Is Cure Possible? Advantages, Disadvantages, and Alternatives to Medical Therapy for Benign Prostatic Hyperplasia

#aging #minimallyinvasive #prostate

ABSTRACT

Older age is a significant risk factor for benign prostatic hyperplasia (BPH). BPH is characterized by an overgrowth of prostate tissue associated with lower urinary tract symptoms (LUTS). Bothersome, and frequently debilitating, symptoms prompt men to seek treatment. Surgery via transurethral resection of the prostate (TURP) is an option for advanced disease, yet it is invasive, thus medical therapy is a preferred alternative when possible. Medications include alpha blockers, which relax the muscles of the urethral sphincter, 5-alpha reductase inhibitors (5-ARIs), which shrink the volume of the prostate, or a combination of both.?While medical therapy for BPH is generally considered safe and effective, studies have shown that serious side effects are not uncommon. Over the past decade, development of minimally-invasive techniques, in particular UroLift? and Rezūm?, has provided improved options to control BPH. Any therapeutic intervention, however, must be appropriately tailored to each patient's disease.

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Keywords: Age-related disease, benign prostatic hyperplasia, medical therapy, minimally-invasive procedure

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INTRODUCTION

According to Prostate Cancer Foundation, “the risk of BPH increases every year after age 40: BPH is present in 20% of men in their fifties, 60% of men in their sixties, and 70% of men by age 70.” Unlike prostate cancer, which begins in the outer zone of the prostate and then invades surrounding tissue, BPH has an inward growth pattern (1), producing, without treatment, worsening symptoms. Besides the standard prostate specific antigen?(PSA) test (2), other clinical biomarkers are important to diagnose BPH. Specifically, telomerase expression levels can be quantitated via quantitative real-time polymerase chain reaction (PCR) (3). In this study, 100% of patients with prostate cancer showed high telomere expression in the assay, while 90% of patients with BPH showed low expression or none. Intriguingly, 10% of patients with BPH showed high levels of telomerase, pointing to BPH in the very early stages of transition to cancer (3). Thus, telomerase can be used as a prognostic indicator for aggressive disease, guiding the course of BPH treatment. Prostate Cancer Foundation estimates that over 350,000 men in the United States require treatment per year to relieve the urinary obstruction caused by BPH. Unless the disease has advanced into an aggressive form, in which case surgery (TURP) is the best option, medical therapy (4) or minimally-invasive procedure (5) are the first-line treatment options for BPH and will be discussed below.

MEDICAL THERAPY

The Medical Therapy of Prostatic Symptoms (MTOPS) double-blind trial was a landmark study that established medical therapy as a standard treatment for BPH. It lasted 4.5 years and enrolled 3,047 BPH patients (4). In contrast, previous trials had lasted one year or less (6, 7), thus long-term safety of medical therapy remained unknown prior to MTOPS study. The goal was to determine whether alpha-blocker doxazosin, 5a-reductase inhibitor finasteride, or combination therapy would delay or prevent clinical progression of BPH. Clinical progression consists of an increase above base line of at least four points, according to the American Urological Association symptom score: acute urinary retention, urinary incontinence, renal insufficiency, or urinary tract infection. MTOPS trial demonstrated that doxazosin or finasteride alone significantly reduced the risk of overall clinical progression of BPH (39% and 34% risk reduction, respectively, as compared with placebo) (4). Combination therapy, however, was significantly more effective than either drug alone (66% risk reduction compared with placebo) (4). This is summarized in Table 2 and Figure 1 in the paper (4). Additionally, the trial demonstrated other significant risk reductions, and, for most of them, it was found that combination therapy was superior to either treatment alone (4). The authors concluded that long-term combination therapy with doxazosin and finasteride was safe and effective in significantly reducing the risk of overall clinical progression of BPH more than did treatment with either drug alone (4). In order to target specific patients for combination treatment, MTOPS study data have been reanalyzed (8), concluding that combination therapy with doxazosin and finasteride is superior to either drug alone in patients with enlarged prostates (≥ 25 ml). Accordingly, a prostate volume of ≥ 25 ml is identified as the threshold in which combination therapy is most useful (9). Since men with a prostate volume of ≥ 31 ml are at a significantly greater risk of clinical progression than those with prostates < 31 ml (9), they represent the patient subset most likely to benefit from MTOPS study combination therapy.

Though effective, medical therapy has adverse effects. Substantially, by the end of the MTOPS study, 27% and 24% of patients had discontinued doxazosin or finasteride, respectively, as well as 18% percent of the patients receiving combination therapy (4). Common adverse events in the doxazosin group were dizziness, hypotension, and asthenia, while in the finasteride group erectile dysfunction, decreased libido, or abnormal ejaculation were most commonly reported (Table 4 in the paper). The adverse effects in the combination-therapy group were similar to those for each drug alone and a few additional ones were reported (4). Conspicuously, breast cancer was diagnosed in four men and was linked to finasteride treatment (4). Other cases of male breast cancer have been reported following finasteride therapy, including a case in Taiwan (10), where a 59-year-old man had received finasteride for BPH for 4?years. Long-term use of finasteride is also associated with an increased risk of high-grade prostate cancer (11).

A major safety concern was communicated in a recent study (12), where it was found that long term management of BPH with 5-alpha reductase inhibitor (5ARI) and/or α-blocker (AB) was associated with cardiac failure, with the highest risk for men exposed to nonselective α-blockers (including doxazosin). Among 175,201 patients older than 66 years diagnosed with BPH between 2005 and 2015, the risk for developing new heart failure was as follows: AB alone (22%), combination therapy (16%), and 5ARI alone (9%) (12). Moreover, nonselective ABs (including doxazosin) were significantly associated with a higher heart failure risk compared with selective ABs (12).

To summarize the above, long-term use of finasteride is associated with increased numbers of high-grade prostate and male breast cancers, while doxazosin use is associated with cardiac failure. Under these circumstances, it is imperative that conversations between doctors and patients focus on alternative approaches to medical therapy for management of BPH, including minimally-invasive treatment procedures.

Finally, it was not explained in the MTOPS study why the number of non-white trial participants was relatively low (9% Black and 7% Hispanic; Table 1, (4)). This is important because race is associated with higher risk of BPH - 41% higher among Black and Hispanic than White men (13). A new trial may address this shortcoming.

MINIMALLY-INVASIVE PROCEDURES

Traditionally, patients that had serious side effects due to medical therapy would undergo TURP (5). However, TURP not only requires general anesthesia, but it has also been associated with many side effects. In the past decade minimally-invasive techniques have been developed that do not require general anesthesia and lack side effects associated with TURP (5). Most notably, the Prostatic Urethral Lift (UroLift) is an endoscopic therapy for treating prostate-related bladder outlet obstruction via insertion of implants under local anesthesia. UroLift has been approved for cases where prostate volume is less than 80g and there is no obstructive middle lobe (5). UroLift was approved by the FDA in 2013 following a double-blind study (14), and was corroborated by another study (15). Adverse effects were minor and transient, and sexual performance was stable over 5 years (5). Unlike the medical therapy approach, with its common sexual dysfunction side effect, with the UroLift approach erectile and ejaculatory functions are preserved (16). Rezum, was approved by the FDA in 2015, is another minimally-invasive technique, which injects sterile water vapor into the adenoma of BPH to disrupt prostate cell membranes (17). This technique has the advantage over UroLift in that it can be performed on patients that have a large median lobe (5, 17). Additionally, re-treatment rates are lower with Rezum (4.4%) than with UroLift (10.7%), although UroLift outperforms Rezum in improvement of ejaculatory dysfunction (18). An elegant and comprehensive comparison of the two procedures can be found in Reference 19.

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CONSLUSIONS

BPH is an age-related disease. With an increase in aging population in the US, treating BPH is of vital importance. Medical therapy is often the standard treatment.?However, newly-recognized side effects linked to its prolonged use in the elderly are concerning. The late Willet F. Whitmore Jr., specialist on tumors of the urologic tracts, asked: “Is?a cure?possible?in those for whom it is necessary, and is it necessary for those in whom it is possible?” (20). With the development of novel minimally-invasive techniques targeting BPH, a cure may be possible in those for whom it is necessary.

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REFERENCES

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7.????Kirby RS, Roehrborn C, Boyle P, Bartsch G, Jardin A, Cary MM, Sweeney M, Grossman EB; Prospective European Doxazosin and Combination Therapy Study Investigators. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology. 2003;61(1):119-26.?

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9.???Marbeger M. The MTOPS Study: New Findings, New Insights, and Clinical Implications for the Management of BPH. European Urology Supplements. Volume 5, Issue 9,?June 2006, Pages 628-633.

10. Jui-Ming Liu, Yang-Jen Chiang, Chen-Lin Chi, Yung-Feng Lo, Chih-Yuan Chou; Male breast cancer after finasteride therapy for benign prostate hyperplasia, Urological Science, Volume 24, Issue 4, 2013, Pages 127-128.

11. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349(3):215-24.?

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13. ?Kristal AR, Arnold KB, Schenk JM, Neuhouser ML, Weiss N, Goodman P, Antvelink CM, Penson DF, Thompson IM. Race/ethnicity, obesity, health related behaviors and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. J Urol. 2007;177(4):1395-400.

14. Roehrborn CG, Gange SN, Shore ND, Giddens JL, Bolton DM, Cowan BE, Brown BT, McVary KT, Te AE, Gholami SS, Rashid P, Moseley WG, Chin PT, Dowling WT, Freedman SJ, Incze PF, Coffield KS, Borges FD, Rukstalis DB. The prostatic urethral lift for the treatment of lower urinary tract symptoms associated with prostate enlargement due to benign prostatic hyperplasia: the L.I.F.T. Study. J Urol. 2013;190(6):2161-7.

15. Roehrborn CG, Barkin J, Gange SN, Shore ND, Giddens JL, Bolton DM, Cowan BE, Cantwell AL, McVary KT, Te AE, Gholami SS, Moseley WG, Chin PT, Dowling WT, Freedman SJ, Incze PF, Coffield KS, Herron S, Rashid P, Rukstalis DB. Five year results of the prospective randomized controlled prostatic urethral L.I.F.T. study. Can J Urol. 2017;24(3):8802-8813.

16. Roehrborn CG, Rukstalis DB. Prostatic Urethral Lift Versus Medical Therapy: Examining the Impact on Sexual Function in Men with Benign Prostatic Hyperplasia. Eur Urol Focus. 2021;S2405-4569(20):30315-1.

17. McVary KT, Gange SN, Gittelman MC, Goldberg KA, Patel K, Shore ND, Levin RM, Rousseau M, Beahrs JR, Kaminetsky J, Cowan BE, Cantrill CH, Mynderse LA, Ulchaker JC, Larson TR, Dixon CM, Roehrborn CG. Minimally Invasive Prostate Convective Water Vapor Energy Ablation: A Multicenter, Randomized, Controlled Study for the Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia. J Urol. 2016;195(5):1529-1538.

18. Elterman D, Shepherd S, Saadat SH, Alshak MN, Bhojani N, Zorn KC, Rijo E, Misrai V, Lajkosz K, Chughtai B. Prostatic urethral lift (UroLift) versus convective water vapor ablation (Rezum) for minimally invasive treatment of BPH: a comparison of improvements and durability in 3-year clinical outcomes. Can J Urol. 2021;28(5):10824-10833.

19. https://www.bostonscientific.com/en-US/medical-specialties/urology/procedures-and-treatments/benign-prostatic-hyperplasia/physicians-perspectives/top-considerations-mit-for-bph.html

20. Montie JE, Smith JA. Whitmoreisms: memorable quotes from Willet F. Whitmore, Jr, M.D. Urology. 2004;63(1):207-9.?