Abstract
Background
Few studies have evaluated cancer risk following venous thromboembolism (VTE). Both VTE and cancer disproportionately affect older adults.
Methods
Using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we evaluated 1.2 million cancer cases and 200,000 controls (66–99 years old, 1992–2005). VTEs occurring before selection were identified using Medicare claims. Logistic regression was used to estimate odds ratios (ORs).
Results
VTE was present in 2.5% of cases and 2.2% of controls. VTE was associated with risk of cancers of the lung (OR 1.18, 95%CI 1.12–1.23), stomach (1.19, 1.09–1.30), small intestine (1.42, 1.17–1.71), colon (1.25, 1.18–1.31), gallbladder (1.39, 1.16–1.67), pancreas (1.53, 1.43–1.64), soft tissue (1.43, 1.21–1.68), ovary (1.35, 1.22–1.50), and kidney/renal pelvis (1.34, 1.23–1.46), and melanoma (1.17, 1.08–1.27), non-Hodgkin lymphoma (1.27, 1.20–1.35), myeloma (1.48, 1.35–1.63), and acute myeloid leukemia (1.35, 1.19–1.54). Strongest risks were observed within 1 year of VTE diagnosis, but risk were elevated more than 6 years after VTE for colon cancer (OR 1.24, 95%CI 1.12–1.37), pancreatic cancer (1.33, 1.15–1.54), and myeloma (1.35, 1.10–1.66). Few differences in risk were observed by VTE subtype. Cancers of the lung, stomach, and pancreas were more likely to have distant metastases within one year after VTE.
Conclusion
Among elderly adults, cancer risk is elevated following VTE diagnosis.
Impact
Short-term associations with cancer are likely driven by enhanced screening following VTE and reverse causation. While obesity, other co-morbidities, and smoking cannot be excluded as explanations, longer-term elevations for select cancers suggest that some VTEs may be caused by cancer precursors.
Keywords: Venous thromboembolism, cancer, Medicare, SEER, United States
Introduction
Venous thromboembolism (VTE) involves obstruction of blood flow caused by the presence of clots and includes pulmonary emboli (PEs) and both deep venous thromboses (DVTs) and superficial venous thromboses (SVTs). VTE affects nearly 500,000 individuals each year. (1, 2) The incidence of VTE increases steeply with age, with rates of 450–600 cases per 100,000 person-years among individuals >65 years of age. (3, 4) Furthermore, VTE risk is four to six-fold higher in individuals diagnosed and treated for cancer. (5, 6) VTE also contributes significant morbidity and mortality among cancer patients, with VTE detected within 1 year prior to cancer diagnosis being associated with advanced stage and poorer post-treatment survival. (7)
While much work has focused on understanding the sources of VTE and its management, (1, 5, 7–10) only a handful of studies have assessed the association of VTE with the subsequent development of malignancies. Population and hospital-based studies have demonstrated a strong risk of cancer within a very short follow-up time interval after VTE (typically less than 1 year). (11–15) Interestingly, prior studies show that those individuals with a longer follow-up time of 2 or more years after VTE also have elevated risk for certain malignancies such as cancers of the digestive tract, ovarian cancer, and lymphomas. (11, 14, 16, 17) These associations appear to be similar across VTE subtypes of PE, DVT, and SVT. (18)
Individuals over the age of 65 years have a disproportionately high burden of both cancer and VTE. We therefore, investigated the relationship of VTE with subsequent development of cancer in a large case- control study of elderly adults in the United States using data from cancer registries and Medicare claims files. The large number of cancer cases and controls in this study afforded us the opportunity to assess the relationship of VTE overall and subtypes of VTE with a wide range of solid-organ and hematologic malignancies.
Materials and Methods
The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program comprises population-based state and metropolitan cancer registries that ascertain cancers occurring in approximately 26% of the US population. (19) Medicare is a federally-funded program that provides health insurance for 97% of the US population aged greater than 65 years. All Medicare beneficiaries are entitled to coverage for inpatient care (Part A), and most purchase additional coverage for physician and outpatient services (Part B). The SEER-Medicare data set was created by electronically linking SEER and Medicare data. (19) The resulting match links 94% of SEER cancer cases aged 65 and older to Medicare data. In addition, data are available for a 5% random sample of Medicare beneficiaries living in SEER regions. The SEER-Medicare data set contains demographic and clinical information, and Medicare claims data (Part A beginning in 1986, Part B beginning in 1991) on these individuals.
The current study is a population-based case-control study derived from the SEER-Medicare data, as previously described. (20) Cases were defined as individuals with first cancers identified in SEER, aged 66 to 99 between the years 1992 to 2005. Cases identified solely at autopsy or by death certificates were excluded. Cases also were required to have at least 13 months of Part A and Part B Medicare coverage, during which they were not enrolled in a health maintenance organization (HMO), prior to diagnosis. Cancers were categorized based on the SEER program “site recode with Kaposi sarcoma and mesothelioma”, which we modified to collapse some rare categories. Non-Hodgkin lymphoma (NHL) was classified based on the World Health Organization scheme and included chronic lymphocytic leukemia. (21)
Controls (N=200,000) were selected from the 5% random sample of Medicare beneficiaries living in SEER areas and were frequency-matched to cases by sex, age (66–69, 70–74, 75–79, 80–84, 85–99 years), and calendar year of selection. As of July 1 of the calendar year of selection, controls were alive, cancer-free, and had at least 13 months of Part A, Part B, and non-HMO Medicare coverage. Controls could have been selected multiple times in different calendar years or could later have become a case.
The first recorded VTE was assessed using Medicare claims in hospital, outpatient, and provider files. We defined VTE based on International Classification of Diseases, 9th revision (ICD-9) codes for PE [415.1], DVT [451.1, 451.2, 451.81, 451.83, 453.2, 453.3, and 453.4], SVT [451.0, and 451.82], and venous thrombosis not otherwise specified (VTE NOS) [451.84, 451.89, 453.1, 453.8, and 453.9].
Unconditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), comparing the prevalence of VTE in cases and controls. Given the incidence density sampling of cases and controls from the Medicare cohort, the odds ratios calculated in this study can be interpreted as estimates of relative risk. We accounted for the repeated sampling of controls and the fact that some controls later became cases in the variance calculation. (20) All analyses were adjusted for sex, age, and calendar year of diagnosis/selection. Given the large number of cancer types assessed in this study, a conservative Bonferroni p-value of <0.001 was used as the cut-off for statistical significance.
For cancers that were associated with VTE, we created additional models to evaluate the strength of the association with cancer in different latency intervals after VTE (<1, 1–2.5, 2.6–4.0, 4.1–6, and >6 years). The interaction of VTE and cancer risk across latency intervals was assessed by including a product term in the logistic regression model. We also fit logistic regression models to evaluate associations for each VTE subtype and used likelihood ratio tests to assess the differential effect of VTE subtypes on cancer risk (i.e., to compare the effects of PE or DVT vs. SVT, or of PE vs. DVT). A p-value of <0.05 was used as the cut-off to determine whether the effect on cancer risk varied by latency or VTE subtype. Lastly, among cases with solid-organ cancers, we compared the distribution of SEER cancer stage (local vs. regional vs. distant) among those with a VTE detected <1 year prior to cancer diagnosis, ≥1 year prior to cancer diagnosis, and those without a VTE.
Results
The characteristics of cases and controls are presented in Table 1. The majority of subjects were male, white, and selected between 1999–2002. Cases and controls were matched with respect to age, sex, and year of diagnosis/selection; they differed slightly by race/ethnicity and duration of Medicare coverage.
Table 1.
Subject characteristics
| Characteristic | Case (N=1, 138, 390) N (%) |
Control (N=200, 000) N (%) |
|---|---|---|
| Age, Years | ||
| 65–69 | 192, 272 (16.9) | 33, 780 (16.9) |
| 70–74 | 296, 027 (26.0) | 52, 008 (26.0) |
| 75–79 | 287, 109 (25.2) | 50, 440 (25.2) |
| 80–84 | 205, 451 (18.1) | 36, 097 (18.1) |
| 85+ | 157, 531 (13.8) | 27, 675 (13.8) |
| Sex | ||
| Male | 604, 333 (53.1) | 106, 172 (53.1) |
| Female | 534, 057 (46.9) | 93, 828 (46.9) |
| Year of Diagnosis or Selection | ||
| 1992–1994 | 178, 515 (15.7) | 31, 364 (15.7) |
| 1995–1998 | 226, 785 (19.9) | 39, 843 (19.9) |
| 1999–2002 | 414, 976 (36.5) | 72, 903 (36.5) |
| 2003–2005 | 318, 114 (27.9) | 55, 890 (27.9) |
| Race/Ethnicity | ||
| White | 973, 236 (85.5) | 166, 827 (83.4) |
| Black | 89, 893 (7.9) | 13, 949 (6.9) |
| Asian | 29, 038 (2.6) | 8, 097 (4.1) |
| Hispanic | 18, 286 (1.6) | 5, 199 (2.6) |
| Native American | 2, 580 (0.2) | 656 (0.3) |
| Other | 21, 965 (1.9) | 4, 713 (2.4) |
| Unknown | 3, 389 (0.3) | 558 (0.3) |
| Duration of Medicare Coverage, Months | ||
| 13–60 | 319, 446 (28.1) | 57, 440 (28.7) |
| 61–120 | 556, 095 (48.9) | 97, 485 (48.7) |
| 121–180 | 210, 858 (18.5) | 35, 805 (17.9) |
| 181–240 | 51, 991 (4.6) | 9, 270 (4.6) |
VTE was observed among 2.5% of cases and 2.2% controls. Overall, VTE was associated with a 15% increased risk of any cancer (OR 1.15, 95%CI 1.11–1.20) (Table 2). Among the 45 solid-organ cancers assessed, 10 were associated with VTE (p<0.001), including cancers of the lung (OR 1.18, 95%CI 1.12–1.23), stomach (1.19, 1.09–1.30), small intestine (1.42, 1.17–1.71), colon (1.25, 1.18–1.31), gallbladder (1.39, 1.16–1.67), pancreas (1.53, 1.43–1.64), soft tissue including the heart (1.43, 1.21–1.68), ovary (1.35, 1.22–1.50), and kidney/renal pelvis (1.34, 1.23–1.46), and melanoma (1.17, 1.08–1.27). Among 7 evaluated hematologic malignancies, VTE was associated with an increased risk of NHL (OR 1.27, 95%CI 1.20–1.35), myeloma (1.48, 1.35–1.63), and acute myeloid leukemia (AML) (1.35, 1.19–1.54). Among NHL subtypes, there was a significant association with diffuse large B-cell lymphoma (1.41, 1.28–1.55).
Table 2.
Associations of venous thromboembolism and cancer
| Total | % of subjects with VTE | OR (95% CI) | p-value | |
|---|---|---|---|---|
| Controls | 200, 000 | 2.2 | 1.0 | |
| All Cancers | 1, 138, 390 | 2.5 | 1.15 (1.11, 1.20) | <0.001 |
| Head and Neck | ||||
| Lip | 2, 340 | 2.1 | 0.98 (0.74, 1.30) | 0.874 |
| Tongue | 4, 486 | 2.0 | 0.96 (0.78, 1.19) | 0.706 |
| Salivary Gland | 2, 482 | 2.5 | 1.07 (0.83, 1.39) | 0.600 |
| Floor of Mouth | 1, 412 | 2.2 | 1.12 (0.78, 1.60) | 0.546 |
| Gum and Other Mouth | 3, 796 | 2.5 | 1.12 (0.91, 1.37) | 0.287 |
| Nasopharynx | 779 | -- | 0.68 (0.36, 1.26) | 0.219 |
| Tonsil | 1, 583 | 2.0 | 1.13 (0.79, 1.61) | 0.494 |
| Oropharynx | 543 | -- | 0.86 (0.44, 1.66) | 0.654 |
| Hypopharynx | 1, 660 | 1.7 | 0.92 (0.63, 1.34) | 0.664 |
| Larynx | 8, 234 | 1.9 | 1.00 (0.85, 1.18) | 0.995 |
| Nasal Cavity | 1, 451 | 2.2 | 0.98 (0.69, 1.40) | 0.924 |
| Respiratory Tract | ||||
| Lung | 179, 880 | 2.5 | 1.18 (1.12, 1.23) | <0.001 |
| Pleura | 78 | -- | 0.53 (0.08, 3.79) | 0.530 |
| Mesothelioma | 3, 333 | 2.4 | 1.08 (0.86, 1.35) | 0.520 |
| Gastrointestinal Tract | ||||
| Esophagus | 11, 442 | 2.4 | 1.15 (1.01, 1.30) | 0.033 |
| Stomach | 22, 860 | 2.8 | 1.19 (1.09, 1.30) | <0.001 |
| Small intestine | 3, 694 | 3.2 | 1.42 (1.17, 1.71) | <0.001 |
| Appendix | 687 | 2.9 | 1.35 (0.86, 2.12) | 0.187 |
| Colon | 107, 265 | 2.9 | 1.25 (1.18, 1.31) | <0.001 |
| Rectosigmoid Junction | 11, 800 | 2.1 | 0.98 (0.86, 1.11) | 0.735 |
| Rectum | 24, 762 | 2.1 | 0.93 (0.85, 1.03) | 0.151 |
| Anus | 2, 633 | 3.0 | 1.35 (1.08, 1.70) | 0.010 |
| Hepatobiliary Sites | ||||
| Liver | 10, 219 | 2.5 | 1.19 (1.04, 1.35) | 0.010 |
| Intrahepatic Bile Duct | 1, 988 | 2.7 | 1.14 (0.87, 1.50) | 0.338 |
| Gallbladder | 3, 777 | 3.4 | 1.39 (1.16, 1.67) | <0.001 |
| Pancreas | 33, 135 | 3.5 | 1.53 (1.43, 1.64) | <0.001 |
| Bone and Soft Tissue | ||||
| Bones and Joints | 760 | — | 0.64 (0.35, 1.16) | 0.139 |
| Soft Tissue including Heart | 4, 728 | 3.3 | 1.43 (1.21, 1.68) | <0.001 |
| Melanoma | 27, 059 | 2.6 | 1.17 (1.08, 1.27) | <0.001 |
| Retroperitoneum | 772 | 3.1 | 1.46 (0.97, 2.20) | 0.072 |
| Kaposi Sarcoma | 652 | 3.7 | 1.54 (1.02, 2.33) | 0.039 |
| Reproductive organs | ||||
| Breast | 134, 274 | 2.3 | 1.01 (0.95, 1.07) | 0.683 |
| Cervix | 4, 033 | 2.3 | 1.05 (0.85, 1.29) | 0.674 |
| Uterus | 26, 889 | 2.4 | 1.11 (1.02, 1.22) | 0.022 |
| Ovary | 16, 112 | 3.1 | 1.35 (1.22, 1.50) | <0.001 |
| Vagina | 927 | 3.3 | 1.36 (0.95, 1.96) | 0.096 |
| Vulva | 3, 288 | 2.4 | 0.90 (0.72, 1.14) | 0.391 |
| Prostate | 215, 219 | 1.7 | 0.92 (0.87, 0.98) | 0.009 |
| Penis | 836 | 2.4 | 1.11 (0.71, 1.74) | 0.638 |
| Urinary Tract | ||||
| Urinary Bladder | 61, 751 | 2.5 | 1.11 (1.04, 1.18) | 0.001 |
| Kidney/Renal Pelvis | 24, 611 | 2.8 | 1.34 (1.23, 1.46) | <0.001 |
| Ureter | 1, 476 | 3 | 1.29 (0.95, 1.75) | 0.099 |
| Neurologic/Endocrine Sites | ||||
| Eye and Orbit | 1, 461 | 2.7 | 1.27 (0.92, 1.74) | 0.140 |
| Brain | 9, 552 | 2.2 | 1.06 (0.92, 1.22) | 0.440 |
| Thyroid | 5, 923 | 2.3 | 1.15 (0.97, 1.37) | 0.115 |
| Hematologic Malignancies | ||||
| Hodgkin Lymphoma | 1, 915 | 2.8 | 1.31 (0.99, 1.72) | 0.057 |
| Non-Hodgkin Lymphoma (NHL) | 55, 195 | 2.9 | 1.27 (1.20, 1.35) | <0.001 |
| Myeloma | 15, 318 | 3.3 | 1.48 (1.35, 1.63) | <0.001 |
| Acute Lymphocytic Leukemia | 736 | 3.5 | 1.61 (1.08, 2.38) | 0.018 |
| Acute myeloid Leukemia (AML) | 8, 489 | 3.1 | 1.35 (1.19, 1.54) | <0.001 |
| Chronic myeloid Leukemia | 3, 626 | 2.9 | 1.23 (1.01, 1.50) | 0.041 |
| Acute Monocytic Leukemia | 508 | -- | 0.74 (0.38, 1.44) | 0.382 |
| NHL subtypes | ||||
| Diffuse Large B-cell Lymphoma | 15, 883 | 3.3 | 1.41 (1.28, 1.55) | <0.001 |
| CLL/SLL/PLL | 14, 571 | 2.7 | 1.19 (1.07, 1.33) | 0.001 |
| Follicular Lymphoma | 7, 264 | 2.3 | 1.06 (0.90, 1.24) | 0.468 |
| Marginal Zone Lymphoma | 3, 223 | 2.7 | 1.14 (0.92, 1.42) | 0.226 |
| T-Cell NHL | 2, 813 | 3.0 | 1.37 (1.10, 1.71) | 0.005 |
| Mantel Cell Lymphoma | 1, 553 | 2.4 | 1.13 (0.82, 1.56) | 0.467 |
| LPL/Waldenstrom | 693 | 2.6 | 1.13 (0.71, 1.82) | 0.607 |
| Burkitt Lymphoma | 260 | -- | 1.31 (0.65, 2.67) | 0.454 |
Abbreviations: CLL – Chronic lymphocytic leukemia, SLL – Small lymphocytic leukemia, PLL – T-cell prolymphocytic leukemia, LPL-lymphoplasmacytic lymphoma; Bolded entries indicate a significant association of VTE with cancer at a p-value of <0.001; In accordance with the SEER-Medicare data use agreement, the percentage of cases with VTE is not shown for cancers when the number of cases with VTE is fewer than 11.
We also investigated the association of VTE and cancer risk across different follow-up times (i.e., latency intervals) after VTE (Table 3). For most cancers, risk was strongest <1 year following VTE and significantly attenuated with longer time intervals (p<0.001); an exception was melanoma, for which risk did not vary by time interval. Most associations were not significant >6 years after VTE. However, cancers for which risk was elevated >6 years after VTE included colon cancer (OR 1.24, 95%CI 1.12–1.37), pancreatic cancer (1.33, 1.15–1.54), and myeloma (1.35, 1.10–1.66).
Table 3.
Associations of VTE with cancer in different latency intervals following VTE
| Total | Period within 1 year before cancer diagnosis or selection | Period from 1–2.5 years before cancer diagnosis or selection | Period from 2.6–4 years before cancer diagnosis or selection | Period from 4.1–6 years before cancer diagnosis or selection | Period more than 6 before cancer diagnosis or selection | P* | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| % with VTE | OR (95% CI) | % with VTE | OR (95% CI) | % with VTE | OR (95% CI) | % with VTE | OR (95% CI) | % with VTE | OR (95% CI) | |||
| Controls | 200, 000 | 0.4 | 1.0 | 0.5 | 1.0 | 0.4 | 1.0 | 0.4 | 1.0 | 0.5 | 1.0 | ---- |
| All Cancers | 1, 138, 390 | 0.6 | 1.51 (1.41, 1.63) | 0.5 | 1.04 (0.97, 1.11) | 0.4 | 1.06 (0.98, 1.15) | 0.4 | 1.09 (1.01, 1.18) | 0.5 | 1.10 (1.02, 1.19) | <0.001 |
| Lung | 179, 880 | 0.7 | 1.75 (1.60, 1.92) | 0.5 | 1.06 (0.97, 1.16) | 0.4 | 1.04 (0.94, 1.15) | 0.4 | 1.07 (0.96, 1.18) | 0.5 | 1.01 (0.92, 1.12) | <0.001 |
| Stomach | 22, 860 | 0.8 | 1.75 (1.47, 2.07) | 0.5 | 1.09 (0.91, 1.31) | 0.4 | 0.99 (0.80, 1.23) | 0.4 | 1.02 (0.83, 1.26) | 0.6 | 1.15 (0.96, 1.38) | 0.003 |
| Small intestine | 3, 694 | 1.1 | 2.42 (1.74, 3.38) | 0.7 | 1.49 (1.02, 2.17) | 0.3 | 0.76 (0.42, 1.39) | 0.7 | 1.72 (1.16, 2.54) | 0.4 | 0.79 (0.48, 1.33) | 0.002 |
| Colon | 107, 265 | 0.7 | 1.64 (1.48, 1.82) | 0.6 | 1.15 (1.04, 1.27) | 0.4 | 1.06 (0.94, 1.19) | 0.5 | 1.17 (1.04, 1.31) | 0.7 | 1.24 (1.12, 1.37) | 0.002 |
| Gallbladder | 3, 777 | 1.5 | 3.28 (2.47, 4.35) | 0.4 | 0.78 (0.48, 1.28) | 0.4 | 1.02 (0.62, 1.67) | 0.6 | 1.29 (0.84, 1.97) | 0.5 | 0.89 (0.56, 1.41) | <0.001 |
| Pancreas | 33, 135 | 1.2 | 2.75 (2.43, 3.12) | 0.6 | 1.19 (1.02, 1.38) | 0.5 | 1.26 (1.06, 1.49) | 0.5 | 1.27 (1.08, 1.50) | 0.7 | 1.33 (1.15, 1.54) | <0.001 |
| Soft tissue | 4, 728 | 1.0 | 2.27 (1.67, 3.07) | 0.7 | 1.39 (0.99, 1.96) | 0.6 | 1.59 (1.10, 2.30) | 0.6 | 1.44 (1.00, 2.10) | 0.4 | 0.67 (0.41, 1.08) | <0.001 |
| Melanoma | 27, 059 | 0.5 | 1.10 (0.91, 1.34) | 0.6 | 1.21 (1.02, 1.42) | 0.4 | 1.02 (0.83, 1.26) | 0.6 | 1.38 (1.16, 1.65) | 0.6 | 1.14 (0.96, 1.35) | 0.570 |
| Ovary | 16, 112 | 1.2 | 2.79 (2.35, 3.32) | 0.5 | 0.95 (0.75, 1.21) | 0.5 | 1.17 (0.91, 1.50) | 0.4 | 0.84 (0.64, 1.11) | 0.6 | 1.13 (0.90, 1.42) | <0.001 |
| Kidney/Renal Pelvis | 24, 611 | 0.9 | 2.18 (1.87, 2.54) | 0.5 | 1.16 (0.97, 1.39) | 0.4 | 1.15 (0.94, 1.41) | 0.4 | 1.07 (0.87, 1.32) | 0.6 | 1.20 (1.00, 1.44) | <0.001 |
| NHL | 55, 195 | 0.9 | 2.06 (1.83, 2.31) | 0.5 | 1.01 (0.88, 1.15) | 0.5 | 1.19 (1.03, 1.37) | 0.4 | 1.05 (0.91, 1.21) | 0.6 | 1.16 (1.02, 1.32) | <0.001 |
| Myeloma | 15, 318 | 0.9 | 2.14 (1.78, 2.58) | 0.6 | 1.34 (1.09, 1.64) | 0.5 | 1.29 (1.02, 1.63) | 0.6 | 1.35 (1.08, 1.69) | 0.7 | 1.35 (1.10, 1.66) | 0.006 |
| AML | 8, 489 | 0.9 | 2.00 (1.57, 2.56) | 0.5 | 1.11 (0.83, 1.48) | 0.5 | 1.17 (0.85, 1.62) | 0.8 | 1.80 (1.40, 2.33) | 0.5 | 0.86 (0.63, 1.18) | 0.009 |
P-value for test of whether OR differs according to time since VTE; Bolded entries indicate a significant association of VTE with cancer at a p-value of <0.001; NHL-Non-Hodgkin lymphoma, AML-Acute myeloid leukemia
In total, 0.7%, 0.4%, 0.1%, and 1.3% of cases and 0.6%, 0.3%, 0.1%, and 1.2% of controls were diagnosed with PE, DVT, SVT, or VTE NOS, respectively. Overall, for most cancers, risk appeared similar following PE and DVT, or for the combination of PE or DVT compared with SVT (Table 4). NHL and AML were exceptions in that risk was significantly higher following DVT as compared with PE.
Table 4.
Associations of pulmonary embolism, deep venous thrombosis and superficial venous thrombosis with cancer
| Total | Pulmonary Embolism (PE) | Deep Venous Thrombosis (DVT) | Superficial venous Thrombosis (SVT) | P1* | P2† | ||||
|---|---|---|---|---|---|---|---|---|---|
| % PE | OR (95% CI) | % DVT | OR (95% CI) | % SVT | OR (95 % CI) | ||||
| Controls | 200, 000 | 0.6 | 1.0 | 0.3 | 1.0 | 0.1 | 1.0 | ----- | ----- |
| All Cancers | 1, 138, 390 | 0.7 | 1.14 (1.06, 1.22) | 0.4 | 1.22 (1.11, 1.34) | 0.1 | 1.24 (1.05, 1.46) | 0.199 | 0.412 |
| Lung | 179, 880 | 0.7 | 1.21 (1.11, 1.32) | 0.3 | 1.08 (0.96, 1.22) | 0.1 | 1.27 (1.04, 1.55) | 0.119 | 0.385 |
| Stomach | 22, 860 | 0.7 | 1.19 (1.01, 1.41) | 0.5 | 1.31 (1.06, 1.63) | 0.1 | 1.20 (0.82, 1.76) | 0.462 | 0.883 |
| Small intestine | 3, 694 | 0.9 | 1.42 (0.99, 2.02) | 0.4 | 1.32 (0.80, 2.18) | --- | 2.16 (1.10, 4.23) | 0.824 | 0.250 |
| Colon | 107, 265 | 0.8 | 1.27 (1.15, 1.39) | 0.5 | 1.27 (1.12, 1.45) | 0.2 | 1.35 (1.08, 1.67) | 0.926 | 0.581 |
| Gallbladder | 3, 777 | 0.8 | 1.24 (0.86, 1.79) | 0.6 | 1.59 (1.04, 2.45) | 0.2 | 1.68 (0.82, 3.44) | 0.391 | 0.602 |
| Pancreas | 33, 135 | 0.9 | 1.47 (1.29, 1.68) | 0.6 | 1.66 (1.41, 1.97) | 0.2 | 1.33 (0.98, 1.82) | 0.245 | 0.374 |
| Soft tissue | 4, 728 | 0.5 | 0.84 (0.56, 1.25) | 0.5 | 1.36 (0.89, 2.08) | 0.2 | 1.65 (0.84, 3.23) | 0.112 | 0.224 |
| Melanoma | 27, 059 | 0.7 | 1.24 (1.07, 1.45) | 0.4 | 1.27 (1.03, 1.57) | 0.1 | 1.03 (0.70, 1.52) | 0.869 | 0.323 |
| Ovary | 16, 112 | 0.9 | 1.44 (1.19, 1.73) | 0.5 | 1.49 (1.16, 1.91) | 0.1 | 1.13 (0.71, 1.79) | 0.825 | 0.281 |
| Kidney/Renal Pelvis | 24, 611 | 0.8 | 1.36 (1.16, 1.59) | 0.5 | 1.53 (1.25, 1.88) | 0.2 | 1.73 (1.24, 2.41) | 0.361 | 0.264 |
| NHL | 55, 195 | 0.7 | 1.11 (0.98, 1.25) | 0.6 | 1.65 (1.43, 1.91) | 0.2 | 1.50 (1.17, 1.93) | <0.001 | 0.273 |
| Myeloma | 15, 318 | 1.0 | 1.65 (1.39, 1.96) | 0.5 | 1.37 (1.07, 1.77) | 0.1 | 1.26 (0.81, 1.97) | 0.230 | 0.371 |
| AML | 8, 489 | 0.6 | 0.96 (0.73, 1.28) | 0.7 | 1.92 (1.46, 2.54) | --- | 1.51 (0.89, 2.58) | 0.001 | 0.597 |
P1=P-value for test of difference in OR between PE and DVT;
P2 = P-value for test of difference in OR between the combination of PE/DVT and SVT; Bolded entries indicate a significant association of VTE with cancer at a p-value of <0.001; NHL-Non-Hodgkin lymphoma, AML-Acute myeloid leukemia; In accordance with the SEER-Medicare data use agreement, percentages are not shown for groups with fewer than 11 subjects.
The stage distribution of solid-organ cancers in relation to VTE diagnosis is shown in Table 5. A significantly higher proportion of distant stage diagnoses were observed among individuals with VTE diagnosed <1 year prior to cancer diagnosis, compared to cases without VTE, for cancers of the lung (60.5% vs. 52.9%, p<0.001), stomach (44.7% vs. 35.5%, p=0.024) and pancreatic cancer (74.4% vs. 59.7%, p<0.001).
Table 5.
Frequency and distribution of cancers by stage among those with and without VTE
| Cancer type | Local | Regional | Distant | p-value |
|---|---|---|---|---|
| Lung | ||||
| No VTE | 31,317 (19.7) | 43,671 (27.4) | 84,299 (52.9) | |
| VTE detected <1 year prior to cancer | 205 (18.4) | 236 (21.1) | 676 (60.5) | |
| VTE detected ≥1 year prior to cancer | 571 (20.2) | 736 (25.9) | 1527 (53.9) | <0.001 |
| Stomach | ||||
| No VTE | 5,876 (31.4) | 6, 187 (33.1) | 6, 646 (35.5) | |
| VTE detected <1 year prior to cancer | 36 (27.3) | 37 (28.0) | 59 (44.7) | |
| VTE detected ≥1 year prior to cancer | 135 (37.6) | 106 (29.5) | 118 (32.9) | 0.024 |
| Small Intestine | ||||
| No VTE | 1,091 (33.9) | 1,165 (36.2) | 962 (29.9) | |
| VTE detected <1 year prior to cancer | 14 (43.8) | 10 (31.3) | 8 (25.0) | |
| VTE detected ≥1 year prior to cancer | 28 (39.4) | 25 (35.2) | 18 (25.4) | 0.652 |
| Colon | ||||
| No VTE | 41,919 (41.9) | 39,974 (40.0) | 18,040 (18.1) | |
| VTE detected <1 year prior to cancer | 288 (42.2) | 259 (37.9) | 135 (19.8) | |
| VTE detected ≥1 year prior to cancer | 979 (43.6) | 909 (40.4) | 360 (16.0) | 0.077 |
| Gallbladder | ||||
| No VTE | 1,194 (34.6) | 1,097 (31.7) | 1,165 (33.7) | |
| VTE detected <1 year prior to cancer | 12 (24.5) | 12 (24.5) | 25 (51.0) | |
| VTE detected ≥1 year prior to cancer | 26 (38.2) | 20 (29.4) | 22 (32.4) | 0.140 |
| Pancreatic | ||||
| No VTE | 2,745 (10.6) | 7,716 (29.7) | 15,524 (59.7) | |
| VTE detected <1 year prior to cancer | 27 (8.7) | 53 (16.9) | 232 (74.4) | |
| VTE detected ≥1 year prior to cancer | 72 (11.3) | 172 (27.1) | 391 (61.6) | <0.001 |
| Soft Tissue | ||||
| No VTE | 2,368 (57.1) | 1,134 (27.4) | 643 (15.5) | |
| VTE detected <1 year prior to cancer | 19 (47.5) | 11 (27.5) | 10 (25.0) | |
| VTE detected ≥1 year prior to cancer | 59 (60.8) | 26 (26.8) | 12 (12.4) | 0.430 |
| Melanoma | ||||
| No VTE | 20,073 (79.9) | 3,781 (15.0) | 1,281 (5.1) | |
| VTE detected <1 year prior to cancer | 88 (77.2) | 20 (17.5) | 6 (5.3) | |
| VTE detected ≥1 year prior to cancer | 423 (78.5) | 91 (16.9) | 25 (4.6) | 0.719 |
| Ovary | ||||
| No VTE | 1,485 (10.5) | 940 (6.7) | 11,706 (82.8) | |
| VTE detected <1 year prior to cancer | 16 (9.4) | 13 (7.7) | 141 (82.9) | |
| VTE detected ≥1 year prior to cancer | 23 (8.6) | 14 (5.2) | 231 (86.2) | 0.637 |
| Kidney/Renal Pelvis | ||||
| No VTE | 11,920 (53.7) | 5,224 (23.6) | 5,040 (22.7) | |
| VTE detected <1 year prior to cancer | 97 (51.6) | 45 (23.9) | 46 (24.5) | |
| VTE detected ≥1 year prior to cancer | 234 (53.7) | 93 (21.3) | 109 (25.0) | 0.684 |
Cases with missing stage information are excluded from the table
Discussion
In our case-control study of over 1 million cancer cases of elderly individuals in the United States, we demonstrate a 15% increased risk of any cancer diagnosis associated with a prior diagnosis of VTE. This increased risk was not present for all cancers but instead was restricted to a large and somewhat heterogeneous subgroup of malignancies: cancers of the lung, stomach, small intestine, colon, gallbladder, pancreas, soft tissue, ovary, and kidney/renal pelvis, as well as for melanoma, NHL, myeloma, and AML. The elevated risks were generally stronger in the 1-year period following VTE diagnosis. Nonetheless, the risk of colon cancer, pancreatic cancer, and myeloma remained significantly elevated after more than 6 years of follow-up time.
The strongly elevated risk of cancer less than 1 year after VTE diagnosis observed in this study is consistent with results from prior population-based and hospital-based studies.(11–15) These previous studies have also shown distinct associations with cancers of digestive tract, pancreas, and NHL, as observed in our study. The short-term associations may be due to medical practice patterns in which clinicians search for cancer in people presenting with VTE. Prompted by VTE, screening tests such as colonoscopy or chest and abdominal/pelvic computed tomography scans could lead to diagnosis of previously unsuspected and asymptomatic malignancies.
Since cancer can itself cause VTE, an additional explanation is that VTE is a presenting manifestation of cancer and is diagnosed simultaneously with or slightly before the cancer. Many of the cancers diagnosed concurrently with VTE present at an advanced stage. (7, 14) Indeed, we demonstrated that a larger proportion of lung, stomach, and pancreatic cancers diagnosed within 1 year of VTE presented with distant metastases, compared to when there was no history of VTE. Conversely, several large registry-based studies documented a significantly higher risk of VTE following diagnosis and treatment of these cancer types as well as kidney cancer, ovarian cancer, NHL, and myeloma.(5, 6, 22) Furthermore, a separate study of over 66,000 cancer cases identified a near two-fold increased risk of VTE associated with distant metastases as compared to a localized malignancy. (23) Mechanistic studies have shown higher concentrations of pro-coagulant factors among individuals diagnosed with cancer. (24, 25) Therefore, the short-term associations of VTE with cancer risk are most likely driven by a combination of enhanced screening for cancer among individuals with VTE (which would lead to detection of early stage cancers) and reverse causation (i.e., cancer causing VTE, with some cases manifesting aggressive biology and advanced stage).
In contrast, the long-term association of VTE with risk of cancer of the digestive tract and hematologic malignancies, for a period of greater than six years following VTE, cannot be readily explained by screening or reverse causation. Unlike the short-term associations with cancer risk, these longer-term associations have not been observed consistently in prior studies. (11, 14, 16–18) Nonetheless, one plausible explanation is that the VTE may be caused by small, slow-growing tumor precursors that exist for extended periods of time. Such precursor tumors may induce procoagulant activity, possibly through production of cytokines and other molecular factors. (26) Of interest, the three cancers in our study that were associated with VTE over a long latency period have a prolonged pre-cancerous phase. Specifically, colon cancer is preceded by pre-neoplastic polyps, pancreatic cancer develops over more than a decade, and myeloma is preceded by monoclonal gammopathy of underdetermined significance (MGUS). (27–29) Indeed, an elevated rate of VTE and arterial thrombosis has been reported among those diagnosed with MGUS, which persists for up to ten years after MGUS diagnosis.(30–32) Furthermore, elevated serum concentrations of prothrombin fragment 1 and 2 are associated with increased risk of digestive tract cancers.(33)
We found very little difference in cancer risk by VTE subtype. This observation is mostly in agreement with a previous study that also assessed VTE subtype-specific associations. (18) However, we observed a higher risk of NHL and AML associated with DVT than PE. While PE is a more severe VTE event that results in higher mortality than DVT, a biological basis for these differences in cancer risk is unclear. Notably, the otherwise general lack of difference in cancer risk by VTE subtype reinforces the need to consider all VTEs, including SVT, with equal importance as they relate to cancer risk.
This study also has several limitations. First, we lacked information on some risk factors which could confound the observed associations. Smoking and obesity both increase the risk of VTE in general and are identified risk factors for the development of cancers of the lung, stomach, pancreas, colon, and ovary. (2, 34–43) In addition to smoking and obesity, other co-morbid conditions that occur at an elevated rate in this elderly population may also play a role as potential confounders. Second, our study was limited to people aged 66 years and older, and we could not ascertain the occurrence of VTE prior to the age of 65. The high prevalence of other cancer risk factors in this elderly Medicare population may explain why the associations observed in our study are weaker than relative risks estimated in other, mostly younger, populations.(11, 17) Third, since information on VTE subtype was based on billing claims submitted by health care providers, rather than a detailed medical record abstraction, there may be some misclassification of VTE subtypes.
This study has several strengths including the large sample size and population-based selection of cases and controls. Furthermore, because we included a large representative sample of elderly adults our results are directly relevant to this population, among whom both VTE and cancer are disproportionately common. In addition, the large sample of this study allowed for systematic evaluation across a range of multiple cancer types. However, given the rarity of VTE, some true associations may have failed to reach statistical significance.
The association of VTE with subsequent diagnosis of cancer, as well as the increased mortality of individuals with cancer who were previously diagnosed with VTE, has led to the suggested use of enhanced cancer screening strategies among individuals diagnosed with VTE. This approach may be most relevant for those cancers with an asymptomatic precursor condition and for which we observed associations with VTE over a latency period of several years (i.e., colon and pancreatic cancers, myeloma). A number of prospective and retrospective studies have indeed demonstrated that the use of basic screening strategies such as physical examination, CT scans, or targeted laboratory testing among individuals diagnosed with unprovoked or idiopathic VTE results in early detection of malignancies, particularly those of the pelvis and abdomen.(44–46) However, a small randomized trial assessing the effect of targeted screening among individuals with VTE showed no increased benefit of early detection on survival.(47) Therefore, cancer screening among individuals with VTE may only increase the lead-time in detecting cancer and may not improve survival among individuals diagnosed early with cancer.
In conclusion, we observed an elevated risk of specific solid-organ and hematologic cancers. The associations were most notable within 1 year following VTE diagnosis, and several cancers were more likely to present with distant metastases when they manifested in this short interval. The elevated risk of three cancers (colon and pancreatic cancers, myeloma) was significant at a period of more than 6 years following VTE diagnosis. Our study lends epidemiologic support to the view that cancer is related to the development of VTE. Additional studies are needed to better understand the underlying biological mechanisms and evaluate the potential clinical role of VTE as an early predictor for the development of cancer.
Acknowledgments
This study used the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program, National Cancer Institute; the Office of Research, Development, and Information, Centers for Medicare and Medicaid Services; Information Management Services, Inc.; and the SEER Program tumor registries in the creation of the SEER-Medicare database. We thank Winnie Ricker (Information Management Services, Rockville, MD) for assistance with database management.
Funding Sources
This work was supported by the Intramural Research Program of the National Cancer Institute at the US National Institutes of Health.
The authors would like to thank Winnie Ricker at Information Management Services (IMS) for assistance with management and analysis of the SEER-Medicare dataset.
Footnotes
Conflicts of Interest:
The authors have no conflicts to disclose.
Financial Disclosures:
This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health (M Marks).
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