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8 Venous thromboembolism and cancer
8 Venous t h r o m b o e m b o l i s m and cancer A. K. K A K K A R * BSc, MB, PhD, FRCS MRC Clinician Scientist Fellow and Senior Surgical Registrar Department of Surgery, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
E DE L O R E N Z O MD, CCST Hon. Lecturer Thrombosis Research Institate, Emmanuel Kaye Building, Manresa Road, Chelsea, London SW3 6LR, UK G . F. P I N E O
MD, FRCP(C), FACP, FCCP
professor of Medicine and Oncology Division nf Hematology, University of Calgary, Calgary, Alberta, Canada Director, Thrombosis Research Unit Faculty of Medicine, Foothills Hospital, Calgary, Alberta 72N 2T9, Canada
R. C. N. W I L L I A M S O N MA, MChir,MD, FRCS Professor of Surgery Department of Surgery, Imperial College School of Medicine, ttammersmith Hospital, Du Cane Road, London W12 ONN, UK
The association of thrombosis with malignant disease has been recognized for well over 100 years. Evidence from experimental and clinical studies indicates that the haemostatic system is involved in the growth, invasion and metastasis of tumours. Laboratory parameters of haemostasis are frequently deranged in patients with cancer and overt thrombosis is common spontaneously where it may be the first sign of malignancy or secondary to therapy. The mechanisms by which coagulation activation facilitates the malignant process remain to be completely elucidated, but it is clear that cells and proteins of the coagulation and fibrinolytic systems are involved at many steps in the processes of tumour growth and dissemination. The low-molecular-weight heparins with their wellproven safety and efficacy profiles offer unique modalities for the prevention and treatment of cancer-associated thrombosis. They may also play a role in overall mortality reduction in patients with malignant disease. Key words: deep vein thrombosis; antithrombotic therapy; cancer therapy. * Corresponding author. Bailli~re'~ Clinical Haematology-Vol. 11, No. 3, September 1998 ISBN 0-7020-2461-9 0950-3536/98/030675 + 13 $12.00/00
675 Copyright © 1998, by Bailli~re Tindall All rights of reproduction in any form reserved
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Cancer-associated mortality is the second most commonly reported cause of death after cardiovascular disease. Several studies have provided data on the high frequency of clinical and subclinical thrombotic phenomena in cancer (Thompson and Rogers, 1952; Goldberg et al, 1987; Bastounis et al, 1996; Naschitz et al, 1996) and of clotting defects uncovered by laboratory tests (Sun et al, 1974; Francis, 1998). The literature suggests that, although the haemostatic system is affected by cancer (Rasche and Dietrich, 1977; Sun et al, 1979), this is not a unidirectional relationship. It now seems that the proteins and cells of the haemostatic system play a role in tumour biology. Improvements in antithrombotic therapy and the availability of the low-molecular-weight heparins (LMWHs) have allowed more effective strategies to be developed for the prevention and treatment of thromboembolic episodes in cancer and have raised the intriguing possibility that such agents could be used to reduce the overall mortality rate. THROMBOSIS AND CANCER: A TWO-WAY ASSOCIATION? Two recent studies have shown an association between primary venous thrombosis and a subsequent diagnosis of cancer (Baron et al, 1998; S0rensen et al, 1998). Using population-based data from the Danish National Registry of Patients and the Danish Cancer Registry, SCrensen et al identified 15 000 patients with deep venous thrombosis (DVT) and more than 10 000 patients with pulmonary embolism. They observed 1737 cases of cancer in the cohort with DVT, as compared with 1372 expected cases. The risk was more elevated during the first 6 months of follow-up. Furthermore, 40% of the patients given a diagnosis of cancer within 1 year after hospitalization for thromboembolism had distant metastases at the time of the diagnosis of cancer. Strong associations were found with cancer of the pancreas, ovary, liver and brain. Baron et al (1998) assessed cancer incidence during 1989 among more than 60000 patients without a previous cancer diagnosis admitted to hospital between 1965 and 1983 for venous thromboembolism (VTE). Within the first year from admission for VTE 4.0% of the patients received a new cancer diagnosis. This risk was much higher than expected. The increased relative risks were similar in men and women and in thromboembolism patients with and without surgery in the months before admission. Patients with two or more VTE admissions presented higher risk in the year after the second episode. They concluded that, in the first year after admission for VTE, the increase over general population rates was greater than fourfold, with particularly high relative risk for cancers of the liver, pancreas, ovary and brain and for Hodgkin lymphoma and polycythaemia vera. Thromboembolism was also a marker of long-term cancer risk; in fact, 10 years on or more there was a 30% increase in overall cancer incidence. In a 6 month follow-up study (Nordstrom et al, 1994) of more than 1000 patients with DVT, five times the risk of cancer in these patients was found compared with the general population. Prandoni et al (1992a) also found that the incidence of cancer in patients with recurrent idiopathic venous
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thrombosis was higher than in patients without this condition. In this study 7.6% of 145 patients with idiopathic VTE had a diagnosis of cancer made within 2 years of presentation, with 17.6% of those developing recurrent VTE subsequently revealing an underlying malignancy, as opposed to only 1.9% of 105 with secondary VTE. The benefit of searching for cancer in a patient with a primary thrombotic event is difficult to assess (Baron et al, 1998; SCrensen et al, 1998). The detection of some cancers requires an extensive work-up and for several cancers, such as pancreas and liver cancers, early detection does not change the prognosis. However, early detection of malignancies of the cervix, breast, ovary and colon might result in a modestly effective treatment (Francis et al, 1998). Therefore, at present an extensive screening combining also the economical and psychological costs is not justified in all VTE patients. On the other hand, it is appropriate when treating patients with idiopathic VTE to investigate the risk of cancer and to base the decision to perform additional diagnostic tests on the findings of an initial medical history, physical examination, routine laboratory tests and chest X-ray. PATHOPHYSIOLOGY OF CANCER-ASSOCIATED THROMBOSIS The activation of the clotting process in cancer is a multifactorial process. The composition of the blood in the cancer patients may be altered. Such patients are more likely to experience prolonged bed rest and recent surgery, and the invasion of blood vessels is common. These and other nonspecific mechanisms such as tissue damage and inflammatory response result in tissue factor (TF) expression and coagulation activation. Platelets circulate in an inactive state but undergo a series of morphological and biochemical changes on stimulation (Gasic et al, 1973; Marcum et al, 1980; Karpatkin and Pearlstein, 1981; Kroll and Schafer, 1989). They may be activated by malignant cells, and tumour-cell-induced platelet activation occurs both in vivo and in vitro (Gordon et al, 1975; Curatolo et al, 1979; Grignani et al, 1989; Ferroni et al, 1995). Mechanisms for the aggregating activity include tumour-induced thrombin generation (Curatolo et al, 1979), an increased density of sialic acid residues on the tumour cell surface which may enhance platelet aggregation, cysteine proteinases, reduction in nitric oxide production (Radomski et al, 1991), thrombospondin binding and glycoprotein IIb-IIIa expression (Oleksowicz et al, 1995). Monocytes are also capable of producing procoagulant after stimulation. Studies of monocytes in patients with malignant disease have demonstrated increased procoagulant activity (Dean et al, 1984; Geczy, 1984; Shands, 1984, Ryan and Geczy, 1988) and the generation of plasminogen activator inhibitor by monocytes is one of the mechanisms postulated to explain this (Rickles and Edwards, 1983; Schwartz and Bradshaw, 1989). Three possible mechanisms have been proposed to explain the way by which tumours can activate the clotting system: the elaboration of the
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cancer procoagulant, which can directly activate factor X in the coagulation cascade, the formation of a prothrombinase complex on the tumour cell surface for the conversion of inactive prothrombin to thrombin and the expression of ceil-surface TF (Francis et al, 1998). TF is the most consistently observed tumour-elaborated procoagulant and is generally accepted to be the principal mechanism by which cancer cells are able to activate the coagulation cascade. It is the physiological initiator of blood coagulation through its cofactor activation of factor VII with subsequent activation of factors IX and X in the downstream coagulation pathway. Immunohistochemical studies have revealed TF to be absent in a variety of normal epithelial tissues (Callander et al, 1992) and that the expression of TF occurs as a result of malignant transformation in human pancreatic adenocarcinoma (Kakkar et al, 1995b), the degree of TF expression correlating with the degree of histological differentiation of the cancer (Table 1). A study by Contrino et al (1996) has indicated that in invasive carcinoma of the breast TF expression, localized on endothelial ceils, is a marker of malignant angiogenesis. In a study to assess the nature of the hypercoagulable state of malignancy Kakkar et al (1995a) compared markers for the activation of coagulation and TF in 106 patients with solid tumour malignancy and 72 control subjects with no cancer. They were able to demonstrate marked increases in circulating levels of TF and factor VIIa in patients with cancer, indicating and extrinsic pathway activation. This was associated with elevated levels of thrombin-anti-thrombin complexes and prothrombin fragments 1+2, markers of excess thrombin generation and a hypercoagulable state. Factor XIIa was elevated in cancer patients with advanced disease and those receiving chemotherapy, suggesting contact activation of the intrinsic pathway as a result of the extensive and unstable neoangiogenic tumour endothelium or cytotoxic endothelial damage. Table 1. Tissue factor expression in human pancreatic adenocarcinoma (Kakkar et al, 1995b).
TF immunoreactivity (%) Normal tissue Grade 1 adenocarcinoma Grade 2 adenocarcinoma Grade 3 adenocarcinoma g 2 linear trend = 6.69, P = 0.0098
0 20 50 77
RISK OF THROMBOEMBOLISM IN CANCER THERAPY
Chemotherapy is recognized as a risk factor for the development of VTE in cancer patients (Kakkar and Williamson, 1995). Two mechanisms for thrombogenesis associated with the use of chemotherapeutic agents are accepted: (a) release of Wocoagulants and cytokines as a result of toxic effects on damaged endothelial cells and (b) a fall in naturally occurring anticoagulants, such as protein C, protein S and anti-thrombin III, during
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therapy (Kakkar and Williamson, 1995). The duration of chemotherapy may be important. In a study comparing the thrombosis risk of either 12 or 36 weeks of multidose combination chemotherapy in 205 pre- and postmenopausal women with stage II breast carcinoma the overall rate of thrombosis was 6.8% (Levine et al, 1988). Thrombosis occurred during chemotherapy with no events in the 12 week group after their treatment ceased. About half the thrombi that occurred in the 36 week group did so after the first 12 weeks. Of patients receiving multidrug chemotherapy for stage IV breast carcinoma, 17% developed thrombosis. Again, active therapy was associated with the majority of thrombi (Goodnough et al, 1984). The Eastern Co-operative Oncology Group reported thromboembolism (venous and arterial) in 6.8% of women receiving adjuvant chemotherapy (Saphner et al, 1991). Tamoxifen heightened the risk above that of a standard chemotherapy regimen from 0.8% to 2.3% for premenopausal women (P = 0.03) and from 2.3% to 8.0% in post-menopausal women (P = 0.03). This added risk of a combination of hormonal and cytotoxic therapy has recently been confirmed with 1.4% of those who received tamoxifen alone as opposed to 9.6% of those receiving tamoxifen and combination chemotherapy (P = 0.0001) developing clinically relevant thrombosis among 705 post-menopausal women (Pritchard et al, 1996). Most events occurred while patients were receiving chemotherapy, and the rate fell thereafter. Other studies (Fisher et al, 1989, 1990; Rifkin et al, 1989) support this added risk of thrombosis when chemotherapy is combined with tamoxifen. Patients with advanced gastrointestinal, pancreatic and gynaecological malignancies are thought to have a heightened risk of thrombosis and a study in patients with ovarian malignancy demonstrated a thrombosis rate of 17%, among those operated on and receiving chemotherapy (yon Templehoff et al, 1997).
Surgical operations Kakkar et al (1970) established cancer as a risk factor for the development of post-operative DVT. A 41% rate of isotopic thrombi was found in cancer patients undergoing abdominal surgery compared with 26% in those with benign disease (P=0.04; relative risk 1.96 for cancer). Other studies including those in patients with gynaecologieal malignancy (Walsh et al, 1974) confirm the occurrence of DVT more commonly. Rahr and SCrensen analysed rates of fatal pulmonary embolism in patients operated on for cancer in the 1975 International Multicentre Trial. Eight of 49l cancer patients randomized to a control group who received no thromboprophylaxis had a fatal pulmonary embolism rate of 1.6% compared with a rate of 0.4% (eight of 1585) in those operated on for benign conditions (P = 0.05) (Rahr and SOrensen, 1992). The recent American College of Chest Physicians consensus guidelines for antithrombotic therapy in 1995 (Clagett et al, 1995) state that 4 0 - 8 0 % of cancer patients undergoing operation without prophylaxis develop a calf vein thrombosis, 10-20% of patients develop a proximal vein thrombus
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and 1-5% of cancer patients will die of post-operative pulmonary embolism. Central venous lines Thrombosis rates of between 37% and 62% have been reported in cancer patients with indwelling central venous catheters (Bern et al, 1990; Monreal et al, 1996). The occurrence of line thrombosis may necessitate the removal of the line, with subsequent loss of venous access. THE PREVENTION OF VENOUS THROMBOEMBOLISM IN C A N C E R Peri-operative thromboprophylaxis
Mechanical Intermittent calf compression is advocated for the prophylaxis of VTE including those with cancer (Clagett and Reisch, 1988). A small number of patients (N = 355) were randomized to calf compression or control from trials that reported results for cancer patients alone. Rates of DVT fell from 21% (control) to 12.8% with intermittent pneumatic calf compression. Studies have yet to confirm that calf compression reduces the risk of fatal pulmonary embolism.
Low-dose heparin The most commonly utilized method of thromboprophylaxis is low-dose heparin (LDH), which is administered in a dose of 5000 units, commencing 2 hours before operation, and continuing 8-12 hourly after operation subcutaneously. Gallus et al (1976) demonstrate DVT rates of 22% (control) and 9% with LDH after cancer surgery, and in a meta-analysis of 10 trials with 919 patients LDH prophylaxis reduced DVT rates from 30.6% in the control group to 13.6% in those receiving the active treatment (P <0.001) (Clagett and Reisch, 1988). LDH is also effective in the prevention of pulmonary embolism including in those whose operation is undertaken for malignant disease, Of 4121 patients randomized to LDH or control arms in the International Multicentre Trial (1975), 953 had malignant disease. Death from fatal pulmonary embolism occurred in eight patients with malignant disease in the control group (1.6%) and in two patients who received heparin (0.4%).
Low-molecular-weightheparin LMWHs are used commonly in the prevention of DVT in general surgical patients. Individual studies comparing the effects of LMWH and unfractionated heparin on DVT rates for thromboprophylaxis in cancer
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patients indicate broadly similar prophylactic efficacies for these two agents (European Fraxiparine Study Group, 1988; Koppenhagen et al, 1992; Bergqvist and Burmark, 1995; Nurmohamed et al, 1995; ENOXCAN Study Group, 1997). A recent study compared 2500 with 5000 units of LMWH in 2000 operated patients, 65% of whom underwent laparotomy for cancer (Bergqvist and Burmark, 1995). DVT rates fell from 14.9% in those receiving 2500 units to 8.5% in those receiving 5000 units (P = 0.001). This study is the first to demonstrate that increasing the dose of LMWH can improve its thromboprophylactic efficacy in cancer, and interestingly bleeding complications did not increase in cancer patients receiving the higher dose.
Thromboprophylaxis during chemotherapy Only limited evidence from randomized trials exists to demonstrate the efficacy of agents for thromboprophylaxis during chemotherapy and not all methods available are suitable for this population. The prolonged outpatient nature of chemotherapy regimes with the attendant concerns about feasibility and cost effectiveness and the perceived added risks of thrombocytopenia and osteoporosis from prolonged heparin have made clinicians reluctant to consider such therapy. Mechanical methods of thromboprophylaxis such as pneumatic calf compression are clearly unsuitable. The need to administer unfractionated heparin two or three times daily even in low doses to achieve adequate thromboprophylaxis is considered unfeasible for patients over a prolonged period. LMWHs are generally not thought to be associated with the same risk of thrombocytopenia (Warkentin et al, 1995) or osteoporosis (Monreal et al, 1994) as unfractionated heparin, and their pharmacological profile allows for oncedaily self-administration (Koch et al, 1997), suggesting that trials to assess their efficacy and safety in the prevention of chemotherapy-associated thrombosis may yield beneficial results of clinical utility. The oral anticoagulant warfarin dose adjusted to maintain an International Normalized Ratio (INR) of 1.3-1.9 has been assessed for the prevention of thrombosis in 311 women with stage II breast carcinoma receiving chemotherapy (Levine et al, 1994). Seven patients in the control group and only one patient in the warfarin group developed venous thromboembolism (P = 0.03), yet clinical oncologists still appear reluctant to use it in this context. Oral anticoagulation is difficult to control in cancer patients (Bona et al, 1995), although the perceived increased risk of bleeding appears not to be increased when compared with non-cancer patients.
Prevention of catheter thrombosis Cancer patients can be protected against thrombosis associated with indwelling venous catheters by both LMWH and oral anticoagulants (Bern et al, 1990; Monreal et al, 1996). Eighty-four patients randomized to
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receive 1 mg of warfarin daily or no anticoagulant therapy were screened by line venography to assess the rate of central line thrombosis. Nine per cent of patients in the warfarin group and 37% in the control group (P = 0.001) developed a thrombosis (Bern et al, 1990). An LMWH has also been shown to be effective given once daily in a dose of 2500 units commenced at the time of central line insertion, with 62% of controls but only 6% of those receiving LMWH demonstrating clinical or radiological evidence of thrombosis (P = 0.05) (Monreal et al, 1996). Treatment of established thrombosis in the cancer patient
The objectives of therapy in established DVT are prevention of death from pulmonary embolism and reduction in morbidity of the leg vein thrombus. These objectives are tempered in the cancer patient by recognition that a thromboembolic episode may be a terminal event and should not always be treated. Justification in such cases includes palliation of symptoms including painful limb swelling from the primary thrombosis and dyspnoea from the embolism (Levine, 1997). Intravenous unfractionated heparin given first as a bolus of 5000 units and then by continuous infusion usually of about 30 000 units per day to maintain an activated partial thromboplastin time (APTT) of 1.5-2.0 times the control value remains the most commonly utilized method for the initial management of DVT. Subcutaneous LMWHs are becoming increasingly popular with numerous well-designed studies confirming their efficacy and safety (Hull et al, 1992; Prandoni et al, 1992b; Koopman et al, 1996; Levine et al, 1996). These studies have included a number of cancer patients, and in two studies out-patient management of thrombosis was evaluated without routine laboratory monitoring (Koopman et al, 1996; Levine et al, 1996). Although such a strategy was proven feasible, the suitability of a fixed dose of LMWH in cancer patients who not only have a complex hypercoagulable state but also may be at risk of thrombocytopenia secondary to chemotherapy and who are at risk of bleeding due to anatomical location of their primary tumour or secondary deposits remains to be established in prospective trials specifically in this high-risk population. Following initial treatment with either unfractionated heparin or LMWH, recurrent thromboembolism is prevented with warfarin anticoagulation for at least 3 months. Such secondary prevention is usually effective in cancer patients, but it requires regular laboratory supervision of the prothrombin time to maintain an INR of 2-3. Despite adequate anticoagulation, cancer patients are at increased risk of developing thromboembolism (relative risk 1.76 versus control subjects) (Prandoni et al, 1996). Cancer patients do not appear to be at greater risk of developing bleeding complications on oral anticoagulant therapy than non-cancer subjects; the incidence of major bleeding was reported to be 3.4% in cancer patients and 3.0% in non-cancer patients during oral anticoagulation (Prandoni et al, 1996) in one study while in another there were 0.004 bleeding events per patient month for cancer patients and 0.003 for non-cancer subjects (Bona et al, 1995).
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Cancer patients did require more frequent out-patient monitoring to maintain adequate and safe oral anticoagulation. Two studies (Pini et al, 1994; Das et al, 1995) have compared LMWH with warfarin for secondary prevention after initial treatment of DVT. Patients, a few of whom had cancer, received either oral anticoagulants, to maintain an INR of 2 - 3 , or a fixed single daily dose of LMWH. LMWH therapy was associated with lower bleeding rates than warfarin, but with only a small number of cancer patients no conclusions can be drawn about the utility of LMWH for secondary prevention in these patients. ANTITHROMBOTIC THERAPY AND CANCER SURVIVAL
The anti-tumour effects of oral anticoagulants in experimental animals have been sufficiently encouraging for trials in human cancer to be initiated (Thornes, 1969). Adjunct warfarin appeared to potentiate chemotherapy in some patients and, when the disease was under control, was sometimes adequate for maintenance therapy when given alone (Thornes, 1972). Patients receiving warfarin and chemotherapy had significantly lower mortality and greater survival than those receiving chemotherapy alone (Zacharski et al, 1984). The Veterans Administration warfarin study (Zacharski et al, 1984), maintaining an INR of 2 - 3 in patients with advanced small-cell lung carcinoma, found an increase in median survival from 26 weeks to 50 weeks (P = 0.05). Recently, in one study (Carpi et al, 1995) cancer incidence and mortality were reviewed in 683 patients with valvular, ischaemic or myocardial disease. The results from more than 300 patients treated with oral anticoagulants were compared with those from more than 300 patients who did not receive this therapy. Cancer mortality in the anticoagulated patients was also compared with that expected on the basis of National Tumor Registry rates. Twelve cancers occurred in the control group as compared with six cancers observed in the oral anticoagulant group. The deaths expected in men and women receiving oral anticoagulants were three and two respectively. These data support the hypothesis that oral anticoagulant may reduce cancer incidence and mortality in humans. In a study of 278 patients with small-cell lung carcinoma who received full anticoagulation, with subcutaneous unfractionated heparin for 5 weeks, or no anticoagulation, heparin increased the incidence of a complete response to chemotherapy from 24% to 37% (P ---0.004) and the median survival from 216 to 317 days (P = 0.01). The heparin dose given subcutaneously in divided doses required regular monitoring with APTT values (Lebeau et al, 1994). A recent analysis of the two initial studies (Hull et al, 1992; Prandoni et al, 1992b) that compared intravenous unfractionated heparin against subcutaneous LMWH for the intial treatment of DVT has shown a lower mortality rate among cancer patients receiving LMWH (Green et al, 1992). The mortality rate 6 0 - 9 0 days after DVT treatment was commenced was dramatically lower in the LMWH group (11% versus 31%) (Green et al,
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1992). Neither of these or subsequent studies of DVT treatment was designed with cancer mortality as a primary endpoint but several have shown a survival advantage for cancer patients receiving LMWH. Randomized placebo-controlled studies of LMWH in cancer are currently being pusued to explore this potential benefit (Kakkar and Williamson, 1997).
CONCLUSION Neoplastic cells can activate the clotting system directly (generating thrombin) or indirectly (generating various procoagulants). Cancer cells and chemotherapeutic agents can injure endothelial cells, thereby intensifying hypercoagulability. In addition, normal endothelial cell function may be disrupted by various defects in platelet function. Several molecular markers of haemostatic activation such as plasma fibrinopeptide A, prothrombin factor 1.2 and thrombin-anti-thrombin complex are implicated in the hypercoagulable state of cancer and could suggest undiagnosed malignancy in thrombophilic patients. The diagnosis of VTE may help to uncover previously occult carcinoma by prompting a complete physical examination, chest X-ray and mammography. However, extensive cancer screening with total-body computerized tomography or magnetic resonance imaging has not been shown to be cost effective for patients with VTE. At present, primary prevention of VTE should be considered for cancer patients during and immediately after chemotherapy, when long-term central venous catheters are placed or when hospitalization for cancer is characterized by prolonged immobilization, trauma and/or surgery. Prevention of recurrent VTE necessitates anticoagulation. In some patients with cancer, the condition is resistant to warfarin, and long-term doseadjusted heparin is required. The treatment of thrombosis in the cancer patient, although more complicated than in those with benign disease, is successfully managed with standard intravenous heparin, but recent studies of subcutaneous LMWHs suggest that they will be equally effective and safe. Finally, LMWH may prolong survival in cancer.
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International Multicentre Trial (1975) Prevention of fatal postoperative pulmonary embolism by low doses of heparin. Lancet ii: 45-5 I. Kakkar AK & Williamson RCN (1995) Thromboprophylaxis in malignant disease. British Journal of Surgety 82: 724-725. Kakkar AK & Williamson RC (1997) Prevention of venous thromboembolism in cancer using lowmolecular-weight heparins. Haemostasis 27 (supplement 1: 32-37. Kakkar AK, Lemoine NR, Scully MF et al (1995a) Tissue factor expression correlates with histological grade in human pancreatic carcinoma. British Journal of Surgery 82:1101-1104. *Kakkar AK, DeRuvo N, Chingswangatanakul V e t al (1995b) Extrinsic pathway activation with elevated tissue factor and factor Vlla in cancer. Lancet 346: 1004--1005. *Kakkar VV, Howe CT, Nicolaides AN et al (19701 Deep vein thrombosis of the leg. Is there a 'high risk' group? American Journal of Surgery 120: 527-530. Kakkar VV, Cohen AT, Edmonson RA et al (1993) Low molecular weight versus standard heparin for prevention of venous thromboembolism after major abdominal surgery. The Thromboprophylaxis Collaborative Group. Lancet 341: 259-265. Karpatkin S & Pearlstein E (1981) Role of platelets in tumour cell metastases. Annab of Internal Medicine 95: 636-641. Koch A, Bouges S, Ziegler S e t al (1997) Low molecular weight heparin and unfi'actionated heparin in thrombosis prophylaxis after major surgical intervention: update of previous meta-analyses. British Journal (~"Surgery 84: 750-759. Koopman MM, Prandoni E Piovella F et al (t9961 Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous lowmolecular-weight heparin administered at home. The Tasman Study Group. New England Journal of Medicine 334: 682-687. Koppenhagen K, Adolf J, Matthes M e t al (1992) Low molecular weight heparin and prevention of postoperative thrombosis in abdominal-surgery. Thrombosis and Hemostasis 67: 627-630. Krolt MH & Schafer AJ (1989) Biochemical mechanisms of platelet activation. Blood 74: I 181-1195. Lebeau B, Chastang C, Brechot JM et al (1994) Subcutaneous heparin treatment increases survival in small cell lung cancer. 'Petites Cellules' Group. Cancer 74: 38-45, Levine MN (19971 Prevention of thrombotic disorders in cancer patients undergoing chemotherapy. Thrombosis and Hemostasis 7 8 : 1 3 3 - t 36. Levine M, Gent M & Hirsh J (1996) A comparison of low molecular weight heparin administered primarily at home with unfractionateA heparin administered in the hospital for proximal deep vein thrombosis. New England Journal of Medicine 334:677-68 l. Levine MN, Gent M, Hirsh J e t al (1988) The thrombogenic effect of anticancer drug therapy in women with stage I1 breast cancel: New England Journal of Medicine 318: 404-407. Levine MN, Hirsh J, Gent M e t al (1994) A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin. Archives of Internal Medicine 154: 49-56. Marcum JM, McGill M & Bastida E (1980) The interaction of platelet, tumour cells, and vascular subendothelium. Journal (g"Laboramry and Clinical Medicine 96: 1046-1053. Monreal M, Lafoz E, Olive Aet al (1994) Comparison of subcutancous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin. Thrombosis and Hemosmsis 71: 7-11. *Monreal M, Alastrue A, Rull M A e t al (19961 Upper extrimity deep venous thrombosis in cancer patients with venous access devices--prophylaxis with a low molecular weight heparin (Fragmin). Thrombosis and Hemosmsis 75:251-253. Naschitz JE, Yeshurun D, Eldar S & Lev LM (1996) Diagnosis of cancer-associated vascular disorders. Cancer 77: 1759-1767. Nordstrom M, Lindbald B, Anderson H et al (1994) Deep venous thrombosis and occult malignancy: an epidemiological study. British Medical Journal 308:891-894. Nurmohamed MT, Verhaeghe R, Haas S e t al (19951 A comparative trial of a low molecular weight heparin (enoxapafin) versus standard heparin for the prophylaxis of postoperative deep vein thrombosis in general surgery. American Journal (~'Surgery 169: 567-571. Oleksowicz I., Mrowiec Z, Schwartz E et al (t995) Characterization of mmour-induced platelet aggregation; the role of immunorelated GPIb and GPllb/llla expression by MCF-7 breast cancer cells. Thrombosis Research 79: 261-274. Pini M, Aiello S, Manotti C et al (1994) Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thrombosis and Hemostasis 72:191 - 197.
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*Prandoni P, Lensing AWA & Buller HR (1992a) Deep vein thrombosis and the incidence of subsequent symptomatic cancer. New England Journal of Medicine 327:1128-1133. Prandoni E Lensing AWA, Buller HR (1992b) Comparison of subcutaneous low molecular weight heparin with intravenous standard heparin in proximal deep vein thrombosis. Lancet 339: 441-445. P~ndoni E Lensing AWA, Logo A et al (1996) The long term clinical course of deep vein thrombosis, Annals ol"lnternal Medicine 125: 1-7. *Pritchard Kt, Paterson All, Paul NA et al (1996) Increased thromboembolic complications with concun'ent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. Journal of Clinical Oncology 14: 2731-2737. Radomski MW, Jenkins DC, Holmes L & Moncada S (1991) Human colorectal adenocarcinoma cells--differential nitric oxide synthesis determines their ability to aggregate platelets. Cancer Research 51: 6073-6078. Rahr HB & SCrensen JV (1992) Venous thromboembolism and cancer. Blood Coagulation and Fibrinolysis 3:451-460. Rasche H & Dietrich M (1977) Haemostatic abnormalities associated with malignant disease. European Journal ~ Cancer 13: 1053-1064. Rickles FR & Edwards RL (1983) Activation of blood coagulation in cancer: Trousseau's syndrome l~evisted. Blood 62: t4-31. Rifkin SE, Constantino J & Redmond C (1989) A randomized clinical trial evaluating tamoxifen in the treatment of patients with node negative breast cancer who have estrogen-receptor positive tumours. New England Journal of Medicine 320: 479-484. Ryan J & Geczy CL (1988) Macrophage procoagutant-inducing factor. Journal of Immunology 141: 2110-2117. Saphner T, Tormey DC & Gray R (1991) Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. Journal of Clinical Oncology 9: 286-294. Schwartz BS & Bradshaw JD (1989) Differential regulation of tissue factor and plasminogen activator inhibitor by human mononuclear cells. Blood 74: 1644-1650. Shands JW (1984) Macrophage procoagulants. Haemostasis 14: 373-377. SCrensen HT, Mellemkjaer L, Steffensen FH et al (1998) The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. New England Journal of Medicine 338:1169-1173. Sun NCJ, McAfee WM, Hmn GJ & Weiner JM (1979) Hemostatic abnormalitics in malignancy, a prospective study of one hundred eight patients. Part 1. Coagulation studies. American Journal of CIiaical Pathology 71: 10-16. Sun NCJ, Bowie EJW, Kazmier FJ et al (1974) Blood coagulation studies in patients with cancer. Mayo Clinic Proceedings 49: 636-641. yon Templehoff GF, Dietrich M, Niemann F et al (1997); Blood coagulation and thrombosis in patients with ovarian malignancy. Thrombosis and Hemostasis 77: 456-461. Thompson CM & Rodgers RL (1952) Analysis of autopsy records of 157 cases of the pancreas with particular reference to the incidence of thromboembolism, American Journal of Medical Science 223: 469-476. Thornes RD (1969) Anticoagalant therapy in patients with cancer. Journal of the Irish Medical Association 62: 426-430. Thornes RD (1972) Fibrin and cancer. British Medical Journal 1: 101-1ll. Walsh JJ, Bonnar J & Wright FW (1974) A study of pulmonary embolism and deep leg vein thrombosis after major gynaecological surgery using labelled fibrinogen-phlebography and lung scanning. Journal ~f' Obstetrics and Gynaecology of the British Commonwealth 81:311-316. Warkentin TE, Levine MN, Hi rsh Jet al (1995) Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfracfionated hepafin. New England Journal of Medicine 332: t330-1335. Zacharski LR, Henderson WG & Rickles FR (1984) Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon head and neck, and prostate. Final report of VA cooperative study #75. Cancer 53: 2046-2052.
E DE L O R E N Z O MD, CCST Hon. Lecturer Thrombosis Research Institate, Emmanuel Kaye Building, Manresa Road, Chelsea, London SW3 6LR, UK G . F. P I N E O
MD, FRCP(C), FACP, FCCP
professor of Medicine and Oncology Division nf Hematology, University of Calgary, Calgary, Alberta, Canada Director, Thrombosis Research Unit Faculty of Medicine, Foothills Hospital, Calgary, Alberta 72N 2T9, Canada
R. C. N. W I L L I A M S O N MA, MChir,MD, FRCS Professor of Surgery Department of Surgery, Imperial College School of Medicine, ttammersmith Hospital, Du Cane Road, London W12 ONN, UK
The association of thrombosis with malignant disease has been recognized for well over 100 years. Evidence from experimental and clinical studies indicates that the haemostatic system is involved in the growth, invasion and metastasis of tumours. Laboratory parameters of haemostasis are frequently deranged in patients with cancer and overt thrombosis is common spontaneously where it may be the first sign of malignancy or secondary to therapy. The mechanisms by which coagulation activation facilitates the malignant process remain to be completely elucidated, but it is clear that cells and proteins of the coagulation and fibrinolytic systems are involved at many steps in the processes of tumour growth and dissemination. The low-molecular-weight heparins with their wellproven safety and efficacy profiles offer unique modalities for the prevention and treatment of cancer-associated thrombosis. They may also play a role in overall mortality reduction in patients with malignant disease. Key words: deep vein thrombosis; antithrombotic therapy; cancer therapy. * Corresponding author. Bailli~re'~ Clinical Haematology-Vol. 11, No. 3, September 1998 ISBN 0-7020-2461-9 0950-3536/98/030675 + 13 $12.00/00
675 Copyright © 1998, by Bailli~re Tindall All rights of reproduction in any form reserved
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Cancer-associated mortality is the second most commonly reported cause of death after cardiovascular disease. Several studies have provided data on the high frequency of clinical and subclinical thrombotic phenomena in cancer (Thompson and Rogers, 1952; Goldberg et al, 1987; Bastounis et al, 1996; Naschitz et al, 1996) and of clotting defects uncovered by laboratory tests (Sun et al, 1974; Francis, 1998). The literature suggests that, although the haemostatic system is affected by cancer (Rasche and Dietrich, 1977; Sun et al, 1979), this is not a unidirectional relationship. It now seems that the proteins and cells of the haemostatic system play a role in tumour biology. Improvements in antithrombotic therapy and the availability of the low-molecular-weight heparins (LMWHs) have allowed more effective strategies to be developed for the prevention and treatment of thromboembolic episodes in cancer and have raised the intriguing possibility that such agents could be used to reduce the overall mortality rate. THROMBOSIS AND CANCER: A TWO-WAY ASSOCIATION? Two recent studies have shown an association between primary venous thrombosis and a subsequent diagnosis of cancer (Baron et al, 1998; S0rensen et al, 1998). Using population-based data from the Danish National Registry of Patients and the Danish Cancer Registry, SCrensen et al identified 15 000 patients with deep venous thrombosis (DVT) and more than 10 000 patients with pulmonary embolism. They observed 1737 cases of cancer in the cohort with DVT, as compared with 1372 expected cases. The risk was more elevated during the first 6 months of follow-up. Furthermore, 40% of the patients given a diagnosis of cancer within 1 year after hospitalization for thromboembolism had distant metastases at the time of the diagnosis of cancer. Strong associations were found with cancer of the pancreas, ovary, liver and brain. Baron et al (1998) assessed cancer incidence during 1989 among more than 60000 patients without a previous cancer diagnosis admitted to hospital between 1965 and 1983 for venous thromboembolism (VTE). Within the first year from admission for VTE 4.0% of the patients received a new cancer diagnosis. This risk was much higher than expected. The increased relative risks were similar in men and women and in thromboembolism patients with and without surgery in the months before admission. Patients with two or more VTE admissions presented higher risk in the year after the second episode. They concluded that, in the first year after admission for VTE, the increase over general population rates was greater than fourfold, with particularly high relative risk for cancers of the liver, pancreas, ovary and brain and for Hodgkin lymphoma and polycythaemia vera. Thromboembolism was also a marker of long-term cancer risk; in fact, 10 years on or more there was a 30% increase in overall cancer incidence. In a 6 month follow-up study (Nordstrom et al, 1994) of more than 1000 patients with DVT, five times the risk of cancer in these patients was found compared with the general population. Prandoni et al (1992a) also found that the incidence of cancer in patients with recurrent idiopathic venous
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thrombosis was higher than in patients without this condition. In this study 7.6% of 145 patients with idiopathic VTE had a diagnosis of cancer made within 2 years of presentation, with 17.6% of those developing recurrent VTE subsequently revealing an underlying malignancy, as opposed to only 1.9% of 105 with secondary VTE. The benefit of searching for cancer in a patient with a primary thrombotic event is difficult to assess (Baron et al, 1998; SCrensen et al, 1998). The detection of some cancers requires an extensive work-up and for several cancers, such as pancreas and liver cancers, early detection does not change the prognosis. However, early detection of malignancies of the cervix, breast, ovary and colon might result in a modestly effective treatment (Francis et al, 1998). Therefore, at present an extensive screening combining also the economical and psychological costs is not justified in all VTE patients. On the other hand, it is appropriate when treating patients with idiopathic VTE to investigate the risk of cancer and to base the decision to perform additional diagnostic tests on the findings of an initial medical history, physical examination, routine laboratory tests and chest X-ray. PATHOPHYSIOLOGY OF CANCER-ASSOCIATED THROMBOSIS The activation of the clotting process in cancer is a multifactorial process. The composition of the blood in the cancer patients may be altered. Such patients are more likely to experience prolonged bed rest and recent surgery, and the invasion of blood vessels is common. These and other nonspecific mechanisms such as tissue damage and inflammatory response result in tissue factor (TF) expression and coagulation activation. Platelets circulate in an inactive state but undergo a series of morphological and biochemical changes on stimulation (Gasic et al, 1973; Marcum et al, 1980; Karpatkin and Pearlstein, 1981; Kroll and Schafer, 1989). They may be activated by malignant cells, and tumour-cell-induced platelet activation occurs both in vivo and in vitro (Gordon et al, 1975; Curatolo et al, 1979; Grignani et al, 1989; Ferroni et al, 1995). Mechanisms for the aggregating activity include tumour-induced thrombin generation (Curatolo et al, 1979), an increased density of sialic acid residues on the tumour cell surface which may enhance platelet aggregation, cysteine proteinases, reduction in nitric oxide production (Radomski et al, 1991), thrombospondin binding and glycoprotein IIb-IIIa expression (Oleksowicz et al, 1995). Monocytes are also capable of producing procoagulant after stimulation. Studies of monocytes in patients with malignant disease have demonstrated increased procoagulant activity (Dean et al, 1984; Geczy, 1984; Shands, 1984, Ryan and Geczy, 1988) and the generation of plasminogen activator inhibitor by monocytes is one of the mechanisms postulated to explain this (Rickles and Edwards, 1983; Schwartz and Bradshaw, 1989). Three possible mechanisms have been proposed to explain the way by which tumours can activate the clotting system: the elaboration of the
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cancer procoagulant, which can directly activate factor X in the coagulation cascade, the formation of a prothrombinase complex on the tumour cell surface for the conversion of inactive prothrombin to thrombin and the expression of ceil-surface TF (Francis et al, 1998). TF is the most consistently observed tumour-elaborated procoagulant and is generally accepted to be the principal mechanism by which cancer cells are able to activate the coagulation cascade. It is the physiological initiator of blood coagulation through its cofactor activation of factor VII with subsequent activation of factors IX and X in the downstream coagulation pathway. Immunohistochemical studies have revealed TF to be absent in a variety of normal epithelial tissues (Callander et al, 1992) and that the expression of TF occurs as a result of malignant transformation in human pancreatic adenocarcinoma (Kakkar et al, 1995b), the degree of TF expression correlating with the degree of histological differentiation of the cancer (Table 1). A study by Contrino et al (1996) has indicated that in invasive carcinoma of the breast TF expression, localized on endothelial ceils, is a marker of malignant angiogenesis. In a study to assess the nature of the hypercoagulable state of malignancy Kakkar et al (1995a) compared markers for the activation of coagulation and TF in 106 patients with solid tumour malignancy and 72 control subjects with no cancer. They were able to demonstrate marked increases in circulating levels of TF and factor VIIa in patients with cancer, indicating and extrinsic pathway activation. This was associated with elevated levels of thrombin-anti-thrombin complexes and prothrombin fragments 1+2, markers of excess thrombin generation and a hypercoagulable state. Factor XIIa was elevated in cancer patients with advanced disease and those receiving chemotherapy, suggesting contact activation of the intrinsic pathway as a result of the extensive and unstable neoangiogenic tumour endothelium or cytotoxic endothelial damage. Table 1. Tissue factor expression in human pancreatic adenocarcinoma (Kakkar et al, 1995b).
TF immunoreactivity (%) Normal tissue Grade 1 adenocarcinoma Grade 2 adenocarcinoma Grade 3 adenocarcinoma g 2 linear trend = 6.69, P = 0.0098
0 20 50 77
RISK OF THROMBOEMBOLISM IN CANCER THERAPY
Chemotherapy is recognized as a risk factor for the development of VTE in cancer patients (Kakkar and Williamson, 1995). Two mechanisms for thrombogenesis associated with the use of chemotherapeutic agents are accepted: (a) release of Wocoagulants and cytokines as a result of toxic effects on damaged endothelial cells and (b) a fall in naturally occurring anticoagulants, such as protein C, protein S and anti-thrombin III, during
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therapy (Kakkar and Williamson, 1995). The duration of chemotherapy may be important. In a study comparing the thrombosis risk of either 12 or 36 weeks of multidose combination chemotherapy in 205 pre- and postmenopausal women with stage II breast carcinoma the overall rate of thrombosis was 6.8% (Levine et al, 1988). Thrombosis occurred during chemotherapy with no events in the 12 week group after their treatment ceased. About half the thrombi that occurred in the 36 week group did so after the first 12 weeks. Of patients receiving multidrug chemotherapy for stage IV breast carcinoma, 17% developed thrombosis. Again, active therapy was associated with the majority of thrombi (Goodnough et al, 1984). The Eastern Co-operative Oncology Group reported thromboembolism (venous and arterial) in 6.8% of women receiving adjuvant chemotherapy (Saphner et al, 1991). Tamoxifen heightened the risk above that of a standard chemotherapy regimen from 0.8% to 2.3% for premenopausal women (P = 0.03) and from 2.3% to 8.0% in post-menopausal women (P = 0.03). This added risk of a combination of hormonal and cytotoxic therapy has recently been confirmed with 1.4% of those who received tamoxifen alone as opposed to 9.6% of those receiving tamoxifen and combination chemotherapy (P = 0.0001) developing clinically relevant thrombosis among 705 post-menopausal women (Pritchard et al, 1996). Most events occurred while patients were receiving chemotherapy, and the rate fell thereafter. Other studies (Fisher et al, 1989, 1990; Rifkin et al, 1989) support this added risk of thrombosis when chemotherapy is combined with tamoxifen. Patients with advanced gastrointestinal, pancreatic and gynaecological malignancies are thought to have a heightened risk of thrombosis and a study in patients with ovarian malignancy demonstrated a thrombosis rate of 17%, among those operated on and receiving chemotherapy (yon Templehoff et al, 1997).
Surgical operations Kakkar et al (1970) established cancer as a risk factor for the development of post-operative DVT. A 41% rate of isotopic thrombi was found in cancer patients undergoing abdominal surgery compared with 26% in those with benign disease (P=0.04; relative risk 1.96 for cancer). Other studies including those in patients with gynaecologieal malignancy (Walsh et al, 1974) confirm the occurrence of DVT more commonly. Rahr and SCrensen analysed rates of fatal pulmonary embolism in patients operated on for cancer in the 1975 International Multicentre Trial. Eight of 49l cancer patients randomized to a control group who received no thromboprophylaxis had a fatal pulmonary embolism rate of 1.6% compared with a rate of 0.4% (eight of 1585) in those operated on for benign conditions (P = 0.05) (Rahr and SOrensen, 1992). The recent American College of Chest Physicians consensus guidelines for antithrombotic therapy in 1995 (Clagett et al, 1995) state that 4 0 - 8 0 % of cancer patients undergoing operation without prophylaxis develop a calf vein thrombosis, 10-20% of patients develop a proximal vein thrombus
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and 1-5% of cancer patients will die of post-operative pulmonary embolism. Central venous lines Thrombosis rates of between 37% and 62% have been reported in cancer patients with indwelling central venous catheters (Bern et al, 1990; Monreal et al, 1996). The occurrence of line thrombosis may necessitate the removal of the line, with subsequent loss of venous access. THE PREVENTION OF VENOUS THROMBOEMBOLISM IN C A N C E R Peri-operative thromboprophylaxis
Mechanical Intermittent calf compression is advocated for the prophylaxis of VTE including those with cancer (Clagett and Reisch, 1988). A small number of patients (N = 355) were randomized to calf compression or control from trials that reported results for cancer patients alone. Rates of DVT fell from 21% (control) to 12.8% with intermittent pneumatic calf compression. Studies have yet to confirm that calf compression reduces the risk of fatal pulmonary embolism.
Low-dose heparin The most commonly utilized method of thromboprophylaxis is low-dose heparin (LDH), which is administered in a dose of 5000 units, commencing 2 hours before operation, and continuing 8-12 hourly after operation subcutaneously. Gallus et al (1976) demonstrate DVT rates of 22% (control) and 9% with LDH after cancer surgery, and in a meta-analysis of 10 trials with 919 patients LDH prophylaxis reduced DVT rates from 30.6% in the control group to 13.6% in those receiving the active treatment (P <0.001) (Clagett and Reisch, 1988). LDH is also effective in the prevention of pulmonary embolism including in those whose operation is undertaken for malignant disease, Of 4121 patients randomized to LDH or control arms in the International Multicentre Trial (1975), 953 had malignant disease. Death from fatal pulmonary embolism occurred in eight patients with malignant disease in the control group (1.6%) and in two patients who received heparin (0.4%).
Low-molecular-weightheparin LMWHs are used commonly in the prevention of DVT in general surgical patients. Individual studies comparing the effects of LMWH and unfractionated heparin on DVT rates for thromboprophylaxis in cancer
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patients indicate broadly similar prophylactic efficacies for these two agents (European Fraxiparine Study Group, 1988; Koppenhagen et al, 1992; Bergqvist and Burmark, 1995; Nurmohamed et al, 1995; ENOXCAN Study Group, 1997). A recent study compared 2500 with 5000 units of LMWH in 2000 operated patients, 65% of whom underwent laparotomy for cancer (Bergqvist and Burmark, 1995). DVT rates fell from 14.9% in those receiving 2500 units to 8.5% in those receiving 5000 units (P = 0.001). This study is the first to demonstrate that increasing the dose of LMWH can improve its thromboprophylactic efficacy in cancer, and interestingly bleeding complications did not increase in cancer patients receiving the higher dose.
Thromboprophylaxis during chemotherapy Only limited evidence from randomized trials exists to demonstrate the efficacy of agents for thromboprophylaxis during chemotherapy and not all methods available are suitable for this population. The prolonged outpatient nature of chemotherapy regimes with the attendant concerns about feasibility and cost effectiveness and the perceived added risks of thrombocytopenia and osteoporosis from prolonged heparin have made clinicians reluctant to consider such therapy. Mechanical methods of thromboprophylaxis such as pneumatic calf compression are clearly unsuitable. The need to administer unfractionated heparin two or three times daily even in low doses to achieve adequate thromboprophylaxis is considered unfeasible for patients over a prolonged period. LMWHs are generally not thought to be associated with the same risk of thrombocytopenia (Warkentin et al, 1995) or osteoporosis (Monreal et al, 1994) as unfractionated heparin, and their pharmacological profile allows for oncedaily self-administration (Koch et al, 1997), suggesting that trials to assess their efficacy and safety in the prevention of chemotherapy-associated thrombosis may yield beneficial results of clinical utility. The oral anticoagulant warfarin dose adjusted to maintain an International Normalized Ratio (INR) of 1.3-1.9 has been assessed for the prevention of thrombosis in 311 women with stage II breast carcinoma receiving chemotherapy (Levine et al, 1994). Seven patients in the control group and only one patient in the warfarin group developed venous thromboembolism (P = 0.03), yet clinical oncologists still appear reluctant to use it in this context. Oral anticoagulation is difficult to control in cancer patients (Bona et al, 1995), although the perceived increased risk of bleeding appears not to be increased when compared with non-cancer patients.
Prevention of catheter thrombosis Cancer patients can be protected against thrombosis associated with indwelling venous catheters by both LMWH and oral anticoagulants (Bern et al, 1990; Monreal et al, 1996). Eighty-four patients randomized to
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receive 1 mg of warfarin daily or no anticoagulant therapy were screened by line venography to assess the rate of central line thrombosis. Nine per cent of patients in the warfarin group and 37% in the control group (P = 0.001) developed a thrombosis (Bern et al, 1990). An LMWH has also been shown to be effective given once daily in a dose of 2500 units commenced at the time of central line insertion, with 62% of controls but only 6% of those receiving LMWH demonstrating clinical or radiological evidence of thrombosis (P = 0.05) (Monreal et al, 1996). Treatment of established thrombosis in the cancer patient
The objectives of therapy in established DVT are prevention of death from pulmonary embolism and reduction in morbidity of the leg vein thrombus. These objectives are tempered in the cancer patient by recognition that a thromboembolic episode may be a terminal event and should not always be treated. Justification in such cases includes palliation of symptoms including painful limb swelling from the primary thrombosis and dyspnoea from the embolism (Levine, 1997). Intravenous unfractionated heparin given first as a bolus of 5000 units and then by continuous infusion usually of about 30 000 units per day to maintain an activated partial thromboplastin time (APTT) of 1.5-2.0 times the control value remains the most commonly utilized method for the initial management of DVT. Subcutaneous LMWHs are becoming increasingly popular with numerous well-designed studies confirming their efficacy and safety (Hull et al, 1992; Prandoni et al, 1992b; Koopman et al, 1996; Levine et al, 1996). These studies have included a number of cancer patients, and in two studies out-patient management of thrombosis was evaluated without routine laboratory monitoring (Koopman et al, 1996; Levine et al, 1996). Although such a strategy was proven feasible, the suitability of a fixed dose of LMWH in cancer patients who not only have a complex hypercoagulable state but also may be at risk of thrombocytopenia secondary to chemotherapy and who are at risk of bleeding due to anatomical location of their primary tumour or secondary deposits remains to be established in prospective trials specifically in this high-risk population. Following initial treatment with either unfractionated heparin or LMWH, recurrent thromboembolism is prevented with warfarin anticoagulation for at least 3 months. Such secondary prevention is usually effective in cancer patients, but it requires regular laboratory supervision of the prothrombin time to maintain an INR of 2-3. Despite adequate anticoagulation, cancer patients are at increased risk of developing thromboembolism (relative risk 1.76 versus control subjects) (Prandoni et al, 1996). Cancer patients do not appear to be at greater risk of developing bleeding complications on oral anticoagulant therapy than non-cancer subjects; the incidence of major bleeding was reported to be 3.4% in cancer patients and 3.0% in non-cancer patients during oral anticoagulation (Prandoni et al, 1996) in one study while in another there were 0.004 bleeding events per patient month for cancer patients and 0.003 for non-cancer subjects (Bona et al, 1995).
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Cancer patients did require more frequent out-patient monitoring to maintain adequate and safe oral anticoagulation. Two studies (Pini et al, 1994; Das et al, 1995) have compared LMWH with warfarin for secondary prevention after initial treatment of DVT. Patients, a few of whom had cancer, received either oral anticoagulants, to maintain an INR of 2 - 3 , or a fixed single daily dose of LMWH. LMWH therapy was associated with lower bleeding rates than warfarin, but with only a small number of cancer patients no conclusions can be drawn about the utility of LMWH for secondary prevention in these patients. ANTITHROMBOTIC THERAPY AND CANCER SURVIVAL
The anti-tumour effects of oral anticoagulants in experimental animals have been sufficiently encouraging for trials in human cancer to be initiated (Thornes, 1969). Adjunct warfarin appeared to potentiate chemotherapy in some patients and, when the disease was under control, was sometimes adequate for maintenance therapy when given alone (Thornes, 1972). Patients receiving warfarin and chemotherapy had significantly lower mortality and greater survival than those receiving chemotherapy alone (Zacharski et al, 1984). The Veterans Administration warfarin study (Zacharski et al, 1984), maintaining an INR of 2 - 3 in patients with advanced small-cell lung carcinoma, found an increase in median survival from 26 weeks to 50 weeks (P = 0.05). Recently, in one study (Carpi et al, 1995) cancer incidence and mortality were reviewed in 683 patients with valvular, ischaemic or myocardial disease. The results from more than 300 patients treated with oral anticoagulants were compared with those from more than 300 patients who did not receive this therapy. Cancer mortality in the anticoagulated patients was also compared with that expected on the basis of National Tumor Registry rates. Twelve cancers occurred in the control group as compared with six cancers observed in the oral anticoagulant group. The deaths expected in men and women receiving oral anticoagulants were three and two respectively. These data support the hypothesis that oral anticoagulant may reduce cancer incidence and mortality in humans. In a study of 278 patients with small-cell lung carcinoma who received full anticoagulation, with subcutaneous unfractionated heparin for 5 weeks, or no anticoagulation, heparin increased the incidence of a complete response to chemotherapy from 24% to 37% (P ---0.004) and the median survival from 216 to 317 days (P = 0.01). The heparin dose given subcutaneously in divided doses required regular monitoring with APTT values (Lebeau et al, 1994). A recent analysis of the two initial studies (Hull et al, 1992; Prandoni et al, 1992b) that compared intravenous unfractionated heparin against subcutaneous LMWH for the intial treatment of DVT has shown a lower mortality rate among cancer patients receiving LMWH (Green et al, 1992). The mortality rate 6 0 - 9 0 days after DVT treatment was commenced was dramatically lower in the LMWH group (11% versus 31%) (Green et al,
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1992). Neither of these or subsequent studies of DVT treatment was designed with cancer mortality as a primary endpoint but several have shown a survival advantage for cancer patients receiving LMWH. Randomized placebo-controlled studies of LMWH in cancer are currently being pusued to explore this potential benefit (Kakkar and Williamson, 1997).
CONCLUSION Neoplastic cells can activate the clotting system directly (generating thrombin) or indirectly (generating various procoagulants). Cancer cells and chemotherapeutic agents can injure endothelial cells, thereby intensifying hypercoagulability. In addition, normal endothelial cell function may be disrupted by various defects in platelet function. Several molecular markers of haemostatic activation such as plasma fibrinopeptide A, prothrombin factor 1.2 and thrombin-anti-thrombin complex are implicated in the hypercoagulable state of cancer and could suggest undiagnosed malignancy in thrombophilic patients. The diagnosis of VTE may help to uncover previously occult carcinoma by prompting a complete physical examination, chest X-ray and mammography. However, extensive cancer screening with total-body computerized tomography or magnetic resonance imaging has not been shown to be cost effective for patients with VTE. At present, primary prevention of VTE should be considered for cancer patients during and immediately after chemotherapy, when long-term central venous catheters are placed or when hospitalization for cancer is characterized by prolonged immobilization, trauma and/or surgery. Prevention of recurrent VTE necessitates anticoagulation. In some patients with cancer, the condition is resistant to warfarin, and long-term doseadjusted heparin is required. The treatment of thrombosis in the cancer patient, although more complicated than in those with benign disease, is successfully managed with standard intravenous heparin, but recent studies of subcutaneous LMWHs suggest that they will be equally effective and safe. Finally, LMWH may prolong survival in cancer.
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