THROMBOPROPHYLAXIS IN CANCER PATIENTS

Transcription

1 CANCER ASSOCIATED THROMBOSIS THROMBOPROPHYLAXIS IN CANCER PATIENTS Cancer is an important risk factor for venous thromboembolism (VTE). Research has shown that 4-20% of 1 patients with cancer experience VTE. In a large Dutch study that included more than 66,000 cancer patients, researchers found a VTE prevalence of 12.3 per 1,000 patients more than six times higher than that of the general population (1 to 2 2 VTEs per 1,000 patients). VTE is a significant cause of morbidity and mortality in patients with cancer. A study that assessed survival rates for patients with cancer-associated thrombosis (CAT) compared with cancer patients without thrombosis (matched for type of cancer, sex, age, and the year of diagnosis) found that the one-year survival rate was 12% for those who with VTE compared with 36% in control patients. 4 3 Thromboembolism is one of the most common causes of death in this vulnerable patient group. Cancer patients who survive a VTE are at risk for sequelae from the initial event, such as increased bleeding, post-thrombotic syndrome, pulmonary hypertension and recurrent 6 5 VTE. For example, cancer-associated thrombosis is associated with a 21% annual risk of recurrent VTE and a 12% annual risk of bleeding complications. The diagnosis of VTE continues to be a challenge as it is often asymptomatic. In one prospective study of hospitalised patients, the rate of PE was 1%, but the diagnosis was unsuspected in 70% of patients who died from acute PE, as revealed at autopsy. Yet, VTE is one of the most common preventable causes of cancer inpatient mortality, making prophylaxis critical in this high-risk group. Effective thromboprophylaxis has been shown to reduce morbidity and mortality due to cancer-associated thrombosis. According to international guidelines, low-molecular-weightheparin (LMWH) is the first choice for the initial and long-term treatment of VTE, as well as for prophylaxis in selected high-risk patients, having largely replaced unfractionated heparin (UFH) and oral vitamin K antagonists such as warfarin. 8 9,10 7 CONTENTS Identifying at-risk patients Identifying at-risk patients

2 Khorana risk scoring model International guidelines on CAT prophylaxis References The pathogenesis of cancer-associated thrombosis (CAT) is complex and multifactorial. The rates of VTE vary widely between different types and stage of cancers. Furthermore, the risk of CAT is influenced by a variety of patient and treatmentrelated factors, and candidate biomarkers such as blood counts, TF, and P-selectin. All of these factors make the prediction of the individual risk of VTE and the identification of patients with cancer that might benefit from thromboprophylaxis major clinical challenges CAT risk factors, which are discussed in a separate article, are as follows: Patient-related: Increased age Ethnicity Co-morbidities Obesity Performance status 13 Treatment-related: Chemotherapy, antiangiogenesis agents, hormonal therapy Radiation therapy Surgery 60 mins ESAs, transfusions Indwelling venous access Cancer-related: Primary site of cancer Stage Histology Time since diagnosis Biomarkers: Platelet count 350 x 10 /L Leukocyte count >11 x 109/L Haemoglobin < 100g/L Khorana risk scoring model 9 In 2008, Dr Alok Khorana published what has become a seminal paper in the field of cancerassociated thrombosis, detailing a risk score protocol that helps predict the risk of VTE in 14 ambulatory patients receiving chemotherapy The Khorana score, as it is known, predicts

3 thrombosis risk based on a collection of simple variables - type of cancer, body mass index (BMI) and complete blood count (platelet, leukocyte, haemoglobin). Each variable in the score is assigned a value. For example, elevated pre-chemotherapy 9 2 platelet count of /L or more, BMI of at least 35 kg/m, and cancer types such as stomach and pancreas cancer each raise the risk. Cancer patients with a Khorana score of 3 or greater are at high risk for developing blood clots and those with a score of 1 2 are at intermediate risk. The Vienna Cancer and Thrombosis Study subsequently validated this model in another cohort of cancer patients and expanded it with two additional laboratory markers - soluble P- selectin ( 53.1 ng/ml = VTE risk score 1), and D-dimer ( 1.44 µg/ml = VTE risk score 1) - increasing the predictive value of estimating a patient's risk of CAT. In June 2013, the American Society of Clinical Oncology (ASCO) issued updated guidelines affirming the use of this slightly modified Khorana score as a well-established risk calculator for thromboembolism. Specifically, new ASCO guidelines recommend that patients with cancer be assessed for VTE risk at the time of chemotherapy initiation and periodically thereafter. International guidelines on CAT prophylaxis Recognising the clinical burden of cancer-associated thrombosis, international guidelines have been issued by the European Society for Medical Oncology (ESMO), ASCO, and the National Comprehensive Cancer Network (NCCN), in which the prophylaxis and treatment of CAT are addressed in several patient groups: surgical cancer patients, hospitalised (medical or surgical) cancer patients, ambulatory cancer patients and also the prevention of thrombosis recurrence in patients with cancer and established VTE. Surgical cancer patients: Cancer patients undergoing a surgical procedure have twice the risk of postoperative VTE as patients who undergo surgery for benign diseases. In addition, after surgery for cancer, patients with VTE experienced a 5.3-fold greater chance of mortality than patients without. In this high-risk patient group, the role of prophylaxis is unquestionable. The Enoxaparin and Cancer (ENOXACAN) trial in patients undergoing curative abdominal or pelvic surgery for cancer showed that, given two hours preoperatively and for approximately 10 days post-surgery, the LMWH enoxaparin at 40 mg once daily is as effective and well tolerated as UFH at 5,000 IU three times daily in reducing the incidence of thromboembolic complications post-surgery, with no significant difference in the incidence of bleeding 19 between the two regimens. ASCO and other international guidelines recommended that patients undergoing major cancer surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days

4 Laporte et al, found that the LWMH tinzaparin is a valuable option for long-term treatment of VTE in patients in whom vitamin K antagonists (VKA) are contraindicated or difficult to monitor. Tinzaparin may have a more favorable benefit-risk ratio than VKA in patients with cancer and VTE. This analysis of five randomised controlled studies on long-term tinzaparin in patients with VTE investigated whether long-term curative doses of tinzaparin is a valuable alternative to VKA for the treatment of symptomatic VTE, especially in patients with cancer who are at higher risk of recurrence and bleeding. In cancer patients, a non-significant 38% VTE risk reduction in favour of tinzaparin was observed on treatment (RR=0.62 [0.30; 1.31]), although the difference was significant at the end of follow-up at one year (RR=0.40 [0.19; 0.82], p<0.01). There was no significant difference in the incidence of major bleeding. Extended prophylaxis to four weeks post-surgery was associated with a greater than 50% reduction in venographic VTE in patients undergoing major abdominal surgery. The FAME study compared the efficacy of one week versus four weeks of thromboprophylaxis with LMWH (dalteparin sodium 5000 IU once daily) in major abdominal surgery patients. Researchers found that the cumulative incidence of VTE was reduced from 16.3% with shortterm thromboprophylaxis (29/178 patients) to 7.3% after prolonged thromboprophylaxis (12/165) (relative risk reduction 55%; 95% CI 15-76; P=0.012), with no increase in bleeding 22 events. In addition, an individual patient data meta-analysis of the two studies of the LMWH tinzaparin confirmed a reduction in risk with extended prophylaxis. As a result, ASCO, ESMO and NCCN guidelines agree that extending postoperative prophylaxis up to four weeks should be considered in those with high-risk features (particularly those undergoing major abdominal or pelvic surgery). Hospitalised patients: Hospitalised patients are at greater risk for developing VTE and this risk is further increased in 24 patients with cancer. However, the literature indicates that these patients are often inadequately anticoagulated, despite strong recommendations for prophylaxis. For example, the International Medical Prophylaxis Registry on Venous Thromboembolism (IMPROVE) registry, which was designed to assess thromboprophylaxis patterns, found that only 45% of eligible cancer patients received prophylaxis. Clinical studies have demonstrated the effectiveness of thromboprophylaxis in reducing VTE events in hospitalised cancer patients: the MEDENOX trial recorded a 63% relative risk reduction (RRR) in patients receiving enoxaparin, compared to those receiving placebo; there was a 45% RRR in patients receiving dalteparin, compared to placebo, in the PREVENT study; and, in the ARTEMIS trial, a RRR of 47% was confirmed in the fondaparinux group, compared to the placebo group. 25 While international guidelines agree that hospitalised patients are at increased risk of thrombosis, they differ on the specifics of which patients should receive pharmacologic thromboprophylaxis (although there is agreement that it should only be administered in the absence of bleeding or other contraindications) ,

5 ACSO recommend that pharmacologic thromboprophylaxis should definitely be given to hospitalised patients who have active malignancy and acute medical illness or reduced mobility; should be considered in hospitalised patients without additional risk factors; and is not recommended in patients admitted for minor procedures or short chemotherapy infusion, or in patients undergoing stem-cell/bone marrow transplantation. The NCCN panel of experts recommend the use of prophylactic anticoagulation therapy in high-risk inpatients, and should be considered in other outpatients at risk. The LMWHs, fondaparinux, and subcutaneous UFH (5,000 units, three times daily) are category 1 options for inpatient prophylactic therapy. The ESMO guidelines specify prophylaxis with UFH, LMWH or fondaparinux in hospitalised cancer patients confined to bed with an acute medical complication. However, extensive, routine prophylaxis for advanced cancer patients receiving chemotherapy is not recommended, but may be considered in high-risk ambulatory cancer patients. Prophylaxis in cancer patients receiving adjuvant chemotherapy and/or hormone therapy is not recommended. With regard to thromboprophylaxis for cancer patients with a central venous access device (CVAD), both the ESMO and NCCN guidelines did not recommend extensive, routine prophylaxis to prevent CVC-related VTE, while the ASCO guidelines made no specific recommendation. Ambulatory cancer patients: While cancer alone is associated with a 4.1-fold risk of thrombosis, the risk is increased 6.5- fold for cancer patients receiving chemotherapy. In addition, the combination of an antiangiogenic agent, such as thalidomide or lenalidomide, with a cytotoxic drug is associated with a statistically significant increase of VTE occurrence. For example, when thalidomide is combined with chemotherapy, VTE rates of 28% in patients with multiple myeloma and 43% in patients with renal cell carcinoma have been reported. Two recent European studies observed a significant reduction in VTE incidence and related deaths among advanced cancer patients receiving chemotherapy and a thromboprophylaxis. A UK study of advanced pancreatic cancer patients who received GEM-based chemotherapy 2 (1000 mg/m weekly), found that those patients also received daily dalteparin injections (therapeutic dose: 200 U/kg once a day for the first month and then 80% of the initial dose for five months) had a 3.5% incidence of VTE during the first three months compared to 25% in 33 the chemo-only group. Lethal VTE and sudden deaths were seen only in the standard arm (9%), with none in the experimental arm. A German research group reported that patients who received both GEM-based chemotherapy in combination with enoxaparin 1 mg/kg daily sc had a decreased rate of symptomatic VTE after three months (1.25% versus 9.87% in chemo-only group) and 12 months (5% versus 15%) , 32

6 Routine thromboprophylaxis in cancer outpatients is not recommended by ASCO, although clinicians may consider LMWH prophylaxis on a case-by-case basis in highly selected outpatients with solid tumours receiving chemotherapy. Although ESMO guidelines do not recommend extensive routine prophylaxis for advanced cancer patients receiving chemotherapy, it can be considered in high-risk ambulatory cancer patients, such as patients with lung or pancreatic cancer. Clinicians are also advised to consider LMWH, aspirin or adjusted-dose warfarin (international normalised ratio [INR] - 1.5) in myeloma patients receiving thalidomide plus dexamethasone or thalidomide plus chemotherapy. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either low molecular weight heparin (LMWH) or low-dose aspirin to prevent venous thromboembolism (VTE), according to the ASCO guidelines. The NCCN panel recommended VTE prophylaxis with either LMWH or dose-adjusted warfarin (INR 2-3) for patients with multiple myeloma who are receiving lenalidomide- or thalidomidebased combination regimens associated with a thrombotic risk or in patients with two or more individual or disease-related risk factors (based on risk assessment model published by Palumbo et al 30 ). Prophylactic aspirin or LMWH in patients with multiple myeloma receiving thalidomide (excluding high-risk combinations) who have no other risk factors for VTE is also recommended. The NCCN does not recommend routine thromboprophylaxis in cancer outpatients undergoing chemotherapy. However, the guidelines include the option of prophylaxis in ambulatory cancer outpatients who are considered to be at risk of VTE based on an assessment of established VTE risk factors. References 1. Karimi M, et al. Cancer Associated Thrombosis. Open Cardiovasc Med J. 2010; 4: Blom JW, Vanderschoot JP, Oostindier MJ et al. Incidence of venous thrombosis in a large cohort of cancer patients: record of a linkage study. J Thromb Haemost. 2006; 4: Lyman GH. Venous thromboembolism in the patient with cancer: Focus on burden of disease and benefits of thromboprophylaxis. Cancer 2011; 117(7): Sørensen HT, Mellemkj r L, Olsen JH, et al. Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 2000; 343: Khorana AA, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007; 5(3): Trujillo Santos J, et al. Predicting recurrences or major bleeding in cancer patients with venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008;100(3): Prandoni P, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest 1995; 108:

7 9. Mandalà M, et al. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2011; 22 (Suppl 6): vi85 vi Lyman G, et al. American Society of Clinical Oncology guidelines: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007; 25(34): Sousou T, Khorana AA. New insights into cancer associated thrombosis. Arterioscler Thromb Vasc Biol 2009; 29(3): Menapace LA, Khorana AA. The role of thromboprophylaxis in cancer patients: Emerging data. Curr Opin Hematol 2010; 17(5): Lyman GH, et al. Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: American Society of Clinical Oncology Practice Guideline Update. J Clin Onco 2013; 31(7): Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy associated thrombosis. Blood. 2008; 111: Ay C, et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116: Streiff MB, et al. NCCN Clinical Practice Guidelines in Oncology for Venous Thromboembolic Disease. J Natl Compr Canc Netw 2011; 9: Kakkar AK, et al. Prevention of venous thromboembolism in cancer patients Semin Thromb Hemost 1999; 25: Trinh VQ, et al. Venous thromboembolism after major cancer surgery: Temporal trends and patterns of care. JAMA Surg 2014; 149(1): ENOXACAN Study Group. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: A double blind randomised multicentre trial with venographic assessment. Br J Surg 1997; 84: Laporte S, et al. Long term treatment of venous thromboembolism with tinzaparin compared to vitamin K antagonists: A meta analysis of 5 randomized trials in non cancer and cancer patients. Thrombo Research 2012; 130(6): Bergqvist D, et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002;346: Rasmussen MS, et al. Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open label study. J Thromb Haemost2006; 4: Jorgensen LN, Lausen I, Rasmussen MS: Prolonged thromboprophylaxis with low molecular weight heparin (tinzaparin) following major general surgery primarily for cancer: An individual patient data meta analysis. J Thromb Haemost 2003; (suppl 1: abstr P1870). 24. Brown A, et al. Preventing venous thromboembolism in hospitalised patients with cancer: improving compliance with clinical practice guidelines. Am J Health Syst Pharm Mar 15;69(6): Tapson VF, et al. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest Sep;132(3): Samama MM, 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: Leizorovicz A, et al, for PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebocontrolled trial of dalteparin for the prevention of venous thromboembolism in acutely iill medical patients. Circulation. 2004; 110: Cohen AT, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomized placebo controlled trial. BMJ. 2006; 332: Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population based case control study. Arch Intern Med. 2000;160: Palumbo A, et al. Prevention of thalidomide and lenalidomide associated thrombosis in myeloma. Leukemia 2008; 22: Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deep vein thrombosis in patients with multiple

8 myeloma receiving thalidomide and chemotherapy. Blood. 2001;98: Desai AA, Vogelzang NJ, Rini BI, et al. A high rate of venous thromboembolism in a multi institutional phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil and daily thalidomide in patients with metastatic renal cell carcinoma. Cancer. 2002; 95: Maraveyas A, et al. Gemcitabine with or without prophylactic weight adjusted dalteparin in patients with advanced or metastatic pancreatic cancer (APC): a multicentre, randomised phase IIB trial (the UK FRAGEM study). Proceedings ECCO abstract Eur J Cancer 2009; 7: Riess H, et al. A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy: final results of the CONKO 004. Proceedings ASCO abstract J Clin Oncol 2010; 28:15s.