Preventing and Treating Venous Thromboembolism in Patients with Cancer

Transcription

1 & ONCOLOGY BIO T ECH NEWS Priority Report Preventing and Treating Venous Thromboembolism in Patients with Cancer Alok A. Khorana, MD, FACP Associate Professor of Medicine and Oncology Vice Chief, Division of Hematology/Oncology James P. Wilmot Cancer Center University of Rochester Rochester, New York Also Inside: The Community-Based Oncologist Perspective Interviews with George Kovach, MD Hematology Medical Oncology Consultants PC Davenport, Iowa Wilson Mertens, MD Medical Director, Cancer Services Baystate Health Springfield, Massachusetts Anthony Nguyen, MD Medical Oncology Comprehensive Cancer Centers of Nevada-Siena Henderson, Nevada Funding provided by Celgene

2 Preventing and Treating Venous Thromboembolism in Patients with Cancer Alok A. Khorana, MD, FACP Associate Professor of Medicine and Oncology Vice Chief, Division of Hematology/Oncology James P. Wilmot Cancer Center University of Rochester Rochester, New York As many as one-fifth of patients with cancer will develop arterial or venous thromboembolism (VTE) during the course of their illness, and it is a leading cause of death for these patients. 1,2 Some experts have estimated that 4% to 20% of patients with cancer will develop VTE. Others believe this is a conservative estimate and the actual prevalence of VTE is notably higher. 2 The high prevalence of VTE in patients with cancer places a tremendous burden on cancer treatment resources, as well as on the patient s quality of life and finances. Elting and associates estimated that a single episode of deep vein thrombosis (DVT) in a patient with cancer costs $1784 per hospital day, averaging >$20,000 (in 2002 US dollars) per patient. 3 These statistics are sobering and demonstrate a genuine imperative to increase awareness in community oncologists of the need to prevent and treat VTE in patients with cancer. It is universally accepted that the best treatment for VTE is prevention, and several sets of guidelines exist for using thromboprophylaxis in patients with cancer at high risk for VTE. 2,4,5 Unfortunately, oncologists have not yet fully embraced thromboprophylaxis. A report by Kakkar and colleagues showed that 50% of surgeons use thromboprophylaxis compared with only 5% of oncologists. 6 Perhaps new tools to facilitate better identification of patients at the greatest risk for VTE will help improve this rate. Once VTE has occurred, it is important to treat patients with an eye on preventing future occurrences. Risk Assessment It is unclear why VTE occurs so frequently in association with cancer, although patients who are hospitalized, have recently undergone surgery, or who are actively receiving therapy appear to be at greatest risk. 2,7-9 Many factors likely come into play, including risks associated with the individual patient, the cancer, and the treatment method (Table 1). 8 Risk assessment is an important component of VTE prevention. Finding effective ways to determine which patients are most likely to develop VTE allows oncologists to identify who will benefit from thromboprophylaxis. New predictive model. Based on the current understanding of risk factors for VTE, Khorana et al recently developed a simple Table 1 Predictors of VTE in Hospitalized Cancer Patients Characteristic Odds Ratio (95% CI) P Value Site of Cancer Brain Endometrium/cervix Lung Pancreas Stomach 2.23 (1.73, 2.87) 1.96 (1.59, 2.46) 1.29 (1.14, 146) 2.80 (2.09, 3.78) 1.60 (1.17, 2.19).0035 Age 65 years 1.12 (1.03, 1.21).005 Arterial thromboembolism 1.36 (1.09, 1.71).008 Comorbidities Infection Obesity Pulmonary disease Renal disease 1.28 (1.20, 1.38) 1.52 (1.10, 2.09) 1.57 (1.45, 1.70) 1.41 (1.30, 1.54) Adapted from Khorana AA et al. J Clin Oncol. 2006;24(3):

3 It is universally accepted that the best treatment for venous thromboembolism is prevention. risk model to determine whether an outpatient with cancer is at low, medium, or high risk for developing VTE. The model assigns a numeric value to 5 easily assessed variables, and the total score determines a patient s level of risk for VTE (Table 2). 10 The greater the score, the greater the level of risk. To test this model, investigators used it to assess risk in >4000 patients with a cancer diagnosis (development cohort, n = 2701; validation cohort, n = 1365). Patients that the model identified as high risk experienced a substantially higher rate of VTE (Figure 1). The National Heart, Lung, and Blood Institute has recently funded a study that will use Khorana s model to stratify outpatients with cancer according to their level of VTE risk; patients identified as high risk will be randomized to receive prophylaxis versus usual care. Investigators expect to initiate enrollment early this year. The study is focusing only on outpatients because evidence already exists to support the use of thromboprophylaxis in hospitalized patients with cancer. Biomarkers. Investigators hope someday to be able to identify biomarkers that indicate VTE risk. Preliminary studies looking at biomarkers such as prechemotherapy platelet count, 10 tissue factor, 11 and C-reactive protein 12 show promise. The possibility of using biomarkers in combination with risk models may provide clinicians with a more precise assessment of a patient s risk for developing VTE. Using models such as Khorana s preventive risk assessment model, possibly in conjunction with biomarkers, would help clinicians ascertain which outpatients are at risk for VTE and therefore require thromboprophylaxis. Preventing VTE Using Thromboprophylaxis It is universally accepted that the best treatment for VTE is prevention. 2,4,5 Clinicians have several options, both pharmacologic and nonpharmacologic, when considering thromboprophylaxis for patients at risk of developing VTE. Pharmacologic intervention. In most cancer patients, pharmacologic intervention constitutes the best option. Heparin, low molecular-weight heparin (LMWH), and fondaparinux (Arixtra) are the 3 main pharmacologic treatments. Clinical trials have demonstrated the benefit of using thrombopro- Table 2 Risk Model Scores Variable Cancer site Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, bladder, testicular) Risk Score Body mass index (BMI) 35 kg/m 2 1 Hg levels <100 g/l or use of red cell growth factors 1 Prechemotherapy leukocyte count >11 x 109/L 1 Prechemotherapy platelet count 350 x 109/L 1 Risk Category 2 1 Total Risk Score Low risk 0 Intermediate risk 1-2 High risk Adapted from Khorana AA et al. Blood. 2008;111(10): Figure 1 Rates of VTE in Cancer Patients Using Risk Model Rate of VTE (%) Development cohort Validation cohort Low Risk Intermediate Risk High Risk Adapted from Khorana AA et al. Blood. 2008;111(10):

4 Rate of VTE (%) Figure 2 Rates of VTE in Acutely Ill Medical Patients Given Thromboprophylaxis Table 3 Summary of ASCO Prophylaxis Treatment Recommendations 2 Patient Group 5.5 MEDONOX TRIAL (Placebo vs Enoxaparin) Hospitalized patients with cancer Ambulatory patients with cancer receiving chemotherapy Patients with cancer undergoing surgery Recommendation VTE prophylaxis with anticoagulants unless patient is bleeding or anticoagulants are contraindicated. LMWH or adjusted-dose warfarin for myeloma patients on thalidomide or lenalidomide plus chemotherapy or dexamethasone. Otherwise, no prophylaxis treatment. Prophylaxis with low-dose unfractionated heparin, LMWH, or fondaparinux. Mechanical methods can be added in high risk patients but should not be given alone unless anticoagulation is contraindicated. ASCO indicates American Society of Clinical Oncology; LMWH, low molecular-weight heparin; VTE, venous thromboembolism. Table 4 Regimens for VTE Prophylaxis in Patients with Cancer 2 Drug Dose Cost/Week a Unfractionated heparin 5000 U SQ, every 8 h $12.06 LMWH Enoxaparin (Lovenox) Dalteparin (Fragmin) PEVENT (Placebo vs Dalteparin) 40 mg SQ, once daily 5000 U SQ, once daily ARTEMIS (Placebo vs Fondaparinux) $ $ Fondaparinux (Arixtra) 2.5 mg SQ, once daily $ LMWH indicates low molecular-weight heparin; VTE, venous thromboembolism. a Cost for injectable drugs is based on Medicare Part B price list effective September 30, 2006 (with no administration fees or other adjustments) phylaxis in hospitalized medical patients (Figure 2), but the safety of these medications in treating patients with cancer has not been properly evaluated. The recent DIRECT (Dalteparin s Influence on Renally Compromised Anti-Ten-A) study found that it was safe to use the LMWH dalteparin (Fragmin) in crucially ill patients with renal insufficiency. 16 The FDA recently warned clinicians, however, that elderly patients with impaired renal function should not take the LMWH tinzaparin (Innohep). 17 Nonpharmacologic options. Nonpharmacologic options include ambulation, graduated compression stockings, and pneumatic compression. Research indicates that these treatments reduce the risk of VTE in postsurgical patients by 50%. To date, the efficacy of using nonpharmacologic options in cancer patients has not been studied properly, and they are typically used only when pharmacologic intervention is contraindicated. When to use thromboprophylaxis. In 2007, the American Society of Clinical Oncology (ASCO) issued guidelines for managing VTE in patients with cancer (Tables 3 and 4). 2 Briefly, ASCO recommends using VTE prophylaxis for hospitalized patients with cancer and for patients with cancer who are undergoing surgery for their disease. The guidelines do not recommend using them in ambulatory patients, with the exception of patients with multiple myeloma whose treatment regimens include thalidomide (Thalomid) or lenalidomide (Revlimid) with chemotherapy or dexamethasone (Decadron, Hexadrol), who are considered to be at high risk for thrombosis. The National Comprehensive Cancer Network (NCCN) recently published its own updated guidelines on managing VTE, 4 which state that It is the directive of the NCCN that all hospitalized adult patients with cancer receive anticoagulant therapy in the absence of contraindications. The American College of Chest Physicians (ACCP) also revised its guidelines and recommends routine thromboprophylaxis for patients with cancer who are undergoing surgery or who are bedridden with an acute medical illness. Treating VTE with LMWH Patients who develop VTE are often asymptomatic, making the condition difficult to diagnose. Typical clinical symptoms of acute DVT include warmth, pain, or tenderness in a calf or upper leg; unilateral edema; and a heavy sensation in the limb distal to the VTE. 4 Pulmonary embolism (PE) is a complication of DVT that occurs when a blood clot dislodges and ends up obstructing the supply of blood to the lungs. PE is often discovered incidentally, but some patients experience dyspnea, chest pain, tachycardia, apprehension, tachypnea, syncope, and oxygen desaturation. 4 Clinical evidence suggests that LMWH is the preferred treatment for 4

5 For long-term therapy, LMWH is recommended over warfarin primarily because of its efficacy in reducing the incidence of VTE. initial and long-term anticoagulation therapy in patients with cancer and VTE. As a result, both ASCO and NCCN have endorsed specific LMWH-treatment regimens for these patient groups. Initial treatment. Initial treatment of VTE is meant to relieve any acute symptoms and prevent thrombus extension or embolization. Until recently, unfractionated heparin followed by long-term warfarin was the standard initial treatment. 8 This changed after multiple studies showed that LMWH reduced the risk of recurrent VTE and was associated with fewer episodes of major bleeding compared with unfractionated heparin ASCO guidelines recommend using LMWH to treat patients for the first 5 to 10 days after VTE is diagnosed (Table 5). Due to the superior efficacy and safety of LMWH therapy and its convenience, LWMH is now the preferred initial treatment for patients with VTE; fondaparinux is also an option. 22 Long-term therapy. Various treatment options exist for longterm therapy following VTE (Table 6). Both the ASCO and NCCN guidelines recommend treatment with LMWH for 6 months following completion of initial therapy. Vitamin K antagonists such as warfarin (Coumadin), targeted to an international normalized ratio (INR) of 2 or 3, can be used when LMWH is unavailable. For long-term therapy, LMWH is recommended over warfarin primarily because of its efficacy in reducing the incidence of VTE. In 2003, Lee and colleagues published results of the CLOT (Randomized Comparison of LMWH vs Oral Anticoagulant Therapy for the Prevention of Recurrent VTE in Patients with Cancer) study. CLOT evaluated the efficacy of 6 months of treatment with dalteparin versus warfarin (following initial therapy with dalteparin) in patients with VTE and found that only 6% (27/388) of patients who received long-term dalteparin treatment experienced a recurrent symptomatic VTE event compared with 16% (53/338) who received warfarin. 23 A recent Cochrane systematic review of 8 eligible randomized controlled trials observed a significantly reduced rate of VTE associated with LMWH versus warfarin. 24 These reports led ASCO and NCCN to recommend LMWH as the treatment of choice for long-term VTE therapy. Dalteparin is currently the only drug approved by the US Food and Drug Administration (FDA) for long-term VTE therapy in patients with cancer and VTE. Recently the FDA warned clinicians about possible risks associated with the use of tinzaparin in elderly patients who have impaired renal function. 17 The manufacturer of Innohep subsequently issued a Dear Healthcare Professional letter advising clinicians to consider alternatives to Innohep when treating such patients for VTE. 25 Patients treated for DVT should be monitored during and after anticoagulation treatment, to watch for clot progression Table 5 Summary of ASCO VTE Treatment Recommendations 2 Patient Group Patients with cancer and established VTE Patients with cancer and no established VTE Recommendation Initial treatment: LMWH for 5-10 days following VTE diagnosis in patients with cancer and established VTE. Long-term: LMWH for 6 months; vitamin K antagonists (targeted to INR 2-3) are acceptable when LMWH is unavailable. Dalteparin is FDA approved as an extended treatment of symptomatic VTE in patients with cancer to reduce the risk of VTE recurrence. Consider indefinite period of anticoagulation therapy for patients with active cancer (metastatic disease; continuing chemotherapy). A vena cava filter is indicated only for patients with contraindications to anticoagulant therapy and those with recurrent VTE despite appropriate long-term LMWH therapy. Anticoagulants currently are not recommended to improve survival in patients with cancer who do not have VTE. ASCO indicates American Society of Clinical Oncology; FDA, US Food and Drug Administration; LMWH, low molecular-weight heparin; VTE, venous thromboembolism. 5

6 Table 6 Regimens for VTE Prophylaxis in Patients with Cancer 2 Treatment Medication Cost/Week a Initial Dalteparin (Fragmin) Enoxaparin (Lovenox) 100 U/kg every 12 hours 200 U/kg daily 1 mg/kg every 12 hours 1.5 mg/kg daily While the guidelines constitute an important step to promoting recognition of the importance of thromboprophylaxis, more studies are needed to identify and quantify risk factors for VTE. Some guidelines currently recommend throm-boprophylaxis for hospitalized patients with cancer but not for ambulatory ones. Yet, some hospitalized patients may be at low risk for developing VTE whereas some ambulatory patients may be at high risk. Using a risk model like Khorana s may be a more effective method for determining who is most likely to benefit from thromboprophylaxis. Heparin Fondaparinux (Arixtra) 80 U/kg IV bolus, then 18 U/kg IV hourly (adjust based on PTT) 2.5 mg daily (<50 kg body wt) 5.0 mg daily ( kg body wt) 7.5 mg daily (>100 kg body wt) References 1. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5(3): Long-term a Tinzaparin (Innohep) Dalteparin b 175 U/kg da 200 U/kg daily for 1 month, then 150 U/kg daily 2. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology Guideline: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25(34):1-16. Enoxaparin Tinzaparin 1.5 mg/kg SC once daily 175 IU/kg SC once daily 3. Elting LS, Escalante CP, Cooksley C, et al. Outcomes and cost of deep venous thrombosis among patients with cancer. Arch Intern Med. 2004;164(15): Warfarin (Coumadin) 5-10 mg PO daily, adjust dose to INR Wagman LD, Baird MF, Bennett CL, et al. Venous thromboembolic disease. J Natl Compr Canc Netw. 2008;6(8): INR indicates international normalized ratio; IV, intravenous; PTT, prothrombin time; VTE, venous thromboembolism. a Long-term treatment recommendations for enoxaparin and tinzaparin were not included in the ASCO guidelines and are based on recent clinical trials (CANTHANOX and ONCENOX and LITE) b Dalteparin was the only low molecular-weight heparin discussed in the ASCO guidelines and is the only one approved by the US Food and Drug Administration. or DVT recurrence following successful treatment. Clinicians should also evaluate patients for signs of chronic injury to the venous system. 4 Conclusion VTE is possibly a life-threatening event and taking steps to prevent initial or recurrent VTE in high-risk patients with cancer is essential. With the looming possibility that regulatory and insurance agencies will further question hospitalacquired VTE, it is also in the best interest of hospitals. The recent publication of no fewer than 3 sets of guidelines promoting the need for thromboprophylaxis in certain patients illustrates the importance of preventing VTE in these patients. Pharmacologic anticoagulation constitutes the mainstay of therapy for VTE. Based on clinical evidence demonstrating the safety and efficacy of LMWH in prevention and treatment, ASCO and NCCN have endorsed specific LMWH-treatment regimens for high-risk patients. 5. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based guidelines (8th Edition). Chest. 2008;113(6):381S- 453S. 6. Kakkar AK, Levine M, Pinedo HM, Wolff R, Wong J. Venous thrombosis in cancer patients: insights from the FRONTLINE survey. Oncologist. 2003;8(4): Heit JA, Silverstein MD, Mohr DN, Petterson TM, O Fallon WM, Melton III LJ. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000;160(6): Khorana AA, Francis CW, Culakova E, Fisher RI, Kuderer NM, Lyman GH. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006; 24(3): Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer. 2005;104(12): Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10): Khorana AA, Ahrendt SA, Ryan CK, et al. Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer. Clin Cancer Res. 2007;13(10):

7 12. Kroger K, Weiland D, Ose C, et al. Risk factors for venous thromboembolic events in cancer patients. Ann Oncol. 2006; 17(2): Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med. 1999;341(11): Leizorovicz A, Cohen AT, Turpie AG, et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110(7): Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo-controlled trial. BMJ. 2006;332(7537): Douketis J, Cook D, Meade M, et al. Prophylaxis against deep vein thrombosis in critically ill patients with severe renal insufficiency with the low molecular-weight heparin dalteparin: an assessment of safety and pharmacodynamics: the DIRECT study. Arch Intern Med. 2008;168(16): Communications about an ongoing safety review: Innohep (tinzaparin sodium injection). comm/tinzaparin.htm. Accessed December 10, Gould MK, Dembitzer AD, Doyle RL, Hastie TJ, Garber AM. Low molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med. 1999;130(10): van Dongen CJ, van den Belt AG, Prins MH, Lensing AW. Fixed dose subcutaneous low molecular-weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2004;(4):CD Dolovich LR, Ginsberg JS, Douketis JD, Holbrook AM, Cheah G. A meta-analysis comparing low molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med. 2000;160(2): Akl EA, Rohilla S, Barba M, et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer: a systematic review. Cancer. 2008;113(7): Buller HR, Davidson BL, Decousus H, et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003;349(18): Lee AY, Levine MN, Baker RI, et al. Low molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2): Akl EA, Barba M, Rohilla S, et al. Low molecular-weight heparins are superior to vitamin K antagonists for the long term treatment of venous thromboembolism in patients with cancer: a Cochrane systematic review. J Exp Clin Cancer Res. 2008;27: Zeldis JB. Important Innohep (tinzaparin sodium injection) Safety Information. Celgene. safety/2008/celgene_innohep_dhcp_letter.pdf. Accessed January 6, Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002;162: Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost. 2006;12(4): Hull RD, Pineo GF, Brant RF, et al. Long-term low molecularweight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006;119(12):

8 Community-Based Oncologist Perspective Interviews with: George Kovach, MD Dr. Kovach is a hematologist/oncologist with Iowa Cancer Specialists PC, Genesis Cancer Institute, in Davenport, Iowa. He is also president of the Iowa Cancer Society and treasurer of the Association of Community Cancer Centers. Wilson Mertens, MD Dr. Mertens is the medical director of Cancer Services at Baystate Health in Springfield, Massachusetts. Anthony Nguyen, MD Dr. Nguyen is a staff hematology oncology physician at Comprehensive Cancer Centers of Nevada, Stephanie Campus, in Henderson, Nevada. What is your opinion of ASCO s guidelines on prophylaxis for venous thromboembolism (VTE), which recommend using them for hospitalized patients, those about to undergo surgery, or for certain high-risk patients with multiple myeloma? Dr. Kovach: The ASCO guidelines are appropriate. They are used routinely in our practice and in our institution for all moderate- to high-risk cancer, medical, and surgical patients. Dr. Mertens: ASCO s guidelines are carefully written and evidence-based. Clear and convincing data support both prophylactic anticoagulation in hospital inpatients, as well as low molecular weight heparin (LMWH) as treatment and secondary prevention for cancer patients who have suffered VTE. Three randomized clinical trials two in metastatic breast cancer and one in advanced non small cell lung cancer support ASCO s recommendation against primary prevention, except in patients undergoing chemotherapy with thalidomide or lenalidomide regimens. Dr. Nguyen: The recommendations are well substantiated, but the myeloma patient recommendations are controversial; there are some conflicting recommendations in the literature regarding fixed-dose warfarin (Coumadin) versus aspirin. As inpatients, ambulatory patients sit in bed most of the time. Do you feel there is a need to initiate prophylactic treatment in more ambulatory patients? Dr. Kovach: Outpatient use should be determined on a case-bycase basis, depending on the patient s ambulatory status and his or her risk of deep vein thrombosis (DVT). Dr. Mertens: For the ambulatory cancer patient who has not had recent surgery, data on the efficacy and cost-effectiveness of LMWH are lacking. Support for clinical trials evaluating questions surrounding ambulatory patients with cancer and the use of anticoagulation are critical. Dr. Nguyen: In very high-risk ambulatory patients, I believe treatment with LMWH should be implemented. 8

9 I think the Khorana model is well thought-out. Lately, I have seen this model placed in the charts of all patients, reminding hospitalists to offer prophylaxis, if appropriate. Anthony Nguyen, MD What is the typical profile of a patient at higher risk of VTE, and how do you manage these patients? Dr. Kovach: High-risk patients are ones with advanced adenocarcinoma, inpatients, and those who are bedridden, have central catheters, a prior history of DVT, or who have undergone a surgical procedure. I typically use prophylaxis for these patients, consisting of LMWH, with or without compression stockings. I rarely use warfarin. I have experienced minimal complications with LMWH. Dr. Mertens: Generally, but not always, the setting is a malignancy that is not curable. Many cancers have impressive reputations for VTE: pancreas, gastric, lung, ovary, and brain, and lymphomas, as well as metastatic disease. Those with poor performance status and limited mobility, recent surgery, or patients beginning systemic therapy seem more prone to VTE. I suspect many admitted cancer patients are not offered appropriate prophylaxis despite the absence of compelling contraindications and they are not receiving appropriate therapy of established VTE with LMWH. Dr. Nguyen: Higher-risk patients include postoperative orthopedic patients with a malignancy such as pancreatic cancer. I use LMWH in patients at risk of DVT of the lower extremities; in patients at risk for pulmonary embolism (PE), I tend to use intravenous heparin. Do you routinely explain the risk of VTE to all cancer patients, even those not at high risk? What warning signs do you instruct patients to watch for? Dr. Kovach: We caution patients with central catheters, inpatients, or those with a history of DVT on the risks of VTE. We monitor them for extremity pain and/or swelling or chest pain with dyspnea. Dr. Mertens: I explain the risks to all patients receiving systemic therapy and to those with limited mobility and poorer performance status, excepting patients being managed for end-of-life care. Warning signs and symptoms discussed include sudden unexplained shortness of breath, unexplained racing heart rate, and leg or arm swelling, especially unilateral. For patients suffering from malignancy, particularly those receiving systemic therapy for their cancers, clinicians and patients alike must be alert for signs and symptoms of VTE and aggressively investigate such complaints and findings. Dr. Nguyen: I explain the risks primarily to orthopedic patients and those being treated with tamoxifen. I advise them to be alert for any leg swelling, chest pain, or dyspnea. What rate of VTE do you see in your practice? Do you see many cases of VTE in patients who do not fall under ASCO s criteria for prophylactic treatment? Dr. Kovach: I do not track the number routinely; however, I would estimate it is close to the published rates. I have noted an increase in incidental PE found on chest computed tomography (CT) scans. These patients were without the classical symptoms of chest pain, dyspnea, or leg swelling. This might reflect the fact that CT scans have better resolution, thus allowing us to find smaller asymptomatic PEs, rather than an actual increase in the incidence of PE. Dr. Mertens: We have seen a decline in VTE diagnosed in hospital since we instituted a routine LMWH inpatient prophylaxis regimen. This is encouraged by pre-written order sets in our computerized practitioner order entry system. On the other hand, I think the incidence of VTE in the ambulatory setting is increasing, thanks to more aggressive and appropriate investigation of suspicious symptoms and more prolonged therapy and survival of cancer patients. The exact rate is hard to quantify, as it would have to be assessed over the entire time the patient is under care. Rates depend on the patient population, the aggressiveness of monitoring, and the duration of observation. Much of a general oncologist s practice consists of patients with early stage disease, particularly breast and colon cancer. Given this, a 5-year rate of 10% to 20% is probably too high; I would think that 5% would be about right. Dr. Nguyen: We see VTE in 20% to 30% of patients. This is more than the community on average, due to our Coumadin clinic, cancer population, and population using indwelling catheters. How do you manage patients who develop VTE? Dr. Kovach: I manage DVT with LMWH followed by warfarin in the outpatient setting, unless the patient is unstable. Dr. Mertens: In our program, VTE patients are generally managed as outpatients, usually with LMWH, using appropriate dosing. Patients suffering from symptomatic PE are admitted. If a patient is able to inject LMWH and it will be paid for, we will continue with this therapy ac- 9

10 It is important that the clinician be aware that the anti-xa activity of patients using therapeutic doses of LMWH needs to be monitored under certain circumstances. George Kovach, MD cording to ASCO/NCCN guidelines; if it is not paid for, then warfarin with appropriate monitoring and INR levels is recommended. Dr. Nguyen: We manage VTE with LMWH followed by a vitamin K antagonist. Insurance makes it difficult to obtain outpatient long-term LMWH, though I believe Fragmin is indicated for 6 months. What is your opinion of the Khorana predictive model as a means to assess an outpatient s risk for VTE and the need for prophylactic treatment? Dr. Kovach: The Khorana model is a valid model. We have used a similar model developed in-house for the last 8 years for surgical and non-surgical inpatients. Dr. Mertens: This predictive model is interesting but, I think, of no practical use to oncologists today. While well constructed and validated against a test set of patients, its usefulness is limited by the absence of clinical trials demonstrating that prophylactic treatment improves survival or quality of life and is cost-effective in patients with cancer. VTE rates of 4% to 20% in patients with cancer suggest that defining a population that requires more or less attention to signs and symptoms will not be useful to clinicians. Khorana, et al, indicate that the rate of VTE in high-risk patients with cancer is similar to that in postoperative patients, but cancer patients have constituted a minority of subjects in studies on postoperative VTE. More importantly, we do not know what drug should be used in a high-risk group, at what dose, and for how long. Dr. Nguyen: I think the Khorana model is well thought-out. Lately, I have seen this model placed in the charts of all patients, reminding hospitalists to offer prophylaxis, if appropriate. It is mandatory to fill this out for all patients. For outpatients, however, it is somewhat more difficult to offer LMWH because of insurance and copayment restraints. Are there any reimbursement or practice management issues associated with treating patients with VTE? Dr. Kovach: The major issue is coverage of LMWH, because it is a self-injectable drug. We often need to spend time arranging coverage or obtaining the drug at a discount from the manufacturer, since most DVT treatment can be safely administered in the outpatient setting. Rarely is coverage a problem in the inpatient setting, it but can become an issue on discharge. Dr Mertens: Securing payment for LMWH is challenging for patients with Medicare and Medicaid coverage. Medicaid generally does not pay for LMWH, and Medicare Part D is often inadequate to cover this medication for several of our patients. Many are started on Coumadin, even though the clear preference is to provide LMWH therapy. Dr. Nguyen: LMWH is expensive and often blocked by insurance or associated with a large medication copayment for patients. It is difficult to convince a cancer patient of the importance of using LMWH in a 15-minute office visit. Also, cancer patients have fluctuating creatinine levels, renal fxns and platelet counts. I typically hold off on using any anticoagulant or LMWH in patients with a platelet count <50. Is there anything you would like to add to this discussion about VTE that you feel is important for community-based oncologists to know? Dr. Kovach: It is important that the clinician be aware that the anti-xa activity of patients using therapeutic doses of LMWH needs to be monitored under certain circumstances. This is especially important in patients who are obese or are renal impaired. The assay is often not available locally, resulting in delays in obtaining values for dose adjustments. Dr. Mertens: Older literature suggests a potential for an overall survival advantage to anticoagulation that seems to rest on an anticancer basis. All oncologists, without prejudgment, should support well-designed and carefully executed studies that contain quality of life and economic analysis components so this important issue can be explored and addressed definitively for ambulatory patients with cancer. The Khorana model might be useful in defining a group of patients with a risk of VTE that is sufficient to support a quality of life, survival, and cost-effectiveness set of endpoints. Dr. Nguyen: Thrombocytopenia is less likely with LMWH. Oncologists should be mindful of the need for dose adjustments of LMWH in patients with impaired renal function. I see full dose LMWH given to dialysis patients by accident in the community. Also, orthopedic surgeons sometimes use aspirin for thromboprophylaxis, and it is hard to convince them to use LMWH. This is less of a concern with internal medicine physicians, who are typically more aware. 10

11 Links to Online Resources for Venous Thromboembolism American Society of Clinical Oncology Guidelines: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer Journal of Clinical Oncology October 29, 2007 jco.ascopubs.org/cgi/reprint/jco v1.pdf ASCO has made several 2008 Educational Books and online presentations on VTE from the ASCO 2008 annual meeting available for download at Cleveland Clinic Center for Continuing Education Venous Thromboembolism Susan M. Begelman diseasemanagement/cardiology/venousthromboembolism ClotCare Online Resource A nonprofit organization providing information on antithrombotic and anticoagulant therapy; the site also houses a patient support group. Prevention of Venous Thromboembolism in Patients with Cancer Charles W. Francis, et al. Health Services Research 2008 Educational Book (PDF available to members) Risk of Venous Thromboembolism in Lung Cancer Margot Tesselaar, et al. August 28, NCCN Clinical Practice Guidelines in Oncology: Venous Thromboembolic Disease v

12 This Priority Report is supported through an educational grant from Eisai, Inc. The information is designed to be a summary of information and not an exhaustive clinical review. & ONCOLOGY BIOT ECH NEWS