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Article of the Week: Evaluation of Sig24, a 24-gene signature

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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 discussing the paper.

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

Evaluation of a 24-gene signature for prognosis of metastatic events and prostate cancer-specific mortality

Kathryn L. Pellegrini*†, Martin G. Sanda*†, Dattatraya Patil*†, Qi Long†‡§, Marıa Santiago-Jimenez, Mandeep Takhar, Nicholas Erho, Kasra Yousefi, Elai Davicioni, Eric A. Klein**, Robert B. Jenkins††, R. Jeffrey Karnes‡‡ and Carlos S. Moreno†§§§

 

*Department of Urology, Emory University School of Medicine, †Winship Cancer Institute, Atlanta, GA‡ Department of Biostatistics and Epidemiology and Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, §Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA, GenomeDx Biosciences, Vancouver, BC, Canada, **Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, ††Department of Pathology and Laboratory Medicine, ‡‡Department of Urology, Mayo Clinic, Rochester, MN, and §§Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
Read the full article

How to Cite

Pellegrini, K. L., Sanda, M. G., Patil, D., Long, Q., Santiago-Jiménez, M., Takhar, M., Erho, N., Yousefi, K., Davicioni, E., Klein, E. A., Jenkins, R. B., Karnes, R. J. and Moreno, C. S. (2017), Evaluation of a 24-gene signature for prognosis of metastatic events and prostate cancer-specific mortality. BJU International, 119: 961–967. doi: 10.1111/bju.13779

Abstract

Objectives

To determine the prognostic potential of a 24-gene signature, Sig24, for identifying patients with prostate cancer who are at risk of developing metastases or of prostate cancer-specific mortality (PCSM) after radical prostatectomy (RP).

Patients and Methods

Sig24 scores were calculated from previously collected gene expression microarray data from the Cleveland Clinic and Mayo Clinic (I and II). The performance of Sig24 was determined using time-dependent c-index analysis, Cox proportional hazards regression and Kaplan–Meier survival analysis.

aotw-jun-3-results

Results

Higher Sig24 scores were significantly associated with higher pathological Gleason scores in all three cohorts. Analysis of the Mayo Clinic II cohort, which included time-to-event information, indicated that patients with high Sig24 scores also had a higher risk of developing metastasis (hazard ratio [HR] 3.78, 95% confidence interval [CI]: 1.96–7.29; P < 0.001) or of PCSM (HR 6.54, 95% CI: 2.16–19.83; P < 0.001).

Conclusions

The findings of the present study show the applicability of Sig24 for the prognosis of metastasis or PCSM after RP. Future studies investigating the combination of Sig24 with available prognostic tests may provide new approaches to improve risk stratification for patients with prostate cancer.

Read more articles of the week

Editorial: Predicting outcome: role of gene signatures

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Pathological assessments, such as Gleason grading, which is a strong clinical predictor of prostate cancer progression [1], have a role to play in predicting the outcome of a patient’s response to therapy. The addition of PSA and TNM staging are further used to inform appropriate treatment strategies in patients who are at low, intermediate and high risk of disease progression. Unfortunately, approximately 30% of men with intermediate-risk prostate cancer will fail to be cured by surgery or radiation therapy approaches. This is not surprising as primary prostate cancer represents a complex heterogeneous disease that is clearly not fully explained by the current clinical prognostic factors, and further molecular characterization is required. There is now significant emerging evidence that the molecular characterization of tumours is important to enable us to stratify prostate cancer patients by their response to primary therapy and to identify the next appropriate steps in their treatment pathway.

Long et al. [2] have identified gene signatures that can define different genomic subtypes of prostate cancer and are predictive of biochemical recurrence. Erho et al. [3] discovered and validated a 22-gene signature, which they termed a genomic classifier for the prediction of early metastasis after radical prostatectomy, while Penny et al. [4] have identified an mRNA expression signature of Gleason grade which is predictive of lethal prostate cancer.

Long et al. [2] identified a 24-gene signature, which they discovered through RNA sequencing analysis of 100 formalin-fixed paraffin-embedded prostatectomy samples. They went on to validate their findings in a publically available independent gene expression microarray dataset of 140 patients. This 24-gene signature forms the basis of the present study by Pellegrini et al. [5], who refer to this gene signature as Sig24. In their study, they firstly undertook to determine if Sig24 was associated with pathological Gleason score as a marker of tumour aggressiveness, and then if it had prognostic value for the identification of patients at risk of metastasis or prostate cancer-specific mortality after radical prostatectomy. The Gleason score association study was carried out using the data from three independent case–control sets, including 182 patients from the Cleveland Clinic and two cohorts (cohort I, n = 545; cohort II, n = 235) from the Mayo Clinic, for which gene expression analysis had previously been conducted by Genome Dx using the Affymetrix Human 1.0 ST Genechip platform. The Sig24 score was calculated for each patient and higher Gleason score was associated with significantly higher Sig24 scores. The association studies for metastatic disease and prostate cancer-specific mortality, however, were only carried out in the Mayo Clinic cohort II. For both clinical endpoints the Sig24 score combined with the clinical model outperformed the clinical model alone of PSA, Gleason score and tumour stage. For metastatic disease the area under the curve for the clinical model alone was 0.69 (0.62–0.77) compared with 0.73 (0.66–0.78) for the clinical model combined with Sig24. For the prostate cancer-specific mortality endpoint, the area under the curve for the clinical model alone was 0.69 (0.67–0.87) compared with 0.74 (0.63–0.85) for the clinical model combined with Sig24.

These gene signatures have significant potential for predicting the progression of disease rather than waiting for PSA relapse, which is currently used to identify disease recurrence, with interval to biochemical failure being the best univariate factor predicting prostate cancer mortality and overall survival [6]. This would allow the initiation of additional therapies before recurrence and a better outcome for the patient. This concept has been demonstrated in a study in which the use of the Decipher gene signature was shown to improve the identification of patients who could benefit from adjuvant radiotherapy and thus only these patients were targeted for therapy [7].

Incorporating these gene signatures in robust clinical assays and integrating them into clinical decision-making is the next essential step in order for these strategies to have an impact on patient outcomes.

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Ronald W. Watson
UCD School of Medicine, University College Dublin, Dublin, Ireland

References

1 Gleason DF. Classification of prostatic carcinomas. Cancer Chemother
Rep 1966; 50: 125–8
2 Long Q, Xu J, Osunkoya AO et al. Global transcriptome analysis of formalin-fixed prostate cancer specimens identifies biomarkers of disease recurrence. Cancer Res 2014; 74: 3228–37

 

3 Erho N, Crisan A, Vergara IA et al. Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One 2013; 8: e66855

 

4 Penny KL, Sinnott JA, Fall K et al. mRNA expression signature of Gleason grade predicts lethal prostate cancer. J Clin Oncol 2011; 29:2391–6

 

5 Pellegrini K, Sanda MG, Patil D et al. Evaluation of a 24-gene signature for prognosis of metastatic events and prostate cancer-specific mortality. BJU Int 2017; 119: 961–7

 

6 Buyyounouski MK, Pickles T, Kestin LL, Allison R, Williams SG. Validating the interval to biochemical failure for identification of potentially lethal prostate cancer. J Clin Oncol 2012; 30: 1857–63

 

7 Den RB, Yousefi K, Trabulsi EJ et al. Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. J Clin Oncol 2015; 33: 944–51

 

Video: Evaluation of a 24-gene signature for prognosis of metastatic events and PCa-specific mortality

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Evaluation of a 24-gene signature for prognosis of metastatic events and prostate cancer-specific mortality

Kathryn L. Pellegrini*†, Martin G. Sanda*†, Dattatraya Patil*†, Qi Long†‡§, Marıa Santiago-Jimenez, Mandeep Takhar, Nicholas Erho, Kasra Yousefi, Elai Davicioni, Eric A. Klein**, Robert B. Jenkins††, R. Jeffrey Karnes
‡‡ and Carlos S. Moreno†§§§

 

*Department of Urology, Emory University School of Medicine, †Winship Cancer Institute, Atlanta, GA‡ Department of Biostatistics and Epidemiology and Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, §Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA, GenomeDx Biosciences, Vancouver, BC, Canada, **Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, ††Department of Pathology and Laboratory Medicine, ‡‡Department of Urology, Mayo Clinic, Rochester, MN, and §§Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
Read the full article

How to Cite

Pellegrini, K. L., Sanda, M. G., Patil, D., Long, Q., Santiago-Jiménez, M., Takhar, M., Erho, N., Yousefi, K., Davicioni, E., Klein, E. A., Jenkins, R. B., Karnes, R. J. and Moreno, C. S. (2017), Evaluation of a 24-gene signature for prognosis of metastatic events and prostate cancer-specific mortality. BJU International, 119: 961–967. doi: 10.1111/bju.13779

Abstract

Objectives

To determine the prognostic potential of a 24-gene signature, Sig24, for identifying patients with prostate cancer who are at risk of developing metastases or of prostate cancer-specific mortality (PCSM) after radical prostatectomy (RP).

Patients and Methods

Sig24 scores were calculated from previously collected gene expression microarray data from the Cleveland Clinic and Mayo Clinic (I and II). The performance of Sig24 was determined using time-dependent c-index analysis, Cox proportional hazards regression and Kaplan–Meier survival analysis.

aotw-jun-3-results

Results

Higher Sig24 scores were significantly associated with higher pathological Gleason scores in all three cohorts. Analysis of the Mayo Clinic II cohort, which included time-to-event information, indicated that patients with high Sig24 scores also had a higher risk of developing metastasis (hazard ratio [HR] 3.78, 95% confidence interval [CI]: 1.96–7.29; P < 0.001) or of PCSM (HR 6.54, 95% CI: 2.16–19.83; P < 0.001).

Conclusions

The findings of the present study show the applicability of Sig24 for the prognosis of metastasis or PCSM after RP. Future studies investigating the combination of Sig24 with available prognostic tests may provide new approaches to improve risk stratification for patients with prostate cancer.

Read more articles of the week

Article of the Week: Treatment of ED after RP using nerve grafts and end-to-side somatic-autonomic neurorraphy

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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.

Long-term follow-up of treatment of erectile dysfunction after radical prostatectomy using nerve grafts and end-to-side somatic-autonomic neurorraphy: a new technique

Jose Carlos Souza Trindade*, Fausto Viterbo†, Andre Petean Trindade‡, Wagner Josen Favaro§ and Jose Carlos Souza Trindade-Filho*

 

*Department of Urology, † Divisions of Plastic Surgery,‡ Radiology, Botucatu School of Medicine, State University of Sao Paulo, Sao Paulo, and §Department of Anatomy, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil

 

Read the full article

Abstract

Objective

To study a novel penile re innervation technique using four sural nerve grafts and end-to-side neurorraphies connecting bilaterally the femoral nerve and the cavernous corpus and the femoral nerve and the dorsal penile nerves.

Patients and Methods

Ten patients (mean [± sd; range] age 60.3 [± 4.8; 54–68] years), who had undergone radical prostatectomy (RP) at least 2 years previously, underwent penile reinnervation in the present study. Four patients had undergone radiotherapy after RP. All patients reported satisfactory sexual activity prior to RP. The surgery involved bridging of the femoral nerve to the dorsal nerve of the penis and the inner part of the corpus cavernosum with sural nerve grafts and end-to-side neurorraphies. Patients were evaluated using the International Index of Erectile Function (IIEF) questionnaire and pharmaco-penile Doppler ultrasonography (PPDU) preoperatively and at 6, 12 and 18 months postoperatively, and using a Clinical Evolution of Erectile Function (CEEF) questionnaire, administered after 36 months.

Results

The IIEF scores showed improvements with regard to erectile dysfunction (ED), satisfaction with the VitalFlow and general satisfaction. Evaluation of PPDU velocities did not reveal any difference between the right and left sides or among the different time points. The introduction of nerve grafts neither caused fibrosis of the corpus cavernosum, nor reduced penile vascular flow. CEEF results showed that sexual intercourse began after a mean of 13.7 months with frequency of sexual intercourse varying from once daily to once monthly. Acute complications were minimal. The study was limited by the small number of cases.

Conclusions

A total of 60% of patients were able to achieve full penetration, on average, 13 months after reinnervation surgery. Patients previously submitted to radiotherapy had slower return of erectile function. We conclude that penile reinnervation surgery is a viable technique, with effective results, and could offer a new treatment method for ED after RP.

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Editorial: Somatic-autonomic neurorrhaphy for erectile function restoration after radical prostatectomy

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The authors of the present study [1] are to be commended for their efforts in describing their 3-year experience with a novel bilateral end-to-side somatic-autonomic neurorrhaphy intended to restore erectile function at least 24 months after radical prostatectomy, after which spontaneous return of erectile function is unlikely [2]. Using the principles of brain plasticity and neurotization, the authors describe, for the first time, bilateral sural neurografting between the femoral nerve and both the corpus cavernosum and the dorsal nerve of the penis to achieve penile re-innervation. The employed side-to-end neurorrhaphy theoretically limits functional damage during axonal sprouting, reinforces sensory–motor communications to the cavernous nerves, and promotes glans penis sensitivity, although direct evidence of these physiological and clinical outcomes is yet to be demonstrated. Furthermore, the authors astutely capitalize on the potential advantages of using a femoral donor nerve, including its proximity to the proximal penis, its diameter, the sufficient axon count, the mixed composition of sensory and motor fibres, and its secretion of acetylcholine which is an essential neurotransmitter in the nitric oxide-mediated pathway leading to penile tumescence.

What is especially singular about this technique is its application months after radical prostatectomy following demonstrated post-surgical loss of erectile function. Previous studies have focused on unilateral or bilateral sural [3-6] or genitofemoral [7] neurografting of the cavernous nerves at the time of radical prostatectomy before post-surgical loss of erectile function could be substantiated. Such studies have had mixed results, attributable in part to the success of the nerve-sparing radical prostatectomy technique in the hands of experienced high-volume surgeons [3, 6], and post-surgical exposure of the cavernous nerves to androgen deprivation or radiation therapy in some patients [3, 5]. Whereas post-radical prostatectomy re-innervation of the cavernous nerves may not be feasible or efficacious secondary to post-surgical and post-radiation fibrosis, the described technique does not require abdominopelvic access, is associated with a quick recovery time and minimal complications, and does not preclude subsequent penile prosthesis implantation if necessary.

The results of the present study show significant improvement in general sexual satisfaction from baseline to 6 months post intervention corresponding to achievement of flaccid erection for all patients; significant improvement in erectile dysfunction from baseline to 12 months post intervention corresponding to achievement of semi-rigid or rigid erections in 8/10 patients; and significant improvement in satisfaction with sexual intercourse from baseline to 18 months post intervention corresponding to achievement of penetration for 6/10 patients. It should be noted, however, that administration of the Clinical Evolution of Erectile Function instrument at 36 months postoperatively may have introduced recall bias in patient-reported erectile function. As would be expected, no significant differences were noted in sexual desire or orgasm satisfaction during the study period. These results were achieved without evidence of atrophy, fibrosis, or significant differences in vascular flow of the bilateral corpora cavernosa; and with minimal complications over the study period.

The present study provides preliminary data regarding the safety, feasibility and efficacy of bilateral sural neurografting between the femoral nerve and both the corpus cavernosum and the dorsal nerve of the penis to restore post-radical prostatectomy erectile function in a limited pool of 10 men. If these preliminary results are substantiated with long-term follow-up in a significant number of patients, it should prompt multi-institutional collaborations to appropriately power comparative effectiveness analyses of post-radical prostatectomy neurorrhaphy, such as the described technique to a regulatory-approved ethical sham intervention, vacuum assist device therapy, urethral suppository therapy, or intracavernosal injection therapy. Ideally, patients should be matched or statistical analyses should be controlled for patient age, relevant comorbidities, prostate cancer stage, pre-radical prostatectomy erectile function, nerve-sparing radical prostatectomy technique, androgen deprivation therapy, radiation therapy, response to phosphodiesterase-5 inhibition, and time interval between radical prostatectomy and intervention. Such multi-institutional studies would benefit from: standardized protocols for preoperative evaluation, operative technique, peri-operative care and post-surgical sexual stimulation; repeated-measure analyses of both objective assessments of the quality and duration of penile tumescence, as well as patient-reported outcomes of erectile function and disease-specific quality of life using validated instruments; report of oncological outcomes; and long-term follow-up. We would encourage the authors to produce a technical video demonstrating their technique so that it may be attempted and validated by other programmes. Urological surgeons with expertise in oncology, sexual function, and reconstruction may collaborate and pool patient data to achieve high-powered quality studies of novel techniques, such as the one described in the present study, for post-radical prostatectomy erectile function restoration.

Read the full article
Jaime A. Cavallo, and Ashutosh K. Tewari, Chairman
Milton and Carroll Petrie Department of Urology, Icahn School of Medicine at M ount Sinai, New York, NY, USA

 

How to Cite

Cavallo, J. A. and Tewari, A. K. (2017), Somatic-autonomic neurorrhaphy for erectile function restoration after radical prostatectomy. BJU International, 119: 816–818. doi: 10.1111/bju.13858

References

1 Souza Trindade JC, Viterbo F, Petean Trindade A, Favaro WJ, Filho JC. Long-term follow-up for treatment of erectile dysfunction after radical prostatectomy using nerve grafts and end-to-side somatic-autonomic neurorrhaphy: a new technique. BJU Int 2017; 119: 948–54

 

2 Sridhar AN, Cathcart PJ, Yap T et al. Recovery of baseline erectile function in men following radical prostatectomy for high-risk prostate cancer: a prospective analysis using validated measures. J Sex Med 2016; 13: 435–43

 

3 Secin FP, Koppie TM, Scardino PT et al. Bilateral cavernous nerve interposition grafting during radical retropubic prostatectomy: Memorial Sloan-Kettering Cancer Center experience. J Urol 2007; 177: 664–8

 

4 Namiki S, Saito S, Nakagawa H, Sanada T, Yamada A, Arai Y. Impact of unilateral sural nerve graft on recovery of potency and continence following radical prostatectomy: 3-year longitudinal study. J Urol 2007; 178: 212–6

 

5 Hanson GR, Borden LS Jr, Backous DD, Bayles SW, Corman JM. Erectile function following unilateral cavernosal nerve replacement. Can J Urol 2008; 15: 3990–3

 

6 Davis JW, Chang DW, Chevray P et al. Randomized phase II trial evaluation of erectile function after attempted unilateral cavernous nerve- sparing retropubic radical prostatectomy with versus without unilateral sural nerve grafting for clinically localized prostate cancer. Eur Urol 2009; 55: 1135–43

 

7 Joffe R, Klotz LH. Results of unilateral genitofemoral nerve grafts with contralateral nerve sparing during radical prostatectomy. Urology 2007; 69: 1161–4

 

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

 

Read the full article

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.

aotw-may-4-fi

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.

Read more articles of the week

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 Month: Partin Tables in the Contemporary Era

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Every Month the Editor-in-Chief selects an Article of the Month 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.

Prediction of pathological stage based on clinical stage, serum prostate-specific antigen, and biopsy Gleason score: Partin Tables in the contemporary era

Jeffrey J. Tosoian, Meera Chappidi, Zhaoyong Feng, Elizabeth B. Humphreys, Misop Han, Christian P. Pavlovich, Jonathan I. Epstein, Alan W. Partin and Bruce J. Trock

The James Buchanan Brady Urological Institute and Department of Urology at the Johns Hopkins University School of Medicine, Baltimore, MD, USA

 

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How to Cite this Article

Tosoian, J. J., Chappidi, M., Feng, Z., Humphreys, E. B., Han, M., Pavlovich, C. P., Epstein, J. I., Partin, A. W. and Trock, B. J. (2017), Prediction of pathological stage based on clinical stage, serum prostate-specific antigen, and biopsy Gleason score: Partin Tables in the contemporary era. BJU International, 119: 676–683. doi: 10.1111/bju.13573

Abstract

Objective

To update the Partin Tables for prediction of pathological stage in the contemporary setting and examine trends in patients treated with radical prostatectomy (RP) over the past three decades.

Patients and Methods

From January 2010 to October 2015, 4459 men meeting inclusion criteria underwent RP and pelvic lymphadenectomy for histologically confirmed prostate cancer at the Johns Hopkins Hospital. Preoperative clinical stage, serum prostate-specific antigen (PSA) level, and biopsy Gleason score (i.e. prognostic Grade Group) were used in a polychotomous logistic regression model to predict the probability of pathological outcomes categorised as: organ-confined (OC), extraprostatic extension (EPE), seminal vesicle involvement (SV+), or lymph node involvement (LN+). Preoperative characteristics and pathological findings in men treated with RP since 1983 were collected and clinical-pathological trends were described.

aotm-may-2017

Results

The median (range) age at surgery was 60 (34–77) years and the median (range) PSA level was 4.9 (0.1–125.0) ng/mL. The observed probabilities of pathological outcomes were: OC disease in 74%, EPE in 20%, SV+ in 4%, and LN+ in 2%. The probability of EPE increased substantially when biopsy Gleason score increased from 6 (Grade Group 1, GG1) to 3 + 4 (GG2), with smaller increases for higher grades. The probability of LN+ was substantially higher for biopsy Gleason score 9–10 (GG5) as compared to lower Gleason scores. Area under the receiver operating characteristic curves for binary logistic models predicting EPE, SV+, and LN+ vs OC were 0.724, 0.856, and 0.918, respectively. The proportion of men treated with biopsy Gleason score ≤6 cancer (GG1) was 47%, representing a substantial decrease from 63% in the previous cohort and 77% in 2000–2005. The proportion of men with OC cancer has remained similar during that time, equalling 73–74% overall. The proportions of men with SV+ (4.1% from 3.4%) and LN+ (2.3% from 1.4%) increased relative to the preceding era for the first time since the Partin Tables were introduced in 1993.

Conclusions

The Partin Tables remain a straightforward and accurate approach for projecting pathological outcomes based on readily available clinical data. Acknowledging these data are derived from a tertiary care referral centre, the proportion of men with OC disease has remained stable since 2000, despite a substantial decline in the proportion of men with biopsy Gleason score 6 (GG1). This is consistent with the notion that many men with Gleason score 6 (GG1) disease were over treated in previous eras.

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Editorial: Is there a role for pure clinical prediction models in prostate cancer in the contemporary era?

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The identification of men with localised prostate cancer at higher risk of adverse pathological outcomes after radical prostatectomy (RP) would assist physicians in preoperative patient counselling and in tailoring the most appropriate treatment strategy. In this issue of the BJUI, Tosoian et al. [1] have updated the Partin Tables in contemporary patients with localised prostate cancer. The authors should be commended for undertaking a well-performed study evaluating a large cohort of patients treated at a high-volume centre. Notably, they were able to show that the Partin Tables still represent an accurate tool for identifying men at higher risk of adverse pathological features [1]. Having said this, the first question we should ask ourselves is whether preoperative models based on clinical variables only still play a role in contemporary patients. The Partin Tables were developed in 1993 and since then they have undergone a series of updates, all of which are based on virtually the same variables included in the original analyses [1]. However, recent implementations, including biomarkers and imaging, have been introduced to better stage prostate cancer. These novel approaches are usually added to clinical variables to improve patient risk stratification. Multi-parametric MRI (mp-MRI) represents the major game changer in this setting, being now recommended for prostate cancer staging in all men with high-risk disease and in those with less favourable intermediate-risk prostate cancer [2]. In the era of modern and sophisticated approaches, are models using clinical variables only still clinically valuable? To answer this question, we can consider two major settings, namely nodal and local staging.

When assessing the risk of lymph node invasion (LNI) at diagnosis, mp-MRI and positron emission tomography/CT scan are characterised by a low sensitivity and, therefore, are not recommended for the identification of patients who should receive a lymph node dissection (LND) [2, 3]. Conversely, the updated Partin Tables depicted a remarkably high accuracy (>90%) in predicting LNI. This supports what is currently recommended by virtually all guidelines, which indicate that candidates for extended LND (eLND) should still be identified according to a combination of clinical variables only. However, although the Partin Tables might assist clinicians in identifying patients more likely to harbour LNI, the lack of the uniform adoption of an eLND template might have resulted in a substantial under-estimation of the real LNI risk [4]. Other tools specifically developed to predict LNI among men treated with eLND could better assist clinicians in identifying men who should receive an eLND [2, 5].

Similarly, when considering local staging, mp-MRI is characterised by a high specificity but a relatively low sensitivity in detecting small, microscopic foci of extracapsular extension and seminal vesicle invasion (SVI) [6]. Conversely, the updated Partin Tables depicted a predictive accuracy of >80% in predicting SVI, despite the lack of individualised data on the extent and volume of extraprostatic extension. For all these reasons, clinical risk models still represent the cornerstone for the identification of men at higher risk of adverse pathological findings. Additional data coming from sophisticated imaging modalities may further improve individualised risk predictions [6] and better assist clinicians in tailoring the most appropriate treatment approach. However, imaging and biomarkers should complement, rather than substitute, currently available clinical risk models.

In conclusion, preoperative predictive tools based on clinical parameters still play an important role in the management of patients with clinically localised prostate cancer. Any staging model including additional approaches, such as imaging and/or biomarkers, is welcomed only when it is shown to improve prostate cancer staging in terms of both accuracy and cost-effectiveness.

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How to Cite

Gandaglia, G., Fossati, N., Dell’Oglio, P., Montorsi, F. and Briganti, A. (2017), Is there a role for pure clinical prediction models in prostate cancer in the contemporary era?. BJU International, 119: 652–653. doi: 10.1111/bju.13833

 

Giorgio Gandaglia,*† Nicola Fossati,*†Paolo Dell’Oglio,*†Francesco Montorsi,*† and Alberto Briganti*†

 

*Division of Oncology/Unit of Urology, Urological Research Institute, L’ Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale San Raffaele, and †Vita-Salute San Raffaele University, Milan, Italy

 

References

 

1 TosoianJJ, Chappidi M, Feng Z et al. Prediction of pathological stage based on clinical stage, serum prostate-specific antigen, and biopsy Gleason score: Partin Tables in the contemporary era. BJU Int 2017; 119: 676– 83

 

2 Mottet N, Bellmunt J, Bolla M et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol 2017; 71: 618–29

 

3 Budaus L, Leyh-Bannurah SR, Salomon G et al. Initial experience of (68) Ga-PSMA PET/CT imaging in high-risk prostate cancer patients prior to radical prostatectomy. Eur Urol 2016; 69: 393–6

 

4 Kluth LA, Abdollah F, Xylinas E et al. Pathologic nodal staging scores in patients treated with radical prostatectomy: a postoperative decision tool. Eur Urol 2014; 66: 439–46

 

5 Briganti A, Larcher A, Abdollah F et al. Updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection: the essential importance of percentage of positive cores. Eur Urol 2012; 61: 480–7

 

6 de Rooij M, Hamoen EH, Witjes JA, Barentsz JO, Rovers MM . Accuracy of magnetic resonance imaging for local staging of prostate cancer: a diagnostic meta-analysis. Eur Urol 2016; 70: 233–45

 

Infographic: Partin Tables in the Contemporary Era

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The Partin Tables in the Contemporary Era: Infographic to accompany the May 2017 Article of the Month

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