scholar]
  9. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971 Nov 18;285(21):1182–1186. doi: 10.1056/NEJM197111182852108. [DOI] [PubMed] [Google Scholar]
  10. Fortier A. H., Nelson B. J., Grella D. K., Holaday J. W. Antiangiogenic activity of prostate-specific antigen. J Natl Cancer Inst. 1999 Oct 6;91(19):1635–1640. doi: 10.1093/jnci/91.19.1635. [DOI] [PubMed] [Google Scholar]
  11. Haslett P. A. Anticytokine approaches to the treatment of anorexia and cachexia. Semin Oncol. 1998 Apr;25(2 Suppl 6):53–57. [PubMed] [Google Scholar]
  12. Jacobson J. M., Greenspan J. S., Spritzler J., Ketter N., Fahey J. L., Jackson J. B., Fox L., Chernoff M., Wu A. W., MacPhail L. A. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N Engl J Med. 1997 May 22;336(21):1487–1493. doi: 10.1056/NEJM199705223362103. [DOI] [PubMed] [Google Scholar]
  13. Koo A. S., Armstrong C., Bochner B., Shimabukuro T., Tso C. L., deKernion J. B., Belldegrum A. Interleukin-6 and renal cell cancer: production, regulation, and growth effects. Cancer Immunol Immunother. 1992;35(2):97–105. doi: 10.1007/BF01741856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. König B., Steinbach F., Janocha B., Drynda A., Stumm M., Philipp C., Allhoff E. P., König W. The differential expression of proinflammatory cytokines IL-6, IL-8 and TNF-alpha in renal cell carcinoma. Anticancer Res. 1999 Mar-Apr;19(2C):1519–1524. [PubMed] [Google Scholar]
  15. La Maestra L., Zaninoni A., Marriott J. B., Lazzarin A., Dalgleish A. G., Barcellini W. The thalidomide analogue CC-3052 inhibits HIV-1 and tumour necrosis factor-alpha (TNF-alpha) expression in acutely and chronically infected cells in vitro. Clin Exp Immunol. 2000 Jan;119(1):123–129. doi: 10.1046/j.1365-2249.2000.01117.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lopez Hänninen E., Kirchner H., Atzpodien J. Interleukin-2 based home therapy of metastatic renal cell carcinoma: risks and benefits in 215 consecutive single institution patients. J Urol. 1996 Jan;155(1):19–25. [PubMed] [Google Scholar]
  17. Mitsuyasu R. T. Update on the pathogenesis and treatment of Kaposi sarcoma. Curr Opin Oncol. 2000 Mar;12(2):174–180. doi: 10.1097/00001622-200003000-00013. [DOI] [PubMed] [Google Scholar]
  18. O'Reilly M. S., Boehm T., Shing Y., Fukai N., Vasios G., Lane W. S., Flynn E., Birkhead J. R., Olsen B. R., Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997 Jan 24;88(2):277–285. doi: 10.1016/s0092-8674(00)81848-6. [DOI] [PubMed] [Google Scholar]
  19. O'Reilly M. S., Holmgren L., Shing Y., Chen C., Rosenthal R. A., Moses M., Lane W. S., Cao Y., Sage E. H., Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994 Oct 21;79(2):315–328. doi: 10.1016/0092-8674(94)90200-3. [DOI] [PubMed] [Google Scholar]
  20. Raje N., Anderson K. Thalidomide--a revival story. N Engl J Med. 1999 Nov 18;341(21):1606–1609. doi: 10.1056/NEJM199911183412110. [DOI] [PubMed] [Google Scholar]
  21. Rak J., Filmus J., Kerbel R. S. Reciprocal paracrine interactions between tumour cells and endothelial cells: the 'angiogenesis progression' hypothesis. Eur J Cancer. 1996 Dec;32A(14):2438–2450. doi: 10.1016/s0959-8049(96)00396-6. [DOI] [PubMed] [Google Scholar]
  22. Rhodes J., Thomas G., Evans B. K. Inflammatory bowel disease management. Some thoughts on future drug developments. Drugs. 1997 Feb;53(2):189–194. doi: 10.2165/00003495-199753020-00001. [DOI] [PubMed] [Google Scholar]
  23. Sampaio E. P., Kaplan G., Miranda A., Nery J. A., Miguel C. P., Viana S. M., Sarno E. N. The influence of thalidomide on the clinical and immunologic manifestation of erythema nodosum leprosum. J Infect Dis. 1993 Aug;168(2):408–414. doi: 10.1093/infdis/168.2.408. [DOI] [PubMed] [Google Scholar]
  24. Sands B. E., Podolsky D. K. New life in a sleeper: thalidomide and Crohn's disease. Gastroenterology. 1999 Dec;117(6):1485–1488. doi: 10.1016/s0016-5085(99)70299-4. [DOI] [PubMed] [Google Scholar]
  25. Sauer H., Günther J., Hescheler J., Wartenberg M. Thalidomide inhibits angiogenesis in embryoid bodies by the generation of hydroxyl radicals. Am J Pathol. 2000 Jan;156(1):151–158. doi: 10.1016/S0002-9440(10)64714-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Singhal S., Mehta J., Desikan R., Ayers D., Roberson P., Eddlemon P., Munshi N., Anaissie E., Wilson C., Dhodapkar M. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999 Nov 18;341(21):1565–1571. doi: 10.1056/NEJM199911183412102. [DOI] [PubMed] [Google Scholar]
  27. Stephens T. D., Fillmore B. J. Hypothesis: thalidomide embryopathy-proposed mechanism of action. Teratology. 2000 Mar;61(3):189–195. doi: 10.1002/(SICI)1096-9926(200003)61:3<189::AID-TERA6>3.0.CO;2-W. [DOI] [PubMed] [Google Scholar]
  28. Tavares J. L., Wangoo A., Dilworth P., Marshall B., Kotecha S., Shaw R. J. Thalidomide reduces tumour necrosis factor-alpha production by human alveolar macrophages. Respir Med. 1997 Jan;91(1):31–39. doi: 10.1016/s0954-6111(97)90134-7. [DOI] [PubMed] [Google Scholar]
  29. Teicher B. A., Holden S. A., Ara G., Korbut T., Menon K. Comparison of several antiangiogenic regimens alone and with cytotoxic therapies in the Lewis lung carcinoma. Cancer Chemother Pharmacol. 1996;38(2):169–177. doi: 10.1007/s002800050466. [DOI] [PubMed] [Google Scholar]
  30. Teicher B. A., Sotomayor E. A., Huang Z. D. Antiangiogenic agents potentiate cytotoxic cancer therapies against primary and metastatic disease. Cancer Res. 1992 Dec 1;52(23):6702–6704. [PubMed] [Google Scholar]
  31. Thiel R., Kastner U., Neubert R. Expression of adhesion receptors on rat limb bud cells and results of treatment with a thalidomide derivative. Life Sci. 2000;66(2):133–141. doi: 10.1016/s0024-3205(99)00571-8. [DOI] [PubMed] [Google Scholar]
  32. Vogelsang G. B., Farmer E. R., Hess A. D., Altamonte V., Beschorner W. E., Jabs D. A., Corio R. L., Levin L. S., Colvin O. M., Wingard J. R. Thalidomide for the treatment of chronic graft-versus-host disease. N Engl J Med. 1992 Apr 16;326(16):1055–1058. doi: 10.1056/NEJM199204163261604. [DOI] [PubMed] [Google Scholar]
  33. Weidmann E., Bergmann L., Stock J., Kirsten R., Mitrou P. S. Rapid cytokine release in cancer patients treated with interleukin-2. J Immunother (1991) 1992 Aug;12(2):123–131. doi: 10.1097/00002371-199208000-00007. [DOI] [PubMed] [Google Scholar]
  34. Yoneda T., Alsina M. A., Chavez J. B., Bonewald L., Nishimura R., Mundy G. R. Evidence that tumor necrosis factor plays a pathogenetic role in the paraneoplastic syndromes of cachexia, hypercalcemia, and leukocytosis in a human tumor in nude mice. J Clin Invest. 1991 Mar;87(3):977–985. doi: 10.1172/JCI115106. [DOI] [PMC free article] [PubMed] [Google Scholar]

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