The influence of cardiovascular morbidity on the prognosis in prostate cancer. Experience from a 12-year nationwide Danish population-based cohort study

Prostate cancer is the most common malignancy in men and the second most common cause of death from cancer in men in Western countries [1]. In Denmark, prostate cancer accounts for 4% of all deaths in men [2]. The median age of patients with newly diagnosed prostate cancer is above70 years, and a large proportion of these men have coexisting diseases (comorbidities) at the time of prostate cancer diagnosis [3]. Several studies have shown that comorbidity increases mortality in prostate cancer patients [3‐6]. In a Danish population-based cohort study of prostate cancer patients diagnosed between 1995 and 2006, comorbidity was present in more than one-third of the patients and was a negative prognostic factor [3]. In that study, prostate cancer survival generally improved over time except among patients with high levels of comorbidity. However, the study did not address the impact of specific types of comorbidity. Comorbidity may indirectly affect prognosis by influencing choice of treatment; e.g. in men with localized prostate cancer those with comorbidity tend to receive conservative/nonsurgical treatment more often than those without [4, 7‐9]. Cardiovascular diseases, including ischemic heart disease (IHD) and stroke, are common diseases and the leading causes of death in most Western countries accounting for nearly half of all deaths in Europe (48%) [10] and of one third of all deaths in the US (34%) [11]. During the last 30 years, mortality from cardiovascular diseases has declined steadily in most European countries due to decreasing incidence combined with improved treatments [10‐14]. Still, little is known on how preexisting IHD and stroke affect the survival in prostate cancer patients. The aim of this study was therefore to estimate the prognostic impact of preexisting IHD and stroke in prostate cancer patients. Accordingly, we conducted a large cohort study of Danish prostate cancer patients using nationwide registries.

We included 30,721 men with a primary diagnosis of prostate cancer in Denmark between 1997 and 2008. The median age at prostate cancer diagnosis was 72 years (range, 34-100 years). At diagnosis, 14% (4,276) had preexisting IHD and 4% (1,331) preexisting stroke. Patients with preexisting IHD or stroke were older, had higher tumour stage, and higher levels of other comorbidities at diagnosis than patients without IHD or stroke (Table 2).

In this nationwide cohort study of more than 30,000 prostate cancer patients, we found that preexisting IHD had only minimal impact on overall mortality, whereas prostate cancer patients with preexisting stroke had higher mortality than those without IHD or stroke.

For patients below70 years of age we observed better survival for patients with preexisting IHD compared with those without IHD. There are several possible explanations of why prostate cancer patients with IHD had better survival than prostate cancer patients without IHD. Because of their cardiovascular disease, these patients were probably in closer contact with the health care system, and were more concerned about their health which could lead to prostate cancer diagnosis at an earlier stage. We found, however, a higher prevalence of localized tumours in patients without IHD or stroke in all three age groups (data not shown), arguing against such surveillance bias. Other possible explanations include the beneficial effect of potential lifestyle changes after cardiovascular disease diagnosis (e.g. smoking cessation, increased exercise, weight loss) and the use of secondary medical prophylaxis, such as statins, which might be associated with reduced risk of advanced prostate cancer [19‐21]. Due to lack of information about subsequent medical treatment this intriguing relationship could not be further explored.

We did not find a similar effect in patients with preexisting stroke; in contrast, these patients had substantially higher mortality than patients without IHD or stroke. We observed the largest increase in mortality among patients with preexisting stroke without any other comorbidities.

Our study revealed a considerable increase in the prevalence of IHD or stroke among prostate cancer patients during the study period. This is consistent with the general increase in prevalence of comorbidity among Danish cancer patients over the last decade [22‐25]. Possibly, patients may be more likely to have a PSA test now than earlier during follow-up visits for IHD or stroke, which has resulted in more patients with IHD or stroke to be diagnosed with prostate cancer in recent years.

We cannot exclude the possibility that IHD or stroke patients who are diagnosed with prostate cancer present a selected group of patients, since these patients have actually survived their cardiovascular disease. This may bias the estimates towards the null and thus partly explain why the difference in mortality between those with and those without a history of cardiovascular disease is not larger than observed in this study.

Choice of treatment of prostate cancer is determined by many factors such as age, D'Amico risk group (PSA, Gleason score, and TNM stage), but comorbidity will also influence which treatment a patient is offered. Previous research on this topic has shown that prostate cancer patients with comorbidities are often offered nonsurgical/conservative treatment [4, 7‐9].

In the present study we found that preexisting stroke increased mortality to a significantly higher degree than preexisting IHD, which suggest a potential importance of differentiating between various kinds of comorbidities. When decisions are made about radical treatment of prostate cancer the type of comorbidity could be relevant to consider and not just the overall burden of comorbidities as expressed in the Charlson score.

The major strengths of our study were its large size, the virtually complete follow-up, and the ten year observation period before prostate cancer diagnosis to identify hospital-diagnosed comorbidity for each prostate cancer patient. The validity of the recorded diagnoses is crucial for the reliability of our findings. The registration of prostate cancers is thought to be virtually complete since free health care is available to all residents in Denmark: guaranteeing free access to hospitals and essentially eliminates all private inpatient or outpatient treatment of prostate cancer [16]. The positive predictive value of ischemic and unspecified stroke in the National Patient Registry has previously been estimated to be above 80% [26], and similar positive predictive values have been found for IHD [27, 28].

Study limitations include use of a modified version of the Charlson Comorbidity index to control for confounding by other comorbidities, and it is unlikely that the index controls for confounding as effectively as clinical data [29]. Unfortunately, our study did not include information on prognostic lifestyle factors such as smoking or obesity or clinical data such as Gleason score, PSA, and treatments for prostate cancer and cardiovascular diseases which may have further informed our estimates.

Our results showed that preexisting IHD had minimal impact on mortality following prostate cancer, whereas mortality was 20% higher in prostate cancer patients with preexisting stroke compared to those without IHD or stroke and even 42% higher for prostate cancer patients with preexisting stroke and no other comorbidities. These results highlight the importance of differentiating between various comorbidities when decisions are made on prostate cancer treatment.

CGJ is a medical doctor and 2^nd year PhD student, MN is PhD and associated professor at the department of clinical epidemiology, TEBJ is PhD, associated professor, and chief surgeon at the department of urology, MS is PhD and post doc at the department of clinical epidemiology, MB is DMSc and professor of urology at the department of urology.