How to Assess the Risk of VTE in Ambulatory Cancer Patients Receiving ChemotherapyMarc Carrier MD FRCPC

SAES.ENO.20.02.0157b FEBRERO 2020

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Objectives

• 1) To review the epidemiology and clinical relevance of venous thromboembolic (VTE) complications in cancer patients

• 2) To discuss the role of different Risk Assessment Models to stratify ambulatory cancer patients according to their underlying risk of VTE

• 3) To review if these Risk Assessment Models can help clinicians in providing VTE awareness to patients and help decision about thromboprophylaxis.

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Incidence

Annual incidence of VTE in the general population is 117 per 100,000• Cancer alone was associated with a 4.1-fold risk of thrombosis• Chemotherapy increased the risk 6.5-fold

Combining these estimates yields an approximate annual incidence of venous thromboembolism (VTE) of 1 per 200 in a population of cancer patients

Heit JA et al. Arch Intern Med. 2000; 160: 809–815.

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Cancer and VTE

5.8 (95% CI 5.7 to 6.0)

Lyman GH, Cancer 2010;7:1334–1349

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Incidence rate of CAT by cancer typeIncidence rate (95% CI) of first VTE per 100 person-years by cancer type

Age Total ≥18

Bladder 2.7 (2.4–3.0)

Breast 3.2 (2.9–3.4)

Colon 6.7 (6.3–7.2)

Lung 10.1 (9.5–10.8)

Prostate 4.4 (4.0–4.7)

Uterus 7.0 (5.9–8.3)

Haematological 4.5 (4.1–4.8)

Brain 12.1 (10.3–14.0)

Ovary 11.9 (10.6–13.2)

Pancreas 14.6 (12.9–16.5)

Stomach 10.8 (9.5–12.3)

Cohen AT et al, Thromb Haemost 2017;117:57–65

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Patient demographicsPatients with active cancer and a first VTE (N=6592)

DVT (n=3055)

PE (n=3537)

Total (N=6592)

Common cancer types, n (%)Prostate (males) 278 (19.1) 287 (16.1) 565 (17.5)Breast (females) 225 (14.0) 281 (16.0) 506 (15.1)Lung 315 (10.3) 603 (17.0) 918 (13.9)Colon 384 (12.6) 443 (12.5) 827 (12.5)Haematological 360 (11.8) 309 (8.7) 669 (10.1)Ovarian (females) 136 (8.5) 182 (10.3) 318 (9.5)Bladder 186 (6.1) 133 (3.8) 319 (4.8)Uterus (females) 83 (5.2) 58 (3.3) 141 (4.2)Pancreas 129 (4.2) 131 (3.7) 260 (3.9)Stomach 104 (3.4) 133 (3.8) 237 (3.6)Brain 79 (2.6) 87 (2.5) 166 (2.5)

Cohen AT et al, Thromb Haemost 2017;117:57–65

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VTE as a cause of morbidity, mortality and costs

Cancer outpatient mortality

71%

9%

9%

4%1%1% 6% 4%

Cancer progression

Thromboembolism

Respiratory failure

BleedingAspiration

Other Unknown

Infection

• Increase morbidity and decrease QALY

• Significant increase in health care costs

• Annual death rate for VTE: 448 per 100,000 cancer outpatients– 47-fold increase over

the general population

Khorana AA et al, J Thromb Haemost 2007;5:632–634; 2. Khorana AA et al, Thromb Res 2010;125:490–493; Cohen AT et al. Thromb Haemost. 2017;117(1):57-65.Lloyd AJ et al. Value Health. 2018;21(4):449-55.

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Assessment for risk of VTE in ambulatory cancer patients

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Individual risk factors

• Advanced age

• Female gender

• Prior VTE

• Patient co-morbidities

• Infection, obesity, anemia, pulmonary or renal disease

• Prolonged immobilization

• Inherited thrombophilic factors

• Site: brain, pancreas, kidney, stomach, lung, bladder, gynecologic, hematologic malignancies

• Stage: advanced stage and initial period after diagnosis

• Hospitalization

• Surgery

• Chemo- and hormonal therapy

• Anti-angiogenic therapy

• Erythropoiesis stimulating agents

• Blood transfusions

Patient-related factors Cancer-related factors

Imberti D et al. Thrombosis Research 140S1 (2016) S103–S108.

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ASCO Guidelines

Individual risk factors, including biomarkers and

cancer site, do not reliably identify patients with

cancer at high risk of VTE. In the outpatient

setting, risk assessment can be conducted based

on a validated risk assessment tool.

Key N et al. J Clin Oncol. 2019 Aug 5:JCO1901461. [Epub ahead of print]

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Risk assessment: Khorana score for outpatients

Patient characteristic Score

Site of cancer

Very high risk: stomach, pancreas

High risk: lung, lymphoma, gynaecologic, bladder, testicular

2

1

Prechemotherapy platelet count ≥350,000/mm3 1

Hemoglobin <10 g/dL and/or use of erythropoiesis-stimulating agents

1

Prechemotherapy leukocyte count >11,000/mm3 1

Body mass index ≥35 kg/m2 1

High-risk score, ≥3; Intermediate-risk, 1-2; Low-risk score, 0.

Khorana AA, et al. Blood 2008;111:4902–907

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Validation of Khorana risk score

• Systematic review and meta-analysis• 45 articles and 8 abstracts• 27,840 patients with 6 month FU

• Of the patients with VTE, 23.4% (95%CI: 18.4-29.4) had ben classified as high risk (≥ 3 points)

• Khorana score can be used to stratify patients according to their underlying risk of VTE

• However, most events occur outside of the high risk groups

Validated in 34,555 patients in multiple countries

Mulder FI et al. Haemoatologica. 2019;104:1277-1287

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Risk assessment: PROTECHT and CONKO score

Patient characteristic Khorana Vienna PROTECHT CONKO

Site of cancer

Very high risk: stomach, pancreas,

High risk: lung, lymphoma, gynaecologic, bladder, testicular

2

1

2

1

2

1

2

1

Prechemotherapy platelet count ≥350,000/mm3 1 1 1 1

Haemoglobin <10 g/dL and/or use of erythropoiesis-stimulating agents 1 1 1 1

Prechemotherapy leukocyte count >11,000/mm3 1 1 1 1

Body mass index ≥35 kg/m2 1 1 1 0

D-dimer - ≥ 1.44 µg/mL 0 1 0 0

sP-selectin - ≥ 53.1 mg/mL 0 1 0 0

Gemcitabine chemotherapy 0 0 1 0

Platinum chemotherapy 0 0 1 0

WHO performance status ≥ 2 0 0 0 1VTE SAFE

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Comparision of risk scores

• Prospective cohort study (n=827)

• 53 (6.1%) had VTE

• C-statistics ranged from 0.50 to 0.57

• High-risk patients had a significantly increased risk of VTE using the Vienna (HR 1.7; 95%CI: 1.0-3.1) and PROTECHT score (HR: 2.1; 95% CI: 1.2-3.6)

Van Es N et al. Haematologica 2017;102:1494-1501.

The Vienna and PROTECHT scores appear to discriminate better between low- andhigh-risk patients but further improvements are needed.

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Can we do better?

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Risk assessment: COMPASS score for outpatients

Patient characteristic Score

Cancer-related risk factorAnti-hormonal therapy for women with hormone receptor-positive breast cancer or on anthracycline therapy

Time sine cancer diagnosis ≤ 6 months

CVC

Advanced stage cancer

6

4

3

2

Cardiovascular risk factors (2 of: personal history of PVD, CVA, HTN, hyperlipidemia, DM and obesity)

1

Recent hospitalization for acute medical illness 5

Personal history of VTE 1

Prechemotherapy platelet count ≥350,000/mm3 2

High-risk score, ≥7; Low/Intermediate-risk, 0-6.

• Patients with:• Breast (61%)• Colorectal (17%)• Lung (13%)• Ovarian cancer (8.6%)

• Symptomatic VTE in 8.5% over 6 months

• High risk: 13.3%• Low/Intermediate: 1.7%

Gerotziafas GT et al. The Oncologist 2017;22:1222-1231

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Risk assessment: Simplified score for outpatients

• Derivation in the CATS cohorts (n=1423)

• Validation in MICA (n=832)

• Tumor type only + D-dimer as continuous variable

• Cross-validated c-indices prediction was adequate at 0.66 (95%CI: 0.63-0.67) in CATS and 0.68 (95% CI: 0.62-0.74) in MICA Nomogram for predicting the 6-month risk of VTE

Pabinger I et al. Lancet Haemost 2018; 5:e289-98

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Risk assessment: TIC-Onco

BJC 2018 TiC Onco KS P value

AUC 0.73 0.58 <0.001

Sensitivity 49% 22% <0.001

Specificity 81% 82% 0.823

PPV 37% 22% 0.004

NPV 88% 83% <0.001

• 391 patients with cancer• 71 VTE

• Clinical and genetic predictors• Clinical:

Type of tumorStageBMIFamiliy history

• Genetic risk score• 12 SNPs in 7 genes, follow

up 6 months

Muñoz AJ et al Brit J Cancer 2018 Apr;118(8):1056-1061.

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Can risk stratification help in real life?

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Can the Khorana risk score be useful for my practice?

Prospective observational cohort of 580 patients

Lustig DB et al. Thromb Res. 2015 Dec; 136(6): 1099-102.

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Can the Khorana risk score be useful in my practice?

• VTE: 19/437 (4%)

Khorana risk score < 2

• (n=143 (25%))

• VTE: 16/143 (11%)

Khorana risk score ≥ 2

Lustig DB et al. Thromb Res. 2015 Dec; 136(6): 1099-102.

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Conclusions

VTE is a frequent and important complication of ambulatory cancer patients receiving chemotherapy

Different Risk Assessment Models can identified patients with high thrombotic rates

Findings should inform future studies to derived better or simpler Risk Assessment Models to inform clinicians about the underlying risk of VTE and help recommendations regarding the potential use of thromboprophylaxis for higher-risk ambulatory cancer patients

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Thank you!

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