© Springer International Publishing AG 2018Laurence Klotz (ed.)Active Surveillance for Localized Prostate CancerCurrent Clinical Urologydoi.org/10.1007/978-3-319-62710-6_17
17. Is There a Role for Pharmacologic Manipulation to Prevent Progression in Men on Active Surveillance? The Role of 5-ARIs, Statins, and Metformin
Department of Urology, Rabin Medical Center, Petah Tikva, Israel
KeywordsProstate cancerActive surveillanceChemoprevention5-ARIsStatinsMetformin
Traditional treatments for Pca, such as surgery or radiation, are associated with significant adverse events and can negatively affect the quality of life of patients and their families [1–3]. Low-risk prostate cancer may be treated with active surveillance since randomized trials have failed to show a beneficial impact of immediate radical treatment on survival . The negative effects of treatment combined with potentially long latency of the disease, late age of onset, and high prevalence make prostate cancer an ideal target for primary and secondary disease prevention. Several medications have been evaluated as potential agents for prostate cancer prevention including 5-α(alpha)-reductase inhibitors (5-ARI), statins, and metformin. Herein we describe possible mechanisms through which these medications act to inhibit prostate cancer development and progression and focus on their role in secondary prevention of low-risk prostate cancer.
5-α(alpha)-Reductase Inhibitors (5-ARI)
The rationale for the specific use of 5-ARIs as chemopreventive agents is based on the androgenic nature of prostate cancer and the uniform absence of prostate cancer among men with congenital deficiency of 5α(alpha)-reductase . The enzyme 5α-reductase resides in prostatic tissue and converts circulating testosterone to localized dihydrotestosterone (DHT) , a more potent agonist of androgen receptors in prostatic cells. 5α(alpha)-reductase has two isoforms : type II 5α(alpha)-reductase is the isoform common in benign prostatic tissue; type I predominates in localized prostate cancer . Finasteride is a selective inhibitor of the type II enzyme, while dutasteride inhibits both isoforms . The decreased levels of DHT induced by 5-ARIs may inhibit prostate cancer development and progression, thus providing the rationale for its role as a chemopreventive agent.
Statin medication effectively lowers serum cholesterol levels by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase . The chemopreventive role of statins for prostate cancer may be the result of cholesterol-mediated and non-cholesterol-mediated pathways .
Discrete portions of the cell membrane consisting of cholesterol-rich domains termed “lipid rafts ” play a central role in intracellular signaling . These membrane rafts may promote prostate cancer development and progression via androgen receptor, epidermal growth factor receptor, and luteinizing hormone receptor pathways . In a xenograft model of LNCaP cells, inhibition of cholesterol synthesis decreased the cholesterol content in lipid rafts, attenuated AKT signaling, and induced tumor cell apoptosis . In addition, cholesterol serves as a precursor for androgen production; thus, lowering cholesterol levels may lower androgen levels. However, observational studies have not supported the association between statin use and reduced androgen levels .
Statins may also directly affect cancer cells, independent of cholesterol levels, and may inhibit prostate cancer growth by exerting proapoptotic, anti-inflammatory, and anti-angiogenic effects .
Metformin reduces hepatic glucose production, increases insulin sensitivity, increases glucose use by peripheral tissues, and thus decreases the blood glucose levels in patients with type 2 diabetes mellitus . Metformin exerts its antineoplastic properties in multiple pathways including AMP-activated protein kinase-dependent and kinase-independent pathways, alteration of insulin and insulin-like growth factor signaling, and suppression of androgen signaling .
AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that regulates cellular energy metabolism. AMPK suppression has been associated with the activation of tumor growth pathways, including the mammalian target of rapamycin (mTOR) pathway . Metformin activates AMPK and thus decreases mTOR signaling which decreases protein and fatty acid synthesis and inhibits cell proliferation . Furthermore, the suppression of de novo lipogenesis is directly responsible for AMPK-mediated inhibition of prostate cancer growth . Multiple AMPK-independent mechanisms, including the reduction of cAMP levels which inhibits protein kinase A activity and blocks glucagon-dependent glucose production, have also been associated with the treatment of diabetes mellitus and the antineoplastic properties of metformin .
Insulin, insulin growth factor (IGF) 1, and IGF 2 act to promote tumorigenesis by binding to the insulin receptor and activating the PI3K/AKT/mTOR pathway leading to abnormal cell proliferation, inhibition of apoptosis, and carcinogenesis . Furthermore, hyperglycemia aids tumor growth since tumor cells are highly reliant on aerobic glycolysis to generate energy (the Warburg effect ). Metformin inhibits gluconeogenesis and decreases circulating glucose and insulin levels thus opposing the tumorigenic effects of hyperinsulinemia and hyperglycemia .
Metformin reduces the activity of cyclin D1 which has been shown to be a central regulator in androgen-dependent transcription and cell cycle progression of prostate cancer cells . In addition, metformin may disrupt androgen signaling by directly acting against androgen receptor pathways. These antiandrogenic effects may act against the development and progression of prostate cancer.
Preventive medicine or preventive care refers to measures taken to prevent diseases (or injuries), rather than curing them or treating their symptoms. Preventive medicine strategies are typically described as taking place at the primary, secondary, and tertiary levels:
Primary prevention strategies intend to avoid the development of disease.
Secondary prevention strategies attempt to diagnose and treat an existing disease in its early stages before it results in significant morbidity.
Tertiary prevention aims to reduce the negative impact of established disease by restoring function and reducing disease-related complications.
The Role of 5-ARIs, Statins, and Metformin in Primary Prevention of Prostate Cancer
There are two positive large randomized controlled studies demonstrating the effect of 5-ARIs in primary prevention of prostate cancer [19, 20]. The Prostate Cancer Prevention Trial (PCPT) reported a 24.8% relative reduction (95% CI 18.6–30.6, p < 0.001) in the risk of prostate cancer in patients receiving finasteride over the 7-year study period . Similarly, the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial reported a relative reduction of 22.8% (95% CI 15.2–29.8, p < 0.001) in prostate cancer events over the 4-year study period . However, in both studies, there was an increased likelihood of developing high-grade tumors when 5-ARIs were given as preventive agents to healthy men, which led the Oncologic Drugs Advisory Committee (ODAC) of the US Food and Drug Administration (FDA) to recommend against prostate cancer chemoprevention labeling for the 5α(alpha)-reductase inhibitors finasteride (Proscar) and dutasteride (Avodart). Therefore, a more appealing strategy would be to use 5-ARIs to delay progression in those men already diagnosed with prostate cancer.
Most clinical data evaluating the effect of statins on the development and progression of prostate cancer are based on observational studies utilizing large databases or meta-analyses of statin randomized control trials. Since these studies were focused on cardiovascular outcomes, they were underpowered to evaluate the true effect of statins on prostate cancer, and most studies did not detect a significant effect . Farwell et al. performed a large observational study comparing men receiving statins to those receiving antihypertensive medication. In this cohort, statin users were 31% less likely (HR 0.69, 95% CI 0.52–0.9) to be diagnosed with prostate cancer, and increased levels of cholesterol were associated with a higher incidence of prostate cancer (HR 1.02, 95% CI 1–1.05). This association was more prominent for high-grade tumors . Other large cohort observational studies did not demonstrate an association between statin use and prostate cancer incidence or grade [23–25].
Conflicting results exist in observational studies evaluating the association between treatment with metformin and prostate cancer risk. In a large retrospective cohort study, no association was demonstrated between metformin use and the risk of prostate cancer (OR 1.03, 95% CI 0.96–1.1), regardless of cancer grade and method of diagnosis . Contrary to these findings, in a case control study base on the Danish Cancer Registry, metformin users had a decreased risk of developing prostate cancer compared with never users (OR 0.84, 95% CI 0.74–0.96) .
5-ARIs in Secondary Prevention
Several studies, including one RCT, have examined the role of 5-ARIs to prevent progression in men with low-risk, localized prostate cancer followed by active surveillance [28–32]. In their initial single-institution, retrospective cohort study, Finelli et al. compared 70 men started on a 5-ARI at variable time points after their diagnostic biopsy to 218 men who were not treated with 5-ARI while on active surveillance for low-risk prostate cancer. Progression was defined as GS >6, maximal core involvement >50%, or >3 positive cores on follow-up biopsy. At a median follow-up of 38.5 months, men treated with 5-ARI experienced lower rates of progression (18.6% vs. 36.7%; p = 0.004) and were less likely to abandon active surveillance (20% vs. 37.6%; p = 0.006). These findings remained significant on multivariate analysis . The study was criticized for not relating to the use of 5-ARI as a time-dependent covariate, thus potentially overestimating its benefit . In a subsequent reanalysis using a Cox proportional hazards model with time-dependent covariates, lack of 5-ARI treatment continued to be associated with pathological progression (HR 4.55, 95% CI 1.61–12.5, p = 0.004) . Contrary to these findings, Ross et al. reported a retrospective study of 587 men enrolled to an active surveillance program, 47 of whom received 5-ARI during surveillance. The main study outcome was progression on surveillance biopsy, and the use of 5-ARI was treated as a time-dependent covariate. On univariate analysis, progression occurred in 17% of 5-ARI users compared to 31% of nonusers (p = 0.04). However, the significance of the association was lost on multivariable analysis when adjusting for age, α-blocker use, PSA level, %free PSA, PSA density, prostate volume, and number/percent biopsy core involvement at diagnosis . Finally , Shelton et al. reported on 82 men with very low-risk prostate cancer and benign prostatic hyperplasia who were followed with active surveillance and received 1 year of treatment with 5-ARI. At their first restaging biopsy, 54% of men had no evidence of prostate cancer, 21% continued to have very low-risk prostate cancer, 20% progressed to low-risk prostate cancer, and 5% to intermediate-risk prostate cancer (Gleason score 7). During 3 years of follow-up, most patients (57/82, 70%) maintained very low-risk prostate cancer or had negative surveillance biopsies; thus, the authors concluded that 5-ARI treatment for patients on active surveillance for very low-risk prostate cancer is a safe treatment option. Furthermore, 5-ARI therapy increases the sensitivity of prostate-specific antigen and can aid in targeting biopsies .
The Reduction by Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial is the only phase III RCT to evaluate the safety and efficacy of 5-ARIs in secondary prevention in men with low-risk prostate cancer followed by active surveillance. In this randomized, double-blind, placebo-controlled trial, men aged 48–82 who had low-volume Gleason score 5–6 prostate cancer, PSA ≤10 ng/ml, and were followed by active surveillance were randomized to receive once daily dutasteride 0.5 mg/day (n = 147) or matching placebo (n = 155). The total follow-up was 3 years, with 12-core biopsy samples obtained at 18 and 36 months. The primary end point was time to disease progression. This was a composite outcome defined as the earliest of the following events: receipt of primary therapy for prostate cancer (e.g., prostatectomy, radiation, hormonal therapy) or pathologic progression (≥4 cores involved, ≥50% of any core involved, or any Gleason score ≥7). Secondary end points included improving anxiety, quality of life (QOL), and urinary symptoms in men undergoing active surveillance. At 3 years of follow-up, 54/144 men (38%) in the dutasteride group had disease progression compared to 70/145 men (48%) in the control group, (HR 0.62, 95% CI 0.43–0.89, p = 0.009). Subjects treated with dutasteride were more likely to have no cancer detected on follow-up biopsies (23% in the placebo arm vs. 36% in the dutasteride arm, p = 0.024). The main difference between the two groups was a reduction in number of cores involved a nd extent of core involvement by Gleason 6 cancer in the dutasteride group compared to placebo, perhaps reflecting the known cytoreduction effect of the drug. Importantly, Gleason score 8 cancer was detected in the final biopsy in two men in the dutasteride group and three controls, and no case of Gleason score 9–10 cancer was noted on the final biopsy. Based on the memorial anxiety scale for prostate cancer (MAX-PC) , overall prostate cancer anxiety assessment remained almost constant for controls and decreased for patients who received dutasteride throughout the study. Specifically, patients at the dutasteride group reported a significantly lower fear of recurrence. Overall rates of adverse events did not differ significantly between dutasteride and placebo. Sexual adverse events and breast-related disorders were apparent in 35 men (24%) receiving dutasteride and 23 men (15%) in the placebo group; however, this difference was not statistically significant. Likewise, no difference was noted in cardiovascular complications . The authors conclude that among men followed for prostate cancer with active surveillance, dutasteride may delay the time for cancer progression and decrease prostate cancer-related anxiety. Therefore, dutasteride may provide a useful adjunct to active surveillance . A limitation of the REDEEM study is that a reduction of volume of Gleason 6 disease with dutasteride was the main difference between the two arms. Since dutasteride reduces prostate epithelial cell volume, this is not surprising. Whether this will translate into a meaningful biological difference remains unce rtain.
Statins in Secondary Prevention
In a large population-based study, Yu et al. identified 11,772 men with newly diagnosed nonmetastatic prostate cancer and reported that the post-diagnostic use of statins was associated with a decreased risk of prostate cancer mortality (HR 0.76, 95% CI 0.66–0.88) and all-cause mortality . Multiple studies have specifically evaluated the role of statins in secondary prevention after radical prostatectomy and curative radiation therapy for localized prostate cancer .