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Inhibition of Angiogenesis: Thalidomide or Low-Molecular-Weight Heparin?

Department of Medical Oncology, Erciyes University M.K. Dedeman Oncology Hospital, Kayseri, Turkey

To the Editor:

In the July 15, 2004, issue of the Journal of Clinical Oncology, Dahut et al¹ showed that the addition of thalidomide to docetaxel resulted in an encouraging prostate-specific antigen decline and overall median survival rate in patients with metastatic androgen-independent prostate cancer. In this study, low-molecular-weight heparin (LMWH) was offered to patients in the combination arm for median 6 months, but not offered to patients in the control arm.¹ Preclinical evidence suggests that angiogenesis is important for tumor progression in prostate cancer.^2,3 LMWH inhibits angiogenesis, and this effect seems to be independent of the anticoagulant actions.^4,5 In a recent randomized study, we tested the effect on patient mortality of a prophylactic dose of LMWH (dalteparin; 5,000 U/d subcutaneously) given in combination with chemotherapy versus chemotherapy alone in patients with small-cell lung cancer (42 patients per group). This trial demonstrated an improvement in overall survival for those patients randomly assigned to receive LMWH.⁶

In another recent randomized study, the FAMOUS (Fragmin Advanced Malignancy Outcome Study) Trial, 385 patients with advanced solid cancers were randomly assigned to receive a prophylactic dose of the dalteparin or placebo for up to 1 year. There was suggestion of a marked survival advantage for patients with a better prognosis receiving LMWH therapy.⁷

We think that LMWH could provide a therapeutic and survival advantage for patients in the thalidomide arm in the Dahut et al study. To understand whether this survival advantage is depending on thalidomide, the authors should have used LMWH on the control arm as well.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Dahut WL, Gulley JL, Arlen PM, et al: Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. J Clin Oncol 22:2532-2539, 2004[Abstract/Free Full Text]

2. Jones A, Fujiyama C: Angiogenesis in urological malignancy: Prognostic indicator and therapeutic target. BJU Int 83:535-555, 1999[CrossRef][Medline]

3. Lissbrant IF, Lissbrant E, Damber J, et al: Blood vessels are regulators of growth, diagnostic markers and therapeutic targets in prostate cancer. Scand J Urol Nephrol 35:437-452, 2001[CrossRef][Medline]

4. Crum R, Szabo S, Folkman J: A new class of steroids inhibits angiogenesis in the presence of heparin or heparin fragment. Science 230:1375-1378, 1985[Abstract/Free Full Text]

5. Folkman J, Langer R, Linhard RJ, et al: Angiogenesis inhibition and tumor regression caused by heparin or heparin fragment in the presence of cortisone. Science 221:719-725, 1983[Abstract/Free Full Text]

6. Altinbas M, Coskun HS, Er O, et al: A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2:1266-1271, 2004[CrossRef][Medline]

7. Kakkar AK, Levine MN, Kadziola Z, et al: Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: The fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol 22:1944-1948, 2004[Abstract/Free Full Text]

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