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Video: Immediate versus delayed exercise in men initiating androgen deprivation

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Immediate versus delayed exercise in men initiating androgen deprivation: effects on bone density and soft tissue composition

Abstract

Objectives

To examine whether it is more efficacious to commence exercise medicine in men with prostate cancer at the onset of androgen‐deprivation therapy (ADT) rather than later on during treatment to preserve bone and soft‐tissue composition, as ADT results in adverse effects including: reduced bone mineral density (BMD), loss of muscle mass, and increased fat mass (FM).

Patients and methods

In all, 104 patients with prostate cancer, aged 48–84 years initiating ADT, were randomised to immediate exercise (IMEX, n = 54) or delayed exercise (DEL, n = 50) conditions. The former consisted of 6 months of supervised resistance/aerobic/impact exercise and the latter comprised 6 months of usual care followed by 6 months of the identical exercise programme. Regional and whole body BMD, lean mass (LM), whole body FM and trunk FM, and appendicular skeletal muscle (ASM) were assessed by dual X‐ray absorptiometry, and muscle density by peripheral quantitative computed tomography at baseline, and at 6 and 12 months.

Results

There was a significant time effect (P < 0.001) for whole body, spine and hip BMD with a progressive loss in the IMEX and DEL groups, although lumbar spine BMD was largely preserved in the IMEX group at 6 months compared with the DEL group (−0.4% vs −1.6%). LM, ASM, and muscle density were preserved in the IMEX group at 6 months, declined in the DEL group at 6 months (−1.4% to −2.5%) and then recovered at 12 months after training. FM and trunk FM increased (P < 0.001) over the 12‐month period in the IMEX (7.8% and 4.5%, respectively) and DEL groups (6.5% and 4.3%, respectively).

Conclusions

Commencing exercise at the onset of ADT preserves lumbar spine BMD, muscle mass, and muscle density. To avoid treatment‐related adverse musculoskeletal effects, exercise medicine should be prescribed and commenced at the onset of ADT.

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Changing the LATITUDE of Treatment for High-Risk Hormone-Naïve Prostate Cancer: STAMPEDE-ing Towards Androgen Biosynthesis Inhibition

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zach-klaassenEarlier this month at the annual American Society of Clinical Oncology (ASCO) meeting in Chicago, IL, Dr. Karim Fizazi and Dr. Nicholas James (@Prof_Nick_James) presented results from the LATITUDE and STAMPEDE trials, respectively. These randomized controlled trials (RCTs) assessed the utility of adding abiraterone acetate (AA) + prednisone to conventional androgen deprivation therapy (ADT) among men with high-risk, hormone-naïve prostate cancer. Since Dr. Charles Huggins’ 1941 Nobel prize winning finding that ADT is highly effective in controlling metastatic prostate cancer, nearly 70 years passed before CHAARTED and STAMPEDE demonstrated in 2015 that the addition of docetaxel to ADT prolongs survival in men with high volume metastatic prostate cancer. The de novo metastatic prostate cancer global incidence is striking: 3% in the US and rising, 6% across Europe, 4-10% in Latin America, and nearly 60% in Asia-Pacific. Historically, ADT has been standard of care, however most men with metastases progress to metastatic castration-resistant prostate cancer (mCRPC) driven by the reactivation of androgen receptor (AR) signaling. The rationale for adding AA + prednisone to ADT for metastatic hormone-naïve prostate cancer patients is threefold: (i) the mechanism of resistance to ADT may develop early, (ii) ADT alone does not inhibit androgen synthesis by the adrenal glands or prostate cancer cells, and (iii) AA + prednisone improves overall survival (OS) in mCRPC patients and reduces tumor burden in high-risk, localized prostate cancer.

LATITUDE

LATITUDE was conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America, and Canada. The objectives of the study were to evaluate the addition of AA + prednisone to ADT on clinical benefit in men with newly diagnosed, high-risk, metastatic hormone-naïve prostate cancer. Patients were stratified by the presence of visceral disease (yes/no) and ECOG performance status (0, 1 vs 2) and then randomized 1:1 to either ADT + AA (1000 mg daily) + prednisone (5 mg) (n=597) or ADT + placebo (n=602). The co-primary endpoints were OS and radiographic progression-free survival (rPFS). Secondary endpoints included time to: (i) pain progression, (ii) PSA progression, (iii) next symptomatic skeletal event, (iv) chemotherapy, and (v) subsequent prostate cancer therapy. The study was powered to detect an HR of 0.67 and 0.81 in favor of AA for rPFS and OS, respectively.
Over a median follow-up of 30.4 months, patients treated with ADT + AA + prednisone had a 38% risk reduction of death (HR 0.62, 95%CI 0.51-0.76) compared to ADT + placebo.

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Median OS was not yet reached in the ADT + AA + prednisone arm compared to 34.7 months in the ADT + placebo arm. OS rates at 3 years for the ADT + AA + prednisone arm was 66%, compared to 49% in the ADT + placebo arm. This OS benefit was consistently favorable across all subgroups including ECOG 0 and 1-2, visceral metastases, Gleason ≥8 disease, and bone lesions >10.

There was also 53% risk of reduction of radiographic progression or death for patients treated with ADT + AA + prednisone (median 33.0 months; HR 0.47, 95%CI 0.39-0.55) compared to ADT + placebo (14.8 months).

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Secondary endpoints showed statistically significant improvement for ADT + AA + prednisone, including time to PSA progression (HR 0.30, 95%CI 0.26-0.35), time to pain progression (HR 0.70, 95%CI 0.58-0.83), time to next symptomatic skeletal event (HR 0.70, 95%CI 0.54-0.92), time to chemotherapy (HR 0.44, 95%CI 0.35-0.56), and time to subsequent prostate cancer therapy (HR 0.42, 95%CI 0.35-0.50).

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Secondary to the results presented at ASCO, the study was discontinued after the first interim analysis. Adverse events were comparable in the two groups. Hypertension only rarely required treatment discontinuation, and only two patients discontinued treatment due to hypokalemia (no hypokalemia-related deaths). Two patients in each arm died of cerebrovascular events, and 10 patients treated with ADT + AA + prednisone compared to 6 patients treated with ADT + placebo died of cardiac disorders.

STAMPEDE

STAMPEDE is a large multi-stage, multi-arm, RCT being conducted in the United Kingdom to assess the utility of novel therapeutic agents in conjunction with ADT. Currently being tested are AA, enzalutamide, zoledronic acid, docetaxol, celecoxib and radiotherapy (RT). The AA arm of the study was presented at ASCO as a late-breaking abstract. Inclusion criteria included men with locally advanced or metastatic prostate cancer, including newly diagnosed with N1 or M1 disease, or any two of the following: stage T3/4, PSA ≥ 40 ng/mL, or Gleason score 8-10. Patients undergoing prior radical prostatectomy or RT were eligible if they had more than one of the following: PSA ≥ 4 ng/mL and PSADT < 6 months, PSA ≥ 20 ng/mL, N1, or M1 disease. Patients were then randomized 1:1 to standard of care (SOC; ADT for ≥2 years, n=957) vs SOC + AA (1000 mg) + prednisone 5 mg daily (n=960). Treatment with RT was mandated in patients with N0M0 disease, while strongly encouraged for N1M0 patients. Primary outcomes were OS and failure-free survival (FFS), where failure was defined as PSA failure, local failure, lymph node failure, distant metastases or prostate cancer death. Secondary outcome included toxicity and skeletal-related events (SREs). The study was powered to detect a 25% improvement in OS for the treatment group (requiring 267 control arm mortalities).
Both groups were balanced and patients were predominantly metastatic (52% M1, 20% N+M0, 28% N0M0), median was PSA 53 ng/mL, and 99% were treated with LHRH analogues. Over a median follow-up of 40 months, there were 262 control arm deaths, of which 82% were prostate cancer-related; there were 184 deaths in the SOC + AA + prednisone arm. There was a 37% relative improvement in overall survival (HR 0.63, 95%CI 0.52-0.76) favoring SOC + AA + prednisone.

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A Forrest plot split on stratification factors demonstrated no evidence of heterogeneity based on any of the factors, including M0/M1 status (p=0.37). Second, SOC+AA + prednisone demonstrated a 71% improvement in FFS (HR 0.29, 95%CI 0.25-0.34), with an early split in the KM curves.

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SOC + AA + prednisone also significantly decreased SREs among the entire cohort (HR 0.46, 95%CI 0.37-0.58), as well as specifically in the M1 cohort (HR 0.45, 95%CI 0.37-0.58). This resulted in a 55% reduction in SREs in the M1 subset analysis.

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When looking at treatment progression, 89% of the SOC arm went on to next line of therapy, whereas 79% of the SOC + AA + prednisone arm received additional therapy, most commonly docetaxel. As expected, the rate of Grade 3-5 adverse events was higher in the SOC + AA prednisone arm (47% vs. 33%), and were primarily cardiovascular (HTN, MI, cardiac dysrhythmias) or hepatic (transaminitis) in nature.

REACTION, INTERPRETATION & FUTURE DIRECTIONS

As has become the norm during academic conferences, there was significant buzz on Twitter over the course of the two days these results were presented:

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This also included the New England Journal of Medicine immediately tweeting after the presentations that LATITUDE and STAMPEDE were published instantaneously:

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Furthermore, immediately following Dr. Fizazi’s presentation of LATITUDE, Dr. Eric Small from @UCSF presented a discussion of LATITUDE. A number of important points were raised. First, although this was a well-designed, placebo controlled, randomized phase III study, early unblinding (although appropriate) resulting in an HR of 0.62 for OS is based on only 50% of the targeted total deaths. Making conclusions based on interim analyses must be made with caution. However, with every endpoint reaching statistical significance and conditional probability modeling, if the study had remained blinded, the probability of reaching the same conclusions is high. Second, since twice as many patients in the ADT + placebo arm received life-prolonging therapy than compared to the ADT + AA + placebo arm, the benefit of AA is not explained by more secondary life-prolonging therapy, strengthening the cause for AA + ADT.

Perhaps the most interesting and pertinent clinical comparison is assessing outcomes of the LATITUDE and CHAARTED (high-volume disease) treatment arms (AA vs docetaxel). With similar median OS outcomes between the ADT control arms of the two trials (suggesting similar populations), the HRs for OS based on treatment are nearly identical:

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Similarly, the rPFS outcomes were comparable between the two trials:

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With nearly identical OS and rPFS outcomes for men receiving ADT + AA or ADT + docetaxel, the question becomes whether the impact of adding AA to ADT is volume or risk dependent. Results from the STAMPEDE trial would suggest remarkably similar outcomes support the use of AA + ADT in patients with less burden of disease. Arguably the most important slide of the meeting was captured and tweeting by Dr. Agarwal (@neerajaiims):

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Dr. Small eloquently summarized future directions into two groups. Unanswered questions regarding efficacy include: (i) Can a genomic classifier be used to select patients more likely to benefit from AA or docetaxel? (ii) Can AA be added in even earlier settings (with radiation? Increasing PSAs?) (iii) Should AA and docetaxel be combined or used sequentially? Additionally, there are also unanswered questions regarding AA resistance, including (i) Will the mechanisms of resistance to AA be the same when used in the non-mCRPC setting? (ii) Will androgen receptor amplification still be observed? (iii) Will there be an increased risk of treatment-associated small cell/neuroendocrine prostate cancer? (iv) Does adding chemotherapy or AA to ADT result in more aggressive disease at the time of resistance? (v) What is the optimal therapy for a patient who progresses on ADT + AA, compared to a patient who progresses on ADT + docetaxel? Given the avoidance of potential chemotherapy related side effects (ie. neutropenic complications) for an oral, long-term treatment, AA + ADT should be considered standard of care for untreated, high-risk metastatic prostate cancer.

But what is the long-term economic landscape like when practice changing trials such as LATITUE and STAMPEDE suddenly thrust an expensive medication such as AA + prednisone directly to the forefront of hormone-naïve disease? Following these presentations, urologic oncologist, Twitter veteran, and Forbes correspondent Dr. Ben Davies (@daviesbj) wrote a provocative piece highlighting the potential ‘financial toxicity’ (particularly in the United States) that may result downstream of these trials:

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A conservative estimate is a wholesale cost of $115,000 per year per patient for AA + prednisone, resulting in a crude estimate of a $2.8 billion annual expenditure for the drug in the United States alone if used in the hormone-naïve setting, according to Dr. Davies. As Dr. Davies also points outs, although the patent for AA expired in 2016 and there are currently 13 applications to make generic AA, the patent for prednisone lasts until 2027, with $30 billion riding on the lawsuit. Dr. David Penson (@urogeek) succinctly summarized via Twitter:

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Strictly academically speaking, LATITUDE and STAMPEDE, in addition to the docetaxel benefits of CHAARTED, have provided clinicians with exciting Level 1 evidence for improving patient care in the high-risk/metastatic setting. The investigators and more importantly the thousands of patients and families are to be thanked and congratulated for their perseverance, hard-work, and willingness to participate in these practice-changing clinical trials. It is our job as clinicians to continue advocating the best treatment for our patients, whether this be through economic barriers in the United States, or access to appropriate care on a global scale.

 

Zach Klaassen, MD

Urologic Oncology Fellow

University of Toronto/Princess Margaret Cancer Centre

Toronto, Ontario, Canada

@zklaassen_md

 

Article of the Week: QoL outcomes from the PATCH trial evaluating LHRHa versus tE2 for ADT in PCa

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Every week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Quality-of-life outcomes from the Prostate Adenocarcinoma: TransCutaneous Hormones (PATCH) trial evaluating luteinising hormone-releasing hormone agonists versus transdermal oestradiol for androgen suppression in advanced prostate cancer

Duncan C. Gilbert*, Trinh Duong*, Howard G. Kynaston†, Abdulla A. Alhasso‡, Fay H. Cafferty*, Stuart D. Rosen§, Subramanian Kanaga-Sundaram, Sanjay Dixit**, Marc Laniado††, Sanjeev Madaan‡‡, Gerald Collins§§, Alvan Pope¶¶, Andrew Welland*, Matthew Nankivell*, Richard Wassersug***, Mahesh K. B. Parmar*, Ruth E. Langley* and Paul D. Abel†††‡‡‡

 

*Medical Research Council Clinical Trials Unit at University College London, London, †Cardiff School of Medicine, Cardiff University, Cardiff, ‡The Beatson West of Scotland Cancer Centre, Glasgow, §National Heart and Lung Institute, Imperial College London, London, Mid-Yorkshire Hospitals NHS Trust, Pinder fields General Hospital, Wakefield, **Scunthorpe General Hospital, North Lincolnshire and Goole NHS Trust, Scunthorpe, ††Frimley Health NHS Foundation Trust, Wexham Park Hospital, Slough, ‡‡Dartford and Gravesham NHS Trust, Darent Valley Hospital, Dartford, §§Stockport NHS Foundation Trust, Stepping Hill Hospital, Stockport, ¶¶The Hillingdon Hospitals NHS Foundation Trust, London, UK, ***University of British Columbia, Vancouver, BC, Canada, †††Imperial College Healthcare NHS Trust, and ‡‡‡Imperial College London, London, UK

 

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Objectives

To compare quality-of-life (QoL) outcomes at 6 months between men with advanced prostate cancer receiving either transdermal oestradiol (tE2) or luteinising hormone-releasing hormone agonists (LHRHa) for androgen-deprivation therapy (ADT).

Patients and methods

Men with locally advanced or metastatic prostate cancer participating in an ongoing randomised, multicentre UK trial comparing tE2 versus LHRHa for ADT were enrolled into a QoL sub-study. tE2 was delivered via three or four transcutaneous patches containing oestradiol 100 μg/24 h. LHRHa was administered as per local practice. Patients completed questionnaires based on the European Organisation for Research and Treatment of Cancer quality of life questionnaire 30-item core (EORTC QLQ-C30) with prostate-specific module QLQ PR25. The primary outcome measure was global QoL score at 6 months, compared between randomised arms.

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Results

In all, 727 men were enrolled between August 2007 and October 2015 (412 tE2, 315 LHRHa) with QoL questionnaires completed at both baseline and 6 months. Baseline clinical characteristics were similar between arms: median (interquartile range) age of 74 (68–79) years and PSA level of 44 (19–119) ng/mL, and 40% (294/727) had metastatic disease. At 6 months, patients on tE2 reported higher global QoL than those on LHRHa (mean difference +4.2, 95% confidence interval 1.2–7.1; P = 0.006), less fatigue, and improved physical function. Men in the tE2 arm were less likely to experience hot flushes (8% vs 46%), and report a lack of sexual interest (59% vs 74%) and sexual activity, but had higher rates of significant gynaecomastia (37% vs 5%). The higher incidence of hot flushes among LHRHa patients appear to account for both the reduced global QoL and increased fatigue in the LHRHa arm compared to the tE2 arm.

Conclusion

Patients receiving tE2 for ADT had better 6-month self-reported QoL outcomes compared to those on LHRHa, but increased likelihood of gynaecomastia. The ongoing trial will evaluate clinical efficacy and longer term QoL. These findings are also potentially relevant for short-term neoadjuvant ADT.

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Editorial: Oestrogen redux: will transdermal delivery rebalance the risk–benefit equation?

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Between 1960 and 1975, the Veterans Association Cooperative Urological Research Group (VACURG) conducted a series of large randomized trials to test several oestrogenic compounds in varying doses and combinations with regard to their efficacy and safety in the treatment of all stages of prostate cancer [1]. The major message conveyed by these trials was the significant cardiovascular morbidity and mortality associated with 5 mg of oral diethylstilbesterol and the adverse impact on overall survival. Much less attention was given to the cancer-specific survival in the oestrogen arms of the study, which prompted the trial statistician to attribute the favourable effect of oestrogen to testosterone-lowering as well as to a direct cytotoxic effect. One half-century later clinical trial investigators in the UK are reevaluating the therapeutic utility of oestrogen delivered via a transdermal rather than an oral route to address and challenge some of the major conclusions of VACURG. The PATCH (Prostate Adenocarcinoma: TransCutaneous Hormone, MRC, PR 09) trial is an ongoing randomized trial comparing transdermal oestrogen with LHRH analogues in men with advanced prostate cancer. Among the critical endpoints will be overall survival, cancer-specific survival, PSA progression and quality of life. Castrate levels of testosterone have been achieved more rapidly in the transdermal oestrogen arm, there is no testosterone flare, and dose escalation may further improve on the 92–93% of patients reaching castrate levels of testosterone. Trial data published thus far have shown that transdermal oestrogen has a significant advantage with regard to maintaining bone health [2].

In the present issue of BJUI, Gilbert et al. [3] address quality-of-life outcomes for 700 patients, representing > 80% of the study cohort, who submitted pre-treatment and 6-month post-treatment questionnaires. For all ages, 6-month global quality of life declined in both arms, but to a statistically lesser extent in the transdermal oestrogen arm compared with the LHRHa arm. There was also a statistically lesser decline in physical function and fatigue and sexual interest with transdermal oestrogen. Sexual interest decline was more pronounced for men aged < 70 years. As expected, hot flashes were significantly lower with transdermal oestrogen and were responsible, along with associated sleep disturbances, for a significant component of the quality-of-life decline in the LHRHa arm. Also, as expected, gynecomastia was more frequent with transdermal oestrogen but was associated with a decline in quality of life only in a small minority (8%) of patients who reported ‘very much’ gynecomastia. Only two patients underwent surgery for gynecomastia. For the small percentage of men for whom gynecomastia/dynia is problematic, more frequent employment of subcutaneous mastectomy could be of benefit. The acceptance of gynecomastia is likely to be quite different between cultures and countries.

The finding that sexual interest was improved in the transdermal oestrogen arm is substantiated by clinical trials specifically investigating the role of oestrogen in male sexual health. Both oestrogen and testosterone are necessary [4]. Endogenous oestrogen in men is derived from testosterone through aromatization. The absence of testosterone translates to the absence of oestrogen. It is beneficial to be only mono-hormone-deprived (testosterone) rather than dual-hormone-deprived (testosterone and oestrogen). Additional benefits associated with oestrogen in the male have been reviewed by Wibowo et al. [5].

The previously reported bone health advantage and the current quality-of-life data would appear quite convincing in favour of transdermal oestrogen as a preferred or at least an alternate option for androgen deprivation therapy; however, the association of oestrogen with cardiovascular toxicity has presented a major hurdle. Interestingly, Byar and Corle [1] noted that on initial publication of the cardiovascular morbidity data, physicians were not convinced and were resistant to changing their support of oral diethylstilbesterol therapy. Today, however, the mindset is the polar opposite: a conviction that oestrogen will expose patients to unacceptable cardiovascular morbidity. However, transdermal delivery, which avoids the enterohepatic first pass through the liver circulation, bypasses the coagulopathies associated with oral oestrogen. A previous report from PATCH confirmed that, with 19-month follow-up there is a similar rate of cardiovascular events between the transdermal oestrogen and LHRHa arms [6].

Finally, my favourable drift in this summary is based on personal bias that warrants disclosure and explanation. When my prostate cancer became castration-resistant 8 years ago, LHRHa androgen deprivation therapy was replaced by transdermal oestradiol. My impression that the progression to metastatic castration-resistant prostate cancer was slowed is subject to debate, but my quality-of-life improvement is not. I say this with some degree of confidence, based on cycling between the two agents. Initially on switching to transdermal oestradiol from LHRHa I ‘felt better’. Entry into a subsequent clinical trial required discontinuation of oestrogen and replacement with LHRHa. I regressed, and ‘felt worse’. On completion of the trial I discontinued LHRHa, resumed transdermal oestrogen and ‘felt better’ once again.

In moving the needle back to the old so that it becomes new again, we are faced with a difficult mindset hurdle. In the case of transdermal oestrogen, I feel, based on quality of life and even perhaps a survival benefit, it is a hurdle well worth exploration.

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How to Cite

Schellhammer, P. F. (2017), Oestrogen redux: will transdermal delivery rebalance the risk–benefit equation?. BJU International, 119: 653–654. doi: 10.1111/bju.13737

References

 

1 Byar DP, Corle DK. Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group Studies. NCI Monogr 1988; 7: 165–70

 

2 Langley RE, Kynaston HG, Alhasso AA et al. A randomised comparison evaluating changes in bone mineral density in advanced prostate cancer: luteinising hormone-releasing hormone agonists versus transdermal oestradiol. Eur Urol 2016; 69: 1016–25

 

3 Gilbert DC, Duong T, Kynaston HG et al. Quality-of-life outcomes from the Prostate Adenocarcinoma: TransCutaneous Hormones (PATCH) trial evaluating luteinizing hormone-releasing hormone agonists versus transdermal oestradiol for androgen suppression in advanced prostate cancer. BJU Int 2017; 119: 667–75

 

4 Finkelstein JS, Lee H, Burnett-Bowie SM et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 2013; 369: 1011–22

 

5 Wibowo E, Schellhammer PF, Wassersug RJ. Role of estrogen in normal male function: clinical implications for patients with prostate cancer on androgen deprivation therapy. J Urol 2011; 185: 17–23

 

6 Langley RE, Cafferty FH, Alhasso AA et al. Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09). Lancet Oncol 2013; 14: 306–16

 

Article of the Week: Patterns of prescription and adherence to EAU guidelines on ADT in PCa

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Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Giuseppe Morgia and Giorgio Ivan Russo, discussing their paper.

If you only have time to read one article this week, it should be this one.

Patterns of prescription and adherence to European Association of Urology guidelines on androgen deprivation therapy in prostate cancer: an Italian multicentre cross-sectional analysis from the Choosing Treatment for Prostate Cancer (CHOICE) study

Giuseppe Morgia1, Giorgio Ivan Russo1, Andrea Tubaro2, Roberto Bortolus3, Donato Randone4, Pietro Gabriele5, Fabio Trippa6, Filiberto Zattoni7, Massimo Porena8, Vincenzo Mirone9, Sergio Serni10, Alberto Del Nero11, Giancarlo Lay12 , Umberto Ricardi13, Francesco Rocco14, Carlo Terrone15, Arcangelo Pagliarulo16, Giuseppe Ludovico17, Giuseppe Vespasiani18, Maurizio Brausi19, Claudio Simeone20, Giovanni Novella21, Giorgio Carmignani22, Rosario Leonardi23, Paola Pinnaro5, Ugo De Paula24, Renzo Corvo25, Raffaele Tenaglia26, Salvatore Siracusano27, Giovanna Mantini28, Paolo Gontero29, Gianfranco Savoca30 and Vincenzo Ficarra31 (Members of the LUNA Foundation, Societa Italiana d’Urologia)

 

1 Department of Urology, University of Catania, Catania, 2 Department of Urology, Sant’ Andrea Hospital, ‘La Sapienza’ University of Roma, Roma, 3 S.O. Oncologia Radioterapica, Pordenone, 4 Urology, Presidio Ospedaliero Gradenigo, Torino, 5 Radiotherapy, IRCC Candiolo, Torino, 6 Radiotherapy, A.O. Santa Maria, Terni, 7 Department of Urology, University of Padova, Padova, 8 Department of Urology, University of Perugia, Perugia, 9 Department of Urology, Universita Federico II of Napoli, Napoli,
10 Department of Urology, University of Firenze, Firenze, 11 Urologia I, Azienda Ospedaliera San Paolo, Milano, 12 Radiotherapy, ASL of Cagliari, Cagliari, 13 Radiotherapy, AOU University S. Giovanni Battista Molinette, Torino, 14 Department of Urology, University of Milano, Milano, 15Urology, University Hospital ‘Maggioredella Carita’, Novara,16 Urology, University of Bari, Bari, 17 Urology, Ospedale Generale Regionale F. Miulli, Acquaviva delle Fonti, 18 Department of Urology, University Tor Vergata, Roma, 19 Urology, Ospedale Civile Ramazzini, Carpi, 20 Department of Urology, University of Brescia, Brescia, 21 Department of Surgery, Urology Clinic, AOUI Verona, Verona, 22 Department of Urology, University of Genova, Genova, 23 Urology, Centro Uro-Andrologico La CURA, Acireale, 24 Radiotherapy, AO S. Giovanni Addolorata, Roma, 25 Radiotherapy, Istituto Nazionale per la Ricerca, Genova, 26 Department of Urology, University of Chieti, Chieti, 27 Department of Urology, University of Trieste, Trieste, 28 Radiotherapy, Policlinico Universitario Agostino Gemelli, Roma, 29 Department of Surgical Sciences, Città della Salutee della Scienza, University of Torino, Torino, 30 Urology, Fondazione Istituto San Raffaele – G. Giglio di Cefalù, Cefalù, and 31 Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy

 

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Objective

To evaluate both the patterns of prescription of androgen deprivation therapy (ADT) in patients with prostate cancer (PCa) and the adherence to European Association of Urology (EAU) guidelines for ADT prescription.

Methods

The Choosing Treatment for Prostate Cancer (CHOICE) study was an Italian multicentre cross-sectional study conducted between December 2010 and January 2012. A total of 1 386 patients, treated with ADT for PCa (first prescription or renewal of ADT), were selected. With regard to the EAU guidelines on ADT, the cohort was categorized into discordant ADT (Group A) and concordant ADT (Group B).

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Results

The final cohort included 1 075 patients with a geographical distribution including North Italy (n = 627, 58.3%), Central Italy (n = 233, 21.7%) and South Italy (n = 215, 20.0%). In the category of patients treated with primary ADT, a total of 125 patients (56.3%) were classified as low risk according to D’Amico classification. With regard to the EAU guidelines, 285 (26.51%) and 790 patients (73.49%) were classified as discordant (Group A) and concordant (Group B), respectively. In Group A, patients were more likely to receive primary ADT (57.5%, 164/285 patients) than radical prostatectomy (RP; 30.9%, 88/285 patients), radiation therapy (RT; 6.7%, 19/285 patients) or RP + RT (17.7%, 14/285 patients; P < 0.01). Multivariate logistic regression analysis, adjusted for clinical and pathological variables, showed that patients from Central Italy (odds ratio [OR] 2.86; P < 0.05) and South Italy (OR 2.65; P < 0.05) were more likely to receive discordant ADT.

Conclusion

EAU guideline adherence for ADT was low in Italy and was influenced by geographic area. Healthcare providers and urologists should consider these results in order to quantify the inadequate use of ADT and to set policy strategies to overcome this risk.

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Editorial: EAU guidelines – do we care? Reflections from the EAU Impact Assessment of Guidelines Implementation and Education group

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There is increasing evidence in the literature that androgen deprivation therapy (ADT) is overused among practising urologists in the setting of localized, and even locally advanced, prostate cancer (PCa) [1, 2]. Morgia et al. [1] report a misuse of ADT prescriptions among Italian urologists in roughly a quarter of cases, mainly in the setting of low-risk/localized disease where ADT may harm patients without proven benefit with regard to disease-specific outcomes [3]. Such clinical practice behaviours are even more unjustifiable given the high level of evidence upon which the current European Association of Urology (EAU) guidelines recommendations on ADT use are based [4].

Morgia et al. [1] should be congratulated for highlighting the magnitude of the problems the urological community currently face in terms of the gap between evidence and practice. Unfortunately, while the authors report significant geographical differences in ADT prescriptions within the same country (Italy), the methods they used in their study do not allow an understanding of the reasons for the discrepancy. It is currently unknown whether the gap between evidence and practice is attributable to physician or patient attitude or to the national health system structure. The inclusion of qualitative methods, such as semi-structured interviews, would have been ideal to probe clinician reasoning for discordant adherence. This is crucial because knowledge of possible barriers to the application of guidelines represents a key step in their implementation process. Indeed, once the issue is raised, the next logical questions to pose would be: how can we reduce such variation in urological practice especially where there is a real risk of causing harm to patients and how can we improve and implement the use of guideline recommendations when clearly underpinned by high-quality evidence?

It is indeed intuitive that any huge evidence–practice gap may have profound implications not only in the process of patient care optimization but also in the context of national healthcare efficiency.

Certainly the issue of ADT overuse raised by Morgia et al. [1] can be considered the perfect setting to scale up and prioritize efforts aimed at improving current urological practice for three main reasons: (i) the high prevalence of the disease studied (namely, PCa); (ii) the availability of an up-to-date evidence-based guideline showing the impact of ADT in terms of patient side effects and costs; and (iii) the now known gap between evidence and practice patterns.

Given this setting, it should then be mandatory to promote ways not only to assess the use of guideline recommendations but also to increase dissemination among users (not only healthcare professionals, but also patients and policy makers) and to evaluate their impact. The aim of this highly articulated process of knowledge translation is eventually to move research findings into clinical practice. Ideally, this approach should be based on the following five crucial questions: (i) What should be transferred? (ii) To whom should research knowledge be transferred? (iii) By whom should research knowledge be transferred? (iv) How should research knowledge be transferred? and (v) To what effect should research knowledge be transferred? [5]. Each of these questions represents a crucial step in any knowledge translation process. To optimize this approach, it is critical to identify barriers to knowledge implementation and to choose the optimum interventions to limit or to overcome them. This ‘global process’ is much more complicated than commonly thought, given the significant cultural, social, economic and health system differences not only between countries but also within the same country, as shown by Morgia et al. [1]. It is likely, therefore, that any knowledge implementation approach should be tailored according to each country and should be based on key steps, such as: selection of a credible ‘messenger’; development of the appropriate technological and organizational instruments to facilitate access to disseminate and use existing high-quality evidence; and the setting up of education programmes to improve clinical research literacy skills.

Finally, we believe that the paper by Morgia et al. [1] strongly supports the notion that ‘evidence-based medicine should be complemented by evidence-based implementation’ [6]. It is indeed likely that creating a knowledge translation setting where the gap between evidence and practice is eventually bridged is as important as producing accurate, scientifically sound and meticulous guidelines that can be trusted by all stakeholders.

Tackling the crucially important problem of discordant guideline adherence is the remit of the recently established EAU Guidelines Office ‘IMAGINE’ project (IMpact Assessment of Guidelines Implementation and Education) which aims to: ascertain adherence to prioritized guideline recommendations; elucidate the barriers and facilitators to change; design bespoke knowledge transfer interventions; and evaluate the impact of the EAU guidelines, thereby optimizing adherence, with the ultimate goal of improving patient care.

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Alberto Briganti*, Steven MacLennan†, Lorenzo Marconi‡, Karin Plass§ and James N’Dow †on behalf of EAU Guidelines Office ‘IMAGINE’ project
*Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy, †Academic Urology Unit, University of Aberdeen, Aberdeen, UK, ‡Department of Urology, Coimbra University Hospital, Coimbra, Portugal and §EAU Central Office, Guidelines Office, Arnhem, The Netherlands

 

References

 

1 Morgia G, Russo GI, Tubaro A et al. Patterns of prescription and adherence to European Association of Urology guidelines on androgen deprivation therapy in prostate cancer: an Italian multicentre cross- sectional analysis from the Choosing Treatment for Prostate Cancer (CHOICE) study. BJU Int 2016; 117: 867–73

 

2 Lycken M, Garmo H, Adolfsson J, Stattin P, Holmberg L, Bill-Axelson A. Patterns of androgen deprivation therapies among men diagnosed with localised prostate cancer: a population-based study. Eur J Cancer 2014; 50: 1789–98

 

3 Lu-Yao GL, Albertsen PC, Moore DF et al. Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA 2008; 300: 173–81

 

4 Heidenreich A, Bastian PJ, Bellmunt J et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 2014; 65: 467–79

 

5 Grimshaw JM, Eccles MP, Lavis JN, Hill SJ, Suires JE. Knowledge translation of research findings. Implement Sci 2012; 7: 50

 

6 Grol R. Beliefs and evidence in changing clinical practice. BMJ 1997; 315: 418–21

 

Video: Patterns of prescription and adherence to EAU guidelines on ADT in PCa

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Patterns of prescription and adherence to European Association of Urology guidelines on androgen deprivation therapy in prostate cancer: an Italian multicentre cross-sectional analysis from the Choosing Treatment for Prostate Cancer (CHOICE) study

Giuseppe Morgia1, Giorgio Ivan Russo1, Andrea Tubaro2, Roberto Bortolus3, Donato Randone4, Pietro Gabriele5, Fabio Trippa6, Filiberto Zattoni7, Massimo Porena8, Vincenzo Mirone9, Sergio Serni10, Alberto Del Nero11, Giancarlo Lay12 , Umberto Ricardi13, Francesco Rocco14, Carlo Terrone15, Arcangelo Pagliarulo16, Giuseppe Ludovico17, Giuseppe Vespasiani18, Maurizio Brausi19, Claudio Simeone20, Giovanni Novella21, Giorgio Carmignani22, Rosario Leonardi23, Paola Pinnaro5, Ugo De Paula24, Renzo Corvo25, Raffaele Tenaglia26, Salvatore Siracusano27, Giovanna Mantini28, Paolo Gontero29, Gianfranco Savoca30 and Vincenzo Ficarra31 (Members of the LUNA Foundation, Societa Italiana d’Urologia)

 

1 Department of Urology, University of Catania, Catania, 2 Department of Urology, Sant’ Andrea Hospital, ‘La Sapienza’ University of Roma, Roma, 3 S.O. Oncologia Radioterapica, Pordenone, 4 Urology, Presidio Ospedaliero Gradenigo, Torino, 5 Radiotherapy, IRCC Candiolo, Torino, 6 Radiotherapy, A.O. Santa Maria, Terni, 7 Department of Urology, University of Padova, Padova, 8 Department of Urology, University of Perugia, Perugia, 9 Department of Urology, Universita Federico II of Napoli, Napoli,
10 Department of Urology, University of Firenze, Firenze, 11 Urologia I, Azienda Ospedaliera San Paolo, Milano, 12 Radiotherapy, ASL of Cagliari, Cagliari, 13 Radiotherapy, AOU University S. Giovanni Battista Molinette, Torino, 14 Department of Urology, University of Milano, Milano, 15Urology, University Hospital ‘Maggioredella Carita’, Novara,16 Urology, University of Bari, Bari, 17 Urology, Ospedale Generale Regionale F. Miulli, Acquaviva delle Fonti, 18 Department of Urology, University Tor Vergata, Roma, 19 Urology, Ospedale Civile Ramazzini, Carpi, 20 Department of Urology, University of Brescia, Brescia, 21 Department of Surgery, Urology Clinic, AOUI Verona, Verona, 22 Department of Urology, University of Genova, Genova, 23 Urology, Centro Uro-Andrologico La CURA, Acireale, 24 Radiotherapy, AO S. Giovanni Addolorata, Roma, 25 Radiotherapy, Istituto Nazionale per la Ricerca, Genova, 26 Department of Urology, University of Chieti, Chieti, 27 Department of Urology, University of Trieste, Trieste, 28 Radiotherapy, Policlinico Universitario Agostino Gemelli, Roma, 29 Department of Surgical Sciences, Città della Salutee della Scienza, University of Torino, Torino, 30 Urology, Fondazione Istituto San Raffaele – G. Giglio di Cefalù, Cefalù, and 31 Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy

 

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Objective

To evaluate both the patterns of prescription of androgen deprivation therapy (ADT) in patients with prostate cancer (PCa) and the adherence to European Association of Urology (EAU) guidelines for ADT prescription.

Methods

The Choosing Treatment for Prostate Cancer (CHOICE) study was an Italian multicentre cross-sectional study conducted between December 2010 and January 2012. A total of 1 386 patients, treated with ADT for PCa (first prescription or renewal of ADT), were selected. With regard to the EAU guidelines on ADT, the cohort was categorized into discordant ADT (Group A) and concordant ADT (Group B).

AOTWJun5Results

Results

The final cohort included 1 075 patients with a geographical distribution including North Italy (n = 627, 58.3%), Central Italy (n = 233, 21.7%) and South Italy (n = 215, 20.0%). In the category of patients treated with primary ADT, a total of 125 patients (56.3%) were classified as low risk according to D’Amico classification. With regard to the EAU guidelines, 285 (26.51%) and 790 patients (73.49%) were classified as discordant (Group A) and concordant (Group B), respectively. In Group A, patients were more likely to receive primary ADT (57.5%, 164/285 patients) than radical prostatectomy (RP; 30.9%, 88/285 patients), radiation therapy (RT; 6.7%, 19/285 patients) or RP + RT (17.7%, 14/285 patients; P < 0.01). Multivariate logistic regression analysis, adjusted for clinical and pathological variables, showed that patients from Central Italy (odds ratio [OR] 2.86; P < 0.05) and South Italy (OR 2.65; P < 0.05) were more likely to receive discordant ADT.

Conclusion

EAU guideline adherence for ADT was low in Italy and was influenced by geographic area. Healthcare providers and urologists should consider these results in order to quantify the inadequate use of ADT and to set policy strategies to overcome this risk.

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Sailing into “UnCHAARTED” waters

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Chemotherapy comes alive for prostate cancer!

staff-chowdhury1Systemic therapy for metastatic prostate cancer has radically changed in the last 10 years with the introduction of several novel agents that have shown significant improvements in progression free and overall survival. These have all been studied in metastatic castrate refractory prostate cancer (mCRPC) and have improved overall survival but in each case by less than 6 months. (The latest major breakthrough is the introduction of a relatively old drug, docetaxel chemotherapy, earlier in the disease for hormone sensitive patients).

In this week’s New England Journal of Medicine we see the eagerly awaited results from the CHAARTED study from Christopher Sweeney and colleagues. This novel study aimed to improve treatment for men with newly diagnosed hormone sensitive metastatic prostate cancer by adding docetaxel chemotherapy to androgen deprivation therapy (ADT).

790 men with newly diagnosed metastatic prostate cancer were randomised to ADT plus docetaxel (6 cycles at 75mg/m2) or ADT alone. The addition of docetaxel to ADT was shown to significantly improve overall survival by 13.6 months (57.6 months vs. 44.0 months; p<0.001). The clinical benefit was greatest in the subgroup with high volume disease where the improvement in overall survival was 17 months (49.2 months versus 32.2 months). High volume disease was defined as the presence of visceral metastases and/or 4 or more bone metastases with at least one beyond the vertebral bodies or pelvis. The combination was well tolerated with approximately 6% of patients having neutropenic fever and one death possibly related to docetaxel.

The results from this study are truly practice changing. Supporting evidence from the UK STAMPEDE study (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) was presented at this year’s American Society of Clinical Oncology (ASCO) meeting. STAMPEDE showed that for men with metastatic hormone sensitive prostate cancer 6 cycles of docetaxel in addition to ADT improved median overall survival by 22 months (43 versus 65 months).

Chemotherapy for metastatic prostate cancer has had a checkered past with a lack of enthusiasm and nihilism from clinicians and patients. The results from CHAARTED and STAMPEDE are already changing those views. The prostate cancer community needs to react to these results and look to make this treatment available to all suitable men. There are issues with regards to costs of chemotherapy (although docetaxel is now generic), workload, sequence, patient selection, toxicity management, etc. The CHAARTED and STAMPEDE investigators must also use this opportunity to interrogate the tumour samples from these studies to see if they can identify biomarkers that predict docetaxel activity. We will not get this opportunity again as docetaxel + ADT will be be standard of care for future studies.

The clinical benefit from the addition of docetaxel to ADT is one of the largest seen in any oncology study. All men presenting with newly diagnosed metastatic prostate cancer should be considered for 6 cycles of docetaxel in addition to ADT.

 

Simon Chowdhury is a Consultant Medical Oncologist at Guy’s, King’s and St Thomas’ Hospitals, London. He is actively involved in clinical trial research into urological cancers.

 

 

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