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

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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?

 

cw-head-shot-smallChristopher 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		 nam_drrobert_portrait-2010-small

 

 

 

 

 

 


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

 

 

 

 

Article of the Week: LAPPRO trial – Oncological and Functional Outcomes 1 Year after RP for Very-Low-Risk PCa

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

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

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Stefan Carlsson, Dr. Anna Wallerstedt and Dr Rodolfo Sanchez, discussing their paper.

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

Oncological and functional outcomes 1 year after radical prostatectomy for very-low-risk prostate cancer: results from the prospective LAPPRO trial

Stefan Carlsson*, Fredrik Jaderling†, Anna Wallerstedt*, Tommy Nyberg‡, Johan Stranne§
, Thordis Thorsteinsdottir, Sigrid V. Carlsson**, Anders Bjartell††, Jonas Hugosson§, Eva Haglind‡‡ and Gunnar Steineck‡,§§

 

*Department of Molecular Medicine and Surgery, Section of Urology, Karolinska Institutet, †Department of Molecular Medicine and Surgery, Section of Radiology, Karolinska Institutet, ‡Department of Oncology and Pathology, Division of Clinical Cancer Epidemiology, Karolinska Institutet, Stockholm, §Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Faculty of Nursing, School of Health Sciences, University of Iceland, Iceland, **Department of Surgery (Urology Service), Memorial Sloan Kettering Cancer Center, New York, NY, USA, ††Department of Urology, Skane University Hospital, Lund University, Lund, ‡‡ Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, and §§Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

 

Read the full article
Carlsson-et-al-infographic-cropped

 

Click on image for full size infographic

 

Objectives

To analyse oncological and functional outcomes 12 months after treatment of very-low-risk prostate cancer with radical prostatectomy in men who could have been candidates for active surveillance.

Patients and Methods

We conducted a prospective study of all men with very-low-risk prostate cancer who underwent radical prostatectomy at one of 14 participating centres. Validated patient questionnaires were collected at baseline and after 12 months by independent healthcare researchers. Biochemical recurrence (BCR) was defined as prostate-specific antigen (PSA) ≥0.25 ng/mL or treatment with salvage radiotherapy or with hormones. Urinary continence was defined as <1 pad changed per 24 h. Erectile function was defined as ability to achieve erection hard enough for penetration more than half of the time after sexual stimulation. Changes in tumour grade and stage were obtained from pathology reports. We report descriptive frequencies and proportions of men who had each outcome in various subgroups. Fisher’s exact test was used to assess differences between the age groups.

AugAOTW3Results

Results

Of the 4003 men in the LAPPRO cohort, 338 men fulfilled the preoperative national criteria for very-low-risk prostate cancer. Adverse pathology outcomes included upgrading, defined as pT3 or postoperative Gleason sum ≥7, which was present in 35% of the men (115/333) and positive surgical margins, which were present in 16% of the men (54/329). Only 2.1% of the men (7/329) had a PSA concentration >0.1 ng/mL 6–12 weeks postoperatively. Erectile function and urinary continence were observed in 44% (98/222) and 84% of the men (264/315), respectively, 12 months postoperatively. The proportion of men achieving the trifecta, defined as preoperative potent and continent men who remained potent and continent with no BCR, was 38% (84/221 men) at 12 months.

Conclusions

Our prospective study of men with very-low-risk prostate cancer undergoing open or robot-assisted radical prostatectomy showed that there were favourable oncological outcomes in approximately two-thirds. Approximately 40% did not have surgically induced urinary incontinence or erectile dysfunction 12 months postoperatively. These results provide additional support for the use of active surveillance in men with very-low-risk prostate cancer; however, the number of men with risk of upgrading and upstaging is not negligible. Improved stratification is still urgently needed.

Read more articles of the week

Editorial: Management Dilemmas in Low-Risk Prostate Cancer

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Prostate cancer is the most commonly diagnosed solid organ tumour and the second leading cause of cancer death in men in the USA. The exact path of these tumours from inception to metastasis is unclear; the same can also be said for those tumours that remain indolent. The varying genetic signatures of these tumours is the underlying determinant of the outcomes of these cancers and therein lies the key to selecting patients that do and do not need treatment for their prostate cancers. Most low-risk tumours are relatively indolent; however, some low-risk tumours have the potential to metastasise and cause mortality. The problem is that currently we do not have the ability to accurately and confidently determine the tumour’s individual risk profiles.

In the recent LAPPRO trial (LAParoscopic Prostatectomy Robot Open – a randomised, open trial of radical prostatectomy (RP) with or without lymph node dissection as part of a prospective, non-randomised, open trial comparing robot-assisted laparoscopic and open RP), the authors reported the RP results of patients with very-low-risk prostate cancer in a population-based study from Sweden compiling the results of open and laparoscopic RP over 14 centres of varying experience [1]. They reported pathological upgrading in 35% of patients and PSA recurrence in 2.1%. Functional outcomes at 1 year featured urinary continence levels of 84% and sexual potency of 44%. The overall trifecta rate at 1 year was 38%. What is important to note is that only 56% had optimal erectile function preoperatively (Sexual Health Inventory for Men score >21) and that it is unknown which patients received a full nerve preservation. Also the amount of postoperative continence and potency rehabilitation is unknown.

The results of the LAPPRO trial are not too dissimilar to data from the Medicare database publications on RP, which also take into account large populations of patients operated on at multiple institutions with variable surgical experience and volume [2]. The challenge with interpreting these data is that they often are quite variable based upon the preoperative status of the patient, type of surgery performed, surgeon experience, and institutional volumes [3]. If you compare the Medicare data or LAPPRO trial outcomes to large-volume single-surgeon series you often will see wide variances in outcomes favouring the single-surgeon experience. Single-surgeon and large-volume series have reported better outcomes often due to improved surgical experience, techniques, and outcomes overall [4].

Active surveillance is usually the primary choice for management of low- and very-low-risk prostate cancer lesions. However, some patients do still chose to undergo surgery due to personal choice, often related to the uncertainty associated with the diagnosis and the unknown risk of progression [5]. One would assume that low-risk tumours have a low risk of progression and metastasis; however, this is not always the case due to the varying genetic signature of the individual tumours. Also, recent studies have shown that in patients diagnosed with low-risk prostate cancer 30–50% have non-low-risk disease harbouring intermediate- or high-risk prostate cancer instead [1, 6]. This uncertainty on the part of the patient and physician can cause anxiety in patients and sometime influence their decision for treatment [7].

One would assume that patients with low- and very-low-risk patients are ideal candidates for the trifecta due to low tumour aggressiveness and volume. However, many factors influence patient outcome beyond the characteristics of the tumour. Preoperative features such as co-morbidities and pre-existing sexual dysfunction or incontinence are influential. Operative and postoperative factors include: surgeon experience, institutional volume, patients body habitus, number of prior biopsies, the ability to fully spare the nerves, and various other challenges during surgery. These are all variables that must be considered when projecting the success of surgical intervention.

While the results of surgery in the LAPPRO trial were not encouraging for surgery, we do have to take the results in context and not apply them broadly or globally without some thought. The results are blurred by combining open and laparoscopic RP, many patients were not optimal candidates’ preoperatively for the trifecta, many did not have a full nerve preservation and also many different institutions with varying levels of surgeon experience are analysed. This population was also ‘captive’, as they had to choose surgeons in their own locality, these ‘local’ surgeons may not have had the necessary experience or technique to achieve optimal outcomes. The conclusion that can be drawn is that if you sample a broad population of surgeons then the results are often quite poor due to the varying levels of skill of the surgeon and the varying level of surgical volume and experience. What the patients should glean from this is the fact that they should consider active surveillance for these types of tumours to avoid the associated morbidity. In addition, if they were to seek therapy they should select centres with higher surgical experience and proven outcomes.

For those patients that have low-risk tumours and seek treatment; judicious counselling of expectations must be performed by their healthcare advocate. Both the patient and physician must take the responsibility in making the correct assumptions and decisions. The physician must re-emphasise the available data and the low likelihood of progression in these tumours adding some caution from the fact that some of these may be upgraded. Patients must be given accurate data in the correct context. Most patients who have treatment for prostate cancer whether it be radiation, ablation or removal have a high chance of some deficit in the quality of life, functional recovery of urinary continence, and sexual potency. Educating the patient and managing realistic expectations is often the most important factor in patient satisfaction. Patients must take into account their own preoperative medical and functional status to properly stratify expectations.

If these patients after appropriate counselling are still intent to undergo surgery they should consider seeking centres with high-volume and individualised surgeons with proven quality outcomes. Large-volume single-surgeon series do show improvements in the trifecta outcomes [4]. However, none have shown perfect trifecta rates. No matter what method of treatment patients chose there would be some varying level of loss of functional outcome. The balance between cancer progression and quality of life must be weighted. For low-risk patients, we need to have a better road map of the genetic signatures of their tumour and only then will we be able to confidently tell our patients who will and who will not have the potential to harbour high-risk disease and potentially have mortality from the tumour. Until we are able to confidently deliver this information to the patient, many with low-risk disease will still seek treatment and endanger their quality of life. The recent increase in the availability of biomarkers to examine prostate biopsy specimens for risk stratification is encouraging, yet still in its infancy. Further study of these biomarkers will enhance our ability to read the genetic signature of prostate cancers at an early state and more appropriately risks stratify our patients.

The LAPPRO trial supports active surveillance as the primary choice for low- and very-low-risk tumours. However, their results are exclusive to their patient population and level of surgical experience. A similar trial with a high-volume experienced surgeon would undoubtedly show more optimistic results. Managing reasonable expectations, risk stratification, and picking expertise and experience, often makes the difference between a good and poor outcome.

Read the full article

 

Vipul R. Patel*† and Hariharan Palayapalayam Ganapathi*†
*Global Robotics Institute, Florida Hospital Celebration Health, and †University of Central Florida School of Medicine, Orlando, FL, USA

 

References

 

1 Carlsson S, Jaderling F, Wallerstedt A et al. Oncological and functional outcomes 1 year after radical prostatectomy for very-low-risk prostate cancer: results from the prospective LAPPRO trial. BJU Int 2016; 118: 205–12

 

2 Barry MJ, Gallagher PM, Skinner JS, Fowler FJ Jr. Adverse effects of robotic-assisted laparoscopic versus open retropubic radical prostatectomy among a nationwide random sample of Medicare-age men. J Clin Oncol 2012; 30: 513–8

 

3 Patel VR, Abdul-Muhsin HM, Schatloff O et al. Critical review of ‘pentafecta’ outcomes after robot-assisted laparoscopic prostatectomy in high-volume centres. BJU Int 2011; 108: 1007–17

 

4 Patel VR, Coelho RF, Chauhan S et al. Continence, potency and oncological outcomes after robotic-assisted radical prostatectomy: early trifecta results of a high-volume surgeon. BJU Int 2010; 106: 696–702

 

5 Simpkin AJ, Tilling K, Martin RM et al. Systematic review and meta-analysis of factors determining change to radical treatment in active surveillance for localized prostate cancer. Eur Urol 2015; 67: 993–1005

 

6 El Hajj A, Ploussard G, de la Taille A et al. Analysis of outcomes after radical prostatectomy in patients eligible for active surveillance (PRIAS). BJU Int 2013; 111: 53–9

 

7 Van den Bergh RC, Essink-Bot ML, Roobol MJ et al. Anxiety and distress during active surveillance for early prostate cancer. Cancer 2009; 115: 3868–78

 

Video: LAPPRO trial – Oncological and Functional Outcomes 1 Year after RP for Very-Low-Risk PCa

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Oncological and functional outcomes 1 year after radical prostatectomy for very-low-risk prostate cancer: results from the prospective LAPPRO trial

Stefan Carlsson*, Fredrik Jaderling†, Anna Wallerstedt*, Tommy Nyberg‡, Johan Stranne§
, Thordis Thorsteinsdottir, Sigrid V. Carlsson**, Anders Bjartell††, Jonas Hugosson§, Eva Haglind‡‡ and Gunnar Steineck‡,§§

 

*Department of Molecular Medicine and Surgery, Section of Urology, Karolinska Institutet, †Department of Molecular Medicine and Surgery, Section of Radiology, Karolinska Institutet, ‡Department of Oncology and Pathology, Division of Clinical Cancer Epidemiology, Karolinska Institutet, Stockholm, §Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Faculty of Nursing, School of Health Sciences, University of Iceland, Iceland, **Department of Surgery (Urology Service), Memorial Sloan Kettering Cancer Center, New York, NY, USA, ††Department of Urology, Skane University Hospital, Lund University, Lund, ‡‡ Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, and §§Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

 

Read the full article

Objectives

To analyse oncological and functional outcomes 12 months after treatment of very-low-risk prostate cancer with radical prostatectomy in men who could have been candidates for active surveillance.

Patients and Methods

We conducted a prospective study of all men with very-low-risk prostate cancer who underwent radical prostatectomy at one of 14 participating centres. Validated patient questionnaires were collected at baseline and after 12 months by independent healthcare researchers. Biochemical recurrence (BCR) was defined as prostate-specific antigen (PSA) ≥0.25 ng/mL or treatment with salvage radiotherapy or with hormones. Urinary continence was defined as <1 pad changed per 24 h. Erectile function was defined as ability to achieve erection hard enough for penetration more than half of the time after sexual stimulation. Changes in tumour grade and stage were obtained from pathology reports. We report descriptive frequencies and proportions of men who had each outcome in various subgroups. Fisher’s exact test was used to assess differences between the age groups.

AugAOTW3Results

Results

Of the 4003 men in the LAPPRO cohort, 338 men fulfilled the preoperative national criteria for very-low-risk prostate cancer. Adverse pathology outcomes included upgrading, defined as pT3 or postoperative Gleason sum ≥7, which was present in 35% of the men (115/333) and positive surgical margins, which were present in 16% of the men (54/329). Only 2.1% of the men (7/329) had a PSA concentration >0.1 ng/mL 6–12 weeks postoperatively. Erectile function and urinary continence were observed in 44% (98/222) and 84% of the men (264/315), respectively, 12 months postoperatively. The proportion of men achieving the trifecta, defined as preoperative potent and continent men who remained potent and continent with no BCR, was 38% (84/221 men) at 12 months.

Conclusions

Our prospective study of men with very-low-risk prostate cancer undergoing open or robot-assisted radical prostatectomy showed that there were favourable oncological outcomes in approximately two-thirds. Approximately 40% did not have surgically induced urinary incontinence or erectile dysfunction 12 months postoperatively. These results provide additional support for the use of active surveillance in men with very-low-risk prostate cancer; however, the number of men with risk of upgrading and upstaging is not negligible. Improved stratification is still urgently needed.

Read more articles of the week

It’s not about the machine, stupid

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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.

DM1

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

DM2b      –   to this from The Telegraph in London

DM3bAs 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:

  1.        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.
  2.       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

 

 

 

Article of the Week: Muscolofascial Reconstruction after RP

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

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

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Francesco Alessandro Mistretta, discussing his paper.

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

Posterior musculofascial reconstruction after radical prostatectomy: an updated systematic review and a meta-analysis

 

Angelica A.C. Grasso*, Francesco A. Mistretta*, Marco Sandri†, Gabriele Cozzi*, Elisa De Lorenzis*, Marco Rosso*, Giancarlo Albo*, Franco Palmisano*, Alex Mottrie‡, Alexander Haese§, Markus Graefen§, Rafael Coelho, Vipul R. Patel¶ and Bernardo Rocco*

 

*Department of Urology, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, University of Milan, Milan, Italy, †DMS StatLab, Data Methods and Systems Statistical Laboratory, University of Brescia, Brescia, Italy, ‡OLV Robotic Surgery Institute, Aalst, Belgium, §Martini Clinic Prostate Cancer Center, University Clinic Eppendorf, Hamburg, Germany, and Global Robotics Institute, Florida Hospital-Celebration Health Celebration, University of Central Florida School of Medicine, Orlando, FL, USA

 

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To evaluate the influence of posterior musculofascial plate reconstruction (PR) on early return of continence after radical prostatectomy (RP); an updated systematic review of the literature. A systematic review of the literature was performed in June 2015, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and searching Medline, Embase, Scopus and Web of Science databases. We searched the terms posterior reconstruction prostatectomy, double layer anastomosis prostatectomy across the ‘Title’ and ‘Abstract’ fields of the records, with the following limits: humans, gender (male), and language (English). The authors reviewed the records to identify studies comparing cohorts of patients who underwent RP with or without restoration of the posterior aspect of the rhabdosphincter. A meta-analysis of the risk ratios estimated using data from the selected studies was performed. In all, 21 studies were identified, including three randomised controlled trials. The overall analysis of comparative studies showed that PR improved early continence recovery at 3–7, 30, and 90 days after catheter removal, while the continence rate at 180 days was statistically but not clinically affected. Statistically significantly lower anastomotic leakage rates were described after PR. There were no significant differences for positive surgical margins rates or for complications such as acute urinary retention and bladder neck stricture. The analysis confirms the benefits at 30 days after catheter removal already discussed in the review published in 2012, but also shows a significant advantage in terms of urinary continence recovery in the first 90 days. A multicentre prospective randomised controlled trial is currently being conducted in several institutions around the world to better assess the effectiveness of PR in facilitating an earlier recovery of postoperative urinary continence.

 

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Editorial: The Jury on Posterior Muscolofascial Reconstruction is still out

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In their systematic review and meta-analysis, Grasso et al. [1] address the question of whether posterior muscolofascial reconstruction (PMR), the so-called Rocco stitch, positively affects urinary continence after radical prostatectomy. The relevance of the question to this structured form of inquiry is that individual studies to date have been inconclusive. We recognize Sir Archie Cochrane, who gave his name to the Cochrane Collaboration that pioneered the methods for conducting systematic reviews, for emphasizing the critical importance of looking at the entire body of evidence in a structured manner when seeking to answer a clinical question [2]. In the present study, which included both randomized controlled trials (RCTs) and observational studies of variable methodological quality, a favourable impact of PMR across all postoperative time points (3–7 days, 30 days, 3 and 6 months) was observed. The effect was most pronounced early on at the time of catheter removal, when the patients undergoing PMR were nearly twice as likely as the control group (risk ratio 1.9; 95% CI 1.3–2.9) to be continent, thereby suggesting a major benefit of this approach. It should be noted, however, that this analysis was dominated by the observational studies, particularly retrospective observational studies, which offer the least degree of methodological rigor.

Even more important, therefore, than the act of pooling across studies is the rating of the quality of evidence for the body of evidence on an outcome-specific basis. Based on the GRADE approach, which has become the most widely endorsed framework for rating the quality of evidence, we would initially place a high and low level of confidence in a body of evidence drawn from RCTs and observational studies, respectively [3]. As a result, one might plan a separate analysis of those two groups of studies first, and only move to pool them if their results were similar. In this case, the results from the RCTs and observational studies were different, with prospective and retrospective studies reporting larger, probably exaggerated effect sizes; however, it is also understood that other aspects such as study limitation (risk of bias), inconsistency, impression, indirectness and risk publication bias may lower our confidence in the effect estimates from RCTs [4]. Focusing on the body of evidence from RCTs alone (Table 1) we have ‘moderate’ confidence that PMR may not improve early continence at the time of catheter removal. Similarly, the few RCTs that contributed to the assessment of continence at later timepoints do not provide evidence that continence is affected favourably, although our confidence for those outcomes is only ‘low’ or ‘very low’, suggesting that future trials may change these estimates of effect. Meanwhile, it should be noted that none of the RCTs appeared to provide information on the potential downsides of PMR, such as rates of urinary retention or bladder neck contracture. As a result, enough uncertainty remains to state that the jury on PMR is still out; this is consistent with the authors’ call for a future high-quality trial, which is reportedly ongoing. While PMR is already widely used by open and robot-assisted prostatectomy surgeons around the globe, this example sheds light on current evidentiary standards of surgical innovation. Following the IDEAL recommendations, it would be much preferred if the urological community committed to well designed trials for novel surgical approaches and device-dependent interventions up front, before moving to widespread dissemination [5].

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Philipp Dahm
Department of Urology, Minneapolis VA Health Care System, Urology Section 112D and University of Minnesota, Minneapolis, MN, USA

 

References

 

1 Grasso AAC, Mistretta FA, Sandri M et al. Posterior musculofascial reconstruction after radical prostatectomy: an updated systematic review and a meta-analysis. BJU Int 2016; 118: 20–34.

 

2 Hajebrahimi S, Dahm P, Buckingham J. Evidence-based urology in practice: the cochrane library. BJU Int 2009; 104: 1048–9

 

3 Canfield SE, Dahm P. Rating the quality of evidence and the strength of recommendations using GRADE. World J Urol 2011; 29: 311–7

 

4 Guyatt GH, Oxman AD, Vist GE et al. GRADE: what is “quality of evidence” and why is it important to clinicians? BMJ 2008; 336: 995–8

 

5 McCulloch P. The IDEAL recommendations and urological innovation. World J Urol 2011; 29: 331–6

 

Video: Posterior Muscolofascial Reconstruction after RP

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Posterior musculofascial reconstruction after radical prostatectomy: an updated systematic review and a meta-analysis

Angelica A.C. Grasso*, Francesco A. Mistretta*, Marco Sandri†, Gabriele Cozzi*, Elisa De Lorenzis*, Marco Rosso*, Giancarlo Albo*, Franco Palmisano*, Alex Mottrie‡, Alexander Haese§, Markus Graefen§, Rafael Coelho, Vipul R. Patel¶ and Bernardo Rocco*

 

*Department of Urology, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, University of Milan, Milan, Italy, †DMS StatLab, Data Methods and Systems Statistical Laboratory, University of Brescia, Brescia, Italy, ‡OLV Robotic Surgery Institute, Aalst, Belgium, §Martini Clinic Prostate Cancer Center, University Clinic Eppendorf, Hamburg, Germany, and Global Robotics Institute, Florida Hospital-Celebration Health Celebration, University of Central Florida School of Medicine, Orlando, FL, USA

 

Read the full article
To evaluate the influence of posterior musculofascial plate reconstruction (PR) on early return of continence after radical prostatectomy (RP); an updated systematic review of the literature. A systematic review of the literature was performed in June 2015, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and searching Medline, Embase, Scopus and Web of Science databases. We searched the terms posterior reconstruction prostatectomy, double layer anastomosis prostatectomy across the ‘Title’ and ‘Abstract’ fields of the records, with the following limits: humans, gender (male), and language (English). The authors reviewed the records to identify studies comparing cohorts of patients who underwent RP with or without restoration of the posterior aspect of the rhabdosphincter. A meta-analysis of the risk ratios estimated using data from the selected studies was performed. In all, 21 studies were identified, including three randomised controlled trials. The overall analysis of comparative studies showed that PR improved early continence recovery at 3–7, 30, and 90 days after catheter removal, while the continence rate at 180 days was statistically but not clinically affected. Statistically significantly lower anastomotic leakage rates were described after PR. There were no significant differences for positive surgical margins rates or for complications such as acute urinary retention and bladder neck stricture. The analysis confirms the benefits at 30 days after catheter removal already discussed in the review published in 2012, but also shows a significant advantage in terms of urinary continence recovery in the first 90 days. A multicentre prospective randomised controlled trial is currently being conducted in several institutions around the world to better assess the effectiveness of PR in facilitating an earlier recovery of postoperative urinary continence.

 

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Article of the Week: Evaluating health resource use and secondary care costs for RP and partial nephrectomy

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

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

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Mr. Jim Adshead, discussing his paper.

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

Health resource use after robot-assisted surgery vs open and conventional laparoscopic techniques in oncology: analysis of English secondary care data for radical prostatectomy and partial nephrectomy

David Hughes*†, Charlotte Camp*, Jamie O’Hara*† and Jim Adshead‡

 

*HCD Economics, Daresbury, †Faculty of Health and Social Care, University of Chester, Chester, and ‡Hertfordshire and South Bedfordshire Urological Cancer Centre, Department of Urology, Lister Hospital, Stevenage, UK

 

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Objectives

To evaluate postoperative health resource utilisation and secondary care costs for radical prostatectomy and partial nephrectomy in National Health Service (NHS) hospitals in England, via a comparison of robot-assisted, conventional laparoscopic and open surgical approaches.

Patients and Methods

We retrospectively analysed the secondary care records of 23 735 patients who underwent robot-assisted (RARP, n = 8 016), laparoscopic (LRP, n = 6 776) or open radical prostatectomy (ORP, n = 8 943). We further analysed 2 173 patients who underwent robot-assisted (RAPN,n = 365), laparoscopic (LPN, n = 792) or open partial nephrectomy (OPN, n = 1 016). Postoperative inpatient admissions, hospital bed-days, excess bed-days and outpatient appointments at 360 and 1 080 days after surgery were reviewed.

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Results

Patients in the RARP group required significantly fewer inpatient admissions, hospital bed-days and excess bed-days at 360 and 1 080 days than patients undergoing ORP. Patients undergoing ORP had a significantly higher number of outpatient appointments at 1 080 days. The corresponding total costs were significantly lower for patients in the RARP group at 360 days (£1679 vs £2031 for ORP; P < 0.001) and at 1 080 days (£3461 vs £4208 for ORP; P < 0.001). In partial nephrectomy, Patients in the RAPN group required significantly fewer inpatient admissions and hospital bed-days at 360 days compared with those in the OPN group; no significant differences were observed in outcomes at 1 080 days. The corresponding total costs were lower for patients in the RAPN group at 360 days (£779 vs £1242 for OPN,P = 0.843) and at 1 080 days (£2122 vs £2889 for ORP; P = 0.570). For both procedure types, resource utilisation and costs for laparoscopic surgeries lay at the approximate midpoint of those for robot-assisted and open surgeries.

Conclusion

Our analysis provides compelling evidence to suggest that RARP leads to reduced long-term health resource utilisation and downstream cost savings compared with traditional open and laparoscopic approaches. Furthermore, despite the limitations that arise from the inclusion of a small sample, these results also suggest that robot-assisted surgery may represent a cost-saving alternative to existing surgical options in partial nephrectomy. Further exploration of clinical cost drivers, as well as an extension of the analysis into subsequent years, could lend support to the wider commissioning of robot-assisted surgery within the NHS.

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Editorial: Cost-effectiveness of robotic surgery; what do we know?

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The introduction of the daVinci robotic surgical system (Intuitive Surgical, Sunnyvale, CA, USA) has led to a continuous discussion about the cost-effectiveness of its use. The capital costs and extra costs per procedure for robot-assisted procedures are well known, but there are limited data on healthcare consumption in the longer term. In this issue of BJUI, a retrospective study investigated the NHS-registered, relevant care activities up to three years after surgery comparing robot-assisted, conventional laparoscopic, and open surgical approaches to radical prostatectomy and partial nephrectomy [1].

The robotic system is particularly useful in difficult to perform laparoscopic surgeries, which are easier to perform with the daVinci system due to improved three-dimensional vision, ergonomics, and additional dexterity of the instruments. Because the use of the robotic system is more costly, to justify its use the outcomes for patients should be improved. Therefore, more detailed information about the clinical and oncological outcomes, as well as the incidence of complications after surgery with the daVinci system, is needed.

Lower rates of positive surgical margins for robot-assisted radical prostatectomy (RARP) vs open and laparoscopic RP have been reported [2]. There also is evidence of an earlier recovery of functional outcomes, such as continence. RARP is associated with improved surgical margin status compared with open RP and reduced use of androgen-deprivation therapy and radiotherapy after RP, which has important implications for quality of life and costs. Ramsay et al. [3] reported that RARP could be cost-effective in the UK with a minimum volume of 100–150 cases per year per robotic system.

Centralisation of complex procedures will not only result in better outcomes, but also facilitate optimal economical usage of expensive medical devices. Furthermore, the skills learned to perform the RARP procedure can be used during other procedures, such as robot-assisted partial nephrectomy (RAPN) and radical cystectomy (RARC). The recent report by Buse et al. [4] confirms that RAPN is cost-effective in preventing perioperative complications in a high-volume centre, when compared with the open procedure. Minimally invasive techniques for complex procedures, such as a RC, take more time to perform, but result in less blood loss. A systematic review by Novara et al. [5] showed a longer operation time for RARC, but fewer transfusions and fewer complications compared with open surgery. However, there is no solid evidence about the cost-effectiveness of this technique to date. The RAZOR trial (randomised trial of open versus robot assisted radical cystectomy, DOI: 10.1111/bju.12699) is likely to provide some answers about differences in cost, complications, and quality of life when the results of the study become available later this year.

Additionally, the robotic system has been shown to shorten the learning curve of complex laparoscopic procedures in simulation models [6]. Recently, a newly structured curriculum to teach RARP has been validated by the European Association of Urology-Robotic Urology Section [7]. The effect of the shorter learning curve on the cost of the procedures has not yet been well studied for cost-effectiveness. However, due to the shorter learning curves, patients have lower risks of complications, which from the patients’ perspective is more important than any increased costs.

The study reported in this issue [1]; however, does not include the ‘out of pocket’ expenses of patients, it does not report on the differences in patient and tumour characteristics, and outcomes such as complications and oncological safety. These issues are all challenges to be addressed in a thorough prospective (randomised) trial on the cost-effectiveness of the use of robot-assisted surgery, including quality-of-life measurements and complications of the surgical procedures. In the Netherlands the RACE trial (comparative effectiveness study open RC vs RARC, www.racestudie.nl) started in 2015 and the results are expected in 2018–2019.

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Carl J. Wijburg
Department of Urology, Robotic Surgery , Rijnstate Hospital, Arnhem, The Netherlands

 

References

 

1 Hughes D, Camp C, O’Hara J, Adshead J. Health resource use after robot-assisted surgery vs open and conventional laparoscopic techniques in oncology: analysis of English secondary care data for radical prostatectomy and partial nephrectomy. BJU Int 2016; 117: 940–7

 

2 HuJC, Gandaglia G, Karakiewicz PI et al. Comparative effectiveness of robot-assisted versus open radical prostatectomy. Eur Urol 2014; 66: 666–72

 

3 Ramsay C, Pickard R , Soomro N et al. Systematic review and economic modelling of the relative clinical benefit and cost-effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with localised prostate cancer. Health Technol Assess 2012; 16: 1–313

 

4 Buse S, Hach CE, Klumpen P et al. Cost-effectiveness of robot-assisted partial nephrectomy for the prevention of perioperative complications. World J Urol 2015; [Epub ahead of print]. DOI:10.1007/s00345-015-1742-x

 

5 Novara G, Catto JW, Wilson T et al. Systematic review and cumulative analysis of perioperative outcomes and complications after robot-assisted radical cystectomy. Eur Urol 2015; 67: 376–401

 

6 Moore LJ, Wilson MR, Waine E, Masters RS, McGrath JS, Vine SJ. Robotic technology results in faster and more robust surgical skill acquisition than traditional laparoscopy. J Robot Surg 2015; 9: 67–73

 

7 Ahmed K, Khan R, Mottrie A et al. Development of a standardised training curriculum for robotic surgery: a consensus statement from an international multidisciplinary group of experts. BJU Int 2015; 116: 93–101

 

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