Venous Thromboembolism in Women with Cancer with an Additional Focus on Breast and Gynecological Cancers

Abstract

Cancer-associated venous thromboembolism (VTE) is common in women with cancer. Many clinical practice guidelines provide guidance for prevention and treatment; however, there are no specific recommendations for women. This is unfortunate because the proportion of women with breast- and gynecological cancers is high among patients with cancer-associated VTE. Thromboembolism often heralds cancer progression and poor prognosis and should—besides adequate anticoagulant management—also prompt reassessment and, if necessary, changes in cancer treatment. Recently, the new class of direct-acting oral anticoagulants (DOACs) has started to replace low-molecular-weight heparin as standard thromboprophylaxis and therapy in cancer patients. They are very effective, but they also carry a relevant risk of bleeding. Therefore, despite their ease of use, not every tumor patient qualifies for a DOAC, and this is especially true for gynecological tumor patients. Each prescription must be weighed individually. This review addresses specific aspects of VTE prophylaxis and management in women with cancer. Every physician who treats breast and gynecological cancers should be familiar with prophylaxis, diagnosis, and therapy of cancer-associated VTE. At the same time, patients should be informed by their physician what symptoms to look for and whom to contact if these symptoms occur, even outside of office hours and on weekends.

Keywords

women with cancer - venous thromboembolism - cancer-associated venous thromboembolism

Publikationsverlauf

Eingereicht: 30. Januar 2022

Angenommen: 14. Juli 2022

Artikel online veröffentlicht:
02. November 2022

• References

• 1 Weir HK, Anderson RN, Coleman King SM. et al. Heart disease and cancer deaths - trends and projections in the United States, 1969-2020. Prev Chronic Dis 2016; 13: E157
• 2 Almohammed OA, Lai L, Khanfar NM, Bleidt B, Aljadhey H. Trends of cancer-associated venous thromboembolism (VTE) in the United States (2005-2014). Thromb Res 2019; 182: 110-115
• 3 Mahajan A, Brunson A, Adesina O, Keegan THM, Wun T. The incidence of cancer-associated thrombosis is increasing over time. Blood Adv 2022; 6 (01) 307-320
• 4 Mulder FI, Horváth-Puhó E, van Es N. et al. Venous thromboembolism in cancer patients: a population-based cohort study. Blood 2021; 137 (14) 1959-1969
• 5 Fuentes HE, Tafur AJ, Caprini JA. et al; RIETE Investigators. Prediction of early mortality in patients with cancer-associated thrombosis in the RIETE database. Int Angiol 2019; 38 (03) 173-184
• 6 Khorana AA, Kuderer NM, McCrae K. et al. Cancer associated thrombosis and mortality in patients with cancer stratified by Khorana score risk levels. Cancer Med 2020; 9 (21) 8062-8073
• 7 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 (03) 632-634
• 8 Farge D, Bounameaux H, Bauersachs RM, Brenner B. Women, thrombosis, and cancer: a gender-specific analysis. Thromb Res 2017; 151 (Suppl. 01) S21-S29
• 9 Hunter R, Noble S, Lewis S, Bennett P. Long-term psychosocial impact of venous thromboembolism: a qualitative study in the community. BMJ Open 2019; 9 (02) e024805
• 10 National Cancer Institute. Common terminology criteria for adverse events (CTCAE). Accessed January 23, 2022, at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm
• 11 Farge D, Frere C, Connors JM. et al; International Initiative on Thrombosis and Cancer (ITAC) advisory panel. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2019; 20 (10) e566-e581
• 12 Lyman GH, Carrier M, Ay C. et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv 2021; 5 (04) 927-974
• 13 Key NS, Khorana AA, Kuderer NM. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2020; 38 (05) 496-520
• 14 NCCN Clinical Practice Guidelines in Oncology. Cancer-associated venous thromboembolic disease. Version 1.2022–March 11, 2022. Accessed May 12, 2022, at: www.nccn.org
• 15 Riess H, Angelillo-Scherrer A, Alt-Epping B, Langer F, Wörmann B, Pabinger-Fasching I. Thromboembolien bei Tumorpatienten (früher: Venöse Thromboembolien (VTE) bei Tumorpatienten). Stand November 2020. Accessed January 15, 2022, at: www.onkopedia.com
• 16 Kirschner M, do Ó Hartmann N, Parmentier S. et al. Primary thromboprophylaxis in patients with malignancies: daily practice recommendations by the Hemostasis Working Party of the German Society of Hematology and Medical Oncology (DGHO), the Society of Thrombosis and Hemostasis Research (GTH), and the Austrian Society of Hematology and Oncology (ÖGHO). Cancers (Basel) 2021; 13 (12) 2905
• 17 Robert Koch-Institut (Hrsg) und die Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (Hrsg). Krebs in Deutschland für 2017/2018. 13. Ausgabe. Berlin; 2021
• 18 Weitz JI, Haas S, Ageno W. et al; GARFIELD-VTE investigators. Cancer associated thrombosis in everyday practice: perspectives from GARFIELD-VTE. J Thromb Thrombolysis 2020; 50 (02) 267-277
• 19 Giustozzi M, Curcio A, Weijs B. et al. Variation in the association between antineoplastic therapies and venous thromboembolism in patients with active cancer. Thromb Haemost 2020; 120 (05) 847-856
• 20 Agnelli G, Gussoni G, Bianchini C. et al; PROTECHT Investigators. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 2009; 10 (10) 943-949
• 21 Agnelli G, George DJ, Kakkar AK. et al; SAVE-ONCO Investigators. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 2012; 366 (07) 601-609
• 22 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) 4902-4907
• 23 Carrier M, Abou-Nassar K, Mallick R. et al; AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med 2019; 380 (08) 711-719
• 24 Khorana AA, Soff GA, Kakkar AK. et al; CASSINI Investigators. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med 2019; 380 (08) 720-728
• 25 Gerotziafas GT, Mahé I, Lefkou E. et al. Overview of risk assessment models for venous thromboembolism in ambulatory patients with cancer. Thromb Res 2020; 191 (Suppl. 01) S50-S57
• 26 Guntupalli SR, Brennecke A, Behbakht K. et al. Safety and efficacy of apixaban vs enoxaparin for preventing postoperative venous thromboembolism in women undergoing surgery for gynecologic malignant neoplasm: a randomized clinical trial. JAMA Netw Open 2020; 3 (06) e207410
• 27 Peterson EA, Lee AYY. Update from the clinic: what's new in the diagnosis of cancer-associated thrombosis?. Hematology (Am Soc Hematol Educ Program) 2019; 2019 (01) 167-174
• 28 Qdaisat A, Soud RA, Wu CC. et al. Poor performance of D-dimer in excluding venous thromboembolism among patients with lymphoma and leukemia. Haematologica 2019; 104 (06) e265-e268
• 29 Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J. ONCENOX Investigators. 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 (04) 389-396
• 30 Hull RD, Pineo GF, Brant RF. et al; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006; 119 (12) 1062-1072
• 31 Lee AY, Levine MN, Baker RI. et al; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349 (02) 146-153
• 32 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 (15) 1729-1735
• 33 Lee AYY, Kamphuisen PW, Meyer G. et al; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA 2015; 314 (07) 677-686
• 34 Kamphuisen PW, Lee AYY, Meyer G. et al; CATCH Investigators. Clinically relevant bleeding in cancer patients treated for venous thromboembolism from the CATCH study. J Thromb Haemost 2018; 16 (06) 1069-1077
• 35 Raskob GE, van Es N, Verhamme P. et al; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378 (07) 615-624
• 36 Kraaijpoel N, Di Nisio M, Mulder FI. et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: results from the Hokusai VTE Cancer Study. Thromb Haemost 2018; 118 (08) 1439-1449
• 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 (SELECT-D). J Clin Oncol 2018; 36 (20) 2017-2023
• 38 Agnelli G, Becattini C, Meyer G. et al; Caravaggio Investigators. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020; 382 (17) 1599-1607
• 39 McBane Ii R, Loprinzi CL, Ashrani A. et al. Apixaban and dalteparin in active malignancy associated venous thromboembolism. The ADAM VTE trial. Thromb Haemost 2017; 117 (10) 1952-1961
• 40 Langer F, Matthes B, Matzdorff A. Vorschlag eines Diagnose- und Therapiealgorithmus für Patienten mit tumorassoziierten Thromboembolien (CAT-Algorithmus). Vasa 2019; 48 (Suppl. 101) 39
• 41 Beyer-Westendorf J, Klamroth R, Kreher S, Langer F, Matzdorff A, Riess H. Non-vitamin K antagonist oral anticoagulants (NOAC) as an alternative treatment option in tumor-related venous thromboembolism. Dtsch Arztebl Int 2019; 116 (03) 31-38
• 42 Johnstone C, Rich SE. Bleeding in cancer patients and its treatment: a review. Ann Palliat Med 2018; 7 (02) 265-273
• 43 Carrier M, Khorana AA, Zwicker J, Noble S, Lee AY. Subcommittee on Haemostasis and Malignancy for the SSC of the ISTH. Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH. J Thromb Haemost 2013; 11 (09) 1760-1765
• 44 Kelkar AH, Rajasekhar A. Inferior vena cava filters: a framework for evidence-based use. Hematology (Am Soc Hematol Educ Program) 2020; 2020 (01) 619-628
• 45 Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 122 (10) 1712-1723
• 46 Walker AJ, West J, Card TR, Crooks C, Kirwan CC, Grainge MJ. When are breast cancer patients at highest risk of venous thromboembolism? A cohort study using English health care data. Blood 2016; 127 (07) 849-857 , quiz 953
• 47 Cuzick J, Sestak I, Bonanni B. et al; SERM Chemoprevention of Breast Cancer Overview Group. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet 2013; 381 (9880): 1827-1834
• 48 Garber JE, Halabi S, Tolaney SM. et al; Cancer and Leukemia Group B. Factor V Leiden mutation and thromboembolism risk in women receiving adjuvant tamoxifen for breast cancer. J Natl Cancer Inst 2010; 102 (13) 942-949
• 49 Abramson N, Costantino JP, Garber JE, Berliner N, Wickerham DL, Wolmark N. Effect of factor V Leiden and prothrombin G20210–>a mutations on thromboembolic risk in the national surgical adjuvant breast and bowel project breast cancer prevention trial. J Natl Cancer Inst 2006; 98 (13) 904-910
• 50 Saha P, Regan MM, Pagani O. et al; SOFT; TEXT Investigators; International Breast Cancer Study Group. Treatment efficacy, adherence, and quality of life among women younger than 35 years in the international breast cancer study group TEXT and SOFT adjuvant endocrine therapy trials. J Clin Oncol 2017; 35 (27) 3113-3122
• 51 Gervaso L, Montero AJ, Jia X, Khorana AA. Venous thromboembolism in breast cancer patients receiving cyclin-dependent kinase inhibitors. J Thromb Haemost 2020; 18 (01) 162-168
• 52 Weeks KS, Herbach E, McDonald M, Charlton M, Schweizer ML. Meta-analysis of VTE risk: ovarian cancer patients by stage, histology, cytoreduction, and ascites at diagnosis. Obstet Gynecol Int 2020; 2020: 2374716
• 53 Ebina Y, Uchiyama M, Imafuku H, Suzuki K, Miyahara Y, Yamada H. Risk factors for deep venous thrombosis in women with ovarian cancer. Medicine (Baltimore) 2018; 97 (23) e11009
• 54 Wright JD, Chen L, Jorge S. et al. Prescription of extended-duration thromboprophylaxis after high-risk, abdominopelvic cancer surgery. Gynecol Oncol 2016; 141 (03) 531-537
• 55 Kandemir EA, Bayraktar-Ekincioglu A, Kilickap S. Assessment of adherence to cancer-associated venous thromboembolism guideline and pharmacist's impact on anticoagulant therapy. Support Care Cancer 2021; 29 (03) 1699-1709
• 56 Kim ES, Baran AM, Mondo EL. et al. Risk of thromboembolism in cisplatin versus carboplatin-treated patients with lung cancer. PLoS One 2017; 12 (12) e0189410
• 57 Grover SP, Hisada YM, Kasthuri RS, Reeves BN, Mackman N. Cancer therapy-associated thrombosis. Arterioscler Thromb Vasc Biol 2021; 41 (04) 1291-1305
• 58 Saerens M, De Jaeghere EA, Kanervo H, Vandemaele N, Denys H, Naert E. Risk of thrombo-embolic events in ovarian cancer: does bevacizumab tilt the scale? A systematic review and meta-analysis. Cancers (Basel) 2021; 13 (18) 4603
• 59 Schiffer CA, Mangu PB, Wade JC. et al. Central venous catheter care for the patient with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2013; 31 (10) 1357-1370
• 60 Winters JP, Callas PW, Cushman M, Repp AB, Zakai NA. Central venous catheters and upper extremity deep vein thrombosis in medical inpatients: the Medical Inpatients and Thrombosis (MITH) Study. J Thromb Haemost 2015; 13 (12) 2155-2160
• 61 Debourdeau P, Farge D, Beckers M. et al. International clinical practice guidelines for the treatment and prophylaxis of thrombosis associated with central venous catheters in patients with cancer. J Thromb Haemost 2013; 11 (01) 71-80
• 62 Kahale LA, Tsolakian IG, Hakoum MB. et al. Anticoagulation for people with cancer and central venous catheters. Cochrane Database Syst Rev 2018; 6 (06) CD006468
• 63 Li A, Brandt W, Brown C. et al. Efficacy and safety of primary thromboprophylaxis for the prevention of venous thromboembolism in patients with cancer and a central venous catheter: a systematic review and meta-analysis. Thromb Res 2021; 208: 58-65
• 64 Ikesaka R, Siegal D, Mallick R. et al; Canadian Venous Thromboembolism Research Network (CanVECTOR). Thromboprophylaxis with rivaroxaban in patients with malignancy and central venous lines (TRIM-Line): a two-center open-label pilot randomized controlled trial. Res Pract Thromb Haemost 2021; 5 (04) e12517
• 65 Bradford NK, Edwards RM, Chan RJ. Heparin versus 0.9% sodium chloride intermittent flushing for the prevention of occlusion in long term central venous catheters in infants and children. Cochrane Database Syst Rev 2015; Nov 23 (11) CD010996
• 66 López-Briz E, Ruiz Garcia V, Cabello JB, Bort-Martí S, Carbonell Sanchis R, Burls A. Heparin versus 0.9% sodium chloride locking for prevention of occlusion in central venous catheters in adults. Cochrane Database Syst Rev 2018; 7 (07) CD008462
• 67 Davies GA, Lazo-Langner A, Gandara E. et al. A prospective study of rivaroxaban for central venous catheter associated upper extremity deep vein thrombosis in cancer patients (Catheter 2). Thromb Res 2018; 162: 88-92
• 68 Grandone E, Di Micco PP, Villani M. et al; RIETE Investigators. Venous thromboembolism in women undergoing assisted reproductive technologies: data from the RIETE Registry. Thromb Haemost 2018; 118 (11) 1962-1968
• 69 Villani M, Favuzzi G, Totaro P. et al. Venous thromboembolism in assisted reproductive technologies: comparison between unsuccessful versus successful cycles in an Italian cohort. J Thromb Thrombolysis 2018; 45 (02) 234-239
• 70 Somigliana E, Peccatori FA, Filippi F, Martinelli F, Raspagliesi F, Martinelli I. Risk of thrombosis in women with malignancies undergoing ovarian stimulation for fertility preservation. Hum Reprod Update 2014; 20 (06) 944-951
• 71 Bates SM. Anticoagulation and in vitro fertilization and ovarian stimulation. Hematology (Am Soc Hematol Educ Program) 2014; 2014 (01) 379-386
• 72 Mancuso A, De Vivo A, Fanara G, Di Leo R, Toscano A. Upper body venous thrombosis associated with ovarian stimulation: case report and review of the literature. Clin Exp Obstet Gynecol 2005; 32 (03) 149-154
• 73 Jacobson-Kelly AE, Samuelson Bannow BT. Abnormal uterine bleeding in users of rivaroxaban and apixaban. Hematology (Am Soc Hematol Educ Program) 2020; 2020 (01) 538-541
• 74 Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (11) 2119-2126
• 75 Boonyawat K, O'Brien SH, Bates SM. How I treat heavy menstrual bleeding associated with anticoagulants. Blood 2017; 130 (24) 2603-2609
• 76 Lee AYY. When can we stop anticoagulation in patients with cancer-associated thrombosis?. Hematology (Am Soc Hematol Educ Program) 2017; 2017 (01) 128-135
• 77 Klok FA, Schreiber K, Stach K. et al. Oral contraception and menstrual bleeding during treatment of venous thromboembolism: Expert opinion versus current practice: combined results of a systematic review, expert panel opinion and an international survey. Thromb Res 2017; 153: 101-107
• 78 Godin R, Roy G, Douketis J. An opinion on the benefits of concomitant oral contraceptive therapy in premenopausal women treated with oral anticoagulants. Thromb Res 2018; 165: 14-17
• 79 Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften V. (AWMF) Leitlinie: Hormonal Contraception. Guideline of the DGGG, SGGG and OEGGG (S3-Level, AWMF Registry No. 015/015, November 2019). Accessed January 15, 2022, at: http://www.awmf.org/leitlinien/detail/II/015-015.html.
• 80 Panahi L, Saenz Ii JA, Nguyen N, Udeani G, Surani S. Hypercoagulation from concomitant administration of tamoxifen and warfarin. Cureus 2020; 12 (05) e8114
• 81 Short NJ, Connors JM. New oral anticoagulants and the cancer patient. Oncologist 2014; 19 (01) 82-93
• 82 Sebuhyan M, Crichi B, Abdallah NA. et al. Drug-drug interaction (DDI) with direct oral anticoagulant (DOAC) in patients with cancer. J Med Vasc 2020;45(6S):S31, S38
• 83 Davis MK, Lim H, Lee AYY. Direct oral anticoagulants in patients with cancer and nonvalvular atrial fibrillation. JACC CardioOncol 2021; 3 (03) 425-427
• 84 Klok FA, Huisman MV. How I assess and manage the risk of bleeding in patients treated for venous thromboembolism. Blood 2020; 135 (10) 724-734
• 85 Kowalewska CA, Noble BN, Fromme EK, McPherson ML, Grace KN, Furuno JP. Prevalence and clinical intentions of antithrombotic therapy on discharge to hospice care. J Palliat Med 2017; 20 (11) 1225-1230
• 86 Huisman BAA, Geijteman ECT, Arevalo JJ. et al. Use of antithrombotics at the end of life: an in-depth chart review study. BMC Palliat Care 2021; 20 (01) 110
• 87 Tardy B, Picard S, Guirimand F. et al. Bleeding risk of terminally ill patients hospitalized in palliative care units: the RHESO study. J Thromb Haemost 2017; 15 (03) 420-428
• 88 Onkologie L. (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Palliativmedizin für Patienten mit einer nicht-heilbaren Krebserkrankung, Langversion 2.2, 2020, AWMF-Registernummer: 128/001OL. Accessed January 15, 2022, at: https://www.leitlinienprogramm-onkologie.de/leitlinien/palliativmedizin/.
• 89 Zabrocka E, Sierko E. Thromboprophylaxis in the end-of-life cancer care: the update. Cancers (Basel) 2020; 12 (03) 600
• 90 Mulder FI, Candeloro M, Kamphuisen PW. et al; CAT-prediction collaborators. The Khorana score for prediction of venous thromboembolism in cancer patients: a systematic review and meta-analysis. Haematologica 2019; 104 (06) 1277-1287
• 91 Al-Samkari H, Connors JM. Managing the competing risks of thrombosis, bleeding, and anticoagulation in patients with malignancy. Blood Adv 2019; 3 (22) 3770-3779
• 92 Constans J, Salmi LR, Sevestre-Pietri MA. et al. A clinical prediction score for upper extremity deep venous thrombosis. Thromb Haemost 2008; 99 (01) 202-207