Frequently Asked Questions about Cancer Associated Thrombosis

+ Frequently Asked Questions about Cancer Associated Thrombosis Atlantic Canada Oncology Group Annual Meeting June 13 th, 2015 Sudeep Shivakumar, Dalhousie University

+ Conflict of Interest Disclosures Pharmaceutical Company Affiliations" None" Grants/Research Support" None" Speakers Bureau/Advisory Boards" Boehringer-Ingelheim" Bayer Inc" Leo Pharma" Consulting Fees" None

+ Objectives! To discuss the link between cancer and thrombosis! To highlight the specific difficulties in patients with malignancies! To present an approach to management of patients with thrombosis in malignancy:! Catheter associated thrombosis! Recurrent thrombosis! Thrombocytopenia! Incidentally discovered pulmonary embolism

+ Background! Venous thromboembolism (VTE)! Deep venous thrombosis (DVT) and pulmonary embolism (PE)

+ Cancer and thrombosis " Patients with cancer more prone to venous thromboembolism (VTE) " Population study of 625 Minnesota patients showed: " Patients with cancer 4.5x more likely to have VTE " Patients with cancer receiving chemotherapy 6.5x more likely to have VTE " Estimated risk: 1 in 200 Heit, Arch Int Med, 2000

+ Cancer and thrombosis " Why do patients with cancer get blood clots? " Immobility " Central venous catheters " Post-surgery " Medications (tamoxifen, thalidomide) " Chemotherapy " Tumour infiltration into vessels " Vessel obstruction

+ Cancer and thrombosis " Are some cancers more prone to VTE? " Swedish autopsy study looking at 21 530 patients with DVT or PE " Highest risk in uterine, brain, ovarian cancer and leukemia " However, data varies between studies " Metastatic adenocarcinoma generally felt to be very thrombogenic Thodiyil, Thromb Haemost, 2002

+ Prognosis of VTE in cancer " Data from national registry of patients in Denmark further analyzed " Compared outcomes of patients with cancer and DVT or PE with patients with cancer without DVT or PE " Concluded that patients with DVT or PE did worse Sorensen, NEJM, 2000

+ Prognosis of VTE in cancer " Patients with VTE had more distant metastases (44% vs 35%) " Prognosis poorer as well: " Those with VTE at time of diagnosis of cancer had 1 year survival of 12% (vs. 36% in those who did not have VTE) Sorensen, NEJM, 2000

+ Prognosis of VTE in cancer! More recent data:! Prospective observational study of cancer patients starting new chemo regimen in US! 4466 patients enrolled! 141 died during observation period (4 cycles of chemo)! Thromboembolism (arterial and venous) = cause of death in 9.2% (tied for 2 nd with infection) Cause of death n (%) Progression of cancer 100 (70.9) Thromboembolism 13 (9.2) Infection 13 (9.2) Respiratory failure 5 (3.5) Bleeding 2 (1.4) Aspiration pneumonia 2 (1.4) Other 9 (6.4) Unknown 5 (3.5) Khorana, JTH, 2007

+ Treatment of VTE! Typically, long term therapy for VTE is with vitamin K antagonists (VKA)! Treat with low molecular weight heparin for at least 5 days! Overlap with warfarin! Once INR is between 2 and 3, stop LMWH! Continue warfarin for 3-12 months (or longer)

+ Treatment of VTE! Difficulties with VKA in patients with cancer:! Unpredictable anticoagulant response! Drug interactions! Changes in vitamin K status! Liver dysfunction! GI disturbances such as vomiting and diarrhea! Need for venipuncture (painful, time consuming)! Difficult to manage b/c of slow onset/offset for procedures, ORs, thrombocytopenia Lee, Best Pract Res Clin Hem, 2009

+ Treatment of VTE! Low molecular weight heparin! No laboratory monitoring! Minimal drug interactions! Subcut administration ensures drug delivery in those who can t eat or have N/V! Easy to withhold for procedures, low platelets, etc! Several trials have compared LMWH to VKAs in patients with cancer

+ CLOT trial! 2003 international randomized trial of 672 patients! All had cancer and symptomatic VTE! All initially received dalteparin for 5-7 days! Randomized to:! Continue dalteparin for total of 6 months! Full dose x 1 month, then 75-80% dose x 5 months, or! Switch to warfarin for 6 months Lee, NEJM, 2003

+ CLOT trial! Results! Reduced relative risk of recurrent VTE in dalteparin group by 52%! 9% in dalteparin group, 17% in warfarin group! No significant differences in bleeding or survival! NNT of 13 Lee, NEJM, 2003 Figure 1. Kaplan Meier Estimates of the Probability of Symptomatic Recurrent Venous Thromboembolism among Patients with Cancer, According to Whether They Received Secondary Prophylaxis with Dalteparin or Oral Anticoagulant Therapy for Acute Venous Thromboembolism.

+ Challenges in cancer associated thrombosis! Catheter associated thrombosis! Recurrent thrombosis while on anticoagulation! Thrombocytopenia! Incidental pulmonary embolism

+ Challenges in cancer associated thrombosis! Catheter associated thrombosis! Recurrent thrombosis while on anticoagulation! Thrombocytopenia! Incidental pulmonary embolism

+ Case: Mr. RB! 68 year old gentleman with newly diagnosed diffuse large B- cell lymphoma, stage 3B! Previously well except for HTN! No history of DVT/PE! Undergoes 2 cycles of R-CHOP chemotherapy, no complications! Very difficult venous access so PICC placed in left arm for further cycles

+ Case: Mr. RB! After 2 further cycles R-CHOP, left arm swollen (wedding band doesn t fit) and painful! Exam shows:! HR 80, BP 162/95, O2 sat 99% on room air, afebrile.! Clear chest, normal heart sounds, benign abdomen.! Left arm swollen, red, warm and tender.! Dilated chest wall veins noted! PICC site clean, not red.! Sent for ultrasound:! Confirms presence of left subclavian vein thrombosis

+ Case: Mr. RB! Does this need treatment?

+! Veins of the upper extremity Gray s Anatomy

+! Veins of the upper extremity Gray s Anatomy

+ Case: Mr. RB! How would you anticoagulate him?

+ Case: Mr. RB! Treatment: 1. Low molecular weight heparin (LMWH) overlapped with warfarin 2. Low molecular weight heparin alone 3. Direct oral anticoagulants

+ Case: Mr. RB! Treatment:! Low molecular weight heparin (LMWH) overlapped with warfarin! Standard treatment for DVT/PE! Low molecular weight heparin alone! CLOT trial! Direct oral anticoagulants! Ongoing studies

+ Treatment! Should the PICC line be removed?! PICC is provoking factor for clot! However, many patients will still require catheter access! Insertion of another line may further increase the thrombotic risk! Is line salvage an option?

+ Treatment! Catheter study! Prospective cohort study of 74 patients! All had symptomatic UE DVT and cancer! All treated with dalteparin overlapped with warfarin! Treated for minimum 3 months! Catheter not removed Kovacs et al, J Thromb Haemost, 2007

+ Treatment! Catheter study! Results:! Majority had PICC lines (77%)! 42 (57%) had catheter in place and functional at 3 months! At 3 months:! 3 episodes of major hemorrhage! No patients with recurrent VTE! 7 deaths: 1 due to hemorrhage, 6 due to malignancy Kovacs et al, J Thromb Haemost, 2007

+ Treatment! Suggests that decision to remove catheter after a thrombotic event should be balanced with other factors:! Need for venous access! Difficulty of venous access! Patient preference! ACCP guidelines consistent with this:! Do not recommend removal of an indwelling catheter if the device is functioning and there is an ongoing need for the catheter (grade 2C) ACCP Guidelines, Chest, 2012

+ Treatment! How long do you anticoagulate for?

+ Treatment! Duration of treatment also controversial! Wide range of treatment durations reported, from weeks to months! ACCP guidelines recommend treatment duration consistent with LE DVT! In those who have a catheter removed, duration should not be shortened to less than 3 months (grade 2C)! Extrapolations:! Treat with anticoagulation for 3 to 6 months, with consideration of LMWH for patients with cancer! Continue anticoagulation as long as catheter is in place?! Indefinite anticoagulation if recurrent VTE ACCP Guidelines, Chest, 2012

+ Case: Mr. RB! Starts on LMWH monotherapy and catheter left in! After 3 months, arm is back to normal, chemo is finished and catheter is removed! Follow up PET shows complete metabolic response! LMWH is stopped

+ Challenges in cancer associated thrombosis! Catheter associated thrombosis! Recurrent thrombosis while on anticoagulation! Thrombocytopenia! Incidental pulmonary embolism

+ Case: Ms. GD! 56 year old female with stage III ovarian cancer with residual disease! Undergoing chemotherapy with Carbo/Taxol! After one cycle, develops right leg swelling and pain! U/S confirms right leg DVT! Treated as per CLOT trial with LMWH monotherapy

+ Case: Ms. GD! Continues on LMWH but after further chemotherapy cycles develops shortness of breath and pleuritic chest pain! CT-PE shows bilateral pulmonary emboli! What do we do now?

+ Management considerations! Confirm that there is no tumour or disease progression! Confirm compliance with anticoagulation! Any weight change?! Any new risk factors?! Any evidence of heparin induced thrombocytopenia (HIT)?

+ Recurrent VTE! Note that 9-17% of patients with cancer in CLOT developed recurrent VTE over 6 months, while on therapy with LMWH or VKA! Overall survival of these patients poor! 60% mortality within 1 year of VTE diagnosis! What treatment options are there?! Little published data

+ Recurrent VTE! Previous CHEST guidelines recommended IVC filters in patients with recurrent VTE while on anticoagulants! Randomized trials have shown decreased PE, but increased DVT! However, risk of recurrent DVT with IVCF as high as 32% in patients with cancer (Elting, Arch Int Med, 2004)! Not recommended in latest (2012) guidelines

+ Recurrent VTE! Increase the dose of LMWH?! Looked at in retrospective cohort study! Patients on VKA switched to LMWH therapeutic dose! Patients on LMWH were dose escalated! If on 75% dose, increased to 100% dose x 6-12 weeks! If on 100% dose, increased to 120-125% dose x 4 weeks! If on low dose, increased to 100% dose x 4 weeks, then 75%! Followed for 3 months Carrier, JTH, 2009

+ Recurrent VTE! Results:! 70 patients with cancer and a recurrent VTE, despite anticoagulation! 6 patients (8.6%) had a second recurrent VTE during 3/12 follow up! All had doses further increased by 20-25%! No further events during 3/12 follow up (ie. no third VTE!)! 4.3% of patients had bleeding complications! Two minor events, and one intracranial bleed assoc. with brain tumour! Suggests increasing LMWH is a reasonable option, with acceptable rates of bleeding Carrier, JTH, 2009

+ Case: Ms. GD! Treated with split dose LMWH! Dalteparin 120 units/kg BID! No further thrombosis!

+ Challenges in cancer associated thrombosis! Catheter associated thrombosis! Recurrent thrombosis while on anticoagulation! Thrombocytopenia! Incidental pulmonary embolism

Case: Ms. MT! 68yo with relapsed lymphoma! Left leg swelling in your office.! Doppler: Occlusive thrombus in the left superficial femoral vein.! egfr: 60 cc/min, Hb: 115 g/l and plt: 200 X 10 9 /L! Started on therapeutic doses of LMWH

+ Case: Ms. MT! Received R-GDP chemotherapy for salvage therapy before autostem cell transplant! Seen in your clinic for two-week follow-up! Symptoms are improving! No signs or symptoms of recurrent VTE! Repeated blood work showed:! egfr: 55 cc/min, Hb 90 g/l, WBC 1.0 (neutro 0,3), and plt: 55 X 10 9 /L.! How would you manage Ms. MT?

+ What would you do? A. Stop LMWH B. Stop LMWH and insert IVC filter C. Continue same dose of LMWH and repeat blood work in one week D. Decrease LMWH to 50% therapeutic doses E. Decrease LMWH to thromboprophylactic doses

+ Important factors to consider 1. Etiology of the thrombocytopenia! e.g. HIT, chemotherapy effect, etc 2. Severity ( or < 50 X 10 9 /L) 3. Expected duration and course! transient or permanent! nadir or will drop further 4. Reversible causes that can be corrected 5. Other risk factors for bleeding! e.g. Advanced age or recent surgery.

+ Management! For acute VTE (< 30 days) Carrier M et al. J Thromb Haemost. 2013 Jun 27. Lee AY et al Blood 2013; epub ahead of print. Monreal M. J Thromb Haemost 2004 Aug;2(8):1311-5 Lee AYY et al. N Engl J Med 2003. 349: 146 153

Management! For sub-acute VTE (> 30 days) Carrier M et al. J Thromb Haemost. 2013 Jun 27. Lee AY et al Blood 2013; epub ahead of print. Monreal M. J Thromb Haemost 2004 Aug;2(8):1311-5 Lee AYY et al. N Engl J Med 2003. 349: 146 153

+ Challenges in cancer associated thrombosis! Catheter associated thrombosis! Recurrent thrombosis while on anticoagulation! Thrombocytopenia! Incidental pulmonary embolism

Case: Mr. MC! 25yo male with testicular cancer! Routine computed tomography (CT) of the chest for cancer staging.! Called by the radiologist because bilateral segmental and subsegmental PE incidentally found on CT.! Patients denies chest pain, shortness of breath or hemoptysis.! How will you manage Mr. MC?

What will you do? A. Observation only (+/- repeating imaging) B. LMWH in combination with VKA for minimum of 6 months C. LMWH only (+/- dose reduction) for minimum of 6 months D. Rivaroxaban 15 mg BID X 3 weeks then 20 mg daily for minimum of 6 months

Risk of incidental PE in cancer patients! Approx 1 to 4% of routine CT Chest staging! In-patients > outpatients! Risk factors:! Metastatic disease! Recent chemotherapy! Types of cancer:! Pancreas! Melanoma/skin! Hepatobiliary! Kidney Browne AM et al. J Thorac Oncol. 2010;5:798-803. Douma RA et al. Thromb Res 2010; 25:e306-e309. Shinagore AB et al. Cancer. 2011; 117:3860-6.

Cumulative risk of recurrent VTE Incidental Vs. Symptomatic PE (all receiving anticoagulation) Incidental PE: n=51 Symptomatic PE: n=144 Figure from: den Exter P L et al. JCO 2011;29:2405-2409

Cumulative Survival Rates Incidental Vs. Symptomatic PE Figure from: den Exter P L et al. JCO 2011;29:2405-2409

Overall survival Treated Vs. untreated incidental PE Figure from: Sun J-M et al. Lung Cancer. 2010;69:330-336

Bottom Line! Patients with treated incidental PE seems to have similar rates of recurrent VTE and mortality than symptomatic events! Untreated incidental PE seems to be associated with lower survival compared to treated incidental events! Incidental PE probably benefit from anticoagulation treatment

+ Thank you!! sudeep.shivakumar@nshealth.ca