25th December 2021, Dr Chee L Khoo
There is increasing evidence that supports an inverse association between statin use and cancer risk. The findings for prostate cancer, particularly advanced disease, are the most promising of all cancers studied. There are studies suggesting the usefulness of statins in secondary and tertiary prevention. For example, patients undergoing radiotherapy for prostate cancer improved their prostate specific survival if they are on statins. The evidence supporting the use of statins for primary prevention of prostate cancer is still lacking.
Before we get into the question of whether statins improves mortality in patients with prostate cancer, we have unanswered questions about the value of screening for prostate cancer with or without statins.
To screen or not to screen
The evidence is still conflicting. There are suggestions that universal screening may result in overdiagnosis of low-risk tumours and universal screening only result in modest reduction in prostate cancer mortality (1,2). The Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC), the largest component of the European Randomized Study of Screening for Prostate Cancer, reported no statistically significant benefit in prostate cancer mortality by systematic prostate-specific antigen (PSA)-based screening (3). However, the benefit became clearer after a minimum of 3 screenings (4). The harm of systematic PSA-based prostate cancer screening is thought to exceed the benefits by causing unnecessary diagnoses of clinically insignificant cancers (1) but this is not universally accepted.
So, does PSA screening amongst patients on statin affect prostate cancer incidence and mortality? We may have some answers from a recent post hoc subgroup analysis of a cohort from the FinRSPC (5).
Between 1996 and 1999, all men aged 55, 59, 63, or 67 years at baseline and living in the Pirkanmaa or Helsinki districts were identified in the Finnish Population Registry and randomised to the screening (31 872 men) or control (48 295 men) groups. Men with prostate cancer diagnosis at baseline were excluded. The screening group was invited to consecutive PSA screenings at 4-year intervals. If PSA levels were ≥ 4 ng/mL, men were invited to their local urological clinic for digital rectal examination, prostate ultrasonography, and prostate biopsy.
Information on prostate cancer diagnoses was obtained from the population-based nationwide Finnish Cancer Registry. Information about prostate cancer deaths was obtained from the cause-of-death registry maintained by Statistics Finland. The study population was linked to the national prescription database to obtain information about statins use during the 1996 to 2009 period.
Screening vs no screening (control)
Prostate cancer cases detected in the screening group were more often Gleason 6 tumours (i.e less aggressive) compared with the control group (5.4 of 1000 person-years vs 3.4 of 1000 person-years) irrespective of statin use. Prostate cancer in the screening group were also less often metastatic compared with prostate cancer cases in the control group (0.75 of 1000 person-years vs 0.89 of 1000 person-years) also irrespective of statin use. Thus, PSA screening was associated with lower incidence of advanced prostate cancer regardless of statins use.
Screening increased overall prostate cancer incidence among non-users (RR, 1.31; 95% CI, 1.24-1.38), whereas among statin users, screening did not increase the risk for prostate cancer overall. Thus, the findings in this study refute the suggestion that screening is associated with overdiagnosis of low-grade prostate cancer at least amongst statin users.
Statin user vs statin non-user
Compared with statin non-users, statin users had a lower incidence of prostate cancer, lower grade tumours and lower metastatic prostate cancers. Prostate cancer mortality remained lower among statin users than non-users in both FinRSPC trial groups.
Accumulation of prostate cancer deaths was slower among statin users regardless of the trial group. In non-users, prostate cancer mortality curves differed in favour of the screening group after 10 years of follow-up. Among statin users, no such difference between trial groups was observed.
Why the difference?
Statin users had a lower median PSA level in this study. Serum PSA is influenced by benign conditions such as prostatic inflammation (7). Some commonly used medications, including statins, influence PSA level (8). PSA levels could result from improved accuracy of PSA screening in detection of clinically relevant cancer owing to lower PSA levels among statin users, with fewer prostate biopsies for borderline PSA elevations and a reduction in detection of clinically irrelevant cancers.
On the other hand, lower PSA levels could presumably also lead to delayed detection of prostate cancer, causing cancers to be diagnosed more often at an advanced stage. We did not see that in this study.
Statin use may be associated with health-conscious behaviour and increased health care service use. This association could have created a bias toward the null when estimating the outcomes of systematic PSA-based screening in this group.
The effects of statins in prostate cancer
Statins, by inhibiting endogenous cholesterol production, block protein prenylation and can influence cancer proliferation and migration (9). Statins may lower PSA by reducing intraprostatic inflammation or by inhibiting androgen signaling (10). Reduction in PSA levels among statin users has been observed in many studies (11–15). However, not all studies report a PSA reduction (17). In a randomised, placebo-controlled clinical trial,16 short-term, high-dose atorvastatin lowered PSA levels compared with placebo in men with high-grade prostate cancer, but not overall. Another trial with a small single intervention group reported a nonsignificant 12% decrease in PSA after fluvastatin intervention (18).
In summary, PSA-based screening was associated with decreased incidence of advanced prostate cancer among both statin users and non-users. There was less detection of low-grade localised tumours in statin users than in non-users. PSA-based screening may cause less harm among statin users while the benefits remain similar.
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