Tag: #ProstateCancer

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Video: International Consultation on Urological Diseases and European Association of Urology International Consultation on Minimally Invasive Surgery in Urology: laparoscopic and robotic adrenalectomy

January 18, 2017/by admin Z.9

International Consultation on Urological Diseases and European Association of Urology International Consultation on Minimally Invasive Surgery in Urology: laparoscopic and robotic adrenalectomy

Mark W. Ball*, Ashok K. Hemal† and Mohamad E. Allaf*

*James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, and †Department of Urology, Wake Forest School of Medicine, Winston-Salem, NC, USA

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Abstract

The aim of this study was to provide an evidence-based systematic review of the use of laparoscopic and robotic adrenalectomy in the treatment of adrenal disease as part of the International Consultation on Urological Diseases and European Association of Urology consultation on Minimally Invasive Surgery in Urology. A systematic literature search (January 2004 to January 2014) was conducted to identify comparative studies assessing the safety and efficacy of minimally invasive adrenal surgery. Subtopics including the role of minimally invasive surgery for pheochromocytoma, adrenocortical carcinoma (ACC) and large adrenal tumours were examined. Additionally, the role of transperitoneal and retroperitoneal approaches, as well as laparoendoscopic single-site (LESS) and robotic adrenalectomy were reviewed. The major findings are presented in an evidence-based fashion. Large retrospective and prospective data were analysed and a set of recommendations provided by the committee was produced. Laparoscopic surgery should be considered the first-line therapy for benign adrenal masses requiring surgical resection and for patients with pheochromocytoma. While a laparoscopic approach may be feasible for selected cases of ACC without adjacent organ involvement, an open surgical approach remains the ‘gold standard’. Large adrenal tumours without preoperative or intra-operative suspicion of ACC may be safely resected via a laparoscopic approach. Both transperitoneal and retroperitoneal approaches to laparoscopic adrenalectomy are safe. The approach should be chosen based on surgeon training and experience. LESS and robotic adrenalectomy should be considered as alternatives to laparoscopic adrenalectomy but require further study.

Article of the Month: CGa and NSE serum levels as predictors of treatment outcome in patients with mCRPC undergoing abiraterone therapy

January 4, 2017/by admin Z.9

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.

Chromogranin A and neurone-specific enolase serum levels as predictors of treatment outcome in patients with metastatic castration-resistant prostate cancer undergoing abiraterone therapy

Matthias M. Heck*, Markus A. Thaler†, Sebastian C. Schmid*, Anna-Katharina Seitz*, Robert Tauber*, Hubert Kubler*, Tobias Maurer*, Mark Thalgott*, Georgios Hatzichristodoulou*, Michael Hoppner*, Roman Nawroth*, Peter B. Luppa†

,Jurgen E. Gschwend* and Margitta Retz*

*Department of Urology, and †Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

Read the full article

Objective

To determine the impact of elevated neuroendocrine serum markers on treatment outcome in patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing treatment with abiraterone in a post-chemotherapy setting.

Patients and Method

Chromogranin A (CGa) and neurone-specific enolase (NSE) were determined in serum drawn before treatment with abiraterone from 45 patients with mCRPC. Outcome measures were overall survival (OS), prostate-specific antigen (PSA) response defined by a PSA level decline of ≥50%, PSA progression-free survival (PSA-PFS), and clinical or radiographic PFS.

Results

The CGa and NSE serum levels did not correlate (P = 0.6). Patients were stratified in to low- (nine patients), intermediate- (18) or high-risk (18) groups according to elevation of none, one, or both neuroendocrine markers, respectively. The risk groups correlated with decreasing median OS (median OS not reached vs 15.3 vs 6.6 months; P < 0.001), decreasing median clinical or radiographic PFS (8.3 vs 4.4 vs 2.7 months; P = 0.001) and decreasing median PSA-PFS (12.0 vs 3.2 vs 2.7 months; P = 0.012). In multivariate Cox regression analysis the combination of CGa and NSE (≥1 marker positive vs both markers negative) remained significant predictors of OS, clinical or radiographic PFS, and PSA-PFS. We did not observe a correlation with PSA response (63% vs 35% vs 31%; P = 0.2).

Conclusion

Chromogranin A and NSE did not predict PSA response in patients with mCRPC treated with abiraterone. However, we observed a correlation with shorter PSA-PFS, clinical or radiographic PFS, and OS. This might be due to an elevated risk of developing resistance under abiraterone treatment related to neuroendocrine differentiation.

Editorial: Circulating biomarkers of NEPC – an unmet challenge

January 4, 2017/by Pasquale Rescigno

Prostate cancer is a global health issue and, although the overwhelming majority (>95%) of metastatic castration-resistant prostate cancers (CRPCs) have adenocarcinoma histology [1], a subset of tumours acquire histopathological and immunohistochemical evidence of neuroendocrine differentiation, with a variety of morphological classifications being reported [1]. Nonetheless, the term ‘neuroendocrine prostate cancer’ (NEPC) should be reserved for tumours with absent or minimal androgen-signalling modulated transcription [2]. NEPC arising in the castration-resistant scenario (treatment-related NEPC or tNEPC) [2] is a disease of unknown prevalence and without an optimum treatment regime. Autopsy studies have shown at least focal neuroendocrine differentiation may be present in up to 33% of patients [3]. The cellular precursor of tNEPC is still debated, but a common clonal origin from adenocarcinoma CRPC (adeno-CRPC) is likely [2]. The assumption of negligible androgen signalling in these tumours implies resistance to agents such as abiraterone and enzalutamide. In this setting, research focused on identifying biomarkers of tNEPC is to be welcomed.

Heck et al. [4] determined the prognostic impact of elevated circulating neuroendocrine biomarkers chromogranin A (CGA) and neuron-specific enolase (NSE) in the serum of patients with CRPC treated with abiraterone in the post-chemotherapy setting. Although CGA and NSE did not predict PSA response, they correlated with clinical and radiographic progression-free survival (PFS), as well as overall survival (OS). The association between these biomarkers and clinical outcomes in metastatic CRPC has been confirmed in retrospective studies [5]. According to the authors, this association, independently of PSA response, underlines the sub-clonality of this disease, and the key role of androgen receptor (AR) signalling, even in advanced disease [4].

The marker NSE is considered to be generic, with high sensitivity but low specificity; CGA is a more specific neuroendocrine tumour biomarker and a common constituent of neuroendocrine tumour secretory granules. Abnormal CGA levels have, however, been significantly associated with intake of proton pump inhibitors in patients treated with abiraterone for metastatic CRPC rather than with duration of treatment [5]. Unfortunately, the use of proton pump inhibitors in that study was not disclosed and may have affected the reported results. Moreover, compared with previous experience, the rate of abnormal NSE was significant higher, probably in keeping with the low specificity of this biomarker.

Interestingly, the authors report an OS and PFS of 12.7 and 3.7 months, respectively [4]. These data are significantly different from the results of the COU-AA 301 study, in which treatment with abiraterone resulted in improved OS (14.8 vs 10.9 months) [6]. Surprisingly, there was no difference in PFS between abiraterone in the study by Heck et al. and the control arm of the COU-AA 301 trial (3.6 months) [6]. This discordance could be attributable to the small sample size of their study rather than the high PSA level at initiation of abiraterone, as claimed by the authors. In support of this alternative possibility, a post hoc analysis of the AFFIRM trial [7] showed consistent benefits in OS and PFS with second-generation hormonal treatments, regardless of baseline disease severity as assessed by PSA level.

Nevertheless, identifying patients with tNEPC is an urgent clinical need; genomic germline and somatic DNA next-generation sequencing as well as transcriptomic analysis of metastatic biopsies should now be considered a key approach to better understanding the heterogeneity of metastatic CRPC and to personalize treatment in order to maximize benefit.

There is substantial genomic overlap between adeno-CRPCs and tNEPC. TMPRSS2-ERG is the most common genomic aberration in prostate cancer and has been reported in NEPC with a similar frequency [2]. Furthermore, both adeno-CRPCs and tNEPCs are enriched for the inactivation of key tumour suppressor genes, such as RB1 and TP53, compared with hormone-sensitive prostate cancer, albeit in different proportions [2]. Although genomic amplification and activating point mutations of the AR in tNEPCs are notably absent, the presence of AR-splicing variants, including ARv7, is still detectable, suggesting that AR signalling is still present in at least a proportion of tNEPCs [2].

Despite a common background of genomic aberrations, tNEPCs have also been reported to have significant overexpression and copy number gains of AURKA and MYCN (40% of NEPC vs 5% of primary prostate cancer tumours), although these findings remain unsubstantiated [3]. As such, these have been postulated to be drivers of this disease phenotype and are under investigation as targets of novel agents.

Genome-wide DNA methylation analysis has, however, also shown that there are marked epigenetic differences between NEPC and adeno-CRPC, suggesting that epigenetic modifiers play a major role in the induction and maintenance of the neuroendocrine status [2].

In conclusion, the identification and definition of NEPC remains challenging. Blood biomarkers such as NSE and CGA cannot be considered to be proven prognostic biomarkers of NEPC as they have only been evaluated in small retrospective studies not adhering to REMARK criteria [8]. Genomic profiling from tissue biopsies or circulating DNA remains a preferable way to identify NEPC and is increasingly feasible, although still not affordable or a standardized procedure for the definition of NEPC.

Read the full article

Pasquale Rescigno*,†, Daniel Nava Rodrigues*,† and Johann S. de Bono*,†

*Institute of Cancer Research, London, UK and †Royal Marsden NHS Foundatio n Trust, London, UK

References

1 Epstein JI, Amin MB, Beltran H et al. Proposed morphologic classiﬁcation of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol 2014; 38: 756–67

2 Beltran H, Prandi D, Mosquera JM et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med 2016; 22: 298–305

3 Mucci NR, Akdas G, Manely S, Rubin MA. Neuroendocrine expression in metastatic prostate cancer: evaluation of high throughput tissue microarrays to detect heterogeneous protein expression. Hum Pathol 2000; 31: 406–14

4 Heck MM, Thaler MA, Schmid SC et al. Chromogranin A and neurone- speciﬁc enolase serum levels as predictors of treatment outcome in patients with metastatic castration-resistant prostate cancer undergoing abiraterone therapy. BJU Int. 2017; 119: 30–7

5 von Hardenberg J, Schwartz M, Werner T et al. Inﬂuence of abiraterone acetate on circulating neuromediators in chemotherapy-naıve castration- resistant prostate cancer. Prostate 2016; 76: 613–9

6 de Bono JS, Logothetis CJ, Molina A et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005

7 Saad F, de Bono J, Shore N et al. Efﬁcacy outcomes by baseline prostate- speciﬁc antigen quartile in the AFFIRM trial. Eur Urol 2015; 67: 223–30

8 McShane LM, Altman DG, Sauerbrei W. REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 2005; 93: 387–91

Article of the Month: Recent advances in immuno-oncology and its application to urological cancers

September 28, 2016/by admin Z.9

In addition to the article itself, there is an accompanying comment 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.

Recent advances in immuno-oncology and its application to urological cancers

Jennifer M. Mataraza and Philip Gotwals

Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, Cambridge, MA, USA

Read the full article

Abstract

Recent advances in immuno-oncology have the potential to transform the practice of medical oncology. Antibodies directed against negative regulators of T-cell function (checkpoint inhibitors), engineered cell therapies and innate immune stimulators, such as oncolytic viruses, are effective in a wide range of cancers. Immune‘based therapies have had a clinically meaningful impact on the treatment of advanced melanoma, and the lessons regarding use of single agents and combinations in melanoma may be applicable to the treatment of urological cancers. Checkpoint inhibitors, cytokine therapy and therapeutic vaccines are already showing promise in urothelial bladder cancer, renal cell carcinoma and prostate cancer. Critical areas of future immuno-oncology research include the prospective identification of patients who will respond to current immune-based cancer therapies and the identification of new therapeutic agents that promote immune priming in tumours, and increase the rate of durable clinical responses.

Comment: Immune checkpoint blockade – a treatment for urological cancers?

September 28, 2016/by Ousama Elhage

Introduction

In the last few years there have been concerted attempts at using the power of the immune system as an effective treatment option for cancer. This has become possible as our understanding of the workings of the immune system has improved. Tumours form because of failure of the organism to destroy a rogue, mutated cell in an appropriate way. Once the tumour is formed it can further develop when the immune system fails to contain and control it and certain equilibrium is lost in favour of the tumour. This is referred to as the immune editing theory. At this point of failure of the immune system, tumour growth and progression become possible and tumours develop various mechanisms to evade the immune systems surveillance. Therefore, a mechanism to restore the lost equilibrium or to tip it in favour of the immune system would be a new modality in anti-cancer treatment. The initial approach was to use stimulators of the immune system systemically such as interleukin 2 and interferon γ i.v. in patients with metastatic cancers including melanoma and renal cancers [1]. A sustained response was shown in 22% of patients with metastatic kidney cancer, lasting for over a year. Although this treatment was not a resounding success, it did highlight an approach that could yield a durable tumour regression in a minority of cases. As our understanding of the immune system–tumour interaction further developed, new research focused on a specific mechanism in the immune system that seems to be exploited by tumours. This is an activation-inhibition mechanism, which controls the extent of adaptive immune response to invading organisms or to mutated cancer cells. In healthy individuals, this mechanism is a ‘safety’ feature allowing cessation of the immune response once it has performed its task. This is controlled by ‘receptor’ molecules at the T-cell surface and their corresponding ‘ligands’ at the surface of the cells interacting with the T-cell, which can be an antigen presenting cell or a tumour cell surface. This mechanism is called the immune checkpoint [2] (Fig. 1). Cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) are the most well-known checkpoints but there are up to 20 others (and counting) [2]. Their main role is to inhibit an immune response by blocking the activation of T-cells when those cells are presented with a foreign antigen or cancer proteins. This inhibition leads to immune ‘tolerance’ of the presence of cancer cells. So the policeman (T cell) is oblivious to the robbery in front of him. Thus an anti-tumour treatment strategy to disrupt the immune checkpoints seems to be a valid one (Table 1).

Figure 1. Blocking checkpoint inhibitors with antibodies is the new immunotherapy strategy to unlock T-cell activation and improve anti-tumour immune response. MHC, major histocompatibility complex; PD-L1, programmed death ligand 1; TCR, T-cell antigen receptor.

Table 1. A selected group of trials of immune checkpoint inhibitors in urological cancers
Tumour	Phase	Treatment	N	Results	Trial.gov identifier
mCRPC, metastatic castrate-resistant prostate cancer; PD-L1, programmed death ligand 1. The total number of current trials of immune checkpoint inhibitors is 46 for lung, breast, ovarian, rectal, prostate, pancreatic, bladder, renal cancers and melanoma.
mCRPC	1	Dendritic cell therapy and ipilimumab	20	Recruiting	NCT02423928
All advanced solid tumours	1	Various combinations of ipilimumab, nivolumab and pembrolizumab	122	Recruiting	NCT02467361
RCC	3	Nivolumab vs everolimus	822	Recruiting	NCT01668784
RCC	3	Atezolizumab (anti PD-L1)	70	Good safety profile with antitumour activity	NCT01375842
mCRPC	3	Ipilimumab vs placebo	799	No improvement of survival in treatment group	NCT00861614
Urothelial	2	Gemcitabine, cisplatin and ipilimumab combinations	36	Recruiting	NCT01524991

In recent years, a plethora of various inhibitors in the form of monoclonal antibodies to the checkpoint molecules were developed and to date three at least have been approved by the USA Food and Drug Administration (FDA) – ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda). They are anti-CTLA4 and anti-PD-1 antibodies. At least another eight checkpoint inhibitors are being developed. These agents have been shown to have survival benefit in some malignancies and limited benefit in others. However, the breakthrough seems to be happening in the treatment of metastatic malignant melanomas where immune checkpoint inhibitors treatment may become the standard of care. Patients with metastatic malignant melanoma who were treated with ipilimumab had a median survival of ~11 months; however, 22% of patients survived for ≥3 years with a plateau in the survival curve and in a subset of patients up to 10 years [3]. This success has not yet been replicated in prostate cancer [4]. In a more recent clinical trial involving patients with melanoma who progressed, nivolumab showed survival benefit of 72% at 1 year as compared with 42% with dacarbazine [5]. The latest approach is to combine anti-CTLA-4 and anti-PD-1 in one treatment regime as they are expected to act synergistically to remove the inhibition to the immune response, and clinical results seem to show survival benefit for combined therapy [6]. Combination of different treatment methods may potentiate the ‘abscopal effect’, which is seen when local radiation therapy can cause regression of tumour distant to the radiation site. This seems to be mediated by the immune system and potentiated by checkpoint inhibitors. Until now checkpoint inhibitors were used in patients with end-stage metastatic cancer, but recently anti-CTLA-4 has been trialled in pre-radical cystectomy patients not as a neoadjuvant therapy but rather to monitor immune response and surgical safety [2]. It is likely that checkpoint inhibitors will have a place in cancer treatment including urological cancers. However, this new class of anti-cancer treatment comes with a price. The emerging risks and side-effect profile of checkpoint inhibitors are completely different from those seen with the conventional chemotherapy and radiotherapy. Those side-effects are related to the activation of the immune system. Although most are not uncommon, they can occasionally have devastating effect on the patients. These side-effects include autoimmune conditions like dermatitis, mild colitis, and occasionally hepatitis. A severe form of colitis resulting in perforation has been reported. Unfortunately, the rate of adverse effects seems to correlate with positive clinical response. A list of some of the side-effects is summarised in Table 2. Treatment is usually with steroids, and clinicians are starting to develop strategies to minimise those risks.

Table 2. Autoimmune-based adverse effects that are associated with immune checkpoint inhibitors treatment. Most are tolerated. Severe ones are rare but can be devastating. Treatment is usually with steroids [2, 5, 6]
Adverse effects
Common	Rare
Diarrhoea	Severe colitis – colonic perforation
Pruritus/dermatitis	Adrenal insufficiency
Rash	Panhypopituitarism
Colitis	Hepatitis
Fatigue	Uveitis
Decreased appetite	Temporal arteritis

The cost of checkpoint inhibitors remains relatively high and a full treatment course of ipilimumab costs >£18 000. One dose of pembrolizumab can cost >£3 500. However, the National Institute for Health and Care excellence (NICE) in the UK deemed this to be cost-effective and approved it for patients with metastatic melanoma that has progressed despite ipilimumab treatment.

Will the 21st century be the era for immunotherapy? It is still too early to tell. At present it remains rather expensive and beyond the means of many patients with cancer.

Read the full article

Oussama Elhage*, Christine Galustian* and Prokar Dasgupta*,†

*Medical Research Council (MRC) Centre for Transplantation, and †National Institute for Health Research (NIHR) Biomedical Research Centre, King’s Health Partners, King’s College London and Guy’s Hospital, London, UK

References

1 Rosenberg SA, Lotze MT, Yang JC et al. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 1989; 210: 474–85

2 Allison JP, Freeman GJ, Gotwals P. Targeting cancer pathways: understanding immune checkpoints. Science Webinar Series. Science 2016; 351: 303

3 Schadendorf D, Hodi FS, Robert C et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015; 33: 1889–94

4 Mataraza J, Gotwals P. Recent advances in immuno-oncology and its application to urological cancers. BJU Int 2016; 118: 506–14

5 Robert C, Long GV, Brady B et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372: 320–30

6 Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373: 23–34

The optimal treatment of patients with localized prostate cancer: the debate rages on

September 14, 2016/23 Comments/by Christopher Wallis

The widely anticipated results of the ProtecT study have now been published. Unfortunately, the results do little to advance our understanding as to whether surgery or radiation provides better outcomes.

In summary

The study followed oncologic and functional outcomes of 545 patients randomized to active monitoring (surveillance), 553 to radical prostatectomy, and 545 to radiotherapy. With a median follow-up of 10 years, the authors report no significant differences in prostate cancer specific (p=0.48) or overall survival (p=0.87) among the three treatment groups. They did demonstrate an increase in disease progression and metastasis among men managed with surveillance.

In an accompanying manuscript, the authors examined patient reported outcome measures out to 6 years following treatment. The authors report worse urinary continence and erectile function following surgery and worse voiding symptoms and bowel function following radiotherapy.

What do we take from this?

The investigators and participating patients should be congratulated for successfully completing this study. Numerous authors have documented their failure to adequately accrue to randomized studies of surgery versus radiotherapy in localized prostate cancer (including MRC PR06 and SPIRIT). The failure of these trials, among others, prompted Dr. Wilt to ask “Can randomized treatment trials in early stage prostate cancer be completed?” These authors have unequivocally proven that the answer is “yes”.

However, there are many caveats in applying these results to our patients:

(1) Study power

The study was clearly underpowered to evaluate the primary outcome of prostate-cancer specific mortality. Drs. Roobol and Bokhorst eloquently described important limitations of the ProtecT study. The authors designed the study assuming prostate cancer mortality of 15% at a median follow-up of 10 years. This was later adjusted downwards to 10% based on updated UK data. In the end, rates were closer to 1%. The conclusions of the primary analysis are based on a total of 17 (17!!) deaths.

(2) Study cohort – enriched with low risk disease

Among the randomized patients, the median PSA was 4.6 ng/mL, 76% had clinical stage T1c disease, and 77% had Gleason score 6 disease. These patients would almost certainly be considered most suitable for active surveillance, rather than active therapy, if seen in clinic today. Clinically meaningful decisions between surgery and radiotherapy are in the realm of treatment of intermediate and high-risk localized prostate cancer and these comprise a small group in this study. Based on this baseline distribution, it will be unlikely that any significant differences will be found in future follow-up studies.

(3) Outcomes for active surveillance

Perhaps the most notable findings of this study involve the significantly higher rates of progression, metastasis and prostate cancer specific mortality for patients treated on the surveillance protocol as compared to those treated actively, though statistical significance was not reached for PCSM. The manuscript does not provide further details regarding the pathologic characteristics of these patients. Relevantly, what was the Gleason score for these patients? This is of particularly importance as many surveillance proponents are advocating an expanding role of AS.

(4) Treatments administered

RCTs typically require significant periods of accrual, follow-up and analysis. As a result, they may be out of date prior to completion. This is certainly true of the ProtecT study. This most prominently affects patients allocated to radiotherapy. In the study protocol, patients received 3D conformal radiotherapy at 74 Gy, not the IMRT which has now become widely used. Thus, proponents of radiotherapy will likely to discount any findings which do not favour radiotherapy.

In addition, the current day relevance of the surgical treatment provided is questionable. First, the vast majority of patients in the surgical arm underwent open RP. More concerning is the quality of surgery provided: 93 patients (24%) of the cohort had positive surgical margins. In contemporary series, the average rate is under 15% with centers of excellence approaching 5%. While PSM rates clearly affect oncologic outcomes, they likely are also a surrogate of surgical quality which may affect functional outcomes.

(5) Comparison of active treatments

In the accompanying editorial, Dr. D’Amico comments on a “trend favouring radiation and ADT over surgery” and suggests that “one may consider radiation and ADT as a preferred option”. The basis for this conjecture is 5 deaths in the surgery group and 4 in the radiotherapy group, hardly a convincing sample. In contrast to these data, there was a higher number of patients with metastasis among those treated with radiotherapy (16 vs 13). These discordant results would certainly suggest that any preference for radiotherapy is premature. Indeed, with additional follow-up one would expect the patients with metastasis to die of prostate cancer, thus favouring those treated surgically.

On a methodological note, while the inclusion of active surveillance is a strength of the study, it poses analytic difficulties. The primary analysis assesses a null hypothesis assuming equality across all study interventions. Thus, as this was non-significant, pairwise testing of surgery and radiotherapy, and each with surveillance, is inappropriate and conclusions on these comparisons should not be drawn.

(6) Functional outcomes and treatment-related complications

Most clinicians are well aware that many complications other than erectile function and urinary incontinence may affect that life trajectory of patients following prostate cancer treatments. ProtecT offers the opportunity to examine the risks of secondary malignancy, repeat urologic and gastrointestinal interventions, surgeries and hospitalizations following treatment. However, these are not currently included in the published data.

Further, the PCOS studies have clearly shown that differences in patient reported urinary, sexual and bowel function change over time with convergence after long term follow-up (15 years). With ongoing maturity, it will be interesting to see if a similar pattern emerges in ProtecT.

In conclusion

The ProtecT study may raise more questions than it answers. Among a low risk group of patients, it has shown that active treatment of PSA-detected prostate cancer can reduce the progression to metastatic disease. Assessment of prostate cancer specific and overall mortality, as well as the comparative efficacy of surgery and radiotherapy, is not possible due to power limitations.

Will you be changing you patient counselling based on these results?

Christopher Wallis, MD
Resident,
Division of Urology,
Department of Surgery,
University of Toronto
Doctoral Student in Clinical Epidemiology and Health Care Research, Institute of Health Policy, Management & Evaluation
University of Toronto

Robert Nam, MD MSc FRCSC
Ajmera Family Chair in Urologic Oncology
Professor,
Division of Urology,
Department of Surgery
University of Toronto
Head, Genitourinary Cancer Site
Odette Cancer Centre
Sunnybrook Health Sciences Centre

It’s not about the machine, stupid

July 27, 2016/57 Comments/by Declan Murphy

Robotic surgery trial exposes limitations of randomised study design

Here it is, the highly anticipated randomised controlled trial of open versus robotic radical prostatectomy published today in The Lancet. Congratulations to the team at Royal Brisbane Hospital for completing this landmark study.

The early headlines around the world include everything from this one in the Australian Financial Review:

– to this from The Telegraph in London

As ever, there will be intense and polarising discussion around this. One might expect that a randomised controlled trial, a true rarity in surgical practice, might settle the debate here; however, it is already clear that there will be anything BUT agreement on the findings of this study. Why is this so? Well let’s look first at what was reported today.

Study design and findings:

This is a prospective randomised trial of patients undergoing radical prostatectomy for localised prostate cancer. Patients were randomised to undergo either open radical prostatectomy (ORP, n=163) or robotic-assisted radical prostatectomy (RARP, n=163). All ORPs were done by one surgeon, Dr John Yaxley (JY), and all RARPs were done by Dr Geoff Coughlin (GC). The hypothesis was that patients undergoing RARP would have better functional outcomes at 12 weeks, as measured by validated patient-reported quality of life measures. Other endpoints included positive surgical margins and complications, as well as time to return to work.

So what did they find? In summary, the authors report no difference in urinary and sexual function at 12 weeks. There was also no statistical difference in positive surgical margins. RARP patients had a shorter hospital stay (1.5 vs 3.2days, p<0.0001) and less blood loss (443 vs 1338ml, P<0.001), and less pain post-operatively, yet, these benefits of minimally-invasive surgery did not translate into an earlier return to work. The average time to return to work in both arms was 6 weeks.

The authors therefore conclude by encouraging patients “to choose an experienced surgeon they trust and with whom they have a rapport, rather than choose a specific surgical approach”. Fair enough.

In summary therefore, this is a randomised controlled trial of ORP vs RARP showing no difference in the primary outcome. One might reasonably expect that we might start moth-balling these expensive machines and start picking up our old open surgery instruments. But that won’t happen, and my prediction is that this study will be severely criticized for elements of its design that explain why they failed to meet their primary endpoint.

Reasons why this study failed:

1. Was this a realistic hypothesis? No it was not. For those of us who work full-time in prostate cancer, the notion that there would be a difference in sexual and urinary function at 12 weeks following ORP or RARP is fanciful. It is almost like it was set up to fail. There was no pilot study data to encourage such a hypothesis, and it remains a mystery to me why the authors thought this study might ever meet this endpoint. I hate to say “I told you so”, but this hypothesis could never have been proved with this study design.

2. There is a gulf in surgical experience between the two arms. The lack of equipoise between the intervention arms is startling, and of itself, fully explains the failure of this study to meet its endpoints. I should state here that both surgeons in this study, JY (“Yax”) and GC (“Cogs”), are good mates of mine, and I hold them in the highest respect for undertaking this study. However, as I have discussed with them in detail, the study design which they signed up to here does not control for the massive difference in radical prostatectomy experience that exists between them. Let’s look at this in more detail:

ORP arm: JY was more than 15 years post-Fellowship at the start of this study, and had completed over 1500 ORP before performing the first case in the trial.
RARP arm: GC was just two years post-Fellowship and had completed only 200 RARP at the start of the study.

The whole world knows that surgeon experience is the single most important determinant of outcomes following radical prostatectomy, and much data exists to support this fact. In the accompanying editorial, Lord Darzi reminds us that the learning curve for functional and oncological outcomes following RARP extends up to 700 cases. Yes 700 cases of RARP!! And GC had done 200 radical prostatectomies prior to operating on the first patient in this study. Meanwhile his vastly more experienced colleague JY, had done over 1500 cases. The authors believe that they controlled for surgeon heterogeneity based on the entry numbers detailed above, and state that it is “unlikely that a learning curve contributed substantially to the results”. This is bunkum. It just doesn’t stack up, and none of us who perform this type of surgery would accept that there is not a clinically meaningful difference in the experience of a surgeon who has performed 200 radical prostatectomies, compared with one who has performed 1500. Therein lies the fundamental weakness of this study, and the reason why it will be severely criticized. It would be the equivalent of comparing 66Gy with 78Gy of radiotherapy, or 160mg enzalutamide with 40mg – the study design is simply not comparing like with like, and the issue of surgeon heterogeneity as a confounder here is not accounted for.

3. Trainee input is not controlled for – most surprisingly, the authors previously admitted that “various components of the operations are performed by trainee surgeons”. One would expect that with such concerns about surgeon heterogeneity, there should have been tighter control on this aspect of the interventions. It would have been reasonable within an RCT to reduce the heterogeneity as much as possible by sticking to the senior surgeons for all cases.

Having said all that, John and Geoff are to be congratulated for the excellent outcomes they have delivered to their patients in both arms of this study. These are excellent outcomes, highly credible, and represent, in my view, the best outcomes to be reported for patients undergoing RP in this country. We are all too familiar with completely unbelievable outcomes being reported for patients undergoing surgery/radiotherapy/HIFU etc around the world, and we have a responsibility to make sure patients have realistic expectations. John and Geoff have shown themselves to be at the top of the table reporting these credible outcomes today.

“It’s about the surgeon, stupid”

To paraphrase that classic phrase of the Clinton Presidential campaign of 1992, this study clearly demonstrates that outcomes following radical prostatectomy are about the surgeon, and not about the robot. Yet one of the co-authors, a psychologist, comments that, “at 12 weeks, these two surgical approaches yielded similar outcomes for prostate cancer patients”. Herein lies one of the classic failings of this study design, and also a failure of the investigators to fully understand the issue of surgeon heterogeneity in this study. It is not about the surgical approach, it is about the surgeon experience.

If the authors had designed a study that adequately controlled for surgeon experience, then it may have been possible for the surgical approach to be assessed with some equipoise. It is not impossible to do so, but is certainly challenging. For example a multi-centre study with multiple surgeons in each arm would have helped balance out the gulf in surgical experience in this two-surgeon study. Or at the very least, the authors should have ensured that they were comparing apples with apples by having a surgeon with in excess of 1500 RARP experience in that arm. Another approach would have been to get a surgeon with huge experience of both procedures (eg Dr Smith at Vanderbilt who has performed >3000 RARP and >3000 ORP), and to randomise patients to be operated on only by a single surgeon with such vast experience. That would have truly allowed the magnitude of the surgical approach effect to be measured, without the bias inherent in this study design.

Robotic surgery bridges the experience gap:

Having outlined these issues with surgeon heterogeneity and lack of equipoise, there is another angle which my colleague Dr Daniel Moon has identified in his comments in the Australian media today and which should be considered.

Although this is a negative study which failed to meet its primary endpoints, it does demonstrate that a much less experienced surgeon can actually deliver equivalent functional and oncological outcomes to a much more experienced surgeon, by adopting a robotic approach. Furthermore, his patients get the benefits of a minimally-invasive approach as detailed in the paper. This therefore demonstrates that patients can be spared the inferior outcomes that may be delivered by less experienced surgeons while on their learning curve, and the robotic approach may therefore reduce the learning curve effect.

On that note, a point to consider would be what would JY’s outcomes have been in this study if he had 13 years and 1300 cases less experience to what he had entering this study? Would the 200 case experience-Yax have been able to match the 1500 case experience-Yax?? Surely not.

And finally, just as a footnote for readers around the world about what is actually happening on the ground following this study. During the course of this study, the ORP surgeon JY transitioned to RARP, and this is what he now offers almost exclusively to his patients. Why is that? It is because he delivers better outcomes by bringing a robotic approach to the vast surgical experience that he also brings to his practice, and which is of course the most important determinant of better outcomes.

Sadly, “Yax” and “Cogs”, the two surgeons who operated in this study, have been prevented from speaking to the media or to being quoted in or commenting on this blog, but we are looking forward to hearing from them when they present this data at the Asia-Pacific Prostate Cancer Conference in Melbourne in a few weeks.

Declan G Murphy
Associate Editor BJUI; Urologist & Director of Genitourinary Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia

Twitter: @declangmurphy

West Coast Urology : Highlights from the AUA 2016 in San Diego… Part 1

May 10, 2016/3 Comments/by Ben Challacombe

By Ben Challacombe (@benchallacombe) and Jonathan Makanjuola (@jonmakurology)

The 2016 AUA returned to the beautiful city of San Diego set on the shores of the Pacific in an excellent conference centre located in the centre of the town adjacent to the Gaslamp district. For a change the wifi was excellent and allowed enhanced levels of social media interaction and urological discussion. Opening these interactions were 2 key sessions which provoked much debate. Firstly the announcement that after over 10 years of trying the FDA has approved HIFU treatment although it seemed to get there through a slightly “de novo” pathway. Apparently the FDA approved it as an ablation tools but not for prostate cancer.

Although not directly approved for use in prostate cancer, that is exactly what it is going to be used for. A packed house saw a debate with evidence from both sides. Dr Nathan Lawrentschuk promoted the 4 Ds of HIFU. His key point was that 56/101 had a post treatment biopsy of which 51 where biopsy positive!

The second big session focussed on the AUA/SAR consensus statement document on prostate cancer diagnostics. This recommended a “High Quality” MRI should be strongly considered if patient has a rising PSA with a previous negative biopsy, has persistent clinical suspicion for prostate cancer or is undergoing a repeat biopsy. There was no mention of MRI for all at the pre-biopsy stage which many had hoped for and only 2 lines on trans-perineal biopsy as an option. This is of course related to health resources and the outpatient office-based nature of most USA urologists.

A welcome innovation was the Crossfire Sessions which pitted 2 well known advocates of one treatment against 2 with the opposite views. It was hardly debating of the Oxbridge variety but none the less did provoke some useful discussions. Topics included radical prostatectomy vs radiotherapy, endoscopic vs nephro-ureterectomy management of upper tract TCC, and enucleation at partial nephrectomy vs formal resection. Standing room only at the back of the halls but no real audience interaction or voting which was a shame.

The session which really woke everyone up was Rene Sotalo’s wonderful complication horror show. Bleeding, bleeding and more bleeding in a variety of ways. How would you handle this he asked? Pray I thought! But this and similar sessions clearly show the benefits of recording all cases and reviewing these DVDs if something goes wrong. The cause of some complications were only identified by review of the intra-operative tapes. Some clinical titbits learn’t included using only a horizontal incision for the camera port at RARP to reduce hernias and turning off pneumocompression stockings if there is a major venous injury to prevent excessive venous bleeding.

From a SoME perspective there was both good and bad. One poster showed that 40% of graduating US residents had publicly accessible unprofessional content on social media. Food for thought at the consultant interview no doubt, but on the other side SoMe ranks third in the acquisition of urological knowledge (and climbing…). One hack produced this tweeting guideline for all to reflect on.

Prof Prokar Dasgupta had the honour of presenting the widely anticipated session on emerging robotic technology . At last there appears to be some real competition to Intuitive’s dominance on the way. There are at least 3 credible robotic systems on the way. He finished with an intriguing slide on Dr Google being the most powerful doctor in the world!

Despite Europe and Asia moving towards the use of PMSA PET , the USA is not moving in this direction due to reimbursement issues if the PMSA molecule.

There was a lot of interest in a packed auditorium to see live surgery for a single use disposable fURS “Lithovue” with some reporting superior vision , optics and deflection.

There were some sceptics amongst the stone community with the environmental impact and cost effectiveness a concern.

With the popular Gaslamp district a stones throw away many delegates went after the conference for a meal and drinks. The local baseball team San Diego Padres was a popular destination with may watching baseball for the 1st time whist others had gone for a run along the harbour and even caught a sighting of some seals!

March #urojc: Radiotherapy for Prostate Cancer – Is it a gift that keeps on giving?

March 18, 2016/4 Comments/by Henry Woo

The International Urology Journal Club on Twitter is now well into its 4^th year. The subject for the March 2016 discussion was a paper published in the BMJ entitled “Second Malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis”.

Lead and senior authors, Chris Wallis and Rob Nam were kind enough to make themselves available to participate in this discussion. Rob Nam made use of the #urojc guest twitter account.

The literature was searched using Medline and Embase and the method of review was the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational studies in Epidemiology (MOOSE) guidelines for reporting of this systematic review and meta-analysis.

Chris Wallis provided an excellent TL:DR summary with the following tweet.

It is well recognized that secondary malignancies following radiation exposure could take many years to become apparent.

The responses were fairly predictable but nevertheless an important point to explore.

Early in the discussion, there was also relevant reminder of the issue of differences in odds ratios and absolute risk. That said, consideration needs to be given to the ‘big ticket’ nature of secondary malignancy where even a small absolute risk drives a great deal of interest in this subject matter.

An interesting finding from the study was that the risk of secondary malignancy was less with brachytherapy compared with external beam radiation.

Further to this, is it possible that there could be a difference between HDR and seed brachytherapy? An interesting thought although not specifically covered in the paper.

A more controversial aspect to the discussion was whether the risk of secondary malignancy would justify screening or surveillance. The following exchange was worthy of note.

Whilst there is nothing in the way of documented guidelines or actual evidence to demonstrate a benefit of surveillance, it seems something worthy of consideration for future practice guidelines – in other words, recommendations one way or the other.

Rob Nam refers to a third paper on radiation outcomes in the context of previous surgery. This BJC paper, the Lancet Oncology paper (previous discussed at a #urojc in 2014) and now the current paper could cheekily be called the Nam Trilogy – make note that you heard this term here for the first time.

To what extent should we be counseling our patients on the risk of secondary malignancy if they are to undergo radiation for prostate cancer? Is this just another factor to encourage surgery over radiotherapy? Will there be no change in practice, particularly in the US where many lucrative radiation oncology services are actually owned by urological surgeon private practice groups?

The state of radiation oncology practice is different outside the US and my own personal thoughts on the matter are that the Nam Trilogy of papers will create a series of well cited ‘evidence’ that will further shift the weight of opinion towards surgery over radiotherapy as a primary treatment for localized prostate cancer.

Anybody who followed the March installment of the #urojc would have been impressed by the high level of interaction by the authors Chris Wallis and Rob Nam. A particular mention should be given to Sabin Motwani who as a radiation oncologist, provided valuable input to the discussion.

Please do join us for the April installment of the #urojc and I encourage you all to email, tweet or DM your suggestions for papers to be discussed. Please also, feel free to volunteer to write up a monthly summary for publication on the BJUI blogs. I would also like to acknowledge the contributions of Rustom Manecksha who was the winner of the 2016 BJUI SoMe Award for #urojc – a reflection to the quality of his participation and support for this online educational activity.

Henry Woo is an Associate Professor of Surgery at the Sydney Adventist Hospital Clinical School of the University of Sydney. He is the coordinator of the International Urology Journal Club on Twitter.

EAU 2016 Congress Day 3

March 18, 2016/1 Comment/by Kari Tikkinen

Das bringt mich weiter! While the sun was shining in Munich, the 3^rd day of the 31^st EAU Annual Congress continued with very well attended plenary and poster sessions. And that is no wonder because the EAU Scientific Committee had created such an attractive program, including amazing plenary sessions during the morning and a plethora of informative poster sessions in the afternoon.

Professor Hendrik Borgmann (@HendrikBorgmann) has already covered highlights of the opening days 1 and 2 of this year’s Congress in his BJUI blog. We will give you some highlights of Day 3 and highly recommend you to take a look on EAU congress website, Day 3, which has archived a huge amount of material to allow you to catch up on sessions you may have missed. Indeed, lots of webcasts are available!

We focused on non-oncology plenary morning sessions and oncology poster sessions afternoon. Here are some of our highlights:

SURGERY IN THE ELDERLY – As our urological patients become older and older, surgery for octogenarians, or even nonagenarians, is increasingly common. The morning session covered various aspects on diagnosis and treatment of benign prostatic hyperplasia and other urological conditions in the ageing patient.

Professor Cosimo De Nunzio began the morning with “Highlights” on lower urinary tract symptoms and prostatic disease presented during this year’s EAU congress. Also this year, as many as every third abstract was on either prostate cancer or prostatic hyperplasia.

Indeed, the plenary session on Day 3 also covered prostatic disease.

Professor Alexander Bachmann talked about surgery for BPO in the elderly. He pointed out that in elderly (high-risk) patients we do not need a complete anatomical tissue removal, we do not need a (very) long-term follow-up and that we do not need tissue for prostate cancer diagnosis. Instead, we need a safe and efficient operation with individual adaptation of the technique and preferably feasibility in an ambulatory setting or local anaesthesia.

Professor Bachmann further emphasized that it would be preferable if surgery for the elderly would be performed by experienced surgeons, and that age per se is not a reason to not operate. There are several new minimally invasive operations available, and especially for elderly less is often more.

HOW AND WHEN TO STOP ANTICOAGULATION – Managing perioperative thromboprophylaxis for patients who already receive anticoagulants remains a challenge. Associate professor Daniel Eberli and Professor Per Morten Sandset covered many of these aspects in their helpful presentations.

Dr. Eberli told us that bridging therapy (options for stopping or not stopping anticoagulation in the above figure) is eminence-based, as no papers exist showing benefits. He also presented data from the recent NEJM trial (BRIDGE study; see Table below), which showed that stopping anticoagulation without bridging was non-inferior to perioperative bridging for the prevention of arterial thromboembolism and decreased the risk of major bleeding.

Dr. Eberli gave us all a take home message to discuss and question our local bridging guidelines as new evidence is very likely not supporting them (concluding slide below).

Professor Sandset recommended that during the perioperative period only use aspirin in high-risk patients, that is, those with recent thrombotic event or extensive coronary heart disease. He also informed us that stopping antiplatelet therapy 5 days before surgery (figure below) is often the way to go, and agreed with Dr. Eberli regarding bridging therapy statements.

Professor Sandset also gave helpful information regarding use of direct oral anticoagulants (DOACs) in urological surgery:

There were numerous poster sessions available on Day 3, as usual, many of them on prostate cancer. We have selected some of the highlight abstracts presented.

PROSTATE CANCER – On Day 3, prostate cancer presentations dominated once again in a number of poster, abstract and thematic sessions but also kidney, bladder, testicular and penile cancer sessions, which provided new interesting data.

Molecular markers, genomic profiling and individualized risk and treatment assessments were presented and discussed in poster session 58, and summarized by Stacy Loeb (@LoebStacy). Further advances in prostate cancer biomarkers in prostate cancer were presented in poster session 84. These new tools are moving from bench to bedside and urologists can hopefully incorporate these new tools to cancer care sooner rather than later.

In sessions on prostate cancer diagnostics, more advanced risk profiling tools were highlighted. For instance, STHLM3 test combines history of the patient, clinical parameters, biochemical markers and genetic markers. It was presented earlier in the congress and on Day 3 further health, economic and clinical evaluations were presented in Thematic session 12. It is one example of the tests showing promising results to potentially decrease the number of prostate biopsies needed. Other similar risk profiling tools were also presented during the congress. In addition to PSA only, evaluation of the smart use of already available clinical and biochemical parameters and the combination of genetic markers may bring individualized risk assessment of prostate cancer to the next level.

In poster session 62 on Day 3, diagnostic proceedings in prostate cancer with co-morbidity evaluation, biopsy strategies and MRI imaging were presented. A combination of molecular markers and imaging may be the way to proceed in future. These aspects were covered nicely in Thematic session 12.

MRIs have been heavily integrated in prostate cancer diagnostics during recent years. Image guidance in prostate biopsies seem to be making a breakthrough in prostate cancer diagnostics. Targeted biopsies with cognitive or MRI-TRUS fusion imaging were shown to be the way to enhance the results and reliability of biopsies and cut down the number of biopsies. However, as biopsies are still needed in prostate cancer diagnostics, use of the pre-biopsy MRI protocols were suggested to be done only in clinical trial setting. Many aspects of MRI diagnostics of prostate cancer were elegantly summarized in Thematic session 11.

New sophisticated imaging technologies in addition to MRI were present in several sessions during the meeting. Diagnostic enhancement has been seen also in metastatic prostate cancer. PSMA-PET seems to be replacing choline-PET-TT in evaluation of relapsing and metastatic prostate cancer (e.g. Thematic session 10). More reliable diagnostics and imaging of prostate cancer are also enhancing the treatment decision and treatment choice of patients with local prostate cancer. Finding the right patients for the active surveillance protocols is also being helped with advanced diagnostics. Indeed, finding only patients who need treatment for prostate cancer should be the ultimate goal for enhanced diagnostics as discussed in poster sessions 66 and 75 on Day 3. There are also high expectations on focal therapy (e.g. poster session 66), which at the moment is still experimental but will likely be a real option for patients with low volume prostate cancer verified by imaging.

The role of quality of life evaluations and patient reported outcomes measured were heavily discussed during the congress in all treatment modalities of both local and advanced prostate cancer. Survivorship issues are an increasingly important issue when more effective treatments both in local and advanced prostate cancer are available.

In metastatic disease, the use of early chemotherapy in combination with hormonal treatment has been implemented very rapidly to clinical use after the results of the CHAARTED and STAMPEED studies. Further evaluation of early chemo in metastatic disease is still needed and the patient selection needs still clarification. Hormonal therapy still has a very marked role in metastatic prostate cancer and new advances can also be found in new strategies of using castration therapy as presented in poster session 67. Urologists should actively follow the changing landscape of the medical treatment of metastatic prostate cancer and be active in treatment planning and treatment of these patients. At the same time with poster session 62 novel drugs and new forms of isotope radiation therapy in castration resistant prostate cancer were discussed in poster session 61. These open new possibilities for potential treatments.

The clinical and scientific content of the program of the Day 3 was of a very high standard, and reflective of the breadth of contemporary research in many areas within urology. Besides this session, it was our pleasure to meet old and new urological friends worldwide. The annual EAU meeting remains a highly effective method of knowledge translation and provides the opportunity for collaboration between surgeon scientists and other researchers in the field. As always in big congresses, there are so many interesting sessions going on at the same time, that it is hard to pick up and follow everything you would like to. We hope that this report provides some memories and take home messages of the Day 3 to the readers of the BJUI and BJUI blogs.

We look forward to future BJUI and EAU happenings!

Kari Tikkinen

Urology resident, adjunct professor of clinical epidemiology

Helsinki University Hospital, Helsinki, Finland

@KariTikkinen

Mika Matikainen

Chief of urology, adjunct professor of urology

Helsinki University Hospital, Helsinki, Finland