Venous Thromboembolism in the Cancer Patient

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Cancer patients are at an increased risk of venous thromboembolism. There have been several guidelines published on the topic from the American College of Chest Physicians (ACCP), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN). Although they agree on some issues regarding prophylaxis and treatment there are several areas that vary. This presentation covers the varying recommendations and the areas of consensus (yellow boxes) among the guidelines while using a patient case to guide their interpretation.

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  • PE treated with LMWH transitioned to warfarin – had difficulty maintaining therapeutic INR, completed unclear from patient’s record how long she underwent treatmentAspirin – tight throat
  • VTE is the formation of a clot in the veins and can occur in the deep veins of the leg, this can lead to disruption of blood flow and swelling of the leg -> Can also lead to PE through the formation of an embolus which then travels back to the heart via pulmonary veins. Can have a major impact on morbidity and mortality – if untreated would have 30% mortality rateCan also include superficial venous thrombosis and splanchnic venous thrombosis, but those will not be the focus of the talk today.
  • First to recognize the connection between cancers and clottingSuperficial thrombophlebitis (blood clot under surface of skin) was associated with a diagnosis of abdominal cancer Trousseau’s signLater in life - diagnosed this same sign in himself and subsequently died of pancreatic cancer
  • Health Claims database analysis found that of solid tumor ambulatory patients undergoing chemo 12.6% (8-19% depending on tumor type) had VTE within the 12 months following chemo initiation; 80% of VTE in cancer patients occur in the outpatient setting Non- cancer patients were a gender and age matched population from the health claims database2nd leading cause of death in cancer patients
  • There are many factors that contribute to the pathophysiology of thrombosis in cancer patients. Vessel compression by tumor and increased exposure to surgical procedures are factorsAnother evolving theory is the release of Procoagulants by tumor cells, specifically tissue factorProcoagulants Tissue FactorVessel wall stasisDirect vessel compressionImmobilizationSurgical ProceduresChemotherapy
  • Cancer types at higher risk – metastatic; brain, pancreas, stomach, bladder, gynecologic, lung, lymphoma, myeloproliferative, kidneyChemotherapy – Thalidomide/Lenolidamide, tamoxifene/raloxifene
  • Luckily or unluckily – there are several guidelines which have evaluated studies of thrombosis in CA patients
  • ACCP – Nonsurgical inpatients who are high risk should get prophylaxis and risk is defined by the padua prediction scale. Surgical inpatients may or may not require prophylaxis depending upon what type of surgery they have undergone and what their underlying risks are. Risk is determined by the roger or caprini score which determines the need for pharmacologic agent, then surgical site alters when is should be administered. For example, a patient undergoing craniotomy or spinal surgery should only be pharmacologically prophylaxed if they are high risk and should not be prophylaxed until hemostasis is established.# Surgical patient risk of VTE dependent upon Rogers/Caprini score*High risk VTE patients undergoing abdominal or pelvic surgery for cancer
  • Patients were followed for symptomatic VTE for 90 days – VTE occurred in 11% of high risk patients who did not receive prophylaxis compared to 0.3% of low risk patients. ACCP acknowledges that this score is not ideally validated, but provides the best available basis for analyzing a medical patient’s baseline risk. Note – patients at a low risk of thrombosis should not undergo prophylaxis pharmacologically or mechanically.
  • Roger - Operation type dictates score most, with cancer contributing a few points and other biomarkers and general physical health can also contributeCaprini – History weighted more heavily along with, then comes age and malignancy is included in the risk score as well.Cancer in either of these scoring systems only contributes moderately to the overall risk and would not on it’s own make the patient a high risk patient.
  • 4 weeks post op for high risk patients undergoing abdominal or pelvic surgeries. ACCP – other risk factors for VTE include: previous VTE, immobilization, hormonal therapy, angiogenesis inhibitors, thalidomide, and lenalidomide. Specifically mention that if Cancer is only risk factor:No prophylaxis andCancer plus indwelling CVC: No prophylaxisIn patients with cancer heparin slightly decreased mortality at 2 years, significantly reduced symptomatic VTE, but failed to determine beneficial or detrimental effects on major and minor bleeding or quality of life. Use of warfarin in cancer patients with no other indication for prophylactic anticoagulation had no significant effect on mortality up to 5 years out and increased the risk of major (RR 4.24) and minor (RR 3.34) bleeding while providing a RR reduction of 85% (RR 0.15; 95% CI 0.02-1.2) on VTE. Risk of bleeding outweighed impact on VTE for warfarin. Benefit of prophylaxis in CVC is unclear
  • Thalidomide + Dex without prophy => 26% rate of VTEACCP recommends patients undergoing this therapy receive LMWH or LDUH as opposed to no prophylaxis, but don’t mention this specific risk classification, nor the use of ASA.ASCO recommends ASA or LMWH for low risk patients and LMWH for high risk patients. No mention of warfarin.No prospective randomized trials have been done to validate the use of this recommendation in decreasing the risk of thromboembolism in patients with multiple myeloma. Instead, this risk stratification was constructed through ‘common sense’ on the topic and expert consensus. Evaluated available literature to find “safest and least cumbersome form of thromboprophylaxis that reduces risk of VTE at least below 10%” Although there were some cases where LMWH was not effective according to this definition, the majority of studies showed that both LMWH and full dose warfarin were effective. Authors state these recommendations should not be considered firm guidelines.VTE is most likely to happen within the first 12 months of diagnosis in cancer patients and within the first 6 months for myeloma, may consider limiting prophylaxis duration in the future. No studies exist to evaluate thromboprophylaxis in patients with recurrent disease, although incidence of VTE in lower in recurrence.
  • If provoked DVT patient should be evaluated after 3 months for continued risk/benefit of ongoing therapy
  • Assumed risk = median control group risk across studiesCorresponding risk = based on assumed risk in the VKA group and the relative effect of the interventionNote – No difference in mortality rate or major/minor bleeding was found.
  • PE treated with LMWH transitioned to warfarin – had difficulty maintaining therapeutic INR, completed unclear from patient’s record how long she underwent treatmentAspirin – tight throat
  • Venous Thromboembolism in the Cancer Patient

    1. 1. Venous Thromboembolism in the Cancer Patient Marti Larriva PharmD Candidate 2014 December 5, 2013
    2. 2. Outline  Goals  Patient Case  Background  Guidelines  Conclusion of Patient Case
    3. 3. Goals  Understand risk of VTE associated with cancer  Take away where the consensus lies among guidelines  Identify gray areas regarding prophylaxis and treatment of VTE in cancer patients
    4. 4. Patient Case  Ms. M is a 43 y/o female with cervical cancer diagnosed 2 years ago  Undergone 4 lines of chemotherapy with progressive disease and painful lymphadenopathy  TIL harvest surgery – L groin mass 2 months ago  Admitted for TIL therapy:  Chemo -> T-cells -> IL-2 -> Supportive Care  PMH: Diabetes, HTN, PE (1 year ago)  Allergies: Aspirin Relevant Labs BMI 47.5 kg/m2 WBC 5.29 x 109/L Hgb 10.3 g/dL Platelets 306 x 109/L
    5. 5. Background VTE Cancer population Risk Factors Guidelines
    6. 6. Venous Thromboembolism
    7. 7. Armand Trousseau, 1860 Trousseau’s sign of malignancy
    8. 8. What is the difference? Cancer Patients Non-Cancer Patients Ambulatory Ambulatory 8-19% 1.4%
    9. 9. Pathophysiology
    10. 10. Patient Related • Increased Age • Obesity • Co-morbidities • Performance Status Treatment Related • Chemotherapy, antiangiogenesis agents, hormonal therapy • Radiation therapy • Surgery • Indwelling venous access Risk Factors Cancer Related • Primary Site • Stage • Histology • Time since diagnosis Biomarkers • Platelets > 350 x 109/L • Leukocyte count > 11x 109/L • Hgb < 10 g/dL
    11. 11. Treatment Options Heparin, LMWH, Fondapari nux Warfarin
    12. 12. Guidelines ACCP 2012, ASCO 2013, NCCN 2013
    13. 13. Inpatient VTE Prophylaxis ACCP ASCO NCCN *Note: These recommendations are all in the absence of contraindications to anticoagulation.
    14. 14. Nonsurgical VTE Risk Padua Prediction Score Risk Factor Points Active Cancer 3 Previous VTE (excluding SVT) 3 Reduced mobility* 2 Already known thrombophilic condition 1 Recent (≤ 1 mo.) trauma/surgery 1 Elderly age (≥ 70y) 1 Heart and/or respiratory failure 1 Acute MI or ischemic stroke 1 Obesity (BMI ≥ 30) 1 Ongoing hormonal treatment 1 *Anticipated bed rest with bathroom privileges for at least 3 days
    15. 15. Surgical VTE Risk Roger  Operation type  Thoracic area highest risk  Cancer  Disseminated cancer  Chemo within 30 days Caprini  Recent Stroke (<1 mo.)  History of VTE  Age  Malignancy  BMI
    16. 16. Outpatient VTE Prophylaxis ACCP ASCO NCCN *Note: These recommendations are all in the absence of contraindications to anticoagulation.
    17. 17. Multiple Myeloma Low Risk High Risk Thalidomide or Lenalidomide therapy Thalidomide or Lenalidomide therapy in combination with:  High dose dexamethasone  Doxorubicin  Multiagent chemo PLUS 0-1 risk factor for VTE Thalidomide or Lenalidomide therapy PLUS ≥ 2 risk factors for VTE Aspirin 81-325 mg once daily LMWH OR Full dose warfarin (INR 2-3)
    18. 18. Khorana Score Patient Characteristic Risk Score Site of Primary Cancer  Very High Risk (stomach, pancreas)  High Risk (lung, lymphoma, gynecologic, bladder, testicular) 2 1 Prechemotherapy platelet count ≥ 350 x 109/L 1 Hgb < 10 g/dL 1 Prechemotherapy leukocyte count ≥ 11 x 109/L 1 BMI 35 kg/m2 1 Total Score 0 1-2 3 or higher Risk of Symptomatic VTE Low (0.8-3%) Intermediate (1.8-8.4%) High (7.1-41%)
    19. 19. DVT/PE ACCP ASCO NCCN *Note: These recommendations are all in the absence of contraindications to anticoagulation.
    20. 20. Cochrane Collaboration: LMWH vs. Warfarin Analysis 1.6. Comparison 1 LMW H versus VKA, O utcome 6 Recurrent venous thromboembolism. Review: Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer Comparison: 1 LMWH versus VKA Outcome: 6 Recurrent venous thromboembolism S tudy or subgroup LMWH VKA n/N n/N 4/61 3/30 6.2 % 0.66 [ 0.16, 2.74 ] Hull 2006 7/100 16/100 17.8 % 0.44 [ 0.19, 1.02 ] Lee 2003 27/336 53/336 66.2 % 0.51 [ 0.33, 0.79 ] Meyer 2002 2/71 3/75 4.1 % 0.70 [ 0.12, 4.09 ] Romera 2009 2/36 7/33 5.7 % 0.26 [ 0.06, 1.17 ] Total (95% CI) 604 574 100.0 % 0.49 [ 0.34, 0.70 ] Deitcher 2006 Risk Ratio MH,Random,95% CI Weight Total events: 42 (LMWH), 82 (VKA) Heterogeneity: Tau2 = 0.0; Chi2 = 1.09, df = 4 (P = 0.90); I2 =0.0% Test for overall effect: Z = 3.91 (P = 0.000094) Test for subgroup differences: Not applicable 0.1 0.2 0.5 Favours LMW H 1 2 5 Favours VKA 10 Risk Ratio MH,Random,95% CI
    21. 21. Conclusions Consensus summary Gray areas Future Research
    22. 22. Consensus Summary  Inpatient prophylaxis should consist of prophylactic doses of LMWH, UFH, or Fondaparinux  Outpatient prophylaxis should be done:  In multiple myeloma patients undergoing therapy with thalidomide or lenalidomide  As an extension of inpatient surgical prophylaxis for high risk abdominal or pelvic surgeries  Treatment of DVT/PE should be done using LMWH rather than Warfarin
    23. 23. Gray Areas  Who should receive prophylaxis as an inpatient?  Should outpatients at high risk for VTE receive prophylaxis based upon the Khorana score?  What is the appropriate length of therapy for VTE/PE in the cancer patient?  What factors impact extension of therapy beyond 36 months?
    24. 24. Future Directions for Research  Determine which cancer patients benefit most from thromboprophylaxis:  Risk stratification tools  Specific cancer types  Identify better biomarkers  Determine ideal duration of anticoagulation:  Prophylaxis - Risk related to time from diagnosis  Treatment - Need for extended therapy
    25. 25. Patient Case  Ms. M is a 43 y/o female with cervical cancer diagnosed 2 years ago  Undergone 4 lines of chemotherapy with progressive disease and painful lymphadenopathy  TIL harvest surgery – L groin mass 2 months ago  Admitted for TIL therapy:  Chemo -> T-cells -> IL-2 -> Supportive Care  PMH: Diabetes, HTN, PE (1 year ago)  Allergies: Aspirin Relevant Labs BMI 47.5 kg/m2 WBC 5.29 x 109/L Hgb 10.3 g/dL Platelets 306 x 109/L
    26. 26. Patient Case  Ms. M has a Padua score of 7 indicating she is at high risk for VTE  According to ACCP and NCCN she should receive prophylaxis as an inpatient:  Enoxaparin 40mg SQ Qday  UFH 5,000 units SQ Q8H  Fondaparinux 2.5 mg SQ Qday  Upon discharge, should she continue prophylaxis?  Intermediate Khorana Risk
    27. 27. References 1. Akl EA, Labedi N, Barba M et al. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2011;(6):CD006650. doi(6):CD006650. 2. Gould MK, Garcia DA, Wren SM et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e227S-77S. 3. Kahn SR, Lim W, Dunn AS et al. Prevention of VTE in nonsurgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e195S-226S. 4. Khorana AA. Cancer-associated thrombosis: Updates and controversies. Hematology Am Soc Hematol Educ Program. 2012;2012:626-30. 5. Lyman GH, Khorana AA, Kuderer NM et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American society of clinical oncology clinical practice guideline update. J Clin Oncol. 2013;31(17):2189-204. 6. Palumbo A, Rajkumar SV, Dimopoulos MA et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414-23. 7. Semchuk WM, Sperlich C. Prevention and treatment of venous thromboembolism in patients with cancer. Can Pharm J (Ott). 2012;145(1):24,29.e1. 8. Streiff MB, Bockenstedt PL, Cataland SR et al. Venous thromboembolic disease. J Natl Compr Canc Netw. 2013;11(11):1402-29.
    28. 28. Questions?

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