In this large population-based study, we compared the risk of thromboembolic disease between Swedish men with prostate cancer and Swedish men in the background population. The findings show that men with prostate cancer are at a higher risk for thromboembolic disease than are men without prostate cancer. The risk was increased for DVT and pulmonary embolism, but not for arterial embolism, and was especially high for men treated with endocrine treatment. Additionally, the relative risk of thromboembolic disease in men treated with endocrine therapy was higher for younger men (<65 years) and for men with metastatic disease, while the absolute risk was similar for all three age groups (<65, 65–74, and ≥75 years). Moreover, a smaller increase in risk was found for men treated with anti-androgens compared with the other types of endocrine treatment.
The underlying mechanisms for the higher risk of thromboembolic disease could have several explanations. First, a baseline risk might be present because of physiological alterations due to the tumour, which seems to be supported by the fact that the risk of thromboembolic disease increases as tumour stage increases. Second, the different patterns of risk associated with different types of treatment indicate that treatments, and the selection of these treatments, can affect the risk of thromboembolic disease. Curative treatment, such as prostatectomy, and surveillance are also associated with an increased risk of thromboembolic disease, and indicate that some men might have received surveillance because of ongoing comorbidities.34
Third, the higher risks, through each stage of the analysis, for men primarily treated with endocrine treatment indicate a risk conferred by endocrine treatment over and above the other treatments and indications for treatment.
People with cancer have an increased risk of thromboembolic disease. Even though this association has long been recognised in clinical practice, few studies have quantified this risk for men with prostate cancer in detail.7,35,36
High rates of thrombosis have been reported in other cancers, especially in people with advanced disease receiving antitumour treatment. Clinical trials on breast cancer reported a rate of thrombosis of 1–10% in women with node-positive breast cancer, whereas development of venous thrombosis was reported in 10% of women with advanced ovarian cancer and in up to 28% of people with malignant gliomas.36
Treatment for prostate cancer can also be associated with an increased risk of thromboembolic disease. A cohort study based on 5951 patients undergoing prostatectomy showed an incidence of 0·5% (95% CI 0·4–0·7) for symptomatic DVT and pulmonary embolism.35
Additionally, a British study including 11 199 men with advanced prostate cancer showed that patients treated with cyproterone acetate had a significantly higher risk for venous thromboembolism than did men who underwent orchiectomy or were prescribed GNRH agonists (adjusted odds ratio 5·23, 95% CI 3·12–8·79).7
We caution that the observed contrasts in thromboembolic disease between different treatment groups should be interpreted as how treatment and treatment selection modify the risk of thromboembolic disease in men with prostate cancer. For several reasons, this study cannot directly quantify how much the observed differences in thromboembolic disease risk between treatment groups are due to the treatments themselves.1
Factors taken into account during the process of selecting treatment might also be associated with risk of thromboembolic disease. During the period of time covered by our study, Swedish men with early-stage prostate cancer who received curative treatment had lower all-cause mortality than the background population. Most men receiving curative treatment were recommended surgery, and had to be healthy enough to undergo radical prostatectomy.34
We made a similar observation in our study: men 75 years or older who had undergone curative treatment had a much lower absolute risk for DVT than men of the same age in the standard population, illustrating a selection bias towards healthy men for radiotherapy and prostatectomy. The increased risk of thromboembolism in the group treated with curative intent occurred mainly during the first 6 months of follow-up, indicating that the surgical intervention was important. However, a selection phenomenon might lead to a wrong conclusion about the effect of surgery in a direct comparison with the first period of follow-up in, for example, men under surveillance.2
There might have been differences in diagnostic activity (frequency of check-ups and differences in the types of testing used) for thromboembolic disease between the groups. However, DVT is likely to be correctly diagnosed and clinically relevant in patients admitted to hospital, who were the only ones included in this study. Therefore, we avoided the possibility that surveillance would lead to the diagnoses of many asymptomatic DVTs not related to the cancer or the treatment. Vigilance for thromboembolic disease is likely to have been similar in men with advanced cancer and those offered curative treatment, but might have been less intense in men under surveillance. It is also possible that a rapidly fatal pulmonary embolism in patients with advanced cancer could be interpreted as the fatal end-stage of the cancer, and therefore not coded in hospital charts. However, this misclassification would only affect a smaller number of patients, and mainly those on endocrine treatment, biasing their estimates towards null.3
The comparison between the treatment groups might be confounded by the introduction of second-line treatment—eg, men treated with curative intent or surveillance will have been exposed to endocrine treatment when the disease progressed.
Experimental findings have suggested a link between prostate cancer and thromboembolic disease, which might lead to hypotheses for further mechanistic studies. Babiker and colleagues37
showed that the early release of prostasomes from prostate cancer cells into the circulation might evoke blood-clotting effects causing thromboembolic disease. Another study by Li and colleagues16
showed a possible link between endocrine treatment and thromboembolic disease, in which they noted that the prevention of experimental arterial thrombosis by the use of androgens at physiological concentrations is mediated by the androgen receptor through modulation of platelet activation. Some studies have also suggested that testosterone has an antithrombotic effect, because higher concentrations are associated with an increase in antithrombin 3.9,38,39
This possible antithrombotic effect of testosterone is supported by our treatment-specific analyses of endocrine treatment, which showed that men treated with anti-androgens have the lowest SIR. Anti-androgens block the androgen receptors in the prostate, but do not decrease the circulating concentrations of total testosterone. Because of the effect of anti-androgens in the hypothalamus, the testosterone concentrations in serum might even be increased, and thus androgen-dependent pathways in other organs can still function.40
The higher SIRs in the youngest age group () can be explained by a lower absolute thromboembolic disease risk for younger men than for older men in the general population, and similar absolute risks for younger and older men with prostate cancer. This age effect was seen within each tumour stage; however, a stronger effect was seen for those with metastatic disease at time of diagnosis, suggesting that advanced cancer potentiates the risk due to the associated predisposition for thromboembolic disease. From a public-health point of view, both the absolute risk and absolute risk difference were largest for men given endocrine treatment. Thus, the largest number of extra cases of thromboembolic disease are likely to be seen in this patient group.
The NPCR database contains data from more than 76 000 men with prostate cancer, and provides complete follow-up for each patient, as well as linkage to other registers that allow for detailed information on thromboembolic disease morbidity. The same information about thromboembolic disease was available for the entire general population, which enabled us to adjust all comparisons for history of thromboembolic disease. Milder, non-hospitalised cases of thromboembolic disease, such as asymptomatic DVT, were not included, thus there is a possible underestimation of SIRs. The bias in the SIRs due to the use of general population rates, which included men with prostate cancer, to estimate expected numbers of thromboembolic disease was found to be negligible. The effect of treatment choice on the results should be small, since both history of thromboembolic disease and stage of disease were adjusted for. However, the above notwithstanding, there might be some residual bias that cannot be accounted for. For example, choice of endocrine treatment is likely to be related to comorbidity, suggesting that there could be a selection bias. However, as suggested by Miettinen,41
the physician or patient's choice of endocrine treatment primarily constitutes a confounder for the study of the intended effect (palliative treatment for prostate cancer), but not for the study of side-effects such as thromboembolic disease. This is because at the time the data were collected, the literature did not suggest a strong association between endocrine treatment and cardiovascular side-effects, thus it was not standard clinical practice to take thromboembolic disease history into account when initiating treatment. The diagnosis of prostate cancer itself can also bias the results, because these men receive more intensive medical care (eg, increased number of clinical visits), and are therefore more likely to be diagnosed with a thromboembolic disease event when it occurs. Furthermore, the combination of prostate cancer, especially advanced disease, with thromboembolic disease might strengthen the indication for hospitalisation, therefore biasing the SIR estimates upwards. Based on the Swedish Drug Registry, it was shown that it takes about 1 month before men with prostate cancer start taking their endocrine treatment (Stattin P, unpublished). The effect of delayed start of treatment was assessed with a sensitivity analysis excluding cardiovascular disease events that occurred within 1 month of the prostate cancer diagnosis, and showed almost no change in SIR estimates (data not shown). Furthermore, an unknown proportion of men treated curatively, on surveillance, or on anti-androgens, subsequently changed to GNRH agonists, which could dilute a true difference in risk between anti-androgens and GNRH agonists. We had no information about smoking habits, diabetes, body-mass index, or hypertension, but none of these factors are strongly associated with prostate-cancer risk, and are therefore unlikely to explain the current findings.42
No information was available on history of comorbidities other than circulatory diseases.
Our findings indicate that it is important to consider thromboembolic side-effects when treating patients with prostate cancer, especially those who require endocrine treatment. Higher risks for thromboembolic disease were also noted for younger men and men with metastatic disease. Risk patterns for thromboembolic disease that differ according to prostate-cancer treatment, age, and tumour stage, are probably explained by the physiological effects of prostate cancer, treatments for prostate cancer, and the factors taken into consideration when selecting these treatments.