To compare our results to those in the literature, we combined our DVT and PE incidence and incidence density estimates to determine an overall VTE incidence, commonly reported by others. Our combined (DVT + PE), one-year, post RCC incidence was 10.7% and incidence density rate was 127/1,000 p-y. These estimates are higher than what has been reported in the literature thus far
[2, 6–8, 10–12].
Our incidence results, however, are difficult to compare to current literature because of method and study population differences. Our analysis followed each patient for a defined period after diagnosis or death to evaluate incidence over the full 12-month period after diagnosis; however, many of the studies calculated an incidence proportion (percent) based on whether the patient had a diagnosis of VTE during their initial hospitalization
[7, 10] or during a randomly selected hospitalization
. Their estimates of VTE among kidney cancer patients ranged from 0.8-7.6% per hospitalization. These are not comparable to our estimate(s) because only one hospitalization has been evaluated per patient. Stein et al. took an approach similar to ours in that they looked at all hospitalizations for each patient over a period of time; however, they also presented their results per hospitalization instead of per person or person-years (VTE incidence of 20/1,000 hospitalizations)
. It is unclear what the average length of follow-up was in their study and their study population was also substantially younger than ours, with ages ranging from 40–79 compared to our study age range of 65–101, with a median age of 75.
A few other studies presented cumulative incidence and incidence density results for kidney cancer patients; however, their study populations were vastly different from ours. Blom et al. found that 1.3% of kidney cancer patients (and 12.6/1,000 p-y) had a VTE in the 6 months after cancer diagnosis; however, researchers only included patients who visited an anticoagulant clinic, not patients who were hospitalized for treatment
. Their estimate is significantly lower than ours (127/1,000 p-y) and likely an underestimate of the rate in the general kidney cancer population because sicker individuals, who were unable to visit this ambulatory clinic, were not given the opportunity to present as a VTE case in their study population. They also had a younger population (median age = 64) than ours. Chew et al. performed their analysis very similarly to ours; however, they excluded all patients with a past diagnosis of VTE
. Their estimates of post kidney cancer VTE incidence (2-yr cumulative incidence: local: 1.3%, regional: 3.8, remote 3.5% and 2-yr incidence densities of 13, 37, and 60 per 1,000 p-y) are likely lower than ours because they have excluded the highest risk group of patients from their analysis. Sallah et al. found that 22.6% of kidney cancer patients developed VTE over an average of 26 months
. Their estimate of cumulative incidence was higher than ours; however, their sample size was very small (n = 31), their study population was much younger (median age = 60 yrs), and their average period of follow-up was twice as long as ours.
Our results indicate that the risk of VTE is highest in the first 90 days after RCC diagnosis. Blom et al. also found the risk of VTE particularly high during the first few months after cancer diagnosis; however, they could draw no conclusion about kidney cancer, in particular, due to limited sample size for that cancer (n = 8)
. The risk of VTE was significantly higher among distant metastasized kidney cancers in the Blom study, as well
. This is similar to our finding that regional and distant RCC patients were at increased risk of VTE compared to local RCC cases.
The major risk factors for venous thromboembolisms among cancer patients reported in the literature are increased age, female sex, African American race, renal disease, infection, pulmonary disease, obesity, arterial thromboembolism, inherited prothrombotic mutations, prior history of VTE, performance status, advanced stage cancer, major surgery, hospitalization, chemotherapy, hormone therapy, anti-angiogenic agents, erythropoiesis-stimulating agents, transfusions, and central venous catheters
[4, 8, 13, 16, 17]. In our predictive model, many of these risk factors proved to be predictors of VTEs in the 12 months after RCC diagnosis. Unadjusted results presented in Table
2 suggested that immunotherapy might be an important predictor of VTEs in our data; however, after adjustment for stage and other important risk factors (Table
3), immunotherapy was not a statistically significant predictor of VTEs.
A few interesting differences are worth discussion. Atherosclerosis was a strong predictor for DVT, PE and OTE events. This condition is not generally mentioned as a risk factor for VTE among cancer patients; however, cardiovascular literature has suggested a link between these two conditions
[18–21]. Another interesting result was that central venous catheter (CVC) and high-risk surgery decreased the risk VTE in our data. Decreased risk in this subgroup of patients is likely due to the close monitoring and prophylactic treatment for venous thromboses in surgical and catheterization situations.
An important component of our analysis was the evaluation of VTE history as a risk factor for future VTE events. Our results suggest that VTE history is the most important factor to consider in evaluating risk of future VTE in RCC patients. There are no other studies in the current literature that quantify the association between VTE history and RCC; however, this result is consistent with broader studies of VTE among cancer patients
Finally, our analysis compared the risk of VTE events in RCC versus non-cancer patients both before and after RCC diagnosis. Our study found that RCC patients were 1.5-1.9 times more likely to have experienced a VTE in the recent past (i.e. 12 month before RCC diagnosis) than non-cancer individuals. White et al. reported a similar result: the standardized incidence ratio of observed versus expected RCC patients was 2.5 among those with a history of VTE
. No other published studies had sufficient numbers to address the relation between VTE and subsequent RCC diagnosis. These results support the common theory that VTE could be a risk marker for an ensuing cancer diagnosis
[4, 23, 24].
Our study found that RCC patients were also 3.6 times more likely to experience a DVT and 4.3 times more likely to experience a PE event in the 12 months after RCC diagnosis than age-matched non-cancer individuals during the same time frame. Stein et al. reported a slightly weaker association: RCC cancer patients were 2.0 times more likely to have a DVT and 1.7 times more likely to have a PE than non-cancer patients
. The study population was significantly younger in the Stein study and they did not adjust for confounders or evaluate effect modifiers. Blom et al. also compared VTE incidence among kidney cancer patients versus non-cancer patients (OR = 6.2, 95% CI 0.8-46.5); however, there were only 8 kidney cancer cases in their case–control study
There are several strengths of note for this study. To our knowledge, this is the first study to examine VTEs among older RCC patients. In this analysis we were able to focus on RCC patients in particular, rather than kidney cancer patients overall, because of the availability of detailed histological information in SEER. The RCC patient cohort was large (n = 11,950) allowing us to produce precise effect measure estimates, even after stratification. Unlike many published studies, which combined TE events into one outcome group, we examined three individual venous outcome groups (DVT, PE and OTEs) based on ICD-9 diagnostic codes. The wealth of the data in the SEER-Medicare database allowed us to quantify the occurrence of TE events before RCC diagnosis and during various time periods after RCC diagnosis, and to make comparisons between RCC patients and age-matched non-cancer individuals. Furthermore, we were able to adjust for and/or stratify by important covariates in our analysis. All estimates for incidence of VTEs among RCCs in previous literature were generated from studies that looked at multiple cancers and presented unadjusted incidence estimates for specific cancers, usually per hospitalization. No studies performed multivariate analyses on RCC patients nor did they investigate the timing of VTE events among RCC patients.
As in any study, limitations were present. The results based on this older cohort (i.e., 65 years or older) are generalizable only to those of the same age group. Also, information on some behavioral risk factors such as smoking, sedentary lifestyle, immobility, and CVD family history was unavailable. Oral prescription information was also unavailable, precluding the evaluation of anti-platelet therapy or anti-coagulant use. Finally, we had no access to information about potential predictive biomarkers such as elevated platelet or leukocyte counts, tissue factor, soluble p-Selectin, D-dimer, factor V Leiden, and prothrombin 20210A mutations
[13, 15, 25].