Cancer Associated Venous Thromboembolism · 12/12/2019 4 ©2017 MFMER | 3749793-19 Occult Cancer in Patients with Idiopathic or Unprovoked VTE • Unprovoked VTE carries a 4 fold

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Cancer Associated Venous Thromboembolism

Robert D McBane II MDGonda Vascular Center

©2017 MFMER | 3749793-2

Financial Disclosure Information

Cancer Associated VTERobert McBane, MD

BMS/Pfizer Research Grants

©2017 MFMER | 3749793-3

Cancer Associated Venous Thrombosis: Discussion Outline

• Nature of the problem

• Appropriate work up for occult cancer

• Cancer VTE treatment trials

• What to do when treatment fails

©2017 MFMER | 3749793-4

Annual VTE Events in the U.S. Population

0

100,000

200,000

300,000

400,000

500,000

600,000

2005 2006 2007 2008 2009 2010

• Current or recent hospitalization : 257,783 (52%)• In-hospital VTE events: 64,747 [25%]

• No recent hospitalization: 237,886 (48%)

Average annual VTE events: 495,669 per year

Heit, JA, Ashrani, AA, et al. Thromb Haemost 2017; 117: 390–400

©2017 MFMER | 3749793-5

Prevalence of Major VTE Risk FactorsBy Calendar Year; 1988 - 2010

Obesity

Hospitalization

Surgery

Pregnancy

Trauma/ fracture

Paresis

Nursing home

Heit, JA, Ashrani, AA, et al. Thromb Haemost. 2017;117(2):390-400

Cancer

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• Cancer accounts for up to 20% of all incident VTE cases

• Cancer without chemotherapy increases risk 4 fold

• Cancer with chemotherapy increases the risk 6.5 fold

• Biological aggressiveness of cancer is associated with thrombogenic potential

Heit, JA, et al., Arch Intern Med. 2000; 160:8.9-815 Heit, JA, et al., Arch Intern Med. 2002; 162:1245-1248

Cancer and Venous Thromboembolism Facts

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Sorensen HT, et al. NEJM 2000; 343;1846-50.

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12% vs 36% survival at 1 year p<0.001

Years after diagnosis

Surv

iva

l (%

of

pa

tients

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Survival following Cancer-Associated VTE

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Cancer Site and Risk of Incident VTECancer Site Cancer site score (SMR)†

Brain 47.2Pancreatic 42.0Other digestive 30.9Lymphoma 28.8

Leukemia 19.8Stomach 18.2Multiple myeloma 14.0Kidney 13.9Lung 13.0

Ovary 13.0Myeloproliferative neoplasm 12.6Bladder 11.0Melanoma 9.7Breast 8.6

Other gynecologic 8.4Prostate 7.9Colon/rectal 7.3

Thrombosis Research. 2014;135:472-8.

† Standardized morbidity ratio

©2017 MFMER | 3749793-9

Cancer Stage and Risk of VTEDanish national registry data 1997-2005

Incidence rate of hospitalization for VTE by cancer stage (Ref: general population)

Stage Incidence /1000 p-y Adjusted Relative Risk

(95% CI)

I 4.4 2,9 (1.5-5.5)

II 4.9 2.9 (2.4-3.5)

III 11.1 7.5 (6.0-9.4)

IV 27.7 17.1 (12.6-23.3)

Br J Cancer. 2010; 103:947 – 953©2017 MFMER | 3749793-10

Time Since Cancer Diagnosis and VTE Risk

Duration between malignancy

diagnosis and VTE

Adjusted Odds Ratio

(95% CI)

0 to < 3 months 53.5 (8.6-334.3)

3 months to < 1 year 14.3 (5.8-35.2)

1 year to < 3 years 3.6 (2.0-6.5)

3 years to < 5 years 3.0 (1.5-5.7)

5 years to < 10 years 2.6 (1.4-4.7)

10 years to < 15 years 2.3 (0.9-5.8)

> 15 years 1.1 (0.6-2.2)

JAMA. 2005;293:715-722

Dutch MEGA case-control study

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Cancer Treatment and VTE Risk• Chemotherapy increases the VTE risk 6.5 fold

• Tamoxifen

• IMIDs (thalidomide, lenalidomide, pomalidomide)

• Cisplatin

• L-asparaginase

• 5-fluorouracil

• Bevacizumab

• Gemtuzumab ozogamicin

• Recombinant erythropoietin

• Leucocyte growth factors (G-CSF and GM-CSF)

Ashrani, AA, Rajkumar SV. Cancer Treat Res. 2009;148:181-206. ©2017 MFMER | 3749793-12

Cumulative VTE Recurrence Rate for Cancer Associated vs Idiopathic vs Other Secondary VTE

Heit, JA, Ashrani, AA, et al. Thrombosis Research 2015;136:298-307.

Idiopathic

Other secondary

Active cancer

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20

10

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Cancer: 43%

Idiopathic: 27%

Other secondary:18%

5-Year Cumulative Recurrence Rate:

Years after incident VTE

VT

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ec

urr

en

ce

-Cu

mu

lati

ve

, %

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CANCER ASSOCIATED VTE: Summary

• One-fifth of all incident VTE is attributed to cancer

• VTE recurrence rate is higher in patients with active cancer than those without cancer

• Cancer site, stage and treatment along with (non-cancer) patient characteristics are associated with risk of incident and recurrent VTE

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58-year-old male Three week history of cough and dyspnea. Recent travel between Rochester and Fargo (6 hours). No additional trauma or surgery.

General: Dyspneic

Vitals: BP: 115/66 Pulse: 92/min.

Heart: Normal JVP. No RV lift. No murmurs or gallops.

Extremities: No edema.

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After recovery and discharge from the hospital, what is the appropriate assessment for occult malignancy for this patient?

1. GME with age/gender appropriate screening

2. #1 plus US abdomen

3. #1 plus CT chest abdomen, pelvis

4. #1 plus FDG PET/CT

5. #1 plus pan-endoscopy

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Occult Cancer in Patients with Idiopathic or Unprovoked VTE

• Unprovoked VTE carries a 4 fold increased risk of occult malignancy.

• 10% will have new cancer diagnosis in 1st yr

• Most common tumors include:

• Ovary

• Pancreas

• Liver

Ann Intern Med 2008;149;323-33

J Thromb Haemost 2011;9:79-84 ©2017 MFMER | 3749793-20

How much screening is necessary to exclude

occult cancer in patients with unprovoked VTE?

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Is extensive screening for cancer in idiopathic VTE warranted?

Prospective controlled cohort study

288 “Limited Screening” group

• H&P, basic labs, chest X-ray

342 “Extensive Screening” group

• CT chest/abd/pelvis and mammography

Baseline cancer detection

• Limited 2.4%

• Extensive 3.5%

• 6 additional cancers detected (3 curable)

J Thromb Haemost. 2011;9:79-84.©2017 MFMER | 3749793-22


J Thromb Haemost. 2011;9:79-84.

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Mortality Rates @ 2.5 years follow up:

• Limited 8.3%

• Extensive 7.6%

• HR 1.22 (95% CI, 0.69-2.22).

Cancer related deaths @ 2.5 years follow up:

• Limited 2.8%

• Extensive 5.0%

• HR 1.79 (95% CI, 0.74-4.35).

J Thromb Haemost. 2011;9:79-84.©2017 MFMER | 3749793-24

Extensive screening for occult malignancy in idiopathic VTE

“SOME Trial"

854 patients

CT abd/pelvis virtual endoscopy

Limited testing

Patients: Idiopathic VTE

Primary endpoint: cancer @ 1 year missed by initial screening

N Engl J Med 2015;373:697-704

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New cancer diagnosis: overall 3.9%

• Limited 3.2% p=0.28

• CT 4.5%

During follow up, 9 additional cancers confirmed

• Limited 4 p=1.0

• CT 5

J Thromb Haemost 2004;2:884-89

Extensive screening for occult malignancy in idiopathic VTE

SOME Trial

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PET/CT for occult malignancy screening in unprovoked VTE

“MVTEP Trial”

399 patients

18F-FDG PET/CT

Limited testing

Patients: Idiopathic VTE

Primary endpoint: # of cancer diagnoses

Lancet Oncol 2016;17:193-99

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PET/CT for occult malignancy screening in unprovoked VTE

“MVTEP Trial”

Lancet Oncol 2016;17:193-99

NO Difference in new cancer diagnoses• PET/CT 5.1%• Limited 2.0%• Risk difference 3.6% (95% CI -0.4 to 7.9, p=0.07)

NO Difference in survival

NO Difference in cancer stage at diagnosis

©2017 MFMER | 3749793-28

Screening for Occult Cancer: Bottom Line

Patients with unprovoked VTE should undergo a through history and physical examination, basic lab testing (CBC, metabolic profile and LFTs) and CXR.

Age and gender-specific cancer screening are also warranted.

Extensive imaging/screening is neither warranted nor cost effective.

J Thromb Thrombolysis. 2016;41:81-91

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Cancer Associated VTE Guidelines

American Society of Clinical Oncology (ASCO)

National Comprehensive Cancer Network (NCCN)

European Society for Medical Oncology (ESMO)

J Clin Oncol. 2013;31:2189-204

https://www.nccn.org

Ann Oncol 2011:22(suppl_6):vi85

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Compared to warfarin, which of the following statements is true regarding VTE treatment in cancer patients?

1. LMWH improves efficacy (recurrent VTE).

2. LWMH improves safety (major bleeding).

3. LMWH improves survival

4. DOAC therapy leads to increased VTE recurrence

5. DOAC therapy leads to increased major bleeding

©2017 MFMER | 3749793-32

Cancer Associated VTE Treatment has a High Risk of Complications

• Risk of anticoagulant associated major bleeding can be as high as 12%.

• Risk of recurrent VTE on warfarin may be as high as 21%.


©2017 MFMER | 3749793-33

Managing VTE in Cancer is Complicated!

Increased thrombosis risk• Cancer-specific prothrombotic activity,

• Hormonal therapy

• Angiogenesis inhibitors,

• Central venous catheters

• Surgery

Increases bleeding risk• Chemotherapy-related hepatic and renal injury,

• Thrombocytopenia,

• Tumor friability

• Surgery

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Morbidity of Cancer-Associated VTE

Hutten BA, et al. J Clin Oncol 2000; 18:3078-83.

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LMWH vs. Warfarin for the Preventionof Recurrent VTE in Cancer Patients

the CLOT Trial

672 patients

Dalteparin 200 IU/kg/d x 1 month150 IU/kg/d x 5 months

Dalteparin bridged to warfarin

Patients: Cancer with acute symptomatic VTE

Primary endpoint: Symptomatic VTE recurrence

N Engl J Med 2003;349:146-53.©2017 MFMER | 3749793-36

Recurrent VTE

N Engl J Med 2003;349:146

HR 0.48 (95%CI, 0.30 to 0.77; P=0.002).NNT 12

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N Engl J Med 2003;349:146

Safety Dalteparin WarfarinMajor bleeding: 6% 4%

LMWH Reduced Thrombosis Outcomes

©2017 MFMER | 3749793-38

Mortality did not Differ

N Engl J Med 2003;349:146

©2017 MFMER | 3749793-39

Cancer VTE Guidelines

• LMW Heparin preferred (2B)

• Extend treatment regardless of bleeding risk (1B)

• Same anticoagulant used for first 3 months

ACCP Guidelines 2016©2017 MFMER | 3749793-40

LMWH has Limitations

Injections painful and cause ecchymoses

Cost prohibitive @ $100/day

Thrombocytopenia

• Cancer or cancer treatments limit its use

• Raise concerns regarding HIT

No effective or proven antidote

Renal failure may limit its use

©2017 MFMER | 3749793-41

What about Novel Anticoagulants?

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Oral Direct Factor Inhibitors

Fibrinogen Fibrin

ThrombinProthrombin

XaVa

X

VIIIa

ApixabanRivaroxabanEdoxaban

Dabigatran

FDA approval (VTE): November 2012

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DOAC and Cancer-Associated VTEXX Trial

XX patients

DOAC

Dalteparin 200IU/d x 1 m, 150 IU/d

Patients: Cancer with acute symptomatic VTE

Primary endpoint: Recurrent VTE or major bleeding

x 6 - 12 months

©2017 MFMER | 3749793-44

EFFICACY: Recurrent VTEHOKUSAI Cancer VTE P-value

Edoxaban 7.9% 0.09

LMWH 11%

ADAM VTE 0.03

Apixaban 0.7%

LMWH 6.3%

SELECT D <0.05

Rivaroxaban 4%

LMWH 11%

©2017 MFMER | 3749793-45

SAFETY: Major BleedingHOKUSAI Cancer VTE P-value

Edoxaban 6.9% 0.04

LMWH 4%

ADAM VTE NS

Apixaban 0%

LMWH 1.4%

SELECT D NS

Rivaroxaban 6%

LMWH 4%

©2017 MFMER | 3749793-46

Overall MortalityHOKUSAI Cancer VTE P-value

Edoxaban 39.5% NS

LMWH 36.5%

ADAM VTE NS

Apixaban 16%

LMWH 11%

SELECT D NS

Rivaroxaban 25%

LMWH 30%

Anticoagulation Satisfaction survey

Favors Apixaban

Favors Dalteparin

Premature discontinuation: Apixaban 6 (4%) vs. Dalteparin 22 (15%), p=0.0012

Favorsdalteparin

Cyc

le (

Mo

nth

s)

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DOACs and Cancer-Associated VTE: Conclusions

Hokusai Cancer VTE (edoxaban), SELECT-D (rivaroxaban), and ADAM VTE (apixaban) suggest that DOACs are as effective as dalteparin in the treatment of cancer associated VTE

Bleeding complications remain a concern particularly GI bleeds in patients with upper GI malignancies

Apixaban appears to lower the rate of major bleeding

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Ongoing Cancer VTE TrialsCARAVAGGIO Trial

Apixaban vs. Dalteparin for acute VTE treatment

Status: Completed

CANVAS Trial

Any DOAC for acute VTE treatment

Status: Enrolling

EVE Trial

Extended Apixaban (2.5 mg vs. 5 mg) for secondary prevention

Status: Enrolling

©2017 MFMER | 3749793-50






©2017 MFMER | 3749793-51

71 y/o Female

2017

August 16 Localized pancreatic cancer

August 23 Expl laparoscopy “negative”

August 26 Port placed, FOLFIRINOX started

October 22 Develops dyspnea and chest pain

©2017 MFMER | 3749793-52

©2017 MFMER | 3749793-53

71 y/o FemaleShe received enoxaparin 1 mg/kg twice daily for 1 month then 1.5 mg/kg daily. December, she notes painless swelling of her right leg.

©2017 MFMER | 3749793-54

What would you recommend now?1. IVC filter

2. Add aspirin

3. Change to a DOAC

4. Increase LMWH dose by 25%

5. Not clear from what you have presented

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Anticoagulation Failures in Cancer PatientsLearning objectives

To understand the nature of the problem

To define a strategy for working through the evaluation and management of AC failures in Cancer patients.

©2017 MFMER | 3749793-56

Anticoagulant Failure in Cancer: Nature of the Problem

USA

• 1,735,350 new cancer diagnoses (2018)

• > 14 M cancer survivors

• 1 in 5 cancer patients develop thrombosis

• ~ 3 M cancer patients with VTE

©2017 MFMER | 3749793-57

What is the risk of developing a new thrombus on anticoagulants

(anticoagulation failure) in cancer patients?

©2017 MFMER | 3749793-58

Risk of Anticoagulant Failure: Oral Agents

Agent TrialTreatment failures

(%)

Trial Duration

(days)

Edoxaban Hokusai Cancer VTE 7.9%365

Rivaroxaban SELECT D 4%180

Warfarin CLOT 16%180

CATCH 10.5%127

©2017 MFMER | 3749793-59

Risk of Anticoagulant Failure: Parenterals

Agent TrialTreatment failures

(%)

Trial Duration

(days)

Dalteparin Hokusai Cancer VTE 13.5%365

SELECT D 11%180

DALTECAN 9%180

CLOT 9%180

14%365

Tinzaparin CATCH 7.2%160

©2017 MFMER | 3749793-60

Lots of data: Let’s summarize AC Failure rates

DOACs: 4% at 6 months (Riva),

8% at 1 year (Edoxa)

Warfarin: ~ 2.5% failure rate per month

(CLOT 16% @ 6 mos. CATCH 10.5% @ 4 mos)

LMWH: 10% at 6 months or

14% at 1 year

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How does this compare to

no therapy?

30% annual recurrence off anticoagulants

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Are there Risk Factors for Anticoagulant Failure in Cancer?

©2017 MFMER | 3749793-63

Cancer Specific Risk Factors

• Stomach or Pancreas vs. Other Cancers

HR 5.55 (95%CI 1.97 – 15.66)

• Lymphoma, Lung, GYN, or Bladder vs. Other Cancers

HR 2.69 (95%CI 1.11 – 6.53)

• Metastatic disease vs. Nonmetastatic disease

HR 2 - 3

SELECT D Trial. J Clin Oncol 2018Blood 2017

©2017 MFMER | 3749793-64

VTE Specific Risk Factors

• Symptomatic vs. Incidental PE

HR 2.78 (95%CI 1.20 – 6.41)

• VTE within 3 months of Cancer Diagnosis

SELECT D Trial. J Clin Oncol 2018Blood 2017

©2017 MFMER | 3749793-65

Anticoagulant Failures in Cancer: Bottom Line

• Cancer associated VTE is common

• Anticoagulation Failures are also common

• These failures are Anticoagulant specific, Cancerspecific, and VTE presentation type specific

©2017 MFMER | 3749793-66

What Factors Should We Consider In

Cancer Patients With Anticoagulant Failure?

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1. Has there truly been an Anticoagulant Failure?

• The original VTE must be reviewed and confirmed (US, venography, CT, or MRI).

• Recurrent VTE must be distinguished from the original by comparing serial imaging.

• To be classified as a recurrent event, there must be new filling defects evident on the second study not appreciated on the original images or an interval study clearly showing thrombus resolution.

©2017 MFMER | 3749793-68

Back to our patientLeg imaging was not performed with the original PE…….

©2017 MFMER | 3749793-69

2. Is drug metabolism normal?

• Is the dose correct?

• Can you check a drug level prior to discontinuing?

• Is the patient “hyper-clearing”? (LMHW, dabigatran, edoxaban)

• Are there drug interactions? (CYP 3A4 inducers)

• Is the patient taking the drug appropriately? (Drug absorption, meals, and rivaroxaban)

• Is there altered GI motility? (Gastric bypass or resection)

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3. Is the patient compliant?

• Drug levels

• Pill counts

• Pharmacy review

• Recent interruptions for procedures

©2017 MFMER | 3749793-71

4. Is there drug specific complications?

• Heparin induced thrombocytopenia

• Antiphospholipid syndrome

©2017 MFMER | 3749793-72

5. Is the anticoagulant failure due to tumor thrombus?

• Renal cell carcinoma

• Sarcoma

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Renal Cell Carcinoma with “Tumor Thrombus”

Int J Urol 2012;9:1-4 Blood 1986 68:394-399

TF positive tumor

©2017 MFMER | 3749793-74

What are the Predictors of VTE Recurrence among Cancer Patients?

©2017 MFMER | 3749793-75

Predicting VTE Recurrence in Cancer Patients

Olmsted County 1966-2000

• 681 incident cases (20% of total)• DVT 60% PE ± DVT 40%

• 66% had stage III/IV cancer

• 30% mortality within 24 hrs

Blood 2014;123:3972©2017 MFMER | 3749793-76

Independent predictors of VTE recurrence among patients with active cancer

Characteristic HR 95% CI

Stage IV Pancreatic 6.38 2.68 – 15.13

Brain 4.57 2.07 – 10.09

Myeloprolif/myelodyspl 3.49 1.59 – 7.68

Ovarian 3.22 1.57 – 6.59

Stage IV cancer 2.85 1.74 – 4.57

Lung 2.73 1.63– 4.55

Cancer stage progression 2.14 1.30 – 3.52

Blood 2014;123:3972

©2017 MFMER | 3749793-77

Cumulative incidence of VTE recurrence by VTE predictor status

Blood 2014;123:39723 fold increased recurrence rate with any predictor

©2017 MFMER | 3749793-78

Treatment Failure: Guidance

Symptomatic recurrent VTE despite therapeutic anticoagulation (non-LMWH agent) transition to therapeutic LMWH.

If symptomatic recurrence on LMWH, increase current dose by 25%.

Avoid IVC filters unless anticoagulation is contraindicated (e.g. active bleeding). Then consider retrievable filter.


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Questions & Discussion

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Cancer Associated Venous Thromboembolism · 12/12/2019 4 ©2017 MFMER | 3749793-19 Occult Cancer in Patients with Idiopathic or Unprovoked VTE • Unprovoked VTE carries a 4 fold