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DOES LOW MOLECULAR WEIGHT HEPARIN PROLONG CANCER PATIENT SURVIVAL?
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A. Kakkar, MD, Hammersmith Hospital, London, UK, offers evidence for further testing whether a low molecular weight heparin such as dalteparin (DALT) prolongs the lives of patients with solid tumors. Cancer chemotherapy and surgery significantly increase the risk for developing lethal venous thromboemboli (VT). Regular heparin effectively prevents VT. The newer heparin fragments also prevent VT, are easier to administer, and may inhibit tumor growth. Please see the US package insert on dalteparin (Fragmin® for approved prescribing information).

Low molecular weight heparin (LMWH) This class of anticoagulants is derived from regular heparin by chemical or enzymatic depolymerization (CHEST 1995;108:267S). LMWHs, fragments about one third the size of heparin, have average molecular weights of 4,000 to 6,000 daltons. The LMWHs, such as DALT, show reduced protein binding, less interaction with platelets, and a progressive loss in catalyzing thrombin inhibition. Commercially available LMWHs are not clinicaly interchangeable. In the US, DALT is indicated for prophylaxis against deep vein thrombosis (DVT) in patients undergoing abdominal surgery.

Cancer chemotherapy and thrombosis Patients undergoing treatment for carcinoma of the breast are especially suceptible to developing thrombosis. Pritchard studied 703 postmenopausal women treated for early disease with tamoxifen alone or combined with adjuvant chemotherapy (J Clin Oncol 1996;14:2731-2738). Thromboembolic complications increased 5-fold in the group receiving added cyclophosphamide, methotrexate, and 5-fluorouracil (p<0.0001). Goodnough's open study on 159 Stage IV breast cancer patients showed a 17.6% incidence of thromboembolism associated with a regimen of cyclophosphamide, methotrexate, 5-flurouracil, vincristine, and prednisone (CANCER 1984;54:1264-1268).

Insertion of a central venous line to deliver chemotherapy, without use of an anticoagulant, increases the risk for thrombosis. Bern and coworkers found very low-dose oral warfarin (1 mg daily) significantly reduced venogram-proven thrombosis by 75% (p<0.001) compared with warfarin-free patients (Ann Int Med 1990;112:423-428). As noted by Monreal, only 6% of the patients receiving once daily DALT developed line-associated thrombosis contrasted with 62% receiving no anticoagulant (Thromb Haemst 1996;75:251-253).

Cancer surgery and postoperative thrombosis According to Kakkar, the American College of Chest Physicians estimates 1% to 5% of cancer surgery patients die of pulmonary emboli in the absence of thromboprophylaxis (CHEST 1995;108: 312S-334S). In another study, the postoperative fatality rate from DVT was 41% after major laparotomy in cancer patients, significantly higher (p=0.04) than the 26% seen after other surgical procedures (Am J Surg 1970;120:527-530).

Do anticoagulants prolong the lives of cancer patients? The published literature supports the usefulness of anticoagulants in prolonging survival in patients receiving cancer chemotherapy. Warfarin, according to a US Veteran's Administration Cooperative Study, increased survival time by 26 weeks (p=0.02) in patients with advanced small cell carcinoma of the lung (SCLC) as compared with warfarin-free controls (CANCER 1984;53:2046-2052). Other cancers (non-small cell lung, colorectal, head and neck, and prostate) did not respond to warfarin treatment in this study.

Lebeau used subcutaneous full-dose heparin or no heparin in 287 SCLC patients receiving standard chemotherapy (CANCER 1994;74:38-45). The heparinized group showed a complete response (CR) rate of 37% compared with 24% in the control group (p<0.01). Median survival time increased by 56 days using heparin (p=0.01).

Two studies compared regular heparin and LMWH in DVT patients. The Hull multicenter study (N Engl J Med 1992;326:975-982) showed an overall mortality rate of 4.7% in the LMWH group and 9.6% in the intravenous heparin group (p=0.05). In a study on 170 DVT patients, Prandoni and coworkers reported 6 of 85 (7.1%) died in the experimental LMWH group and 12 of 85 (14.1%) in the heparin group during a 6-month follow-up period (Lancet 1992;339:441-445). In this study the difference in mortality rate was not statistically significant (p=0.13). Cancer and noncancer patients were not analyzed separately in either study.

Green (Lancet 1992;339:1476) reanalyzed the cancer deaths of both studies using the following data:

 Prandoni StudyHull Study
 Heparin LMWHHeparin LMWH
Cancer Pts. 18 15 49 47
No. Dead 8 1 13 6
Percent 44 7 26 13

Combining the mortality data, Green showed 21/67 (31%) died in the regular heparin group and 7/62 (11%) in the LMWH group (p=0.01).

Individual study analysis and combined evaluation support the undertaking of a multicenter, placebo-controlled trial to determine whether LMWH significantly improves the survival of patients with advanced cancer. Kakkar described the initiation of a prospective, randomized study using 5,000 units of DALT once daily for one year in patients with advanced cancer of the gastrointestinal tract, lung, ovary, and breast.

Investigator discussion In Kakkar's opinion, the antithrombotic effect of anticoagulants in cancer patients probably involves a direct effect on the tumor and interference with excess thrombin production. Counteracting tumor production of procoagulants could interfere with the zymogen precursors of coagulation proteases. LMWH is probably best suited for long-term therapy by having an extended half-life to allow once daily dosing, no significant effect on platelet aggregation, fibrinolysis, or global clotting tests, and a reduced risk for causing hemorrhage.

Conrad comments Please see the related report of Folkman in this issue of Conrad Notes. According to the publisher, Kakkar's article (Haemostasis 1997;27(suppl 1):32-37) covering "Prevention of Venous Thromboembolism in Cancer Using Low-Molecular-Weight Heparins" is accessible online at: http://BioMedNet.com/karger

For professional correspondence, please contact Dr. Kakkar by Fax: 44 171 351 8317 or E-mail: aKKakkar@tri-london.ac.uk

Eugene A. Conrad

Presented at The American Society of Hematology (ASH) Meeting, December 5-9, 1997
Copyright © 1998 Conrad Group, Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / February 1998
Send comments to: ConradNote@aol.com

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