Cancer Associated Thrombosis

Cancer Associated Thrombosis Pantep Angchaisuksiri, MD Professor of Medicine Mahidol University, Thailand Adjunct Associate Professor University of North Carolina, Chapel Hill, USA

Piccioli A. J Thromb Haemostasis 2004;2:885. Prandoni P. NEJM 1992;327:1128. Silverstein et al. Arch Int Med 1998;158:585-93. Blom JW et al. JAMA 2005;293:715. VTE and Cancer: Epidemiology Cancer is an important and common risk factor for VTE Of all cases of VTE: - About 20% occur in cancer patients - Annual incidence of VTE in cancer patients ~ 1 in 250 - Cancer increases risk of VTE by 4- to 6-fold

Piccioli A. J Thromb Haemostasis 2004;2:885. Prandoni P. NEJM 1992;327:1128. Silverstein et al. Arch Int Med 1998;158:585-93. Blom JW et al. JAMA 2005;293:715. VTE and Cancer: Epidemiology Of all cancer patients: - 15% will have symptomatic VTE - As many as 50% have VTE at autopsy Risk is highest in the first few months after the diagnosis of malignancy and in the presence of distant metastases

Risk (Odds Ratio) Risk of VTE Varies Over Natural History of Cancer 8 7 6 5 4 3 2 Hospitalization End of life Chemotherapy Metastasis Diagnosis Remission Risk of VTE in the cancer population 1 0 Time Risk of VTE in the general population Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis;2007.

Regional variation in the proportion of VTE patients with cancer Asia is defined as: China, Hong Kong, Japan, South Korea, Malaysia, Taiwan and Thailand Date of analyses: 24 th April 2017 Unpublished Data

Top 5 most common sites of cancer in VTE patients Rank 1st 2nd 3rd 4th 5th 500 events in 471 men Lung 18.8% Prostate 14.0% Colorectal 13.4% Urological 10.2% Lymphoma 8.8% GARFIELD-VTE registry GLOBOCAN Reference group 526 events in 510 women Gynaecological 21.1% Breast 18.3% Lung 10.8% Lymphoma 9.9% Colorectal 8.4% 1026 events in 981 patients Lung 14.7% Gynaecological 10.8% Colorectal 10.8% Breast 9.6% Lymphoma 9.4% Men Women Overall Lung Breast Breast Prostate Colorect al Colorect al Cervical Prostate Lung Stomach Lung Colorect al Liver Uterus Cervix Unpublished Data http://globocan.iarc.fr/pages/fact_sheets_population.aspx

Piccioli A. J Thromb Haemost 2004;2:885. Prandoni P. NEJM 1992;327:1128. Silverstein et al. Arch Int Med 1998;158:585. Blom JW et al. JAMA 2005;293:715. Clinical Features of VTE in Cancer Compared to patients without cancer: - Higher risk of recurrent VTE (HR 3.2) - Higher risk of bleeding on anticoagulants (HR 2.2) - Higher risk of dying VTE is the second leading cause of death in hospitalized cancer patients

Pathophysiology of VTE in Cancer : Virchow s Triad Endothelial Injury Venous Stasis Tumor invasion Cytokines Chemotherapy Venous catheters Thrombosis Immobilization Tumor compression Changes in viscosity Hypercoagulability Complex interaction between tumor cells and host Virchow R. Gesammelte Abhandlungen zur Wissenschaftlichen Medizin 1856

Risk Factors for VTE in Patients with Cancer Patient-related factors Older age History of VTE Performance status Thrombophilia Comorbidities Cancer-related factors Advanced stage Initial period after diagnosis Site of cancer Histology Treatment-related factors Recent major surgery Hospitalization Chemotherapy Hormonal therapy Anti-angiogenic agents ESAs, Transfusions Biomarkers Platelet & leukocyte counts, Hb D-dimers, CRP, factor VIII Soluble P-selectin Tissue factor, microparticles Tagalakis V, et al. Semin Thromb Hemost 2013;39:127-40.

VTE and Cancer: Tumor Type High risk Pancreatic, ovarian, brain, stomach, gynecologic and hematologic Intermediate risk Colon, lung Low risk Breast, prostate Hisada V, et al. Blood 2017;130:1499.

Proposed Pathways of Venous Thrombosis in Different Types of Cancer Tumor type Lung and colorectal Lung Ovarian Pancreatic Brain Proposed primary pathway Leukocytosis Neutrophilia and NETs Thrombocytosis TF + MVs PDPN + MVs NETs = neutrophil extracellular traps; TF = tissue factor; MVs = microvesicles; PDPN = podoplanin Hisada V, et al. Blood 2017;130:1499.

Cancer Type-specific Biomarkers NETs = neutrophil extracellular traps Neutrophilia increases thrombosis in lung cancer Hisada V, et al. Blood 2017;130:1499.

Cancer Type-specific Biomarkers TPO = thrombopoietin Thrombocytosis increases thrombosis in ovarian cancer Hisada V, et al. Blood 2017;130:1499.

Cancer Type-specific Biomarkers Tumor-derived TF+ MVs trigger thrombosis in pancreatic cancer Hisada V, et al. Blood 2017;130:1499.

Cancer Type-specific Biomarkers PDPN = podoplanin Tumor-derived PDPN+ MVs trigger thrombosis in brain cancer Hisada V, et al. Blood 2017;130:1499.

Occult Cancer in Patients with VTE

Cumulative incidence (%) Cumulative Incidence of Cancer in Different Patient Groups 20 18 16 14 12 10 8 6 4 2 0 Recurrent idiopathic thrombosis (n=35) All idiopathic thrombosis (n=145) Secondary thrombosis (n=105) 0 13 26 39 52 65 78 91 104 Weeks 18% 7.6% 1.9% Prandoni et al. N Engl J Med 1992; 327:1128-33.

Period Prevalence of Cancer in First 12 Months of Follow-up Summary period prevalence = 5.2% (95% CI, 4.1% to 6.5%) van Es, et al. Ann Intern Med 2017;167:410-417.

Point Prevalence of Cancer at 12 Months Stratified by Age Cohorts OR 7.1 van Es, et al. Ann Intern Med 2017;167:410-417.

Period Prevalence of Cancer According to Time Points OR 2.0 van Es, et al. Ann Intern Med 2017;167:410-417.

1. Patients with unprovoked VTE should undergo limited cancer screening, including a thorough medical history and physical examination, laboratory investigations (CBC, calcium, urinalysis, and liver function tests), and chest X-ray. 2. Age-specific and gender-specific cancer screening (colon, breast, cervix, and prostate) should also be performed according to national recommendations. 3. In patients with a recurrent unprovoked VTE, a lower threshold for cancer detection may be reasonable. Delluc A et al. J Thromb Haemost 2017;15:1-4.

4. In patients with provoked VTE, routine cancer screening is not recommended. 5. In patients with splanchnic vein thrombosis or cerebral vein thrombosis, JAK2 V617F testing was suggested. 6. In patients with splanchnic vein thrombosis and aplasia or hemolytic anemia, and in patients with Budd Chiari syndrome, PNH testing was suggested. Delluc A et al. J Thromb Haemost 2017;15:1-4.

Cancer Associated Thrombosis: Risk Assessment Although population incidences and identifying general risk factors for VTE are useful, the ability to estimate an individual patient s risk of VTE is more clinically relevant. Identification of patients most at risk for VTE and use of thromboprophylaxis in these patients can potentially improve morbidity, mortality, cancer-related outcomes and decrease use of health care resources.

Risk Assessment Models 1) Khorana Score Predicts chemotherapy-associated VTE using baseline clinical and laboratory variables Data obtained from ambulatory patients initiating a new chemotherapy regimen followed for febrile neutropenia Mainly breast, lung, ovarian, sarcoma, colon, lymphoma Median follow up: 73 days Khorana AA, et al. Blood 2008;111:4902

Predictive Model for Chemotherapy-associated VTE Patient characteristic Site of cancer Risk score Very high risk (stomach, pancreas) 2 High risk (lung, lymphoma, gynecologic, 1 bladder, testicular) Prechemotherapy platelet count > 350 x 10 9 /L 1 Hb level < 100 g/l or use of red cell growth factors 1 Prechemotherapy WBC count > 11 x 10 9 /L 1 BMI 35 kg/m 2 or more 1 Khorana AA, et al. Blood 2008;111:4902

Rate of VTE (%) Rates of VTE According to Scores from the Risk Model in the Development and Validation cohorts 8% 7% 6% 5% 4% 3% 2% 1% Venous Thromboembolism.10.08.06.04.02 0.00 0 10 P < 0.001* 20 30 40 *Overall test of significance 50 Time (Days) 100 110 120 0.8% 0.3% 1.8% 2.0% 60 70 80 Intermediate 90 High Low P<.001 P<.001 7.1% 6.7% 0% n=734 n=374 Low (0) n=1627 n=842 Intermediate (1-2) Risk category (score) n=340 n=149 High (>3) Khorana AA, et al. Blood 2008;111:4902

Risk Assessment Models 2) Ay Score (Khorana score + 2 biochemical markers) Predicts VTE risk in ambulatory cancer patients Addition of soluble P-selectin and D-dimer to Khorana model Applied RAM to the Vienna Cancer and Thrombosis Study (CATS) prospective cohort study Followed prospectively for symptomatic VTE over 2 years RAM = risk assessment model Ay et al. Blood 2010;116:5377-82.

Two Different Risk Models for Identification of Cancer Patients at High Risk of VTE + brain + kidney, MM (Ay)

VTE Risk using the Ay Score Cumulative probability of VTE after 6 months: Score 5: 35.0% Score 4: 20.3% Score 3: 10.3% Score 2: 3.5% Score 1: 4.4% Score 0: 1.0% Ay et al. Blood 2010;116:5377-82.

Current Limitations RAMs can identify patients at high or low risk of VTE but thromboprophylaxis trials using these RAMs are needed. It also remains to be elucidated whether RAMs specifically designed for certain cancer types further improve VTE risk assessment. RAMs = risk assessment models

Thromboprophylaxis in Cancer Patients

Rationale for Thromboprophylaxis in Cancer Patients Diagnoses of DVT and PE are often more difficult The treatment of overt VTE is less successful and is associated with more bleeding complications Cancer is an independent risk factor for development of postoperative DVT

VTE Prevention in Cancer Patients Use of thromboprophylaxis in cancer patients can be considered in 3 settings: 1) Ambulatory cancer patients (outpatients) +/- chemotherapy 2) Cancer patients admitted to hospital with acute illness 3) Cancer patients undergoing surgery

Prophylaxis in Ambulatory Cancer Patients Receiving Chemotherapy Primary thromboprophylaxis in ambulatory cancer patients reduces VTE effectively with a RR reduction of up to 60%. However, the absolute risk reduction is low due to the low VTE incidence in placebo groups.

Prophylaxis in Medical Patients Outpatient (Evidence: moderate) 1) Routine pharmacologic thromboprophylaxis is not recommended in cancer outpatients. 2) Based on limited RCT data, clinicians may consider LMWH prophylaxis on a case-by-case basis in highly selected outpatients with solid tumors receiving chemotherapy. ASCO Guideline 2014

Prophylaxis in Medical Patients Outpatient (Evidence: moderate) 3) Patients with multiple myeloma receiving thalidomide or lenalidomide-based regimens with chemotherapy and/or dexamethasone should receive pharmacologic thromboprophylaxis with either aspirin or LMWH for low-risk and LMWH for high-risk patients. ASCO Guideline 2014

Prophylaxis in Medical Patients Inpatient (Evidence: strong) 1) Hospitalized patients who have active malignancy with acute medical illness or reduced mobility should receive pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications. ASCO Guideline 2014

Prophylaxis in Medical Patients Inpatient (Evidence: moderate) 2) Hospitalized patients who have active malignancy without additional risk factors may be considered for pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications. ASCO Guideline 2014

Prophylaxis in Surgical Patients (1) All patients with malignant disease undergoing major surgical intervention should be considered for pharmacologic thromboprophylaxis with either UFH or LMWH unless contraindicated because of active bleeding or a high risk of bleeding. (2) Prophylaxis should be commenced preoperatively. (Evidence: moderate) (Evidence: strong) ASCO Guideline 2014

Prophylaxis in Surgical Patients (3) Mechanical methods may be added to pharmacologic thromboprophylaxis, but should not be used as monotherapy for VTE prevention unless pharmacologic methods are contraindicated. (4) A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy, especially in the highest-risk patients. (Evidence: moderate) (Evidence: moderate) ASCO Guideline 2014

Prophylaxis in Surgical Patients (5) Pharmacologic thromboprophylaxis should be continued for at least 7-10 days in all patients. Extended prophylaxis with LMWH for up to 4 weeks postoperatively should be considered for patients undergoing major abdominal or pelvic surgery for cancer who have high-risk features. (Evidence: strong) ASCO Guideline 2014

Treatment of VTE in Cancer Patients

Treatment Challenges in Cancer Patients with VTE VTE treatment complicated by chemotherapy Anticoagulant management during invasive diagnostic and treatment procedures Individualization of anticoagulant treatment duration based on: Clinical status and stage of the cancer Risk of recurrent VTE and bleeding Patient s preference

Treatment of VTE - Initial LWMH is as effective as UFH for initial therapy in cancer patients. LMWH was associated with a statistical reduction in mortality at 3 months follow-up when compared with UFH (RR, 0.71; 95% CI, 0.52-0.98). Akl EA, et al. Cochrane Database Syst Rev 2011;6(6):CD006649.

Long-term Anticoagulant Therapy Problems with warfarin Narrow therapeutic window Drug interaction Delayed onset and clearance of action Frequent blood sampling

Advantages of LMWH over Warfarin in Long-Term Treatment of VTE Routine laboratory monitoring not needed Weight-adjusted dosing Lack of interaction with diet/drug Accommodate invasive procedures and thrombocytopenia More effective than warfarin

Long-term LMWH compared with Warfarin in Cancer Patients with VTE Forest Plot of the RR for Recurrent VTE 0.60 (0.45, 0.79) Thromb Res 2015;136:582

Long-term LMWH compared with Warfarin in Cancer Patients with VTE Forest Plot of the RR for Major Bleeding 1.07 (0.66, 1.73) Thromb Res 2015;136:582

Guideline Recommendations for Treatment of Cancer-Associated Thrombosis

Limitations of LMWH & VKA Result in Poor Adherence to Guideline-Recommended Therapies for Treatment of CAT LMWH limitations Parenteral administration Perceived higher treatment burden Quality of life Weight-adjusted dosing Cost Small risk of HIT Oral VKA limitations Narrow therapeutic window Frequent monitoring and dose adjustment required Interaction with food and drugs, making INR control challenging Less effective than LMWH Retrospective analysis of a US medical database 1 Patients with CAT treated with anticoagulants as outpatients (n=52,911) 50% received warfarin (despite guidelines preferring LMWH) 28% of these patients switched to another anticoagulant within 98 days (median) of initiation 40% received LMWH (in accordance with guideline recommendations) 44% of these patients switched to another anticoagulant within 23 days (median) of initiation 1.Khorona A et al, Circ Cardiovasc Qual Outcomes 2015;8:Abstract A210.

Anticoagulation during the first 30 days after diagnosis of CAT Date of analyses: 24 th April 2017 Unpublished Data

VTE Treatment in Patients with Cancer: Addressing Unmet Needs A simplified, oral anticoagulant treatment to overcome the limitations of the standard of care (LMWH) Improve adherence, quality of life and treatment duration to prevent recurrent VTE Provision of uninterrupted anticoagulation despite ongoing cancer therapy (chemotherapy and sideeffects, surgery, radiation therapy) Practical management advice for anticoagulation in patients with cancer (e.g. management with interventions)

New Oral Anticoagulants Predictable pharmacokinetics Fixed (daily or twice-daily) dose Few important drug interactions Minimal need for laboratory testing

Limitations of DOACs for Treatment of Cancer Associated Thrombosis Too few patients included in clinical trial studies No direct comparison against long-term LMWH Liver and renal dysfunction common in cancer Reduced absorption from gastrointestinal tract Interactions with anti-cancer therapy

Acute VTE treatment: DOACs have been compared with warfarin in multiple trials RE-COVER / RE-COVER II 1,2 (Dabigatran) EINSTEIN DVT 3 (Rivaroxaban) EINSTEIN PE 4 (Rivaroxaban) AMPLIFY 5 (Apixaban) Hokusai-VTE 6,7 (Edoxaban) Patients, N 5107 3449 4832 5395 8240 Mean age (years) 55 56 58 57 56 Female (%) 40 43 47 41 43 CrCl <50 ml/min (%) NR 7 8 6 7 DVT only (%) 69 99 65 60 PE±DVT (%) 31 0.7 100 34 40 Unprovoked (%) NR 62 65 90 65 Cancer (%) 4 6 5 3 9* Previous VTE (%) 22 19 20 16 18 *History of cancer; active cancer was observed in 2.5% of patients overall; CrCl, creatinine clearance; NR, not reported 1. Schulman et al. N Engl J Med 2009; 2. Schulman et al. Circulation 2014; 3. EINSTEIN Investigators. N Engl J Med 2010; 4. EINSTEIN PE Investigators. N Engl J Med 2012; 5. Agnelli et al. N Engl J Med 2013; 6. Hokusai-VTE Investigators. N Engl J Med 2013; 7. Raskob et al. Presented at ASH 2013. Abstract 211.

Efficacy and safety profiles of DOACS similar to warfarin in cancer patients with acute VTE Recurrent VTE RR (95% CI) Major or CRNM bleeding RR (95% CI) RE-COVER I and II 0.78 (0.35 1.76) 1.10 (0.63 1.92) EINSTEIN-DVT 0.60 (0.17 2.18) 0.91 (0.47 1.74) EINSTEIN-PE 0.64 (0.11 3.74) 1.33 (0.62 2.86) HOKUSAI 0.52 (0.16 1.72) 0.73 (0.43 1.22) Total 0.66 (0.38 1.17) 0.94 (0.70 1.28) Favours NOAC Favours VKA Favours NOAC Favours VKA 0.01 0.1 1 10 100 0.01 0.1 1 10 100 Head-to-head data on DOAC vs LMWH in cancer patients required Meta-analysis of 5 studies involving 19 060 patients, 973 of whom had active cancer Van der Hulle. J Thromb Haemost 2014

Ongoing Trials of Cancer Associated VTE Trial Size (n) Design Drug Comparator Primary outcome FU duration CAP 300 Single arm observational Apixaban NA VTE recurrence; major Bleeding 6 months ADAM VTE 300 Randomized open label Apixaban Dalteparin Major Bleeding 6 months CONKO 450 Randomized open label Rivaroxaban LMWH Patient-reported treatment satisfaction COSIMO 500 Observational Rivaroxaban NA Patient-reported treatment satisfaction 3 months 6 months SELECTeD 530 Randomized open label Rivaroxaban Dalteparin - VTE recurrence; major Bleeding. Safety and efficacy of continued therapy, if residual thrombus present at 5 months CASTA DIVA 200 Randomized open label Rivaroxaban Dalteparin VTE recurrence; major Bleeding Hokusai VTEcancer 1000 Randomized open label, non-inferiority CANVAS 940 Randomized open label Any DOAC LMWH alone or with VKA Edoxaban Dalteparin Composite primary outcome of recurrent VTE and major bleeding VTE recurrence 12 months 3 months 12 months 6 months

CASSINI Trial Design VTEp Phase IIIb Study in Cancer Patients at High Risk of VTE Rationale: Assess the efficacy and safety of rivaroxaban versus placebo for VTE prophylaxis in ambulatory cancer patients initiating systemic cancer therapy and at high risk of VTE 1 Rivaroxaban 10 mg od Patients with various cancer types initiating systemic chemotherapy at high risk of VTE* N~700 # R 180±3 days treatment period with follow-up visits every 8 weeks (±7days) 30-day follow-up Placebo CUS CUS CUS CUS End of study Short design: Multinational, multicentre, randomized, double-blind, placebo-controlled phase IIIb superiority study Indication: VTEp patients with cancer FPFV: Q4/2015 LPLV: TBC *As indicated by a Khorana risk score 2 1 ; # subjects will be stratified at randomization by tumour type (pancreatic or other; up to ~ 25% of the subjects randomly assigned are those with advanced pancreatic cancer); systemic cancer therapy will be initiated within 72 hrs of the first dose of study drug when at all possible, or within ±1 week of receiving the first dose of study drug with the intention of continuing systemic cancer therapy during the double-blind treatment period CUS, compression ultrasound (at screening and Follow-up visits) 1. NCT02555878 (https://clinicaltrials.gov/ct2/show/nct02555878?term=rivaroxaban+ambulatory&rank=1) 2. Khorana AA et al, Blood 2008;111:4902 4907

Diagram for VTE Treatment in Cancer Patients Patients with active cancer and acute VTE LMWH case-by-case basis (reduce dose or full dose following transfusion) Yes Platelet <50 x 10 9 /L No LMWH for 3-6 months End LMWH Yes Complete Remission No Patient s preference Continue LMWH Yes Ongoing Anticancer Therapy No Stable Disease VKA or DOAC Continue LMWH

Conclusion Cancer associated thrombosis is common and associated with poorer outcomes. The risk of thrombosis varies by type, stage, treatment of cancer, and other risk factors. Risk assessment models may help individualize therapy.

Conclusion LMWH remains the preferred therapeutic option. Duration for treatment depends on status of patients, other risk factors, and patient s preference. DOACs should be investigated more carefully before being used in cancer patients.