CANCER-ASSOCIATED THROMBOSIS Prediction, Prevention and Treatment

CANCER-ASSOCIATED THROMBOSIS Prediction, Prevention and Treatment Alok A. Khorana, MD, FACP Sondra and Stephen Hardis Chair in Oncology Research Vice-Chair, Taussig Cancer Institute Case Comprehensive Cancer Center

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Our Moderator Associate Professor in the Faculty of Medicine, Department of Medicine and Scientist in the Clinical Epidemiology Program of The Ottawa Hospital Research Institute. Holds a Tier 2 Research Chair in Venous Thromboembolism and Cancer from the University of Ottawa and New Investigator Award from the Heart and Stroke Foundation of Canada. Marc Carrier, MD, MSc, FRCPC Clinical research is focused in venous thromboembolic disease and cancer.

Our Speaker Alok A. Khorana, MD Sondra and Stephen Hardis Chair in Oncology Research; Vice Chair (Clinical Services) and Director, GI Malignancies Program at the Taussig Cancer Institute, Cleveland Clinic Professor at the Cleveland Clinic Lerner College of Medicine. Specializes in prediction, prevention and treatment of cancer-associated thrombosis Highly sought after speaker, Dr. Khorana has presented at numerous national and international conferences

Disclosures Dr. Khorana disclosed he has been a consultant for: Pﬁzer Bayer AngioDynamics Leo Janssen No oﬀ- label use of any product will be discussed in this presentafon

Continuing Education for Physicians and Nurses This educational activity is approved for 1 contact hour. This activity is jointly provided by SynAptiv and Saxe Healthcare Communications SynAptiv is accredited by the Accreditation Council for Continuing Medical Education (ACCME) for 1 AMA PRA Category Credit. Saxe Healthcare Communications is accredited as a provider for continuing education. Provider #14477 and the Florida Board of Nursing Provider # 50-17032 A link to obtain CE credits will be available at the conclusion of the webinar Support for this educational activity from AngioDynamics

Learning Objectives Upon completion of this activity, the participant will be able to: Identify risk of thrombosis in cancer patients Develop practice plans to institute appropriate prophylaxis and treatment strategies.

Why You Should Care: Prevalence, Consequences, Costs PredicFng VTE in Cancer PrevenFng and TreaFng VTE in Cancer

Risk of Cancer and VTE Risk Factor/Characteristic Recent surgery w/ institutionalization Trauma Institutionalization without recent surgery Malignancy with chemotherapy Prior CVAD or pacemaker Prior superficial vein thrombosis Malignancy without chemotherapy Neurologic disease w/ extremity paresis Serious liver disease Heit JA, et al. Thromb Haemost. 2001;86(1):452-463. Odds Ratio 21.72 12.69 7.98 6.53 5.55 4.32 4.05 3.04 0.10

Why You Should Care: VTE and Mortality Bleeding 1% AspiraFon Other 6% 1% Unknown 4% Respiratory failure 4% InfecFon 9% Thrombo- embolism 9% 1. Khorana AA et al. J Thromb Haemost 2007 2. Kuderer NM et al ASCO 2008 # 9521 2nd leading cause of death in cancer patients Ø Accounts 1 Cancer progression 71% for 9% of deaths Ø Associated with early mortality during chemotherapy (HR=6.98)2 Ø 47-fold increased risk of mortality from VTE1

Why You Should Care: VTE and Mortality 1.00 HR=3.04* [95% CI: 1.31-7.15; P<0.01].99.98 No VTE Overall Survival.97.96.95.94.93 VTE.92.91.90 0 10 20 30 40 50 60 70 80 90 100 110 120 Time (Days) Kuderer et al. ASCO 2009 *Adjusted for major confounders: Age, gender, race, cancer type, stage, year of therapy, chemotherapy type and dose intensity, major laboratory abnormalities, PS, BMI, and comorbid conditions

Why You Should Care: VTE and Public Health Burden Patients with cancer: 19.8% All DVT and PE One-fifth of all VTE occurs in patients with cancer Heit JA. et al. Arch Intern Med. 2002;162:1245-1248.

MSKCC Retrospective Analysis DVT+PE, 13.60% Arterial alone, 8.30% DVT+art, 3% DVT alone, 49.70% PE alone, 25.40% 932 patients receiving cisplatin-based chemotherapy at MSKCC in 2008 TEE occurred in 18.1% Moore et al, JCO 2011

Why You Should Care: Costs Cancer patients with VTE had 3 times increase in all-cause hospitalizations (mean 1.38 versus 0.55 per patient) days in hospital (10.19 versus 3.37) (all P < 0.0001). Cancer patients with VTE incurred higher overall all-cause inpatient costs (mean $21,299 versus $7459 per patient), outpatient costs ($53,660 versus $34,232 per patient), and total health care costs ($74,959 versus $ 41,691 per patient) (all P < 0.0001). MeanVTE-related costs : $9247 / patient / year Adjusted mean incremental all-cause costs of VTE : $30,538 /patient Khorana et al, Clin Econ Outcomes Res; 2013

Why You Should Care: Costs Khorana et al, Clin Econ Outcomes Res; 2013

Why You Should Care: Prevalence, Consequences, Costs PredicFng VTE in Cancer PrevenFng and TreaFng VTE in Cancer

Risk Factors Primary Site Histology Grade IniFal period Platelet counts Leukocyte counts Hemoglobin Tissue factor D- dimer P- selecfn Thrombin generafon potenfal Cancer- related Treatment- related Biomarkers PaFent- related Surgery/ hospitalizafon Chemotherapy AnF- angiogenics CVCs ESA/transfusions Age Ethnicity ComorbidiFes

Risk of VTE by Primary Site N = 17,284 Control 1.4 % Patients Stomach 15.8 PancreaFc Ovarian 11 Bladder P<0.0001 for all comparisons vs controls 19.2 8.2 10.6 Colorectal Lung 13.9 0 Khorana AA et al, Cancer 2012 5 10 15 20

Risk with Bevacizumab 14 12 10 8 6 4 2 0 13 9.9 Chemo + bev Chemo alone 2-fold increased risk of arterial events1 Possible increased risk of VTE [RR=1.29 (95% CI, 1.03-1.63)]2 Not significant if adjusted for exposure time [RR 1.10 (95% CI, 0.89-1.36)]3 Not seen in a newer pooled analysis (OR 1.14; 95% CI, 0.96 to 1.35; P =.13)4 et al JNCI 2007;99(16):1232-9; 2 Nalluri SR, et al. JAMA. 2008;300:2277-2285; 3Chu & Wu JAMA. 2009;301(14): 1434-1436; 4Hurwitz et al JCO 29(13):1757-6 1Scappaticci

Risk with Other Targeted Therapies Anti-EGFR agents are associated with risk of VTE RR 1.32 (95% CI 1.07 1.63; P = 0.01) Risk primarily with antibodies (RR 1.34; P = 0.01) rather than oral TKIs (RR 1.16; P = 0.65) Petrelli et al Ann Onc 2012 Jul;23(7):1672-9

VTE in Cancer Is Primarily An Outpatient Illness Khorana et al ASH 2011

CVCs and Thrombosis

PICCs vs CVCs Chopra et al, Lancet 2013

Incidence of VTE and Catheters 3 months 12 months All events Symptomatic events All events Symptomatic events Subclavian DVT 3.0% (1.9 4.0) 2.1% (1.2 3.1) 5.9% (4.5 7.8) 4.1% (2.7 5.4) PE 3.0% (1.9 4.0) 1.4% (0.7 2.1) 5.5% (4.1 6.9) 2.7% (1.6 3.7) Catheter-related event (subclavian DVT or PE) 5.9% (4.4 7.3) 3.6% (2.4 4.7) 11.3% (9.4 13.2) 6.7% (5.1 8.4) Lower extremity or visceral DVT 2.2% (1.3 3.1) 1.3% (0.6 2.1) 4.6% (3.3 5.9) 2.8% (1.7 3.9) All thrombotic events 7.6% (6.0 9.3) 4.7% (3.4 6.0) 15.3% (13.1 17.6) 9.3% (7.3 11.2) Incidence of thrombotic events at 3 months and 12 months (proportion and CI95). Moinat et al J Oncol 2014

Fig. 1 Cumulative Incidence of Symptomatic Implanted port-related Venous Thromboembolism. Siavash Piran, Vincent Ngo, Sheryl McDiarmid, Grégoire Le Gal, William Petrcich, Marc Carrier Incidence and risk factors of symptomatic venous thromboembolism related to implanted ports in cancer patients Thrombosis Research, Volume 133, Issue 1, 2014, 30-33

Evaluation of Risk Score N=10, 694 Study Type, durafon N Low- risk (score = 0) Intermediate- risk (score = 1-2) High- risk (score 3) Khorana et al, 2008 Development cohort, 2.5 months 2701 0.8% 1.8% 7.1% Khorana et al, 2008 ValidaFon cohort, 2.5 months 1365 0.3% 2% 6.7% Kearney et al, 2009 RetrospecFve, 2 years 112 5% 15.9% 41.4% Price et al, 2010 RetrospecFve, pancreafc, NA 108 - * 14% 27% Ay et al, 2010 ProspecFve, 643 days 819 1.5% 9.6% (score= 2) 3.8% (score=1) 17.7% Khorana et al, 2010 ProspecFve**, 3 months 30 - *** - 27% Moore et al, 2011 RetrospecFve, cisplafn- based chemo only 932 13% 17.1% 28.2% Mandala et al, 2012 RetrospecFve, phase I pafents only, 2 months 1415 1.5% 4.8% 12.9% NA=not available; *=pancreatic cancer patients assigned a score of 2 based on site of cancer and therefore no patients in the low-risk category; **included 4-weekly screening ultrasonography; ***enrolled only high-risk patients

Predictors of Catheter-Associated VTE Univariate analysis or (95% CI) P value Multivariate analysis or (95% CI) P value 5.3 (1.98 to 14.1) P = 0.0001 5.45 (1.87 to 15.87) P = 0.002 Khorana score 3 2.65 (0.88 to 8.0) P = 0.08 3.50 (1.00 to 12.30) P = 0.05 Low performance status 4.82 (1.08 to 21.4) P = 0.03 4.68 (0.97 to 22.4) P = 0.054 Metastatic stage 2.33 (0.86 to 6.37) P = 0.09 1.21 (0.41 to 3.61) P = 0.73 Previous VTE event 1.76 (0.54 to 5.86) P = 0.34 Age > 70 0.69 (0.24 to 2.00) P = 0.50 3 Months catheter-related VTE event Lung cancer Platinum based chemotherapy 1.72 (0.66 to 4.45) P = 0.26

Risk Assessment: The Present ASCO 2013 New Recommendation

Why You Should Care: Prevalence, Consequences, Costs PredicFng VTE in Cancer PrevenFng and TreaFng VTE in Cancer

PrevenMng VTE in Cancer Cancer PaMents Clinical selng Major cancer surgery ENOXACAN-1 Canadian Colorectal DVT Prophylaxis ENOXACAN-2 FAME CANBESURE HospitalizaFon for acute medical illness MEDENOX PREVENT EXCLAIM OutpaFent chemotherapy PROTECHT CONKO- 004 FRAGEM SAVE- ONCO

Despite Evidence, Prophylaxis Is Underused ENDORSE1 No. of patients At risk for VTE Received prophylaxis (ACCP) IMPROVE2 Medical Surgical 37,356 30,827 42% 64% 40% 59% 1. Cohen AT et al. Lancet. 2008;371:387-394. 2. Tapson VF et al. Chest. 2007;132:936-945. No. of patients VTE prophylaxis United States Other Countries 3,410 11,746 1852 (54%) 5788 (49%) LMWH 476 (14%) 4657 (40%) UFH 717 (21%) 1014 (9%)

CVC Prophylaxis with Heparins Outcomes Death Symptomatic DVT Major bleeding Infection Thrombocytopenia Relative effect (95% CI) No of Participants (studies) RR 0.85 (0.53 to 1.37) RR 0.54 (0.28 to 1.05) RR 0.68 (0.1 to 4.78) RR 0.91 (0.49 to 1.68) RR 0.85 (0.49 to 1.46) 1192 (5 studies) 1173 (6 studies) 891 (4 studies) 626 (3 studies) 836 (3 studies) Quality of life - not reported Akl et al. Cochrane Database of SystemaFc Reviews. 2011 Risk with no heparin Risk with heparin 65 per 1000 55 per 1000 (34 to 89) 26 per 1000 (14 to 51) 3 per 1000 (1 to 24) 65 per 1000 (35 to 119) 56 per 1000 (32 to 96) 49 per 1000 5 per 1000 71 per 1000 66 per 1000 Quality of the evidence (GRADE) moderate moderate moderate moderate moderate

CVC Prophylaxis with Warfarin Outcomes Relative effect No of Participants Quality of the (95% CI) (studies) Risk with no VKA Risk with VKA evidence (GRADE) Death RR 0.97 (0.82 to 1.15) RR 0.63 (0.35 to 1.11) RR 6.93 (0.86 to 56.08) Symptomatic DVT Major bleeding Quality of life - not reported 1093 (2 studies) 1235 (4 studies) 1093 (2 studies) 312 per 1000 90 per 1000 2 per 1000 303 per 1000 (256 to 359) low 57 per 1000 (31 to 100) low 14 per 1000 (2 to 112) low

Thromboprophylaxis in patients with cancer and CVC ACCP 9th Antithrombotic Guidelines: In outpatients with cancer and indwelling central venous catheters, we suggest against routine prophylaxis with LMWH or LDUH (GRADE 2B) and suggest against the prophylactic use of vitamin K antagonists (GRADE 2C)

Treatment: Current Recommendations The most current guidelines1 4 and expert reviews5 9 recommend LMWH for at least six months to treat VTE in pafents with acfve cancer. ExcepFons for compliance, cost, HIT VKAs are not recommended as ﬁrst line therapy based on inferiority to LMWH in randomized trials. DOACs are not recommended due to lack of data in cancer pafents 1. Kearon C et al. CHEST 2016. 2.Lyman G et al. J Clin Oncol 2015; 3. NCCN Guidelines VTE v1.2015; 4. NICE Guidelines 2012 (2015 validafon); 5. Burneq AE et al. J Thromb Thrombolysis 2016; 6. Khorana AA et al. J Thromb Thrombolysis 2016; 7. van Es H, Büller HR. Hematol 2015; 8. Prandoni P. Expert Opin Pharmacother 2015; 9. Carrier M et al. Current Oncol 2015.

Treatment Debate: LMWHs vs DOACs LMWH superior to CLOT 15 yrs old warfarin, based on 2 CATCH ARR lower, semi- RCTs conﬁrmatory NOAC data versus warfarin is not cancer- speciﬁc Cancer subgroup analyses of NOAC RCTs have N similar to RCT True, but also means no RCTs No RCTs comparing showing LMWHs superior to NOACs to LMWHs NOACs Pooled analyses suggest NOACs also superior to warfarin in (Therefore) guidelines cancer Real- world data show < 1/3 of pafents remain on LMWHs at 3 recommend LMWH months monotherapy ﬁrst- Cost of LMWH 2-3 fold higher line

CVC-associated Thrombosis 5% to 10% of VTE involves upper extremity/cvcs Secondary (provoked by catheters/cancer) accounts for 75% of cases. DVT in upper extremity is not harmless; complications include: Symptomatic PE (~5%) Recurrent DVT (~8%) Post-thrombotic syndrome ( ~20%) Paradoxically, CVCs are also associated with increased risk of bleeding

Management of upper-extremity thrombosis. Kamphuisen P W, and Lee A Y Y Hematology 2012;2012:638-644

Treating CVC-associated thrombosis In most patients with UEDVT associated with a CVC, we suggest that the catheter not be removed if it is functional and there is an ongoing need for the catheter (Grade 2C) In patients with UEDVT that involves the axillary or more proximal veins, we suggest a minimum duration of anticoagulation of 3 months over a shorter period (Grade 2B)

Treating CVC-associated Thrombosis In patients with cancer who have UEDVT that is associated with a CVC that is removed, we suggest 3 months of anticoagulation over a longer duration of therapy (Grade 2C). In patients with cancer who have UEDVT that is associated with a CVC that is not removed, we recommend that anticoagulation is continued as long as the CVC remains, over stopping after 3 months of treatment (Grade 1C)

Conclusions The problem is bigger than we imagined Unacceptably high burden VTE is an emerging major clinical problem Association with cancer outcomes, including mortality We have made progress Multiple RCTs have addressed prevention of CAT in the outpatient setting New technology/devices that reduce catheterassociated VTE can contribute to the solution

Our Moderator Marc Carrier, MD, MSc, FRCPC

Continuing Education for Physicians and Nurses This educational activity is approved for 1 contact hour. This activity is jointly provided by SynAptiv and Saxe Healthcare Communications To obtain CE credits for attending this webinar, please log onto www.saxetesting.com/sa/ Complete the evaluation form and the post-test Upon successful completion, you will be able to print your certificate of completion for either CNE or CME SynAptiv is accredited by the Accreditation Council for Continuing Medical Education (ACCME) for 1 AMA PRA Category Credit. Saxe Healthcare Communications is accredited as a provider for continuing education. Provider approved by California Board of Nursing. Provider #14477 and the Florida Board of Nursing Provider # 50-17032 Support for this educational activity from AngioDynamics

On-Demand Webinar The on-demand version of this webinar will be available at www.safe-access-iv.org shortly The on-demand version will be accredited for CME and CNE as a self-paced activity After you have viewed the on-demand version in its entirety, you can obtain CE credit by logging into www.saxetesting.com/sa/ Complete the post-test and evaluation and you will be able to print your certificate of completion

QuesFons Marc Carrier Alok Khorana

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