Peter Østergren

The use of exercise interventions to overcome adverse effects of androgen deprivation therapy

Androgen deprivation therapy (ADT) induces severe hypogonadism and is associated with several adverse effects that negatively affect health and quality of life in patients with prostate cancer. ADT changes body composition characterized by an increase in fat mass and a reduction in muscle mass and strength. Insulin sensitivity is also diminished and population-based studies indicate an increased risk of diabetes mellitus and cardiovascular disease in men receiving ADT. Particularly the first 6 months of treatment seem to hold an additional risk of new cardiovascular events for patients with already existing cardiovascular disease. In this initial phase of ADT, metabolic changes are also most prominent. In addition, ADT increases the rate of bone loss and fracture risk. Currently available evidence supports the use of exercise interventions to improve physical function and mitigate ADT-induced fatigue. Some studies also indicate that exercise might moderate ADT-related changes in body composition. However, beneficial effects of exercise interventions on other ADT-related conditions have not been conclusively proven. Trials investigating the effects of ADT on fracture risk and development of diabetes mellitus and cardiovascular disease are still warranted. Furthermore, studies investigating safety and effects of physical activity in men with bone metastases are lacking.

Are We Ready for Active Surveillance for Clinical Stage IS Testicular Cancer

Active surveillance is gaining importance in the clinical approach to urological cancers as it ideally limits overtreatment and treatment-related adverse effects on quality of life without compromising survival rates. For postorchiectomy management of clinical stage I germ-cell tumors (GCTs) it has been debated whether to treat all patients with adjuvant therapy, associated with mild to moderate toxicity, or to reserve treatment for those who experience disease relapse, potentially associated with more severe and long-term toxicity [1]. In this regard, Kollmannsberger et al [2] recently demonstrated the value of active surveillance in a cohort of 2483 patients with clinical stage I GCT following orchiectomy. Here, the relapse rates without adjuvant therapy were 19% for nonseminomatous GCT (NSGCT) and 13% for seminomatous GCT (SGCT), and the overall 5-yr survival was >99%. Similarly, Daugaard et al [3] reported a 5-yr relapse risk of 30.6% and 15-yr cancerspecific survival of >99% in a cohort of 1226 men with NSGCT followed on an active surveillance program. These clear results suggest that overtreatment can be safely avoided in the majority of these patients. Meanwhile, the approach has long been controversial in a subgroup of men with persistently elevated serum tumor markers following orchiectomy (stage IS disease) as these patients are considered to harbor systemic disease [2]. However, the evidence supporting adjuvant therapy in this group is limited, as highlighted in the latest edition of the European Urology Association guidelines [4]. Therefore, the report on treatment patterns and patient outcomes for clinical stage IS testicular cancers by Kamran and colleagues [5] in this issue of European Urology is of great clinical relevance.

Disorders of sex development presenting as unilateral cryptorchidism.

Abstract Disorders of sex development (DSD) present in different forms but, in most cases, with visible anomalies of the external genitalia. The diagnosis of DSD can have a vast impact on an individual; in addition to concerns about fertility and a higher risk of neoplasia, it may have severe psychosocial impact on the patient. This report presents two apparently healthy cases referred for operation because of unilateral undescended testis. In these two patients, uterine remnants were found during the operation, and underlying DSD conditions were unexpectedly diagnosed. One patient had a 45,X/46,XY mosaic karyotype, while the second patient had persistent müllerian duct syndrome, probably due to an anti-müllerian hormone receptor defect. Both conditions are extremely rare, but the findings reinforce that DSD should be considered in patients with cryptorchidism, especially if other clinical signs are present.

No convincing evidence on differences in metabolic effects of medical and surgical castration in the treatment of prostate cancer

hemoglobin and hematocrit (p < 0.001). Thus, the effects of ADT may not be directly comparable between groups. Overall, the authors report a group difference in the homeostasis model assessment-estimated insulin resistance (HOMA-IR) (p = 0.044) and bone mineral density (BMD) (p = 0.002) favoring those patients submitted to orchiectomy. A group difference does not imply if there was a difference in treatment effect and can be the result of differences already present at baseline. A difference in treatment effect is tested using the analysis of variance (ANOVA) for repeated measures and reported as the p value of the interaction term “group × time.” These p values calculated by Vargas et al. are all non-significant (p > 0.05) except when testing for changed hemoglobin and hematocrit (p < 0.001). Thus, the authors cannot conclude that there are any differences in metabolic treatment effects. In addition, the proposed underlying mechanisms explaining the findings of this study may be questioned. The authors argue that detrimental effects on insulin resistance by LHRH agonists compared to orchiectomy might be mediated by a greater reduction in adrenal androgens by LHRH agonists. However, the study did not measure adrenal androgens and the argument is mainly based on the findings of another small non-randomized observational study (n = 17), which indicated that dehydroepiandrosterone was decreased by LHRH agonist treatment but not with orchiectomy [2]. Contrary to this, our group has recently demonstrated that there is no difference in the effects of pharmacological and surgical castration on adrenal androgens in a randomized setting [3]. Furthermore, the authors reference a SEER-Medicare database study by Keeting et al. [4] which found that the cardiovascular risk may be higher with medical ADT compared to surgical castration. However, it is important to note that not all studies have found such a difference [5].

“Kicked out into the real world”: prostate cancer patients’ experiences with transitioning from hospital-based supervised exercise to unsupervised exercise in the community

PurposeRegular exercise is recommended to mitigate the adverse effects of androgen deprivation therapy in men with prostate cancer. The purpose of this study was to explore the experience of transition to unsupervised, community-based exercise among men who had participated in a hospital-based supervised exercise programme in order to propose components that supported transition to unsupervised exercise.MethodsParticipants were selected by means of purposive, criteria-based sampling. Men undergoing androgen deprivation therapy who had completed a 12-week hospital-based, supervised, group exercise intervention were invited to participate. The programme involved aerobic and resistance training using machines and included a structured transition to a community-based fitness centre. Data were collected by means of semi-structured focus group interviews and analysed using thematic analysis.ResultsFive focus group interviews were conducted with a total of 29 men, of whom 25 reported to have continued to exercise at community-based facilities. Three thematic categories emerged: Development and practice of new skills; Establishing social relationships; and Familiarising with bodily well-being. These were combined into an overarching theme: From learning to doing. Components suggested to support transition were as follows: a structured transition involving supervised exercise sessions at a community-based facility; strategies to facilitate peer support; transferable tools including an individual exercise chart; and access to ‘check-ups’ by qualified exercise specialists.ConclusionsHospital-based, supervised exercise provides a safe learning environment. Transferring to community-based exercise can be experienced as a confrontation with the real world and can be eased through securing a structured transition, having transferable tools, sustained peer support and monitoring.

Treatment effects of phosphodiesterase-5 inhibitors may improve with time following nerve-sparing radical prostatectomy

Abstract Objective: Erectile dysfunction (ED) is common following radical prostatectomies, and phosphodiesterase type 5 inhibitors (PDE5 inhibitors) are generally considered the first choice of treatment. The purpose of this study was to analyze the long-term efficacy of PDE5 inhibitors in a group of men who did not achieve sufficient erectile function from the medication in the short term following surgery. Materials and methods: Prospectively collected data from patients with postprostatectomy ED, initial failure of PDE5-inhibitor treatment at 3 and/or 6 months and at least 12 months’ follow-up were included. All patients had completed the International Index of Erectile Function short-form questionnaires (IIEF-5) before surgery and at follow-up visits. Response to PDE5 inhibitors was defined as an IIEF-5 score of at least 17. Results: The inclusion criteria were fulfilled by 349 patients. At 12 months, 228 patients were still using PDE5 inhibitors. Of these patients, 92 had undergone bilateral and 120 had undergone unilateral nerve-sparing radical prostatectomies. Overall, 42 PDE5-inhibitor users (18%) were responders at 12 months. Bilateral nerve sparing was the only independent predictor of a late response (odds ratio = 2.9). Thus, 28% of bilaterally nerve-spared patients were responders, while corresponding numbers for unilaterally nerve-spared patients and non-nerve-spared patients were 13% and 6%, respectively. Conclusions: Patients who have undergone bilateral nerve-sparing radical prostatectomy should be rechallenged periodically with PDE5 inhibitors even if the treatment is unsuccessful initially. Unilaterally nerve-spared patients and especially non-nerve-spared patients are likely to need more aggressive treatment.

Results of 14 years of brachytherapy for localized prostate cancer in Denmark: the Herlev cohort

Abstract Objective: Brachytherapy is one of several curative treatments for localized prostate cancer (PCa). The objective of this study was to report biochemical recurrence-free survival (BRFS), metastatic-free survival (MFS) and PCa-specific mortality after low-dose brachytherapy, stratified according to the D’Amico risk classification in a large Danish cohort. Materials and methods: The study population comprised 502 men treated with brachytherapy in 1998–2012. BRFS was defined by the Phoenix criteria. Kaplan–Meier survival analysis was used to estimate BRFS and MFS. The cumulative PCa mortality was analysed using competing risk analyses. Multivariable Cox regression analysis was used to estimate risk of biochemical recurrence. Results: In total, 206 men were classified with low-risk PCa, 265 men with intermediate-risk PCa and 33 men with high-risk PCa. Median follow-up was 6.6 years [95% confidence interval (CI) 6.2–7.0]. The 10 year BRFS was 90% (95% CI 83–97), 75% (95% CI 65–87) and 75% (95% CI 59–92) in men with low-, intermediate- and high-risk PCa, respectively. The 10 year MFS was 95% (95% CI 89–100), 93% (95% CI 88–98) and 78% (95% CI 57–99) in men with low-, intermediate- and high-risk PCa, respectively. The 10 year cumulative incidence of PCa mortality was 1% (95% CI 0–3), 5% (95% CI 0–12) and 11% (95% CI 0–25) for men with low-, intermediate- and high-risk PCa, respectively. Conclusions: Low-dose brachytherapy offers good short- to intermediate-term cancer control in selected men with localized PCa. Further studies are needed for safety analyses and for comparison with other treatment modalities.

Is low-intensity shockwave therapy for erectile dysfunction ready for clinical practice?

Over recent years, Low-intensity Shockwave Therapy (LiESWT) has emerged as a potential cure for erectile dysfunction (ED) and this has created considerable excitement [1]. The predominate theoretical background for improvements in erectile function with Li-ESWT is that the treatment may promote the formation of new blood vessels and improve endothelial function in the corpora cavernosa [2]. However, in spite of promising pilot studies, the results of randomised controlled trials have been mixed with some finding effect on ED and some showing no differences between active treatment and sham control [3]. Therefore, Li-ESWT remains controversial. In this month’s issue of International Journal of Impotence Research, Yamaçake et al. [4] published the results of a randomised, double blinded, sham-controlled study investigating the effects of Li-ESWT for ED in Kidney Transplant Recipients [4]. This study is the first of its kind to evaluate the treatment in this specific group of patients. The study is also the first to investigate the specific LiESWT device used, the Dolorclast® Smart (Electro Medical Systems, Switzerland). The authors find an apparent effect of 6 treatments sessions with 7/10 patients in the treatment group experiencing an improvement of at least 5 points on the IIEF-5 scale vs. only 1/10 in the sham group. At first glance this seems to confirm a possible effect of Li-ESWT and suggests that the treatment could be offered specifically to patients with kidney transplants. However, when examining the study closer, there may be reason for caution. First of all, the authors included only 20 patients which is likely too few to evaluate the effects of a treatment for ED. Thus, the study is by far the smallest RCT on the topic to date with previous power calculations showing that as many as 112 men are needed to show a clinically meaningful benefit compared to placebo [5]. In addition, there seem to be important differences between the groups. Most notably, the baseline IIEF-5 score is lower in the Li-ESWT group compared with the sham group (10.9 vs. 14.9). This is important because a given numeric improvement in the IIEF-5 score is likely to have less clinical meaning with low scores compared to higher scores [6]. In addition, statistically speaking, lower scores are more likely to spontaneously increase, while higher scores are more likely to decrease due to a concept termed “regression toward the mean” [7]. The finding that the changes in Erection Hardness Score (EHS) scores do not differ over time between the groups and the lack of difference in penile hemodynamic parameters should raise concerns that confounding factors may in fact have played a role. Other important factors are that the patients in the Li-ESWT group had their transplants shorter than the men in the sham group, which means that they may have adapted better to their new situation during the study and that more patients in the sham group suffered from diabetes. Even though these differences do not reach individual statistical significance, their combination may have had an influence in the small group of patients. In spite of these issues, the authors do not consider that their IIEF-5 findings may be due to confounding factors. Instead they question only the lack of improvements in EHS and hemodynamics, which skews their conclusions towards a positive appraisal of Li-ESWT. The enthusiasm for Li-ESWT by Yamaçake et al. is understandable, as the treatment offers a potential cure for ED. This is something both patients and clinicians have been wanting for a long time [8]. However, such enthusiasm is problematic because it may cloud our judgement when designing trials and examining our clinical data. In this regard, a range of case series on Li-ESWT is often quoted when discussing the treatment. However, it is well known that the placebo effect in ED treatments may exceed 30% * Mikkel Fode mikkelfode@gmail.com