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. 2000 Feb;82(4):812–817. doi: 10.1054/bjoc.1999.1004

Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer

T Eisen 1,1, C Boshoff 1, I Mak 2, F Sapunar 1, M M Vaughan 1, L Pyle 1, S R D Johnston 1, R Ahern 1, I E Smith 1, M E Gore 1
PMCID: PMC2374399  PMID: 10732751

Abstract

To grow and metastasize, solid tumours must develop their own blood supply by neo-angiogenesis. Thalidomide inhibits the processing of mRNA encoding peptide molecules including tumour necrosis factor-alpha (TNF-α) and the angiogenic factor vascular endothelial growth factor (VEGF). This study investigated the use of continuous low dose Thalidomide in patients with a variety of advanced malignancies. Sixty-six patients (37 women and 29 men; median age, 48 years; range 33–62 years) with advanced measurable cancer (19 ovarian, 18 renal, 17 melanoma, 12 breast cancer) received Thalidomide 100 mg orally every night until disease progression or unacceptable toxicity was encountered. Three of 18 patients with renal cancer showed partial responses and a further three patients experienced stabilization of their disease for up to 6 months. Although no objective responses were seen in the other tumour types, there were significant improvements in patients' sleeping (P< 0.05) and maintained appetite (P< 0.05). Serum and urine concentrations of basic fibroblast growth factor (bFGF), TNF-α and VEGF were measured during treatment and higher levels were associated with progressive disease. Thalidomide was well tolerated: Two patients developed WHO Grade 2 peripheral neuropathy and eight patients developed WHO grade 2 lethargy. No patients developed WHO grade 3 or 4 toxicity. Further studies evaluating the use of Thalidomide at higher doses as a single agent for advanced renal cancer and in combination with biochemotherapy regimens are warranted. © 2000 Cancer Research Campaign

Keywords: Thalidomide, TNF-α, renal cell carcinoma

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Selected References

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  1. Asscher W. Safety of thalidomide. BMJ. 1994 Jul 16;309(6948):193–194. doi: 10.1136/bmj.309.6948.193c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Battegay E. J. Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J Mol Med (Berl) 1995 Jul;73(7):333–346. doi: 10.1007/BF00192885. [DOI] [PubMed] [Google Scholar]
  3. Burrows F. J., Thorpe P. E. Vascular targeting--a new approach to the therapy of solid tumors. Pharmacol Ther. 1994 Oct;64(1):155–174. doi: 10.1016/0163-7258(94)90037-x. [DOI] [PubMed] [Google Scholar]
  4. Bussolino F., Albini A., Camussi G., Presta M., Viglietto G., Ziche M., Persico G. Role of soluble mediators in angiogenesis. Eur J Cancer. 1996 Dec;32A(14):2401–2412. doi: 10.1016/s0959-8049(96)00390-5. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Crawford C. L. Use of thalidomide in leprosy. Adverse Drug React Toxicol Rev. 1994 Winter;13(4):177–192. [PubMed] [Google Scholar]
  7. 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]
  8. Eisenbud L., Horowitz I., Kay B. Recurrent aphthous stomatitis of the Behçet's type: successful treatment with thalidomide. Oral Surg Oral Med Oral Pathol. 1987 Sep;64(3):289–292. doi: 10.1016/0030-4220(87)90006-5. [DOI] [PubMed] [Google Scholar]
  9. Erhard H., Rietveld F. J., van Altena M. C., Bröcker E. B., Ruiter D. J., de Waal R. M. Transition of horizontal to vertical growth phase melanoma is accompanied by induction of vascular endothelial growth factor expression and angiogenesis. Melanoma Res. 1997 Aug;7 (Suppl 2):S19–S26. [PubMed] [Google Scholar]
  10. 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]
  11. Fajardo L. F., Kwan H. H., Kowalski J., Prionas S. D., Allison A. C. Dual role of tumor necrosis factor-alpha in angiogenesis. Am J Pathol. 1992 Mar;140(3):539–544. [PMC free article] [PubMed] [Google Scholar]
  12. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995 Jan;1(1):27–31. doi: 10.1038/nm0195-27. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Gasparini G. Clinical significance of the determination of angiogenesis in human breast cancer: update of the biological background and overview of the Vicenza studies. Eur J Cancer. 1996 Dec;32A(14):2485–2493. doi: 10.1016/s0959-8049(96)00376-0. [DOI] [PubMed] [Google Scholar]
  15. Hamada J., Cavanaugh P. G., Lotan O., Nicolson G. L. Separable growth and migration factors for large-cell lymphoma cells secreted by microvascular endothelial cells derived from target organs for metastasis. Br J Cancer. 1992 Aug;66(2):349–354. doi: 10.1038/bjc.1992.269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Ingber D., Fujita T., Kishimoto S., Sudo K., Kanamaru T., Brem H., Folkman J. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature. 1990 Dec 6;348(6301):555–557. doi: 10.1038/348555a0. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. 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]
  20. 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]
  21. Miller A. B., Hoogstraten B., Staquet M., Winkler A. Reporting results of cancer treatment. Cancer. 1981 Jan 1;47(1):207–214. doi: 10.1002/1097-0142(19810101)47:1<207::aid-cncr2820470134>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  22. Mizutani Y., Bonavida B., Nio Y., Yoshida O. Overcoming TNF-alpha and drug resistance of human renal cell carcinoma cells by treatment with pentoxifylline in combination with TNF-alpha or drugs: the role of TNF-alpha mRNA downregulation in tumor cell sensitization. J Urol. 1994 Jun;151(6):1697–1702. doi: 10.1016/s0022-5347(17)35347-8. [DOI] [PubMed] [Google Scholar]
  23. Parman T., Wiley M. J., Wells P. G. Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity. Nat Med. 1999 May;5(5):582–585. doi: 10.1038/8466. [DOI] [PubMed] [Google Scholar]
  24. Powell R. J., Gardner-Medwin J. M. Guideline for the clinical use and dispensing of thalidomide. Postgrad Med J. 1994 Dec;70(830):901–904. doi: 10.1136/pgmj.70.830.901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Schiffenbauer Y. S., Abramovitch R., Meir G., Nevo N., Holzinger M., Itin A., Keshet E., Neeman M. Loss of ovarian function promotes angiogenesis in human ovarian carcinoma. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13203–13208. doi: 10.1073/pnas.94.24.13203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Talbot D. C., Brown P. D. Experimental and clinical studies on the use of matrix metalloproteinase inhibitors for the treatment of cancer. Eur J Cancer. 1996 Dec;32A(14):2528–2533. doi: 10.1016/s0959-8049(96)00398-x. [DOI] [PubMed] [Google Scholar]
  27. Tramontana J. M., Utaipat U., Molloy A., Akarasewi P., Burroughs M., Makonkawkeyoon S., Johnson B., Klausner J. D., Rom W., Kaplan G. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med. 1995 May;1(4):384–397. [PMC free article] [PubMed] [Google Scholar]
  28. Voest E. E., Kenyon B. M., O'Reilly M. S., Truitt G., D'Amato R. J., Folkman J. Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst. 1995 Apr 19;87(8):581–586. doi: 10.1093/jnci/87.8.581. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. 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]
  31. Weidner N. Intratumor microvessel density as a prognostic factor in cancer. Am J Pathol. 1995 Jul;147(1):9–19. [PMC free article] [PubMed] [Google Scholar]
  32. Weidner N., Semple J. P., Welch W. R., Folkman J. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med. 1991 Jan 3;324(1):1–8. doi: 10.1056/NEJM199101033240101. [DOI] [PubMed] [Google Scholar]
  33. Wettstein A. R., Meagher A. P. Thalidomide in Crohn's disease. Lancet. 1997 Nov 15;350(9089):1445–1446. doi: 10.1016/s0140-6736(05)64206-7. [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]
  35. Ziegler J. Angiogenesis research enjoys growth spurt in the 1990s. J Natl Cancer Inst. 1996 Jun 19;88(12):786–788. doi: 10.1093/jnci/88.12.786. [DOI] [PubMed] [Google Scholar]

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