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[ Conrad Notes Index | ASH Index ]
a timely medical meeting newsletter
DOES LOW MOLECULAR WEIGHT HEPARIN PROLONG CANCER PATIENT SURVIVAL?
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| 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.
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| 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).
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| 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).
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| 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:
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.
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| 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.
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| 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
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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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