Venous Thromboembolism and Cancer: What the Practicing Oncologist - - PowerPoint PPT Presentation

Venous Thromboembolism and Cancer: What the Practicing Oncologist Needs to Know in 2019

Deborah L. Ornstein, MD Associate Professor of Pathology & Laboratory Medicine Medical Director, Hemophilia & Thrombosis Center

Disclosure Statement

• I do not have any financial interests related to this

material.

• I do not intend to discuss off-label use(s) of a product or

device.*

• I attest that I am not receiving direct payments from a

commercial entity with respect to this activity.

Venous Thromboembolism and Cancer Objectives

❑ Understand the options for prevention and treatment of venous thromboembolism in cancer patients ❑ Appreciate the gaps in our knowledge of optimal prevention and treatment of VTE in cancer patients

59 yo woman with metastatic breast cancer

Infiltrating ductal carcinoma diagnosed initially in 2005. Surgery, radiation, adjuvant chemotherapy Mediport-associated axillary, subclavian vein DVT Rx 6 months of enoxaparin Mediport removed after completion of therapy NED until recurrent and metastatic disease (visceral, bone) diagnosed in 2017. Bilateral, proximal LE DVT diagnosed in August 2019. Popliteal → femoral veins; CTPA not done What are your treatment choices in 2019?

Multicenter, open-label, randomized study Primary endpoint: Symptomatic VTE recurrence

R Cancer patients with proximal DVT, PE or both N = 676 Dalteparin bridge to VKA Dalteparin

CLOT in Cancer Trial

Lee et al., N Engl J Med 2003;349:146-153.

CLOT in Cancer Trial – Results: Efficacy

Lee et al., N Engl J Med 2003;349:146-153.

5 10 15 20 25

Days After Randomization

30 60 90 120 150 180 210

Probability of Recurrent VTE, % Risk reduction = 52% P-value = 0.0017 Dalteparin VKA

LMWHs for Cancer-Associated VTE ❑ Dalteparin is the only LMWH to show statistically superior efficacy over VKA ❑ Enoxaparin, Tinzaparin statistically equivalent to VKA (nonsignificant trend). ❑ Meta-analysis suggests superiority of LMWH

Posch et al., Thromb Res 2015;136:582-589.

DOACs for Cancer-Associated VTE ❑ Anti-Xa agents most widely studied ❑ Edoxaban, rivaroxaban, apixaban

Posch et al., Thromb Res 2015;136:582-589.

DOACs for Treatment of Cancer-Associated VTE

From: S. Moll. The Hematologist. Home Columns Clinical Trials Corner July-August 2019, Volume 16, Issue 4 NEJM 2018 JCO 2018 ASH 2018

DOACs for Cancer-Associated VTE ❑ Hokusai trial, multicenter RCT (Raskob et al. NEJM 2018;378:615-24)

❖ Cancer patients with VTE randomized to dalteparin v dalteparin → edoxaban x 6 – 12 months (N = 1046) ❖ Primary endpoint: Composite recurrent VTE + major bleeding ❖ Main result: Edoxaban “non inferior” for the combined endpoint ❖ More bleeding (7% vs 4%), less recurrent VTE (7% v 11%) with edoxaban

❑ SELECT-D, multicenter RCT (Young et al. JCO 2018;378:615-24)

❖ Cancer patients with VTE randomized to dalteparin v rivaroxaban x 6 months (N = 406) ❖ Primary endpoint: Recurrent VTE; Secondary: Bleeding ❖ Main results: Rivaroxaban less recurrent VTE (4% vs 11%) but more bleeding 4% vs 6%, esp GI tract and esp esophageal cancer (excluded halfway through)

DOACs for Cancer-Associated VTE ❑ ADAM, multicenter RCT (McBane et al. ASH 2018)

❖ Cancer patients with VTE randomized to dalteparin v apixaban x 6 months (N = 300) ❖ Primary endpoint: Major bleeding; Secondary: Composite bleed/VTE ❖ Main result: Simlar bleeding (6% each) ❖ Less recurrent VTE with apixaban (0.7% vs 6%) ❖ Higher satisfaction and lower premature discontinuation rate with apixaban

❑ CARAVAGGIO (Agnelli et al., Thromb Haemost 2018)

❖ Cancer patients with VTE randomized to dalteparin v apixaban x 6 months (N = 1168) ❖ Primary endpoint: Recurrent VTE; Secondary: Bleeding

DOACs for Cancer-Associated VTE – “Real World” Analyses ❑ Mayo (Wysokinski et al. Am J Hematol 2019)

❖ Cohort of cancer patients with VTE over 5 years at Mayo clinics, rx with enoxaparin or DOAC and followed prospectively (N = 750) ❖ Primary endpoint: Recurrent VTE; Secondary: Major bleeding ❖ Main results: Similar recurrence rates and major bleeding ❖ More minor, but clinically relevant bleeding with rivaroxaban

❑ Cleveland Clinic (Park et al., ASH 2018)

❖ Cohort of cancer patients with VTE over ~3.5 years at Cleveland Clinic, rx with enoxaparin or rivaroxaban and followed prospectively (N = 258) ➢Enoxaparin was standard, then rivaroxaban ➢72% received enoxaparin; remainder mostly rivaroxaban ❖ Endpoints: Recurrent VTE, major bleeding ❖ Main results: Similar recurrence and bleeding rates; nonsignificant trend toward reduced VTE recurrence with DOAC

2019 Guidelines for Initial Treatment of Cancer-Associated VTE

❑ International Initiative on Thrombosis & Cancer (Farge et al., Lancet Oncol

2019)

❖ LMWH over UFH if CrCL ≥30 mL/min (grade 1b) ❖ Rivaroxaban or LMWH -> Edoxaban if not at high risk for GI/GU or other bleeding if CrCl ≥30 mL/min (grade 1b) ❖ Minimum duration 6 months (grade 1a) ➢ Catheter-associated 3 months (guidance, “expert opinion”) ❖ Risk/benefit after 6 months (guidance)

❑ ASCO (Key et al., JCO 2019)

❖ LMWH, DOACs (rivaroxaban, edoxaban). Strong recommendation ❖ VKAs inferior, but may be used if LMWH, DOACs unavailable ❖ Minimum duration 6 months (strong recommendation)

❑ NCCN

❖ 1A for Dalteparin monotherapy and LMWH → Edoxaban

❑ Canada

❖ LMWH for GI/GU, high bleeding risk, drug-drug interactions ❖ Rivaroxaban, edoxaban for everybody else

❑ ISTH

❖ Rivaroxaban, edoxaban unless a good reason not to

Choosing an anticoagulant

DOAC LMWH VKA

Noninferior alternative to LMWH, better patient satisfaction & adherence Prefer in non GI/GU malignancies & in low bleeding risk patients Avoid if GI bleed, mucosal toxicity, malabsorption, high bleeding risk Avoid if significant drug-drug interaction expected May be first choice based on experience Prefer in GI/GU malignancies & in high bleeding risk patients May be good initial choice for patients with VTE associated with cancer recurrence Drug-drug interactions not much concern Best option for patients unable to use or access DOAC or LMWH Consider if stable disease or remission Avoid in GI toxicity, cachexia, liver failure Lab monitoring essential

Don’t be afraid to use a hybrid approach

Adapted from A Lee ISTH 2019.

59 yo woman with metastatic breast cancer

Bilateral, proximal LE DVT diagnosed in August 2019. Popliteal → femoral veins; CTPA not done What are your treatment choices in 2019? Hybrid approach selected Weight based enoxaparin for a month → apixaban, 5 mg twice daily

40 yo man with diffuse large B-cell lymphoma.

Stage IIIA diffuse large B-cell lymphoma, GC subtype. CT chest as part of staging showed isolated subsegmental PE (SSPE) R-CHOP anticipated He is asymptomatic from this radiographic finding and wants to get on with it. What do you do with him now?

Incidental PE in cancer patients ❑ Prevalence: up to 15% of cancer patients ❑ Accounts for ~50% of all PE in cancer ❑ Prognosis in isolated SSPE

❖ Non-cancer: Similar with or without anticoagulation (Carrier et al., JTH 2010) ❖ Cancer: Increased risk for recurrence even with anticoagulation (van der

Hulle et al., JTH 2016; Kraaijpoel et al. JCO 2019)

❑ ASCO 2019: Treat with anticoagulation

❖ Informal consensus, low quality evidence

❑ ISTH:

❖ Compression ultrasound of both legs ➢If DVT → TREAT ➢If no DVT → “Individualize”

▪ Think for a minute about risk/benefit and most likely treat

❖ If you don’t treat → Follow closely

40 yo man with diffuse large B-cell lymphoma.

Stage IIIA diffuse large B-cell lymphoma, GC subtype. CT chest as part of staging showed isolated subsegmental PE R-CHOP anticipated He is asymptomatic from this radiographic finding and wants to get on with it. What do you do with him now? Bilateral LE duplex studies → bilateral calf DVTs Treated with standard schedule rivaroxaban

66 yo woman with newly dx extensive SCLC

Will be starting outpatient platinum/etoposide chemotherapy shortly. She has no evidence for VTE at this time. CBC: WBC 13K/uL Hgb 11 g/dL Plts 385K/uL BMI: 29 kg/M2 The thoracic oncologist just received an email notification about a NEJM study showing that prophylactic anticoagulation prevents VTE in cancer patients and wants to know if he should be starting everybody on it.

Thromboprophylaxis in ambulatory cancer patients ❑ VTE risk increased 4 – 7-fold in cancer; 5-10% incidence in the first year after diagnosis ❑ LMWH v placebo in ambulatory patients with cancer

❖ 5 Meta-analyses ❖ Reduce VTE risk by ~ 50%; ~80% reduction in pancreatic cancer ❖ Increase bleeding to a variable degree ❖ No effect on survival ❖ NNT in unselected patients >40-50

Key et al., JCO 2019

Thromboprophylaxis in ambulatory cancer patients

Bleeding, high cost, inconvenience/pain of LMWH injections

Khorana Score

Khorana et al. Blood 2008;111:4902-4907

Ambulatory cancer patients 115 sites in U.S. Patients with common solid tumors targeted for enrollment All cancers but acute leukemia & stem cell transplants N = 2701 in derivation cohort N = 1365 in validation cohort Median f/u 2.5 mo

Khorana Score

Khorana et al. Blood 2008;111:4902-4907

Low: 0 Intermediate: 1-2 High: >/= 3 Patient Characteristics Risk Score Cancer site

Very high risk (stomach, pancreas) High risk (lung, lymphoma, gyn, bladder, testicular)

2 1 Pre-chemotherapy platelet count >350K/uL 1 Pre-chemotherapy WBC count >11K/uL 1 Hemoglobin <10 g/dL OR use of ESA 1 BMI >35 kg/M2 1

Khorana Score Meta-Analysis

Khorana et al. Blood 2008;111:4902-4907

Lower threshold Risk Group 6-month VTE (%) Low (0-1) 5.5 High (>/=2) 8.9 Lung, Heme → Lower risk GI/GU → Higher risk

Mulder et al. Haematologica 2019;104:1277-87

55 cohorts; 34555 ambulatory cancer patients 80% with 6 month follow up

DOACs for Primary Prophylaxis in Cancer – Khorana score >/=2

Carrier et al. NEJM 2019;380:711-9

Parameter AVERT CASSINI

Drug

Apixaban, 2.5 mg twice daily Rivaroxaban, 10 mg once daily N of patients 563 841 Median duration rx 5.2 mo 4.3 mo Screening US No Yes; asx DVT excluded Myeloma, Brain Yes Excluded 1o efficacy

• utcome

Sx DVT, Sx or incidental PE, VTE-related death Sx or asx VTE (screened), VTE-related death 1o safety outcome Major bleeding Major bleeding Result: VTE A: 4.2%; P: 10.2% (P<0.001) R: 6.0%; P: 8.8% (NS) Result: Bleed A: 3.5%; P:1.8% R: 2.0%; P: 1.0% NNT 17 26 NNH 100 101

Khorana et al. NEJM 2019;380:720-8

2019 Guidelines for Primary Prophylaxis in Ambulatory Patients ❑ All agencies give similar guidance ❑ Not recommended in unselected patients ❑ Offer DOAC to high risk patients who are not at increased bleeding risk

❖ Apixaban, Rivaroxaban

❑ Offer LMWH if at high VTE risk but with increased bleeding risk ❑ Aspirin or LMWH for myeloma patients with thalidomide, lenalidomide

Suggested Primary Prophylaxis Algorithm a la AVERT Trial

Pancreas Stomach Brain Lung Lymphoma Gyn Bladder Testicular Myeloma Kidney Others Evaluate for additional Khorana risk parameters: 1. Pre-chemotherapy platelet count >350K/uL 2. Pre-chemotherapy Hgb <10 g/dL 3. Pre-chemotherapy WBC >11K/uL 4. BMI >35 kg/m2 Evaluate for AVERT exclusion parameters: 1. Increased risk for bleeding 2. Coagulopathy from liver disease 3. Platelets <50K/uL 4. GFR <30 mL/min 5. Pregnant/breast feeding 6. Weight <40 kg 7. Life expectancy <6 months Consider prophylaxis +1 +2

From: S. Moll. The Hematologist. Home Columns Clinical Trials Corner March-April 2019, Volume 16, Issue 2

66 yo woman with extensive SCLC

Will be starting outpatient platinum/etoposide chemotherapy shortly. She has no evidence for VTE at this time. CBC: WBC 13K/uL Hgb 11 g/dL Plts 385K/uL BMI: 29 kg/M2

+1 +1 +1 Khorana score = 3, high risk No excessive bleeding risk Offer prophylaxis

Poorly Answered Questions Going into 2020

❑ Duration of anticoagulation in cancer-associated VTE?

❖ Can you reduce the dose after 6 months?

❑ What to do in the setting of anticoagulant failure and recurrence? ❑ How to handle anticoagulation with thrombocytopenia? ❑ What is the best tool to use to assess bleeding risk? ❑ Arterial thrombosis prophylaxis and treatment? ❑ Shouldn’t it be illegal to insert an IVC filter?