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Article of the Week: Association between T2DM, curative treatment and survival in localized 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 discussing the paper.

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

Association between type 2 diabetes, curative treatment and survival in men with intermediate- and high-risk localized prostate cancer

Danielle Crawley*, Hans Garmo*, Sarah Rudman†, Par Stattin‡§, Bjorn Zethelius**, Lars Holmberg*, Jan Adolfsson†† and Mieke Van Hemelrijck*

 

*Division of Cancer Studies, Cancer Epidemiology Group, King’s College London, †Guy’s and St Thomas’ NHS Foundation Trust and King’s College London’s Comprehensive Biomedical Research Centre, London, UK, ‡Department of Surgical Sciences, Uppsala University, Uppsala, §Department of Surgical and Peri-operative Sciences, Urology and Andrology, Umea University, Umea, Department of Public Health and Geriatric, Uppsala University, **Medical Products Agency, Uppsala, and ††Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden

 

Abstract

Objective

To investigate whether curative prostate cancer (PCa) treatment was received less often by men with both PCa and Type 2 diabetes mellitus (T2DM) as little is known about the influence of T2DM diagnosis on the receipt of such treatment in men with localized PCa.

Subjects and Methods

The Prostate Cancer database Sweden (PCBaSe) was used to obtain data on men with T2DM and PCa (n = 2210) for comparison with data on men with PCa only (n = 23 071). All men had intermediate- (T1–2, Gleason score 7 and/or prostate-specific antigen [PSA] 10–20 ng/mL) or high-risk (T3 and/or Gleason score 8–10 and/or PSA 20–50 ng/mL) localized PCa diagnosed between 1 January 2006 and 31 December 2014. Multivariate logistic regression was used to calculate the odds ratios (ORs) for receipt of curative treatment in men with and without T2DM. Overall survival, for up to 8 years of follow-up, was calculated both for men with T2DM only and for men with T2DM and PCa.

Results

Men with T2DM were less likely to receive curative treatment for PCa than men without T2DM (OR 0.78, 95% confidence interval 0.69–0.87). The 8-year overall survival rates were 79% and 33% for men with T2DM and high-risk PCa who did and did not receive curative treatment, respectively.

Conclusions

Men with T2DM were less likely to receive curative treatment for localized intermediate- and high-risk PCa. Men with T2DM and high-risk PCa who received curative treatment had substantially higher survival times than those who did not. Some of the survival differences represent a selection bias, whereby the healthiest patients received curative treatment. Clinicians should interpret this data carefully and ensure that individual patients with T2DM and PCa are not under- nor overtreated.

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Editorial: Selecting patients for PCa treatment: the role of comorbidity

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The risk of dying from prostate cancer is strongly influenced by competing causes related to age and comorbidity. In the past, indiscriminate screening and treatment of prostate cancer in men with limited life expectancy have been heavily criticized. In the SPCG-4 study, Bill-Axelson et al. [1] showed that patient age significantly modified the likelihood of benefit from radical prostatectomy: while patients aged <65 years at the time of treatment saw significantly decreased risk of overall mortality, prostate cancer mortality, and metastases, those aged >65 years did not have a significant improvement in survival, despite significantly decreased risk of metastases [1]. Significant progress has since been made with regard to treatment, in offering surveillance to men unlikely to die from their prostate cancer, either because of indolent disease or competing risks.

In this issue of BJUI, Crawley et al. [2] describe the association between type 2 diabetes and receipt of curative treatment for patients newly diagnosed with intermediate- and high-risk prostate cancer. Using the Prostate Cancer database Sweden (PCBaSE), the authors convincingly show us that patients who received oral therapies or insulin for type 2 diabetes were significantly less likely to undergo curative treatment after a prostate cancer diagnosis compared with men without diabetes. They also demonstrated a gradient of effect, as men treated with insulin (with presumably more severe diabetes) were even less likely to receive curative therapies than those treated with oral agents (odds ratios 0.62 and 0.91, respectively, both compared with men without diabetes). This could have been better assessed with more objective measures of disease severity including micro- and macrovascular complications or glycated haemoglobin levels. Interestingly, the authors found that men with diabetes had more aggressive disease, with higher Gleason scores, a greater proportion of biopsy cores involved with cancer, and higher PSA levels. We therefore must consider the question, is withholding curative therapy from these patients undertreatment or appropriate?

Mortality rates for men with diabetes are significantly higher than for those without. Among men aged ≥50 years, life expectancy is 7.5 years (95% CI: 5.5–9.5) shorter for those with diabetes [3]. The effect of diabetes on mortality is mediated through cardiovascular disease, the leading cause of mortality among men diagnosed with prostate cancer [4]. Thus, competing risks of mortality, rather than prostate cancer mortality, are likely to be the limiters of these patients’ life expectancy.

Interestingly, the authors found that men with diabetes who received pharmacotherapy for dyslipidaemia or cardiovascular disease had a similar likelihood of receiving treatment as men treated for diabetes alone [2].

The authors then assessed whether receipt of curative treatment was associated with overall survival among patients with diabetes. The authors conclude that curative treatment was associated with improved overall survival among these men [2], with differences in both prostate cancer and non-prostate cancer mortality. We should be sceptical of these findings, however, because of significant selection bias and confounding as the authors present only unadjusted results. The greater comorbidity and more aggressive cancers among men with diabetes in this cohort may explain a large portion of the differences in non-prostate cancer mortality and prostate cancer-mortality, respectively, separate from the effect of local treatment. This is supported by the authors’ observation that men with type 2 diabetes treated with curative intent had better overall survival than men with type 2 diabetes without prostate cancer [2]. In fact, non-prostate cancer causes contributed to the majority of deaths in these men with intermediate- and high-risk cancer, regardless of receipt of curative treatment. Lastly, with respect to survival, it should be noted that previous analyses have demonstrated a protective effect of metformin on overall and prostate cancer mortality among men with diabetes [5].

What are we to take from this paper? First, men with diabetes appear to present with more aggressive disease at the time of diagnosis. This may relate to decreased prostate cancer screening, lower PSA levels among screened men leading to a decreased index of suspicion [6], or a lower likelihood of biopsy at a given PSA level. Further, we believe that this paper shows that Swedish urologists are understandably providing curative prostate cancer treatment to men with the potential to benefit from these interventions, while sparing men with significant medical comorbidity the side effects of such therapies which are unlikely to benefit them. Caution should be applied in using these data to reflexively justify more aggressive screening and treatment in all men with diabetes. Individualized decision-making should be made on a case-by-case basis based on the best estimates of risks of prostate cancer and non-prostate cancer mortality.

Christopher J.D. Wallis,*† Raj Satkunasivam,*† and Bimal Bhindi‡
*Division of Urology, Department of Surgery, University of Toronto, †Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada and ‡Department of Urology, Mayo Clinic, Rochester, MN, USA

 

 

References

 

1 Bill-Axelson A, Holmberg L, Garmo H et al. Radical prostatectomy or watchful waiting in early prostate cancer. New Engl J Med 2014; 6: 932–42

 

2 Crawley D, Garmo H, Rudman S et al. Association between type 2 diabetes, curative treatment and survival in men with intermediate and high risk localized prostate cancer. BJU Int 2018; 121: 209–16

 

3 Franco OH, Steyerberg EW, Hu FB, Mackenbach J, Nusselder W. Associations of diabetes mellitus with total life expectancy and life expectancy with and without cardiovascular disease. Arch Intern Med 2007; 167: 1145–51

 

4 Ketchandji M, Kuo YF, Shahinian VB, Goodwin JS. Cause of death in older men after the diagnosis of prostate cancer. J Am Geriatr Soc 2009;57: 24–30

 

5 Margel D, Urbach DR, Lipscombe LL et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol 2013; 31: 3069–75

 

6 Werny DM, Saraiya M, Gregg EW. Prostate-specific antigen values in diabetic and nondiabetic US men, 2001–2002. Am J Epidemiol 2006; 164: 978–83

 

Article of the Month: Partin Tables in the Contemporary Era

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

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

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

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

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

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

 

Read the full article

How to Cite this Article

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

Abstract

Objective

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

Patients and Methods

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

aotm-may-2017

Results

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

Conclusions

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

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partin-tables-infographic-patients

Click on image for full infographic

 

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

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

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

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

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

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How to Cite

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

 

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

 

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

 

References

 

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

 

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

 

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

 

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

 

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

 

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

 

Article of the Week: Detecting PSMs – using LRS on ex vivo RP specimens

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

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

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

Detecting positive surgical margins: utilisation of light-reflectance spectroscopy on ex vivo prostate specimens

Aaron H. Lay*, Xinlong Wang†, Monica S. C. Morgan*, Payal Kapur‡, Hanli Liu†,Claus G. Roehrborn* and Jeffrey A. Cadeddu*

 

*Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, †Department of Bioengineering, University of Texas at Arlington, Arlington, TX, and ‡Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

 

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Abstract

Objective

To assess the efficacy of light-reflectance spectroscopy (LRS) to detect positive surgical margins (PSMs) on ex vivo radical prostatectomy (RP) specimens.

Materials and Methods

A prospective evaluation of ex vivo RP specimens using LRS was performed at a single institution from June 2013 to September 2014. LRS measurements were performed on selected sites on the prostate capsule, marked with ink, and correlated with pathological analysis. Significant features on LRS curves differentiating malignant tissue from benign tissue were determined using a forward sequential selection algorithm. A logistic regression model was built and randomised cross-validation was performed. The sensitivity, specificity, accuracy, negative predictive value (NPV), positive predictive value (PPV), and area under the receiver operating characteristic curve (AUC) for LRS predicting PSM were calculated.

aotwdec-4-results

Results

In all, 50 RP specimens were evaluated using LRS. The LRS sensitivity for Gleason score ≥7 PSMs was 91.3%, specificity 92.8%, accuracy 92.5%, PPV 73.2%, NPV 99.4%, and the AUC was 0.960. The LRS sensitivity for Gleason score ≥6 PSMs was 65.5%, specificity 88.1%, accuracy 83.3%, PPV 66.2%, NPV 90.7%, and the AUC was 0.858.

Conclusions

LRS can reliably detect PSMs for Gleason score ≥7 prostate cancer in ex vivo RP specimens

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Editorial: Light reflectance spectroscopy is one more emerging technique with the potential to adjust excision limits during radical prostatectomy

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In this issue of BJUI, Lay et al. [1] report that light reflectance spectroscopy (LRS) can detect Gleason ≥7 positive surgical margins (PSMs) with 92.5% accuracy. In this initial study, the authors have reported the use of LRS in an ex situ setting to analyse the prostate surface; however, this technology could ultimately be developed to identify PSMs before choosing the surgical plane of dissection, which could allow the surgeon to immediately perform a wider complementary excision.

As long as PSMs are detected ex situ, it is not clear why spectroscopy should be preferred to frozen sections. NeuroSAFE, for example, is a standardized and validated margin evaluation procedure in pathology [2]. It does not lengthen operating time, does not require any new equipment and provides a pathological assessment which is the best level of evidence for PSM status; however, as a conventional pathological procedure, it is not conceivable in situ, and real-time detection of PSMs that ensures the safest oncological resection during a nerve-sparing dissection is needed.

In this effort to examine in vivo/in situ prostate PSMs, several other technologies can be considered. During radical prostatectomy, optical coherence tomography (OCT) has been used in situ in humans, but only to identify the neurovascular bundles [3]. Field of view and depth of penetration were limited and OCT has never been evaluated in situ for prostate PSM detection. Confocal endomicroscopy has recently been reported during robot-assisted radical prostatectomy [4]. With this technique, optical biopsies were feasible in situ but the PSM detection rate and the overall efficiency of this confocal endomicroscopy in prostate specimens remain unknown. Similarly, illumination microscopy has been used to generate gigapixel images of the full prostate circumference in vivo for the detection of PSMs [5]. Illumination microscopy allows images to be interpreted readily by pathologists, but the feasibility series was too small to assess the accuracy of this technique for PSM detection. Ex situ multi-photon microscopy (MPM) is an optical technique that enables the imaging of prostatic and periprostatic tissue at sub-micron resolution to a depth of up to 0.5 mm [6]. On a fresh specimen, it generates three-dimensional images of periprostatic nerves, blood vessels and capsule, but also underlying acini and pathological changes such as prostate cancer. MPM technology has also been miniaturized and its accuracy in situ is currently under investigation.

In this context, the study by Lay et al. [1] shows that, for the time being, LRS is one more promising technique on the road to real-time PSM detection. More will undoubtedly be done to overcome the spectroscope’s light absorption in the presence of blood and, subsequently, to evaluate its reliability in situ; however, the recent developments of these protocols and technologies (endomicroscopy, illumination microscopy, OCT, MPM, LRS) show a progressive effort amongst clinicians to obtain intra-operative feedback on the PSM status. Fortunately, this is taking place while the urological community is increasingly considering surgical treatment even for the high-risk disease, where oncological adequacy is of paramount importance. While we are witnessing these promising evolutions in high-grade prostate cancer, the optimum technique which will safely end margin-blind radical prostatectomy in an actual surgical field (filled with blood and often distorted because of inflammation) still needs to go through clinical trials and validation; however, the future is bright as a result of these newer developments.

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Thomas Bessede*†‡ and Ash Tewari*

 

*Department of Urology, Icahn School of Medicine at Mount Sinai, New York , NY, USA, †U1195, INSERM, Universite Paris-Saclay, and ‡Department of Urology, APHP, Hopitaux Universitaires Paris-Sud, Le Kremlin-Bicetre, France

 

References

 

1 Lay AH, Wang X, Morgan MSC et al. Detecting positive surgical margins: utilisation of light-reflectance spectroscopy on ex vivo prostate specimens. BJU Int 2016; 118: 885–9

 

2 Beyer B, Schlomm T, Tennstedt P et al. A feasible and time-efficient adaptation of NeuroSAFE for da Vinci robot-assisted radical prostatectomy. Eur Urol 2014; 66: 138–44

 

3 Aron M, Kaouk JH, Hegarty NJ et al. Second prize: preliminary experience with the Niris optical coherence tomography system during laparoscopic and robotic prostatectomy. J Endourol 2007; 21: 814–8

 

4 Lopez A, Zlatev DV, Mach KE et al. Intraoperative optical biopsy during robotic assisted radical prostatectomy using confocal endomicroscopy. J Urol 2016; 195: 1110–7

 

5 Wang M, Tulman DB, Sholl AB et al. Gigapixel surface imaging ofradical prostatectomy specimens for comprehensive detection of cancer-positive surgical margins using structured illumination microscopy. Sci Rep 2016; 6: 27419

 

6 Tewari AK, Shevchuk MM, Sterling J et al. Multiphoton microscopy for structure identification in human prostate and periprostatic tissue: implications in prostate cancer surgery. BJU Int 2011; 108: 1421–9

 

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: 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

 

Read the full article

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.

Read more articles of the week

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.

Read the full article
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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