1. The heart and science of medicine.
UVMHealth.org/CancerCenter
Enhancing the Khorana score: traditional VTE risk factors are important in predicting long term VTE risk in cancer outpatients initiating chemotherapy
Daniel Douce MD
Steven Ades MD, MSc
Chris Holmes MD, PhD
Mary Cushman MD, MSc Charles MacLean MD Neil Zakai MD, MSc
American Society of Hematology Conference Atlanta, Georgia December 10th, 2017

2. Disclosures
No disclosures to report

3. Background
Individuals with cancer are at risk of Venous Thromboembolism (VTE)
One fifth of all VTE occurs in patients with cancer¹
Second leading cause of death in patients with cancer²
Khorana et al³ were instrumental in publishing a prediction model for VTE but has several limitations:
6 month VTE risk only
Targeted enrollment of specific tumor types, chemotherapy
Convenience sample
Lee, A. Y. (2005). "Management of thrombosis in cancer: primary prevention and secondary prophylaxis." Br J Haematol 128(3):
Sorensen, H. T., et al. (2000). "Prognosis of cancers associated with venous thromboembolism." N Engl J Med 343(25):
Khorana, A. A., et al. (2008). "Development and validation of a predictive model for chemotherapy-associated thrombosis." Blood 111(10):

4. Khorana score Patient characteristic Points
Very high risk cancer (stomach, pancreas) 2
High risk (lung, lymphoma, gynecologic, bladder, testicular 1
Pre-chemotherapy platelet count 350 x10⁹/L or more
Hemoglobin level less than 10 g/dl, or use of red cell growth factors
Pre-chemotherapy leukocyte count more than 11 x10⁹/L
BMI 35 kg/m² or more
Score ≥3=high risk, 2=intermediate risk, 0-1=low risk
Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):

5. Aims
Are age, sex, prior VTE and hospitalization risk factors for VTE in people with cancer?
Do traditional factors enhance the Khorana Score?

6. Methods
All individuals starting chemotherapy at University of Vermont Cancer Center from
Included internal jugular vein & portal vein thromboses, as well as superficial thrombophlebitis treated with full anticoagulation
Prior history of VTE defined as occurring more than 90 days prior to starting chemotherapy
Case ascertainment: VTE screened for using ICD-9 codes and confirmed by clinical chart review by a physician.

7. Analysis Traditional VTE risk factors (Age, Sex, VTE history)
assessed in univariate analysis
Logistic regression: 6 month interval since starting chemotherapy
Cox proportional hazard ratios over the 3 year observation period
Khorana score assessed using both Logistic regression and Cox models
Traditional VTE risk factors adjusted for covariates
derived from the Khorana score
Hospitalizations assessed using time-varying covariates using Cox models

8. Results 1583 patients in the cohort 187 (11.8%) VTE events
64% of VTE events occurred within 6 months of starting chemotherapy
40% with lower extremity DVT
37% with PE
11% with both PE and DVT
6% with upper extremity DVT
5% with Portal Vein or IVC thrombus

9. Results Developed VTE No VTE Patient characteristic Mean age (SD)
61 (12)
60 (14)
Sex (% male)
52.3
47.3
Mean Baseline BMI (SD)
32.6 (12.3)*
30.8 (11.4)*
Hospitalizations (per person-year)
1.408**
0.829**
Type of cancer (%):
Lung
26 (13.9)
160 (11.5)
Breast
12 (6.4)**
217 (15.5)**
Gastrointestinal (colorectal, pancreas, biliary, stomach, esophagus, liver)
49 (26.2)**
221 (15.8)**
Genitourinary (prostate, kidney, urothelial, bladder, testicular)
20 (10.7)
102 (7.3)
Gynecologic (ovarian, uterine, cervical)
13 (7.0)
92 (6.6)
Hematologic (leukemia, lymphoma, myeloma, myelodysplastic syndrome)
41 (22)
387 (27.8)
Other (includes head & neck, brain, melanoma, sarcoma)
212 (15.2)
* P < 0.05
** P< 0.01

10. Traditional Risk Factors
Odds Ratio (OR) and
Hazard Ratios (HR) 95%
Confidence interval (CI)
Risk Factors for 6-
Month Rate of VTE
(129 VTE)
OR (95% CI)
Risk Factors for Incidence of
VTE over 3 year period (187
VTE)
HR (95% CI)
Age (per 10 years older)
1.08 (0.95, 1.24)
1.04 (0.95, 1.15)
Male Sex
1.36 (0.95, 1.96)
1.59 (1.21, 2.08)
Prior history of VTE
1.46 (0.76, 2.82)
2.17 (1.44, 3.25)

11. Factors in Khorana Score
Risk Factors for 6-
Month Rate of VTE
OR (95% CI)
Risk Factors for
Incidence of VTE over
3 year period
HR (95% CI)
High risk cancer type
1.61 (1.22, 2.11)
1.43 (1.16, 1.76)
Platelets ≥ 350 x 109/L
1.09 (0.67, 1.78)
0.88 (0.59, 1.31)
Hgb <10 g/dL
1.44 (0.91, 2.27)
1.78 (1.28, 2.47)
WBC ≥ 11 x 109/L
1.16 (0.76, 1.78)
1.17 (0.85, 1.63)
BMI ≥ 35 kg/m2
1.73 (1.16, 2.59)
1.21 (0.89, 1.65)

12. Unadjusted Hazard Ratio
Hospitalizations
Unadjusted Hazard Ratio
HR (95% CI)
Adjusted for Khorana
Risk Factors
HR (95% Cl)
Hospitalization only
1.75 (0.72, 4.28)
1.30 (0.47, 3.51)
Hospitalization +30 days
3.09 (2.12, 4.51)
2.87 (1.97, 4.20)
Hospitalization + 90 days
2.87 (2.06, 4.00)
2.69 (1.92, 3.75)

13. Addition of Traditional Risk Factors to Khorana Score
Risk Factors for 6-
Month VTE Risk, Adjusting for Khorana Score OR (95% CI)
Risk Factors for Incidence of
VTE over 3 year period, Adjusting for Khorana Score
HR (95% CI)
Age (per 10 years older)
1.08 (0.94, 1.24)
1.05 (0.95, 1.16)
Male Sex
1.36 (0.94, 1.96)
1.57 (1.21, 2.07)
Prior history of VTE
1.41 (0.73, 2.75)
2.12 (1.41, 3.18)

14. Does adding male sex and prior VTE ‘enhance’ the Khorana score?
C-Statistic for Khorana score in first 6 months: 0.61 (95% CI 0.56, 0.65)
C-index for Khorana score over 3 years: 0.59
C-index for Khorana score + male sex and VTE history: 0.61

15. Conclusions
Addition of traditional VTE risk factors to the Khorana score does not improve predictive accuracy in the first 6 months of therapy
Traditional risk factors of male sex and prior VTE history significantly impact VTE incidence after the first 6 months
Recent hospitalizations were a stronger predictor of VTE risk than any other variable evaluated
Risk of cancer-related VTE varies over time, risk needs to be re-evaluated over the course of a patient’s treatment

16. Limitations
Retrospective Data: Administrative database using ICD-9 codes: chance of misclassification
Limited to patients starting chemotherapy, not all cancer patients
Could not adjust for performance status
VTE events at outside hospitals may have been missed
Single institution study

17. Acknowledgements
Jeffords Institute for Quality, The UVM Medical Center
Supported in part by an educational grant from the Lake Champlain Cancer Research Organization Inc.

18. Risk Factors for 6-Month Incidence of VTE
Risk Factors for Incidence of VTE
over 3 year observation period
Unadjusted
Odds Ratio
Odds Ratio adjusted for Khorana Risk Factors
Hazard Ratio
Hazard ratio Adjusted for Khorana Risk Factors
129 VTE events within 6 months
187 VTE events over 3 years
Khorana Score Components
High risk cancer type
1.61 (1.22, 2.11)
1.43 (1.16, 1.76)
Platelets ≥ 350 x 109/L
1.09 (0.67, 1.78)
0.88 (0.59, 1.31)
Hgb <10 g/dL
1.44 (0.91, 2.27)
1.78 (1.28, 2.47)
WBC ≥ 11 x 109/L
1.16 (0.76, 1.78)
1.17 (0.85, 1.63)
BMI ≥ 35 kg/m2
1.73 (1.16, 2.59)
1.21 (0.89, 1.65)
Traditional Risk Factors
Age (per 10 years older)
1.08 (0.95, 1.24)
1.08 (0.94, 1.24)
1.04 (0.95, 1.15)
1.05 (0.95, 1.16)
Male Sex
1.36 (0.95, 1.96)
1.36 (0.94, 1.96)
1.59 (1.21, 2.08)
1.57 (1.21, 2.07)
Prior history of VTE
1.46 (0.76, 2.82)
1.41 (0.73, 2.75)
2.17 (1.44, 3.25)
2.12 (1.41, 3.18)
Hospitalization
Hospitalization + 90 days
2.87 (2.06, 4.00)
2.69 (1.92, 3.75)
Hospitalization +30 days
3.09 (2.12, 4.51)
2.87 (1.97, 4.20)
Hospitalization only
1.75 (0.72, 4.28)
1.30 (0.47, 3.51)