Oncologist. The. Venous Thrombosis in Cancer Patients: Insights from the FRONTLINE Survey ABSTRACT

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1 The Oncologist Venous Thrombosis in Cancer Patients: Insights from the FRONTLINE Survey AJAY K. KAKKAR, a MARK LEVINE, b H.M. PINEDO, c ROBERT WOLFF, d JOHN WONG e a Department of Surgical Oncology and Technology, Imperial College, London, United Kingdom; b Department of Clinical Epidemiology and Biostatistics, McMaster University and the Hamilton Regional Cancer Center, Hamilton, Ontario, Canada; c Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands; d Department of GI Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA; e Department of Clinical Oncology, Faculty of Medicine, National University Hospital, Singapore Key Words. Venous thrombosis Primary prevention Drug therapy Thromboembolism Health care surveys Neoplasms ABSTRACT Background. Venous thromboembolism (VTE) is a common complication in cancer patients and a significant cause of morbidity and mortality. However, little information is available on oncologists perceptions of the risk of VTE and its management. The Fundamental Research in Oncology and Thrombosis (FRONTLINE) study is the first comprehensive global survey of thrombosis and cancer. The study was designed to collect data on the perceived risk and patterns of practice with regard to VTE in cancer patients undergoing surgical and medical management of their malignancy and to provide information on international and regional practice patterns, allowing for the design of research studies to answer the concerns of practicing clinicians. Methods. Literature reviews were performed to provide a current evidence base against which to compare the findings, and a survey was developed under the guidance of an advisory board. A paper-based replypaid questionnaire was distributed globally between July and November 2001 to clinicians involved in cancer care and was made available on a dedicated website. Findings. A total of 3,891 completed responses were available for analysis. Brain and pancreatic tumors were considered to carry a high risk for VTE, and 80% of respondents considered the use of central venous lines to be associated with a high risk of VTE. Marked differences were seen in the use of thromboprophylaxis for surgical and medical cancer patients, with over 50% of surgeons reporting that they initiated thromboprophylaxis routinely, while most medical oncologists reported using thromboprophylaxis in less than 5% of medical patients. Low molecular weight heparin (LMWH) was the most popular method of thromboprophylaxis employed in both surgical and medical patients and was more favored by European than U.S. clinicians. Some 20% of respondents reported using aspirin for prophylaxis, despite there being no reliable evidence for this agent as effective in prevention in this population. For the treatment of VTE, LMWH was again the most common initial treatment, although, for the long-term, oral anticoagulation therapy was widely adopted. Many patients were treated for VTE on an outpatient basis, and secondary prevention of VTE was typically continued for 3 to 6 months after an episode of deep vein thrombosis or for longer in the case of pulmonary embolism. Interpretation. The results of the FRONTLINE survey demonstrate a need for guidelines to direct clinical practice in line with evidence-based data concerning cancer and VTE. Oncologists need to be educated regarding the true risks of VTE associated with certain cancers and on strategies for prevention and treatment to reduce the morbidity and mortality associated with VTE in all cancer patients. The study has also helped identify areas for future research. The Oncologist 2003;8: Correspondence: A.K. Kakkar, M.D., Department of Surgical Oncology and Technology, Imperial College, Hammersmith Campus, Du Cane Road, London, United Kingdom. Telephone: ; Fax: ; a.kakkar@imperial.ac.uk Received December 12, 2002; accepted for publication May 6, AlphaMed Press /2003/$12.00/0 The Oncologist 2003;8:

2 Kakkar, Levine, Pinedo et al. 382 INTRODUCTION Venous thromboembolism (VTE) is a common complication in cancer patients and an important cause of morbidity and mortality. Development of VTE is associated with a poor prognosis in cancer patients. Patients with concurrent VTE and malignancy have a greater than threefold higher risk of recurrent thromboembolic disease and death (from any cause) than patients with VTE without malignancy [1]. One in every seven hospitalized cancer patients who die do so from a pulmonary embolism (PE) [2]. Of the patients who die from a PE, 60% have localized cancer or limited metastatic disease, which would otherwise have allowed for reasonably long survival in the absence of a fatal PE [2]. The association between VTE and cancer appears to be two way: cancer patients are at a greater risk for thrombotic episodes [3], while idiopathic VTE may be the first sign of occult malignancy [4]. Abnormalities as manifested by changes in hemostatic parameters are frequently encountered in cancer patients [3]. These include elevations in markers of activity, including factor VIIa, thrombinantithrombin complex, and the initiator of blood coagulation tissue factor. These abnormalities are not predictive of thrombosis risk [3]. Patients with cancer are more likely to develop VTE than patients without malignancy [1]. The risk varies with different tumor types and is thought to be highest in tumors of the ovary, pancreas, and central nervous system [5]. Many factors are thought to contribute to the risk of VTE, including the primary tumor site, age, immobility, and type of therapeutic intervention [6, 7]. For example, operations for cancer are associated with a higher risk of VTE and fatal PE than noncancer surgery [8]. Chemotherapy, particularly when combined with hormone therapy, also increases the risk of VTE [9]. A high risk of thrombosis has been reported in patients with indwelling central venous catheters [9, 10]. Despite the availability of published literature demonstrating an association between cancer and VTE, very little information is available on perceptions about the magnitude of this risk or about patterns of practice for prophylaxis and treatment of VTE in cancer patients among medical and surgical oncologists. The Fundamental Research in Oncology and Thrombosis (FRONTLINE) study is the first global comprehensive survey of thrombosis in cancer, designed to address perception and patterns of practice within the cancer and thrombosis area. The results presented here provide insights into how the risk of VTE is perceived to impact on medical and surgical oncological practice and current strategies employed for thromboprophylaxis and treatment of VTE. The excellent international and regional response rates allowed for comparisons in practice and identified variations in management, all of which suggest the need for better education and consensus on the best approach to preventing and treating VTE in cancer patients, as well as the need for further research. METHODS Survey Design and Recruitment The survey was developed by an advisory group of medical and surgical oncologists. After a review of the literature to establish the current evidence base, a questionnaire was developed and tested in a pilot survey. The final survey questionnaire, available in seven languages (English, French, German, Italian, Spanish, Russian, and Japanese), was launched during the annual meeting of the American Society of Clinical Oncology in May 2001 and then distributed globally from July until November 2001 to oncologists who were recruited by a series of mailings, advertisements, and congress activities. This period covered both the XVIII Congress of the International Society on Thrombosis and Haemostasis and the European Cancer Conference 11. The survey was also made available on a dedicated website, with access controlled by a unique personal identification number. The goal was to target clinicians in both academic and community centers across the globe who treat cancer patients, including surgeons, radiation oncologists, medical oncologists, and hematologists. The survey questionnaire included separate sections on management of surgical patients (19 questions) and medical (nonsurgical) patients (29 questions) and a section on thrombosis associated with vascular access devices for all respondents (10 questions). Questions addressed the risk of VTE in various cancer types; the use, choice, and duration of thromboprophylaxis; and the choice and duration of treatment for deep vein thrombosis (DVT) and PE. In the final optional section, participants were given the opportunity to register anonymous details of their most recent case of a cancer patient who developed VTE. Data Management The data were entered using double-entry fully verified data input, and all analyses were carried out using Questionnaire Processing System software (MRS Ltd.; Wallington, Oxford, UK). Pairwise comparisons were made using Z tests for the equality between two proportions (binomial distribution) [11]. As well as analyzing the total sample, responses were analyzed according to the type of hospital, the age (qualifying before/after 1985) and specialty of the respondent, and by region of respondent (Western Europe, Eastern

3 383 Venous Thrombosis in Cancer Patients Europe and Russia, North America, and the rest of the world). Responses were compared by practice for either surgical or medical patients. RESULTS Demographics In total, 3,891 completed questionnaires were returned, 3,400 paper versions and 491 via the website. Demographics of respondents are shown in Table 1. Responses were received from a total of 74 countries. Nearly half (43%) of all respondents were based in Western Europe. Responses were split almost equally between clinicians practicing in academic/university hospitals and community/district hospitals. The majority of respondents practiced one of three main specialties: medical oncology (35%), surgery (28%), or hematology (20%). Respondents in the survey reported the routine treatment of more than 17 types of cancer. Of these, colorectal and breast cancers were most commonly treated (by 57%- 60% of respondents), with lymphoma, esophageal/stomach, lung, pancreatic, and ovarian the next most common cancers (treated by 35%-45% of respondents). Perceptions of Risk by Cancer Type Respondents rated certain cancers as high risk for development of VTE, including cancers of the brain and pancreas and colorectal, ovarian, prostate, cervical, and esophageal/ gastric cancers. When asked which cancers were associated with a greater than 20% risk of VTE, medical and surgical experts broadly agreed that brain and pancreatic cancers carried very high risks. Data from those treating medical cancer patients, for cancer types with more than 100 responses, are shown in Figure 1. There were few responses for brain cancer, but 14% of 36 respondents who treat this tumor type surgically and 15% of 85 who treat it medically rated the risk of VTE as greater than 20%. However, there appear to be some inconsistencies in the perception of risk according to tumor type depending upon whether patients were managed surgically or medically, where most medically treated cancer patients were thought to have low risks, below 10%. Patterns of Thromboprophylaxis Use of Thromboprophylaxis Comparisons between responses from those treating surgical and medical patients suggest very different approaches with regard to the prevention of VTE. While 52% of respondents would routinely utilize thromboprophylaxis for surgical patients (and 43% would decide on a Table 1. Demographics of survey respondents Total number of responses 3,891 Paper-based 3,400 Web-based 491 Response breakdown Surgical patients (part B) 1,882 Medical patients (part C) 2,640 Catheter use (part D) 3,714 Case study (part E) 2,541 Region where practicing (% of respondents) Western Europe 43% Eastern Europe/Russia 13% North America (U.S./Canada) 19% Rest of the world 22% Not stated 4% Type of hospital setting where practicing (% of respondents) Academic/University 53% Community/District 46% Not stated 1% Specialty (% of respondents) Surgeon (any) 28% Medical oncologist 35% Hematologist 20% Radiation oncologist 9% Other/Not stated 20% case-by-case basis), most respondents only considered thromboprophylaxis routinely in less than 5% of their medical oncology patients (Fig. 2). Even among patients with tumors perceived to be at high risk, use of VTE prophylaxis in medical patients was low. Choice of Agent Participants in the survey were asked to note their general approach to thromboprophylaxis for both medical and surgical patients in terms of all types of treatment used (Table 2). Over 70% of respondents indicated the use of low molecular weight heparin (LMWH) for thromboprophylaxis in both of those populations. Unfractionated heparin (UFH) was the preferred choice for 17% of respondents treating surgical patients and 15% of those treating medical patients. Physical methods, such as compression stockings and pneumatic compression, were the second most popular method of thromboprophylaxis selected for surgical patients, while, for medical patients, oral anticoagulants were popular if prophylaxis was adopted. The use of aspirin for VTE prophylaxis was reported by 11% of those treating surgical patients and by 24% of those treating medical patients. This trend was particularly evident among clinicians from Eastern Europe, where 34% reported using aspirin for prophylaxis in surgical patients, compared with 6% from Western Europe and 7% from North America (p 0.01 for both comparisons); for medical patients,

4 Kakkar, Levine, Pinedo et al. 384 Figure 1. Respondents estimates of the risk of medical patients developing VTE without prophylaxis by tumor type. Figures in parentheses are numbers responding for each tumor type. Respondents (%) aspirin use was 52% in Eastern 60 Europe, compared with 19% in Western Europe and 15% in North 40 America (p 0.01 for both comparisons). In North America, the use of 20 LMWH (55% for surgical patients and 51% for medical patients) was less than that seen in Western 0 Europe (87% and 80%, respectively; p 0.01 for both comparisons), with clinicians appearing to favor oral anticoagulants as prophylaxis. Reasons for not using thromboprophylaxis in surgical patients included concerns about a high risk of bleeding (55% of respondents) and the belief that there was a low risk of thromboembolic complications (38% of respondents) in the patients concerned. The majority of respondents (61%) reported stopping aspirin/nonsteroidal anti-inflammatory drug (NSAID) therapy prior to surgery for cancer. Respondents were asked about the frequency of placement of a vena cava filter as prophylaxis for VTE in surgical patients. Results showed that, overall, the majority of respondents (63%) never used this procedure as a prophylactic measure, while 23% rarely used vena 100 cava filters for thromboprophylaxis. In North America, significantly higher use of vena cava 80 filters was reported: 14% sometimes used (compared with 3% of 60 Western European respondents; p 0.01), 41% rarely used, and 37% 40 never used (compared with 72% of Western European respondents; p 0.01). 20 Respondents (%) Bladder (119) Cervical (149) Head/neck (145) Lung (923) Esophageal/stomach (191) Pancreatic (290) Uterine (122) >20 Estimated risk of VTE (%) All cancers for which there were 100 responses Breast (1,131) Colorectal (917) Leukemia (505) Lymphoma (717) Ovary (265) Prostate (279) Duration of Thromboprophylaxis Thromboprophylaxis was continued for the duration of the patient s hospital stay for 39% of surgical patients, 45% of medical patients overall, 42% of patients receiving adjuvant therapy, and 34% of chemotherapy patients with advanced disease, where thromboprophylaxis was given (most respondents gave prophylaxis to 5% or less of medical patients). For surgical patients, VTE prophylaxis was typically administered during the hospital stay or for up to 10 days. For medical patients receiving adjuvant Bladder (119) Cervical (149) Head/neck (145) Lung (923) Esophageal/stomach (191) Pancreatic (290) Uterine (122) Breast (1,131) Colorectal (917) Leukemia (505) Lymphoma (717) Ovary (265) Prostate (279) Figure 2. Respondents estimates of the proportion of medical patients receiving prophylaxis by tumor type. Figures in parentheses are numbers responding for each tumor type Patients receiving prophylaxis (%) All cancers for which there were 100 responses >50

5 385 Venous Thrombosis in Cancer Patients Table 2. General approach to thromboprophylaxis (% of respondents) Surgical Medical patientspatients LMWH 77%* 70% Physical methods 54%* 35% UFH 17%* 15% Aspirin 11%* 24% Oral anticoagulant 10%* 40% No thromboprophylaxis ** 7% No response 7%* 7% Most respondents reported that they give thromboprophylaxis in 5% of medical patients. *p 0.01 surgical versus medical. Physical methods included, for example, compression hosiery, pneumatic compression. Note: respondents could give more than one answer, therefore, responses add up to >100%. chemotherapy, the duration of VTE prophylaxis, if it was given, was variable, but most commonly up to 90 days, while for chemotherapy patients with advanced disease, there was a trend to continue thromboprophylaxis indefinitely. Indefinite thromboprophylaxis was significantly (p 0.05) more common for patients receiving chemotherapy for advanced disease (35% of survey respondents) than for those receiving adjuvant chemotherapy (15%) or undergoing surgery (5%). This suggests that respondents who do give thromboprophylaxis in medical patients may continue it for as long as there is evidence of active cancer. Ninety-one percent of respondents reported that thromboprophylaxis was not routinely given to radiotherapy patients in their care. However, of those respondents who did routinely give thromboprophylaxis, 55% would give thromboprophylaxis to patients receiving radiotherapy for brain metastases. Treatment of VTE Choice of Treatment The survey included questions asking respondents to list their standard initial treatment for an episode of VTE. In the case of surgical patients, the question related to all VTEs, while for medical patients, information was sought on DVT and PE separately. As with prophylaxis, LMWH was the most common choice for standard initial treatment in all patients (54%-75%) (Table 3). UFH was also commonly employed as an initial treatment for PE in medical patients. A higher usage of thrombolytic therapy for initial treatment of thrombosis was reported in Eastern Europe, compared with elsewhere in the world (22% in treatment of DVT in medical patients versus 4% in Western Europe and 3% in North America; p 0.01 for both comparisons; similar pattern observed in treatment of PE in medical patients and VTE in surgical patients). Oral anticoagulation was favored by respondents (66%- 80%) as the standard long-term anticoagulant treatment after an initial episode of VTE (DVT or PE). A significantly higher number of respondents from Western Europe selected LMWH as the standard long-term anticoagulant treatment after an episode of DVT in medical patients (22% versus 11% for North American respondents; p 0.01). In addition, a significantly higher level of aspirin use was reported by Eastern European respondents, compared with those from other regions of the world (34% versus 4% in Western Europe and 2% in North America; p 0.01 for both comparisons). Only 8% of respondents reported sometimes using a vena cava filter as treatment for VTE in surgical patients, with 29% using them rarely and 50% never using this method. The corresponding figures for the use of vena cava filters in medical patients with DVT were 13%, 39%, and 41%, respectively. Hospital Versus Outpatient Treatment Outpatient treatment of DVT was common. Some 40% of respondents reported routinely treating DVT in surgical patients out of hospital, compared with 59% for medical oncology patients (p 0.05). However, the majority of respondents usually managed PE occurring in medical patients in hospital (76%). Factors commonly justifying hospital admission for patients under these circumstances Table 3. Initial treatment of VTE (% of respondents) Surgical Medical Medical patients VTE patients DVT patients PE UFH 33% 26%* 41%* LMWH 63% 75%* 54%* Oral anticoagulant 21% 28%* 17%* Vena cava filter 4% 3%* 3%* Thrombolytic agent 8% 7%* 12%* Refer patient 3% ** ** No response 7% 6%* 4%* *p 0.05 versus other groups. Note: respondents could give more than one answer, therefore, responses add up to >100%.

6 Kakkar, Levine, Pinedo et al. 386 were: neutropenia, thrombocytopenia, fever/infection, concern for PE, bleeding, concern for patient compliance, and other comorbidities. Duration of Treatment The duration of long-term anticoagulant therapy after an episode of VTE in either surgical or medical patients was reported by the majority of respondents to be between 3 and 6 months (63% for VTE in surgical patients, 72% for DVT in medical patients, and 58% for PE in medical patients) (Fig. 3). A high number of respondents reported continuing longterm anticoagulant treatment for either 7-12 months (19%) or indefinitely (18%) for medical patients after an episode of PE. Oral anticoagulants were the favored choice for longterm treatment. As with primary prevention, it was noted that, for long-term secondary prevention, clinicians in Eastern Europe used a substantial amount of aspirin (approximately 30% of respondents from that region). Thrombosis Associated with Venous Access Devices Perceptions of Risk One section of the survey, open to all participants, dealt with the subject of thrombosis associated with the use of vascular access devices. Eighty percent of respondents associated central venous access with an increased risk of thrombosis. While Western Europeans typically considered Table 4. Treatment of patients with central venous access device (% of respondents) Use of Removal of line/device thromboprophylaxis when thrombosis develops Never 19% 4% Rarely 26% 13% Sometimes 22% 31% Usually 31% 46% No response 2% 6% Figure 3. Duration of anticoagulation treatment after VTE episode. Respondents (%) * 0 1 Month 3 Months 6 Months 7-12 Months *p < 0.05 versus other groups * * Surgical patients all VTE Medical patients with DVT Medical patients with PE * Indefinitely No response Table 5. Thromboprophylaxis regimen used in patients with central venous access % of respondents LMWH 52 Fixed low-dose oral anticoagulant 28 Adjusted-dose oral anticoagulant 14 Aspirin 14 s.c. UFH 13 Heparin line flushes 27 Note: respondents could give more than one answer, therefore, responses add up to >100%. central venous access devices to be associated with a 0%- 20% risk of VTE (74% perceived the risk to be in this range), in North America, clinicians believed the risk to be higher (p 0.05). Fifty-three percent of North American respondents considered that, without prophylaxis, 11%- 30% of patients with central venous access devices would develop thrombosis. Use of Thromboprophylaxis More than half the respondents reported usually or sometimes giving thromboprophylaxis to patients with central venous access devices (Table 4). LMWH was the most popular method employed overall (by 52% of respondents) (Table 5), although the use of LMWH in North America was significantly lower (21%, compared with 60% in Western Europe and 69% in Eastern Europe; p 0.01 for both comparisons). Conversely, fixed low-dose oral anticoagulation was used significantly more frequently in North America than in other regions of the world (71% versus 20% in Western Europe and 9% in Eastern Europe; p 0.01 for both comparisons). Nearly half the respondents usually removed the device/line when thrombosis developed in a patient with a central venous access device (Table 4). Nearly three-quarters of respondents continued treatment for up to 6 months, while 12% continued treatment indefinitely. DISCUSSION The results of the FRONTLINE survey provide valuable data on the perceptions and treatment practices of a large number of clinicians who regularly care for patients with common types of cancer. In the survey, LMWH was found to be a common choice for thromboprophylaxis in both surgical and medical patients, where oral anticoagulants were also used, although aspirin was employed by a smaller number of respondents, despite the lack of clinical evidence to support its use. The use of aspirin for thrombo-

7 387 Venous Thrombosis in Cancer Patients prophylaxis, especially in Eastern Europe, is a cause for concern as there is little evidence for the efficacy of this agent in preventing DVT or PE. The majority of respondents reported using thromboprophylaxis in surgical patients for the duration of the hospital stay, although 25% would continue treatment for 5-10 days. At the time of the survey (July-November 2001) there was no published evidence to support prolonged prophylaxis, although the risk of thromboembolism remains high in the month following major surgery [12]. A recently published study shows that thromboprophylaxis with LMWH for 4 weeks after surgery for abdominal or pelvic cancer significantly reduced the incidence of thrombosis, compared with treatment for just 1 week postsurgery [13]. The decision not to employ thromboprophylaxis in surgical patients appears to be driven by a fear of bleeding. However, 30% of surgeons are prepared to operate on patients receiving aspirin/nsaids. The higher use of vena cava filters seen in the subgroup of North American respondents also appears to be driven by the perceived high risk of bleeding. The second most common reason cited for not giving thromboprophylaxis to surgical patients is that the risk of VTE was thought to be low. This belief that cancer is not associated with a high risk of VTE is at odds with patient registry data from this survey, which showed that many patients who developed VTE did not receive primary prophylaxis for this reason (data not shown). LMWH was demonstrated to be a common choice for thromboprophylaxis, particularly among European respondents, in medical patients, once a decision to use thromboprophylaxis had been taken. However, provision of thromboprophylaxis for medical patients was reported to be very low, in line with the lack of published evidence that prophylactic treatment is beneficial in medically managed cancer patients. Prospective research to establish the necessity for routine prophylaxis in nonsurgical cancer patients is urgently required. The observed trend for thromboprophylaxis to be continued for longer in patients undergoing chemotherapy for advanced cancer, compared with those receiving adjuvant chemotherapy, suggests that respondents who do give thromboprophylaxis in medical patients may continue it for as long as there is evidence of active cancer. The observation that DVT was more likely to be managed on an outpatient basis in medical patients, compared with surgical patients, may simply reflect the fact that, in surgical patients, DVT may occur while the patient is still in hospital, and hence, treatment is initiated in hospital postoperatively and then continued at home. The study showed that PE was more likely to be treated in hospital than DVT, reflecting the clinicians views of this as a more serious and potentially life-threatening condition. For standard initial treatment of VTE, most respondents would use LMWH and a smaller proportion would use UFH. It is likely that the reported initial use of oral anticoagulants reflects ambiguity in the question and that this class was used in addition to some form of heparin. The high use of thrombolytic agents for initial therapy in Eastern Europe was a surprising finding. In terms of long-term treatment after an episode of DVT, the majority of respondents would, as expected, use an oral anticoagulant. One-fifth of respondents from Western Europe reported that they would use LMWH, despite a lack of supporting clinical evidence in cancer patients. Furthermore, LMWH use in Western Europe was double that reported for North America. A significantly higher use of aspirin as long-term anticoagulant therapy was reported for Eastern Europe/Russia, compared with other regions, again with little evidence to support this. Respondents in North America perceived the risk of thrombosis associated with central venous access to be higher than did respondents in other regions, and this was reflected in the greater use of thromboprophylaxis. There is wide variation in the rates reported in the literature. Thrombosis rates of less than 5% have been reported for patients with implanted access ports managed with heparin flushes [14-16]. In a series of 92 patients with implanted devices managed with heparin flushes and, in high-risk patients, a low-dose oral anticoagulant, Lokich et al. reported a 16% thrombosis rate, which they contrasted with the 43% thrombosis rate in a previous series of patients with tunneled subclavian catheters [17]. Thrombosis rates of 37%-62% were observed in the control groups of two small trials [18, 19]. LMWH was reported to be a common choice for thromboprophylaxis in patients with a central venous access device by respondents from most parts of the world except North America. In North America, fixed low-dose oral anticoagulants were the more common treatment. Both of these strategies are supported by small prospective studies [18, 19]. In the event that thrombosis developed when a central venous access device was in use, most physicians favored removal of the device and additional therapy. Although the majority of respondents would continue additional therapy for up to 6 months, a significantly higher number of North American physicians indicated that they would continue treatment indefinitely. This suggests that North Americans have greater concerns about the potential longer term sequelae of catheterassociated thrombosis. Further research into the management of catheter-related thrombosis in cancer patients is required. Clearly there are a number of limitations to the conclusions that can be drawn from the FRONTLINE survey. Since a large number of questionnaires was distributed

8 Kakkar, Levine, Pinedo et al. 388 Table 6. Further research needed More studies are needed in cancer patients to address, especially: Primary thromboprophylaxis in medically managed cancer patients Optimum management of VTE in cancer patients Prevention and treatment of VTE associated with central venous catheters and the survey was available on the Internet, it is not possible to define the response rate or to determine if there were any biases in responses. Hence, the sample may not be representative of clinical practice. Specifically, it is possible that clinicians with a special interest in the subject may have been particularly motivated to participate. The survey asked respondents about how they would treat a patient, but did not audit practices, and there may be important differences between clinicians reported practices and their actual practices [20]. Finally, no outcome data were collected. CONCLUSION The FRONTLINE survey provides global data on the problem of thrombosis in cancer patients. There is a clear need for further studies to confirm and extend findings from the FRONTLINE survey and for more clinical trials to provide a firm evidence base to guide clinical practice (Table 6). The results from the FRONTLINE survey demonstrate a need for guidelines to assist clinicians in their clinical decision making and for education for oncologists about the risks of VTE and strategies for treatment and prevention. ACKNOWLEDGMENT FRONTLINE was supported by an unrestricted educational grant from Pfizer Corporation. REFERENCES 1 Levitan N, Dowlati A, Remick SC et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore) 1999;78: Shen VS, Pollak EW. Fatal pulmonary embolism in cancer patients: is heparin prophylaxis justified? South Med J 1980;73: Kakkar AK, DeRuvo N, Chinswangwatanakul V et al. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet 1995;346: Prandoni P, Lensing AW, Büller HR et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992;327: Thodiyil PA, Kakkar AK. Variation in relative risk of venous thromboembolism in different cancers. Thromb Haemost 2002;87: Kakkar VV, Howe CT, Nicolaides AN et al. Deep vein thrombosis of the leg. Is there a high risk group? Am J Surg 1970;120: Pritchard KI, Paterson AH, Paul NA et al. Increased thromboembolic complications with concurrent 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. J Clin Oncol 1996;14: Rahr HB, Sørensen JV. Venous thromboembolism and cancer. Blood Coagul Fibrinolysis 1992;3: Levine MN. Prevention of thrombotic disorders in cancer patients undergoing chemotherapy. Thromb Haemost 1997;78: Kakkar AK, Williamson RC. Antithrombotic therapy in cancer. Low molecular weight heparins may have a direct effect on tumours. BMJ 1999;318: Kanji GK. 100 Statistical Tests. London: Sage Publications, 1999; Huber O, Bounameaux H, Borst F et al. Postoperative pulmonary embolism after hospital discharge. An underestimated risk. Arch Surg 1992;127: Bergqvist D, Agnelli G, Cohen AT et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002;346: Barrios CH, Zuke JE, Blaes B et al. Evaluation of an implantable venous access system in a general oncology population. Oncology 1992;49: Kock HJ, Pietsch M, Krause U et al. Implantable vascular access systems: experience in 1500 patients with totally implanted central venous port systems. World J Surg 1998;22: Poorter RL, Lauw FN, Bemelman WA et al. Complications of an implantable venous access device (Port-a-Cath ) during intermittent continuous infusion of chemotherapy. Eur J Cancer 1996;32A: Lokich JJ, Bothe A Jr, Benotti P et al. Complications and management of implanted venous access catheters. J Clin Oncol 1985;3: Bern MM, Lokich JJ, Wallach SR et al. Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomized prospective trial. Ann Intern Med 1990;112: Monreal M, Alastrue A, Rull M et al. Upper extremity deep venous thrombosis in cancer patients with venous access devices prophylaxis with a low molecular weight heparin (Fragmin). Thromb Haemost 1996;75: Hobbs FD, Jones MI, Allan TF et al. European survey of primary care physician perceptions on heart failure diagnosis and management (Euro-HF). Eur Heart J 2000;21: