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Extended Pharmacologic Prophylaxis for Venous Thromboembolism after Colorectal Cancer Surgery Is Associated with Improved Long-Term Survival: A Natural Experiment in the Chemotherapeutic Benefit of Heparin Derivatives
*Alexander T. Booth, *Daniel Brinton, *Colleen Donahue, *Maggie Westfal, *Virgilio George, *Pinckney J. Maxwell, *Kit N. Simpson, David Mahvi, *Thomas Curran
Medical University of South Carolina, Charleston, SC

Objective:
Heparin-derivatives may confer an anti-neoplastic effect via a variety of mechanisms (e.g., inhibiting angiogenesis in the tumor microenvironment, decreasing metastatic potential via platelet disaggregation). Studies evaluating the oncologic benefit of heparin derivatives have been limited. Extended venous thromboembolism (VTE) prophylaxis (ePPx) with 30-days of low molecular weight heparin (LMWH) is recommended by society guidelines after abdominopelvic cancer surgery to reduce VTE risk. We assessed whether ePPx was associated with improved long-term survival in a national cohort undergoing colorectal cancer (CRC) resection.

Methods:
Surveillance, Epidemiology, and End Results-Medicare data were used to identify all patients (age 65+) undergoing primary resection for CRC from 2016 to 2017. Patients were excluded for pre-existing thrombosis, prior anticoagulation, and 30-day postoperative death. The primary outcomes were cancer-specific survival (CSS) and overall survival (OS). Inverse propensity treatment weighting was followed by log-rank testing and multivariable Cox regression to compare CSS and OS in patients who received ePPx versus those that did not. Covariates included patient factors: age, sex, race, a composite index of socioeconomic status, rural/urban residence, Charlson comorbidity index, cancer stage, receipt of chemotherapy, and treatment year. Adjustments were also made for hospital factors including bed size quartile, teaching status, and National Cancer Institute (NCI) designation.

Results:
21,218 patients were analyzed in the propensity-matched cohort. 854 (4.0%) received ePPx. CSS and OS were significantly higher in patients who received ePpx as shown in the survival curves (Figures 1 and 2). Patients receiving ePpx were younger (mean 76.6 vs 74.9 years, p<0.0001) and had overall lower comorbidity burden by Charlson score. ePpx was more commonly given at larger hospitals, teaching hospitals, and those with an NCI designation. There were no significant differences in disease stage, however patients who received ePpx were more likely to be treated with chemotherapy (25.2% vs 21.5%, p=0.0104). Displayed in Table 1, multivariable Cox regression showed improved CSS (HR: 0.555, 95% CI: 0.404 – 0.763) and OS (HR: 0.695, 95% CI: 0.603 - 0.801) with ePPx after controlling for patient, treatment, and hospital factors.

Conclusions:
ePPx after resection for CRC was independently associated with improved CSS and OS. These results suggest a potential anti-neoplastic effect from LMWH when used in the context of ePPx. Further study may validate these findings in this and other solid organ cancers.

Table 1: Multivariable Cox Regression model for cancer-specific and overall survival
CovariateAdjusted HR for Mortality [95% CI]
 Cancer-SpecificOverall
ePpx0.555 [0.404 – 0.763]0.695 [0.603 – 0.801]
Age1.050 [1.042 – 1.057]1.048 [1.045 – 1.052]
Male0.903 [0.815 – 1.000]1.101 [1.046 – 1.158]
Race (Ref: White)  
Black1.246 [1.048 – 1.483]0.993 [0.907 – 1.088]
Other0.948 [0.774 – 1.161]0.790 [0.705 – 0.885]
Socioeconomic Status
(by index units of increasing disadvantage)
0.776 [0.711 – 0.847]1.100 [1.054 – 1.148]
Charlson comorbidity index (Ref: 0)  
11.298 [0.893 – 1.886]1.436 [1.185 – 1.739]
21.131 [0.974 – 1.313]1.097 [1.014 – 1.188]
31.057 [0.847 – 1.318]1.538 [1.389 – 1.702]
41.503 [1.239 – 1.822]1.956 [1.780 – 2.149]
51.701 [1.337 – 2.163]2.332 [2.086 – 2.606]
62.199 [1.857 – 2.603]2.524 [2.306 – 2.763]
7+2.303 [1.941 – 2.732]2.935 [2.687 – 3.207]
Chemotherapy1.330 [1.183 – 1.495]0.856 [0.801 – 0.915]
Stage (Ref: Localized)  
Regional3.564 [3.058 – 4.154]1.828 [1.719 – 1.945]
Distant10.475 [8.650 – 12.685]4.932 [4.504 – 5.402]
Hospital bed # quartile (Ref: 1st, smallest)  
2nd0.978 [0.850 – 1.127]0.923 [0.857 – 0.994]
3rd0.902 [0.776 – 1.047]0.882 [0.817 – 0.953]
4th (largest)0.829 [0.699 – 0.982]0.878 [0.807 – 0.955]
Hospital category (Ref: Teaching, Non-NCI)  
NCI0.564 [0.439 – 0.723]0.667 [0.597 – 0.744]
Non-Teaching, Non-NCI
Teaching
1.180 [1.050 – 1.325]0.982 [0.925 – 1.044]
   


Figure 1: Kaplan-Meier curve for Cancer-Specific Survival with vs without ePpx (p=0.0012)

Figure 2: Kaplan-Meier curve for Overall Survival with vs without ePpx (p=0.0002)
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