Лечение рак-ассоциированного тромбоза: от рекомендаций к реальной клинической практике
Лечение рак-ассоциированного тромбоза: от рекомендаций к реальной клинической практике
Сомонова О.В., Елизарова А.Л., Блиндарь В.Н. и др. Лечение рак-ассоциированного тромбоза: от рекомендаций к реальной клинической практике. Современная Онкология. 2019; 21 (1): 60–65. DOI: 10.26442/18151434.2019.1.190247
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Somonova O.V., Elizarova A.L., Blindar V.N. et al. Treatment of cancer-related thrombosis: from recommendations to real clinical practice. Journal of Modern Oncology. 2019; 21 (1): 60–65. DOI: 10.26442/18151434.2019.1.190247
Лечение рак-ассоциированного тромбоза: от рекомендаций к реальной клинической практике
Сомонова О.В., Елизарова А.Л., Блиндарь В.Н. и др. Лечение рак-ассоциированного тромбоза: от рекомендаций к реальной клинической практике. Современная Онкология. 2019; 21 (1): 60–65. DOI: 10.26442/18151434.2019.1.190247
________________________________________________
Somonova O.V., Elizarova A.L., Blindar V.N. et al. Treatment of cancer-related thrombosis: from recommendations to real clinical practice. Journal of Modern Oncology. 2019; 21 (1): 60–65. DOI: 10.26442/18151434.2019.1.190247
Цель. Осветить современные возможности лечения и вторичной профилактики рецидивов венозных тромботических осложнений у пациентов с онкологическим заболеванием. Материалы и методы. Рассмотрены данные 40 научных источников, опубликованных в российской и зарубежной печати в 1997–2018 гг. Результаты. Онкологические больные подвержены высокому риску тромботических осложнений, которые ухудшают исходы противоопухолевого лечения и занимают одно из лидирующих мест среди причин смерти. Низкомолекулярные гепарины (НМГ) являются препаратами первого выбора для лечения рак-ассоциированных тромбозов. Учитывая сложности применения НМГ, многие пациенты либо прекращают прием рекомендованной терапии, либо переходят на прием пероральных форм антикоагулянтов. Например, по данным проспективного регистра Garfield, прямые оральные антикоагулянты назначаются 25% онкологических больных. Наиболее перспективным препаратом в этой группе является ривароксабан (Ксарелто). В настоящее время проводится ряд исследований в рамках программы CALLISTO, направленных на изучение разных вопросов ведения пациентов с онкоассоциированными тромбозами: первичная и вторичная профилактика тромбозов с помощью ривароксабана, оценивается качество жизни и приверженность терапии. В ретроспективном исследовании The Mayo Clinic Thrombophilia database продемонстрирована сопоставимая эффективность ривароксабана и НМГ, а в исследованиях US claims analysis и US Humana database отмечено снижение числа рецидивов тромбоэмболических осложнений при лечении ривароксабаном по сравнению с НМГ при одинаковой частоте больших кровотечений. В субанализе проспективного исследования XALIA показан благоприятный профиль эффективности и безопасности при терапии ривароксабаном у онкологических больных, т.е. результаты подтверждены данными реальной практики. Заключение. Результаты представленных исследований позволили ряду международных обществ, таких как Международное общество по проблемам тромбоза и гемостаза и Общество национальной сети многопрофильных онкологических учреждений США в 2018 г. рекомендовать ривароксабан в качестве одного из вариантов терапии пациентов с онкоассоциированными тромбозами при низком риске кровотечения и отсутствии лекарственных взаимодействий с текущей системной терапией. Ривароксабан может быть рассмотрен как альтернатива низкомолекулярным гепаринам для лечения и вторичной профилактики тромбозов у онкологических больных.
Aim. To highlight the modern treatment and secondary prevention of recurrent thrombotic complications in patients with cancer. Materials and methods. We studied 40 scientific sources published in the Russian and foreign press in the period of 1997 to 2018. Results. Oncology patients are at higher risk of thrombotic complications which can worse outcomes of antitumor treatment and occupy one of the leading places among causes of death. Low molecular weight heparins (LMWHs) are the drugs of first choice for the treatment of cancer-associated thrombosis. Taking into account the complexity of LMWH application, many patients stop receiving the recommended therapy and are switching to oral anticoagulants. For instance, according to the GARFIELD-AF prospective registry direct oral anticoagulants (DOACs) are used in 25% of cancer patients. The most promising drug in this group is rivaroxaban (Xarelto). Multiple studies are currently undergoing in the framework of CALLISTO Program, designed to study various issues of managing patients with cancer-associated thrombosis: primary and secondary prevention of thrombosis using rivaroxaban, to study quality of life and the treatment adherence. In the Mayo Clinic Thrombophilia database retrospective study was demonstrated comparable efficacy of rivaroxaban and LMWH and in the studies US claims analysis and US Humana database were noted the reduction of recurrences of thromboembolic complications on using rivaroxaban treatment in comparison with LMWH on the same frequency of severe bleeding. In subanalysis of the prospective XALIA study was showed a favorable profile of efficacy and safety of rivaroxaban therapy in cancer patients, so the results proved the results of real practice. Conclusion. In 2018 the results of submitted studies helped several international societies, such as International Society on Thrombosis and Hemostasis and The National Comprehensive Cancer Network, to recommend rivaroxaban as one of the treatment options for patients with cancer-associated thrombosis with low risk of bleeding and no drug-drug interactions with current systemic therapy. Rivaroxaban can be considered as an alternative to low molecular weight heparins for treatment and secondary prevention of thrombosis in cancer patients.
1. Agnelli G, Verso M. Management of venous thromboembolism in patients with cancer. J Thromb Haemost 2011; 9 (Suppl. 1): 316–24. DOI: 10.1111/j.1538-7836.2011.04346.x
2. Barsam SJ, Patel R, Arya. Anticoagulation for prevention and treatment of cancer-related venous thromboembolism. Br J Haematol 2013; 161 (Iss. 6): 764–77. DOI: 10.1111/bjh.12314
3. Wun T, White RH. Epidemiology of cancer-related venous thromboembolism. Best Pract Res Clin Haemotol 2009; 22 (1): 9–23. DOI: 0.1016/j.beha.2008.12.001
4. Shaib W, Deng Y, Zilterman D et al. Assessing risk and mortality of venous thromboembolism in pancreatic cancer patients. Anticancer Res 2010; 30 (10): 4261–4.
5. Kakkar AK, Haas S, Walsh D et al. Prevention of perioperative venous thromboembolism: outcome after cancer and non-cancer surgery (abstract). Thromb Haemost 2001; 86 (Suppl.): 0c1732. DOI: 10.5144/0256-4947.2015.95
6. Ogren M, Bergqvist D, Wahlander K et al. Trousseaus syndrome – what is the evidence? A population – based autopsy study. Thromb Haemost 2006; 95: 541–5. DOI: 10.1160/TH05-10-0694
7. Liebman HA. Cancer prognosis in patients with venous thromboembolism (VTE) and patients with clinical and laboratory biomarkers predictive of VTE risk. Thromb Res; 2018; 164 (Suppl. 1): S19–22. DOI: 10.1016/j.thromres.2018.01.040.
8. Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343: 1846–50. DOI: 10.1056/NEJM200012213432504
9. Robin P, Carrier M. Revisiting occult cancer screening in patients with unprovoked venous thromboembolism. Thromb Res 2018; 164 (Suppl. 1); S7-S11. DOI: 10.1016/j.thromres.2017.12.024
10. Magnus N, D’Asti E, Meehan B et al. Oncogenes and the coagulation system – forses that modulate dormant and aggressive states in cancer. Thromb Res 2014; 133 (Suppl. 2): S1–S9. https://doi.org/ 10.1016/S0049-3848(14)50001-1
11. Falanga A, Marchetti M. Hemostatic biomarkers in cancer progression. Thromb Res 2018; 164 (Suppl. 1): S54–S61. DOI: 10.1016/j.thromres.2018.01.017
12. Cedervall J, Hamidi A, Olsson A-K. Platelets, NETs and cancer. Thromb Res 2018; 164 (Suppl. 1): S48-S52. DOI: 10.1016/j.thromres.2018.01.049
13. Nazari PMS, Riedy J, Pabinger I, Cihan Ay. The role of pododlanin in cancer-associated thrombosis. Thromb Res 2018; 164 (Suppl. 1): S34–S39. DOI: 10.1016/j.thromres.2018.01.020
14. Ten CH, Falanga A. Overview of the postulated mechanisms linking cancer and thrombosis. Pathophysiol Haemost Thromb 2007; 36: 122–30. DOI: 10.1159/000175150
15. Agnelii G, Verso M. Thromboprophylaxis during chemotherapy in patients with advanced cancer. Thromb Res 2010; 125 (Suppl. 2): S17–S20. DOI: 10.1016/S0049-3848(10)70007-4
16. Сомонова О.В. Диагностика нарушений гемостаза и принципы их коррекции при тромботических осложнениях в онкологии. Дис. … д-ра мед. наук. М., 2008.
[Somonova O.V. Diagnostika narushenii gemostaza i printsipy ikh korrektsii pri tromboticheskikh oslozhneniiakh v onkologii. Dis. … d-ra med. nauk. Moscow, 2008 (in Russian).]
17. Российские клинические рекомендации по диагностике, лечению и профилактике венозных тромбоэмболических осложнений (ВТЭО). Флебология. 2015; 9 (4; Вып. 2): 2–52.
[Rossiiskie klinicheskie rekomendatsii po diagnostike, lecheniiu i profilaktike venoznykh tromboembolicheskikh oslozhnenii (VTEO). Flebologiia. 2015; 9 (4; Vyp. 2): 2–52 (in Russian).]
18. Franchini M, Bonfanti C, Lippi G. Cancer-associated thrombosis: investigating the role of new oral anticoagulants. Thromb Res 2015; 135 (5): 777–81. DOI: 10.1016/j.thromres.2015.02.024
19. Mandala M, Tondini C. Adjuvant therapy in breast cancer and venous thromboembolism. Thromb Res 2012; 130: S66-S70. DOI: 10.1634/theoncologist.2012-0261
20. Levine MN. Prevention of thrombotic disorders in cancer patients undergoing chemotherapy. Thromb Haemost 1997; 78: 133–6.
21. Goodnough L, Saito A, Manni A. Increased incidence of thromboembolism in stage IV breast cancer patients treated with five-drug chemotherapy regimen: a study of 150 patients. Cancer 1984; 78: 133–6. DOI: 10.4061/2011/394740
22. Otten HM, Mathijssen J, Ten CH et al. Symptomatic venous thromboembolism in cancer patients treated with chemotherapy: an underestimated phenomenon. Arch Inter Med 2004; 164: P190–4. DOI: 10.1001/archinte.164.2.190
23. Kearon C, Akl EA, Ornelas J et al. Antithrombotic therapy for VTE disease. Chest 2016; 149 (2): 315–52. DOI: 10.1016/j.chest.2 015.11.026
24. Watson HG, Keeling DM, Laffan M et al. On behalf of British Committee for Standarts in Haemotology. Guideline on aspects of cancer-related venous thrombosis. Br J Haematol 2015; 170 (Issue 5): 640–8. DOI: 10.1111/bjh.13556
25. Lee AY, Levine MN, Baker MD 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: 146–53. DOI: 10.1056/NEJMoa025313
26. Piran S, Schulman S. Management of recurrent venous thromboembolism in patients with cancer: a review. Thromb Res 2018; 164 (Suppl. 1): S172–S177. DOI: 10.1016/j.thromres.2017.12.019
27. Khorana AA, Yannicelli D, McGrae KR et al. Evaluation of US prescription patterns: are treatment guidelines for cancer-associated venous thromboembolism being followed? Thromb Res 2016; 14: 51–3. DOI: 10.1016/j.thromres.2016.07.013
28. Weitz J еt al. Clinical characteristics and initial treatment of patients with CAT. Results from Garfield VTE registry. Poster PB 460 presented at ISTH 2017.
29. Prints MH, Lensing AW, Bauersachs R et al. Oral rivaroxaban versus standart therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013; 11: 21–31. https://doi.org/ 10.1186/1477-9560-11-21
30. Prints MH, Lensing AWA, Brighton TA et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomized controlled trials. Lancet Haematol 2014; 1: e37–e46. DOI: 10.1016/S2352-3026(14)70018-3
31. Büller HR, Prins MH, Lensin AW et al. Oral Rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287–97. DOI: 0.1056/NEJMoa1113572
32. Van der Hulle T, den Exter PL, Kooiman J et al. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost 2014; 12 (7): 1116–20. DOI: 10.1111/jth.12605
33. Khorana AA, McCrae K, MilentiJevic D et al. VTE recurrence and safety of anticoagulants among patients with cancer treated for venous thromboembolism. Blood 2017; 130: 4631.
34. McBane RD et al. presented at ACC 2016, abstract 1243M-05. DOI: 10.7899/JCE-13-14
35. Khorana AA et al. presented at ASH 2017, abstract 4631.
36. Ageno W, Mantovany LG, Haas S et al. Subgroup analysis of patients with cancer in XALIA: a noninterventional study of rivaroxaban versus standard anticoagulation for VTE. TH Open 2017; 1 (1e): e33–e42. https://doi.org/.10.1055/s-0037-1603924
37. Young AM, Marshall A, Thirlwall J et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SEL ECT-D). J Clin Oncol 2018; 36 (20): 2017–23. DOI: 10.1200/JCO.2018.78.8034
38. Khorana AA, Noble S, Lee AY et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance fr om the SSC of the ISTH. J Thromb Haemost 2018; 16: 1891–4. DOI: 10.1111/jth.14219
39. Streiff MB, Holmstron B, Angelini D et al. NCCN Guidelines Insights. Cancer-associated venous thromboembolic disease, version 2.2018. Featured updates to the NCCN Guidelines. J. of the National Comprehensive cancer network. 2018; 16(11): 1289–303. DOI: 10.6004/jnccn.2018.0084
________________________________________________
1. Agnelli G, Verso M. Management of venous thromboembolism in patients with cancer. J Thromb Haemost 2011; 9 (Suppl. 1): 316–24. DOI: 10.1111/j.1538-7836.2011.04346.x
2. Barsam SJ, Patel R, Arya. Anticoagulation for prevention and treatment of cancer-related venous thromboembolism. Br J Haematol 2013; 161 (Iss. 6): 764–77. DOI: 10.1111/bjh.12314
3. Wun T, White RH. Epidemiology of cancer-related venous thromboembolism. Best Pract Res Clin Haemotol 2009; 22 (1): 9–23. DOI: 0.1016/j.beha.2008.12.001
4. Shaib W, Deng Y, Zilterman D et al. Assessing risk and mortality of venous thromboembolism in pancreatic cancer patients. Anticancer Res 2010; 30 (10): 4261–4.
5. Kakkar AK, Haas S, Walsh D et al. Prevention of perioperative venous thromboembolism: outcome after cancer and non-cancer surgery (abstract). Thromb Haemost 2001; 86 (Suppl.): 0c1732. DOI: 10.5144/0256-4947.2015.95
6. Ogren M, Bergqvist D, Wahlander K et al. Trousseaus syndrome – what is the evidence? A population – based autopsy study. Thromb Haemost 2006; 95: 541–5. DOI: 10.1160/TH05-10-0694
7. Liebman HA. Cancer prognosis in patients with venous thromboembolism (VTE) and patients with clinical and laboratory biomarkers predictive of VTE risk. Thromb Res; 2018; 164 (Suppl. 1): S19–22. DOI: 10.1016/j.thromres.2018.01.040.
8. Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343: 1846–50. DOI: 10.1056/NEJM200012213432504
9. Robin P, Carrier M. Revisiting occult cancer screening in patients with unprovoked venous thromboembolism. Thromb Res 2018; 164 (Suppl. 1); S7-S11. DOI: 10.1016/j.thromres.2017.12.024
10. Magnus N, D’Asti E, Meehan B et al. Oncogenes and the coagulation system – forses that modulate dormant and aggressive states in cancer. Thromb Res 2014; 133 (Suppl. 2): S1–S9. https://doi.org/ 10.1016/S0049-3848(14)50001-1
11. Falanga A, Marchetti M. Hemostatic biomarkers in cancer progression. Thromb Res 2018; 164 (Suppl. 1): S54–S61. DOI: 10.1016/j.thromres.2018.01.017
12. Cedervall J, Hamidi A, Olsson A-K. Platelets, NETs and cancer. Thromb Res 2018; 164 (Suppl. 1): S48-S52. DOI: 10.1016/j.thromres.2018.01.049
13. Nazari PMS, Riedy J, Pabinger I, Cihan Ay. The role of pododlanin in cancer-associated thrombosis. Thromb Res 2018; 164 (Suppl. 1): S34–S39. DOI: 10.1016/j.thromres.2018.01.020
14. Ten CH, Falanga A. Overview of the postulated mechanisms linking cancer and thrombosis. Pathophysiol Haemost Thromb 2007; 36: 122–30. DOI: 10.1159/000175150
15. Agnelii G, Verso M. Thromboprophylaxis during chemotherapy in patients with advanced cancer. Thromb Res 2010; 125 (Suppl. 2): S17–S20. DOI: 10.1016/S0049-3848(10)70007-4
16. Somonova O.V. Diagnostika narushenii gemostaza i printsipy ikh korrektsii pri tromboticheskikh oslozhneniiakh v onkologii. Dis. … d-ra med. nauk. Moscow, 2008 (in Russian).
17. Rossiiskie klinicheskie rekomendatsii po diagnostike, lecheniiu i profilaktike venoznykh tromboembolicheskikh oslozhnenii (VTEO). Flebologiia. 2015; 9 (4; Vyp. 2): 2–52 (in Russian).
18. Franchini M, Bonfanti C, Lippi G. Cancer-associated thrombosis: investigating the role of new oral anticoagulants. Thromb Res 2015; 135 (5): 777–81. DOI: 10.1016/j.thromres.2015.02.024
19. Mandala M, Tondini C. Adjuvant therapy in breast cancer and venous thromboembolism. Thromb Res 2012; 130: S66-S70. DOI: 10.1634/theoncologist.2012-0261
20. Levine MN. Prevention of thrombotic disorders in cancer patients undergoing chemotherapy. Thromb Haemost 1997; 78: 133–6.
21. Goodnough L, Saito A, Manni A. Increased incidence of thromboembolism in stage IV breast cancer patients treated with five-drug chemotherapy regimen: a study of 150 patients. Cancer 1984; 78: 133–6. DOI: 10.4061/2011/394740
22. Otten HM, Mathijssen J, Ten CH et al. Symptomatic venous thromboembolism in cancer patients treated with chemotherapy: an underestimated phenomenon. Arch Inter Med 2004; 164: P190–4. DOI: 10.1001/archinte.164.2.190
23. Kearon C, Akl EA, Ornelas J et al. Antithrombotic therapy for VTE disease. Chest 2016; 149 (2): 315–52. DOI: 10.1016/j.chest.2 015.11.026
24. Watson HG, Keeling DM, Laffan M et al. On behalf of British Committee for Standarts in Haemotology. Guideline on aspects of cancer-related venous thrombosis. Br J Haematol 2015; 170 (Issue 5): 640–8. DOI: 10.1111/bjh.13556
25. Lee AY, Levine MN, Baker MD 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: 146–53. DOI: 10.1056/NEJMoa025313
26. Piran S, Schulman S. Management of recurrent venous thromboembolism in patients with cancer: a review. Thromb Res 2018; 164 (Suppl. 1): S172–S177. DOI: 10.1016/j.thromres.2017.12.019
27. Khorana AA, Yannicelli D, McGrae KR et al. Evaluation of US prescription patterns: are treatment guidelines for cancer-associated venous thromboembolism being followed? Thromb Res 2016; 14: 51–3. DOI: 10.1016/j.thromres.2016.07.013
28. Weitz J еt al. Clinical characteristics and initial treatment of patients with CAT. Results from Garfield VTE registry. Poster PB 460 presented at ISTH 2017.
29. Prints MH, Lensing AW, Bauersachs R et al. Oral rivaroxaban versus standart therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013; 11: 21–31. https://doi.org/ 10.1186/1477-9560-11-21
30. Prints MH, Lensing AWA, Brighton TA et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomized controlled trials. Lancet Haematol 2014; 1: e37–e46. DOI: 10.1016/S2352-3026(14)70018-3
31. Büller HR, Prins MH, Lensin AW et al. Oral Rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287–97. DOI: 0.1056/NEJMoa1113572
32. Van der Hulle T, den Exter PL, Kooiman J et al. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost 2014; 12 (7): 1116–20. DOI: 10.1111/jth.12605
33. Khorana AA, McCrae K, MilentiJevic D et al. VTE recurrence and safety of anticoagulants among patients with cancer treated for venous thromboembolism. Blood 2017; 130: 4631.
34. McBane RD et al. presented at ACC 2016, abstract 1243M-05. DOI: 10.7899/JCE-13-14
35. Khorana AA et al. presented at ASH 2017, abstract 4631.
36. Ageno W, Mantovany LG, Haas S et al. Subgroup analysis of patients with cancer in XALIA: a noninterventional study of rivaroxaban versus standard anticoagulation for VTE. TH Open 2017; 1 (1e): e33–e42. https://doi.org/.10.1055/s-0037-1603924
37. Young AM, Marshall A, Thirlwall J et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SEL ECT-D). J Clin Oncol 2018; 36 (20): 2017–23. DOI: 10.1200/JCO.2018.78.8034
38. Khorana AA, Noble S, Lee AY et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance fr om the SSC of the ISTH. J Thromb Haemost 2018; 16: 1891–4. DOI: 10.1111/jth.14219
39. Streiff MB, Holmstron B, Angelini D et al. NCCN Guidelines Insights. Cancer-associated venous thromboembolic disease, version 2.2018. Featured updates to the NCCN Guidelines. J. of the National Comprehensive cancer network. 2018; 16(11): 1289–303. DOI: 10.6004/jnccn.2018.0084
ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н.Блохина» Минздрава России. 115478, Россия, Москва, Каширское ш., д. 24
*somonova@mail.ru
________________________________________________
Oksana V. Somonova*, Anna L. Elizarova, Valentina N. Blindar, Marina B. Dobrovolskaya, Yulia A. Nesterova, Natalia N. Borisenko, Ustin A. Kornyushenko, Tatiana V. Davidova
N.N.Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation. 24, Kashirskoe sh., Moscow, 115478, Russian Federation
*somonova@mail.ru