Association inhibiteurs de la Phosphodiestérase type 5 et cancer de la prostate : revue systématique de la littérature

25 octobre 2018

Auteurs : Fouad Aoun, Amine Slaoui, Al Hajj Obeid Walid, Simone Albisinni, Grégoire Assenmacher, Elea de Plaen, Jean-Michel Azzo, Alexandre Peltier, Thierry Roumeguère
Référence : Prog Urol, 2018, 12, 28, 560-566




 




Introduction


Prostate cancer is the most common cancer found in men. It represents nearly 26% of all male cancers. The prognosis of this cancer remains excellent and survival at 10years for localized stages is around 90% [1]. Most often, treatment with curative intent consists of a radical prostatectomy with preservation of neurovascular bundles after taking into account the age of patient and the characteristics of the tumor [1]. However, this surgery is responsible for functional complications that impair the patient's quality of life. Erectile dysfunction is the most common encountered complication with an incidence varying between 25 and 75% depending on the series [2]. A postoperative management or early pharmacologic rehabilitation may be proposed and most often uses phosphodiesterase type 5 inhibitors (PDE5I). PDE5I leads to increased concentrations of cyclic guanosine monophosphate (cGMP) in the muscle cell inducing relaxation of smooth muscles in cavernous bodies promoting blood flow and cavernous tissue oxygenation. This oxygenation will prevent fibrosis in cavernous bodies, apoptosis of smooth muscle cells and veno-occlusive dysfunction [3]. Many clinical studies support this principle of early pharmacologic rehabilitation with an improvement of erections and quality of life in patients after radical prostatectomy. Recently, the impact of taking PDE5I on the development, progression and recurrence of prostate cancer has been evoked. Several preclinical and clinical studies have evaluated this association with conflicting results. The purpose of this review is to identify the possible implication of phosphodiesterase type 5 inhibitors in the development and progression of prostate cancer.


Material and methods


Research Strategy


A web search was conducted during December 2017 based on Pubmed data, Embase and Cochrane Bookstore. The use of filters made it possible to limit the search to preclinical and clinical trials written in either English or French. The keywords used (MesH language) were: "Phosphodiesterase type 5 inhibitors" and "Prostate cancer".


Selection of articles (PICO/PRISMA method)


The eligibility of articles was defined using the PICOS method, in concordance with the PRISMA recommendations: Participants (P), Interventions (I), Comparators (C), Outcomes (O) and Study Design (S) [4]. An article was considered relevant for this review of the literature if it evaluated: a population at risk of developing prostate cancer or having had prostate cancer treated with curative intent (P); treated with PDE5 inhibitors (I); compared the association with prostate cancer or the oncological outcome after curative treatment (C); in terms of incidence and biochemical recurrence (O). Only 30original articles, preclinical research articles and clinical studies have been included in this review (S). Articles reporting only the functional results have been omitted. The series of prospective or retrospective cases without comparison arms but with reported oncological results were retained. Two of the authors (GA, AS) reviewed all the abstracts and selected the relevant articles. These were fully read by a third author (FA) before proceeding to final eligibility.


Extraction of data


Data extraction was performed by two authors (GA, AS). The data collected were arranged by type of study, country of origin, time interval and the date of publication. The quality of studies, the number of patients, the presence of a comparison arm, the incidence of prostate cancer and the oncology results were also reported.


Evaluation of the quality of studies and level of proof


Randomized clinical trials were evaluated by their adherence to the CONSORT 2010 checklist [5]. Non-randomized trials (case-control studies or case series) were evaluated using the Newcastle-Ottawa scale. This scale gives a score with stars according to the quality of the selection (4stars), the comparability between selected population and the control group (2stars), and the finding of results in relation to the exposure (3stars). The maximum score being 9stars, a study with a score≥7 was considered of good quality. The level of evidence provided by each study was reported following the recommendations of the Oxford Center for Evidence-Based Medicine [6].


Results and discussion


Selected articles


Seventeen pre-clinical and seven clinical trials (Table 1) were included in the final synthesis (Figure 1). Among clinical trials, no prospective randomized trial and no prospective study were found in the literature. The seven clinical trials were retrospective case-control studies, comparing the effect of PDE5 inhibitors on development, progression or biochemical recurrence of prostate cancer.


Figure 1
Figure 1. 

Flow chart indicating the strategy of research, screening and selection of article for our systematic review of the literature.




Phosphodiesterase type 5 is expressed in prostatic tissue


PDE5 is an enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP), the second intracellular messenger of nitric oxide (NO). This enzyme is mainly present in the smooth muscle of the corpora cavernosa. It has also been identified in the smooth muscle cells of the genitourinary tract especially at the level of the bladder [7]. Uckert and al. had used immunofluorescence to establish its presence in the prostate [8]. This enzyme is also found in the stroma and glandular structures of the transition zone of the prostate. Zenzmaier et al. had demonstrated the presence of this enzyme in the fibro-muscular stroma mainly [9]. Two other studies had demonstrated that this enzyme is present in the fibro-muscular tissue but is more abundant in endothelial cells and prostatic smooth muscle cells [10, 11]. This latter result was validated by two animal studies examining this time the entire prostate and not only tissue from the transitional zone or the fibro-muscular stroma [12, 13]. The expression of PDE5 is indeed seen mainly in the juxta-glandular muscle cells and to a lesser extent in the glandular epithelium and endothelial cells [7]. This enzyme plays a key role in determining levels of cGMPs that have an impact on the relaxation of smooth muscle cells.


Role of phosphodiesterase type 5 in prostate carcinogenesis


The importance of the NO/cGMP signaling pathway in carcinogenesis had lead several teams to investigate the expression of PDE5 within tumors and the potential impact of its inhibition on development, growth, proliferation and progression of cancer cells. Early studies had observed overexpression of PDE5 in human carcinomas (squamous cell carcinoma and transitional bladder carcinoma comparatively to normal urothelium) as well as at the level of animal tumors in comparison with normal homologous tissues [14]. PDE5 had also been identified as the predominant isoform in many cell lines of carcinomas in culture, including prostate cancer (LNCAP, PC3 lines) [15]. Direct evidence of PDE5 involvement in cell growth regulation and apoptosis of tumorous prostatic cells arise on one hand from studies on the pre-apoptotic effects and inhibitors of tumor growth of NO/cGMP, and secondly, of its resistance to hypoxia [16]. Indeed, NO is a molecule that induces apoptosis when it is produced at high doses. Cellular hypoxia induces inhibition of the intracellular signaling pathway mediated by NO-cGMP and transforms prostate cancer cells into increasingly aggressive cells [17, 18]. Another mechanism is the involvement of PDE5 in the Hippo signaling pathway [15]. This pathway plays a crucial role in inhibiting contact between cancer cells, its alteration being strongly associated with malignant manifestations. The authors suggest that in vitro inhibition of PDE5 may improve the differentiation and make prostatic stem cells less resistant to chemotherapy [19].


Role of PDE5 inhibitors on prostate carcinogenesis


A potential association between PDE5 inhibitors and prostate cancer progression dates back to the early 2000s when several preclinical studies have suggested a protective effect. Suppression of human prostatic cell growth in a mouse model was made possible through the use of Exisulind an anti-cancer agent derivative of Sulindac that inhibits PDE5 [20, 21]. In a similar study, a low dose of Exisulind combined with a typical type 2 cyclooxygenase inhibitor actually had inhibited tumor growth by improving apoptosis [22]. Serafini et al. had demonstrated stimulation of anti-tumor immunity by increasing nitric oxide and arginine by PDE5 inhibitors [23]. More recently, it had been shown that the PDE5 enzyme was strongly expressed in the prostatic stroma and only low doses of inhibitors were able to inhibit the proliferation of stromal cells [9]. By resisting hypoxia, PDE5I were also able to attenuate the proliferation of human prostate cancer cells in an animal model [17]. Indeed, cellular hypoxia induces an inhibition of the intracellular signaling pathway mediated by NO-cGMP and transforms prostate cancer cells into chemotherapy-resistant cells, capable of escaping immuno-surveillance. Treatment with PDE5I could, according to the authors make cancerous prostatic cells less resistant to chemotherapy.


Das et al. had demonstrated, in an in vitro study, an increase in the anti-tumor activity of Doxorubicin in prostate cancer cells treated with PDE5I [24]. Thus they have found an increase in the generation of free radicals and overexpression of caspase 3, an enzyme that plays a central role in cell apoptosis adding to a reduction in the expression of Bcl-xL, an anti-apoptotic protein. A more recent study conducted by the same team, had highlighted a new mechanism of synergy between PDE5 inhibitors and Doxorubicin involving NF-&kgr; B inactivation associated with anti-apoptotic factors in prostatic cells expressing CD95 [25]. By increasing the influx in tumoral tissues, PDE5I could play a facilitating role in combination with other anti-cancer molecules allowing them a better intra-tumoral penetration and restoration of their cytotoxic and/or immunomodulatory activities.


The clinical impact of PDE5 inhibitors on the development of prostate cancer


In 2013, a retrospective study had shown a reduced incidence of prostate cancer in patients treated with PDE5 inhibitors [26]. Of the 4974patients suffering from erectile dysfunction, patients treated with PDE5I had a 60% reduction in risk of developing prostate cancer during the course of the study (OR=0.4, 95% CI: 0.3-0.5). This association between taking PDE5I and the reduced risk of prostate cancer could be related to increased ejaculatory frequency in treated patients compared to patients with erectile dysfunction without pharmacologic treatment. This increased ejaculatory frequency had been significantly associated with a reduced risk of prostate cancer in the large prospective cohort of Leitzmann [27].


However, a more recent cohort study with case-control had demonstrated no association between the use of PDE5I and prostate cancer risk [28].


In this study, 55.6% of patients who developed prostate cancer were on PDE5 inhibitors. In the group that did not develop prostate cancer 57.4% of patients were under PDE5I. A secondary analysis of the recently published "REDUCE" trial had also demonstrated the lack of association between the use of PDE5I and prostate cancer risk [29]. In this study, men with negative prostate biopsies were included and repeated biopsy at 2 and 4 years. The detection rate of prostate cancer in this study was 19.5% in patients treated with PDE5I vs. 22.7% in patients not receiving PDE5I (OR=0.83, 95% CI 0.63-1.08, P =0.161). No statistically significant association was found between taking PDE5 inhibitors and the aggressiveness of cancer.


The clinical impact of PDE5 inhibitors use on progression and biochemical recurrence in prostate cancer


The abundancy of preclinical data on the potential protective effect of PDE5 inhibitors on prostate cancer cells had stimulated several teams to examine the impact of these PDE5I on biochemical recurrence after radical prostatectomy. A first study by the team of the Martini Clinic in Germany had found an increase in biochemical recurrence after radical prostatectomy in patients treated with PDE5I compared to patients not taking PDE5I [30]. Out of the 4752 patients included in the study and followed for a median of 5years, 1110 patients had received PDE5I post-operatively. In multivariate analysis, intake of PDE5I was an independent risk factor of biochemical recurrence (RR 1.38, 95% CI: 1.11-1.70, P =0.0035). Another retrospective analysis of a cohort of 2579 patients with a detailed data taking into account the dose and frequency of PDE5I had revealed contradictory results [31]. In this study, the use of PDE5I on demand or in daily dose was not associated with biochemical recurrence at 5years. The number of pills taken by the patient was not a risk factor for biochemical recurrence after radical prostatectomy. A Korean study of 1082 patients had found similar results [32]. In this study, the duration of use and the type of PDE5 inhibitor used as well as the delay before initiating this pharmacologic rehabilitation after surgery were not risk factors for biochemical recurrence. Moreover, a large study of prostate cancer registry in Sweden and the register of prescribed drugs demonstrated the lack of association between the use of PDE5I and biochemical recurrence after radical prostatectomy (OR 0.78, 95% CI: 0.59-1.03) or primary radiotherapy (OR 0.98.95% CI: 0.49-1.97) [33]. On the basis of these data, it seems there is no association between taking PDE5I after radical prostatectomy and the risk of biochemical recurrence.


Conclusion


Preclinical trials demonstrate a protective effect of PDE5 inhibitors against the development and progression of prostate cancer. However, clinical evidence of this association has not been demonstrated. There also does not seem to be an increased risk of biochemical recurrence among PDE5I users. A modification of our practice in relation to pharmacologic rehabilitation after radical prostatectomy is not justified. There is also no evidence to use this kind of treatment for primary or secondary prevention of prostate cancer


Disclosure of interest


The authors declare that they have no competing interest.




Table 1 - Clinical studies investigating the impact of PDE5I on the development of prostate cancer and on biochemical recurrence after primary treatment with a curative intent.
Design of the study (author, country)  Date of publication (study interval)  Level of evidence  Quality of the study  Total number of patients  Impact on the development of prostate cancer  Impact on biochemical recurrence 
R case-match (Chavez, Etats-Unis)  2013 (2000-2006)  3b  4974  Less risk to develop prostate cancer in the group treated with PDE5I   
R case-match (Jamnagerwalla, Etats-Unis)  2016 (2003-2009)  3b  6501  No association   
R case-match (Luke Machen, Etats-Unis)  2017 (2000-2011)  3b  5717  No association   
R case-match (Michl, Allemagne)  2015 (2000-2010)  3b  4752    Increased biochemical recurrence in the group treated with PDE5I 
R case-match (Gallina, Italie)  2015 (2004-2013)  3b  2579    No association 
R case-match (Jo, Corée de sud)  2016 (2005-2014)  3b  1082    No association 
R case-match (Loeb, Suède)  2016 (2006-2007)  3b  6060    No association 




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