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Editorial: PCa BCR after SRT – first look into risk stratification and prognosis

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As salvage radiation therapy (SRT) is commonly offered as a treatment option to select patients with prostate cancer who have biochemical recurrence (BCR) after radical prostatectomy (RP), the uro-oncology community is in strong need of tangible data regarding patients who have a ‘second’ BCR after such therapy. The multi-institution team led by Tumati and Jackson [1] provides new insight into the outcomes of second biochemical failures, offering a novel risk stratification system with the help of prognostic factors. Their analysis of 286 patients offers retrospective prognostic clues that could guide further work trying to better understand the natural history and management of such patients.

At the core of their findings is two risk stratification grouping systems predicting event rates for freedom from distant metastases (FFDM) and for prostate cancer-specific survival (PCSS), both based on multivariate analysis. Variables such as interval from RP to second BCR, Gleason score, and concurrent androgen-deprivation therapy (ADT) proved to be of significance. Of note, their cohort also allowed them to establish an overall survival from time of second BCR diagnosis of 13 years, a surprisingly hopeful figure for such treatment-resistant disease.

Whilst the classification proposed by Tumati et al. [1] brings valuable numbers to this poorly understood patient group, some questions remain about parts of the analysis performed. First, it came as a surprise to our team that, on multivariate analysis, FFDM and PCSS did not significantly correlate with clinical staging or nodal involvement, two well-established predictors of poor outcomes after RP [2]. Although both risk factors either reached or approached statistical significance on univariate analysis, we have difficulty explaining why such clear prognosticators would not reach significance with other factors controlled. Maybe the lack of systematic, complete lymph node sampling could partially explain the lack of significant correlation with N staging. Also, whilst some may find it surprising that positive surgical margins were insignificantly associated with better long-term outcomes, other published studies have actually shown similar results, sometimes with statistical significance [3, 4]. This could have very important implications, as it suggests that treatment options for patients with positive margins might be applied more selectively, and that systematic SRT might not be necessary in most cases.

We also would like to question the risk grouping proposed in the article to predict FFDM after 6 years (6-year FFDM). By combining patients with no risk factors (6-year FFDM = 75.8%) to those with either Gleason score 8–10 (6-year FFDM = 54.3%) or concurrent ADT (6-year FFDM = 64.0%) in a single group, the favourable prognosis of patients without any risk factor seems inappropriately merged with the two poorer-outcome risk factors, leading to an overall 6-year FFDM of 71% in that group. Based on the tables presented, separating patients with no risk factors from those with a high Gleason score or with concurrent ADT to create a separate risk group seems essential to optimise stratification given the striking difference in FFDM rates. We are also wondering why a similar weighted-risk grouping was not performed for PCSS, given that hazard ratios for the same variables were similar between FFDM and PCSS.

Another important limitation, as acknowledged by the authors, lies in the lack of analysis based on the period of treatment over their 27-year review (1986–2013). Although they provide second BCR rates for every decade, they do not to perform complete subgroup analyses for separate periods. As discussed in the article, 2004 marked an important change in the technique of RT at their institutions (three-dimensional planning vs intensity-modulated RT) and could have been used as a threshold to stratify patients based on era, which would have removed this possible confounder. Other important factors, also mentioned by the authors (e.g. increase in CT sensitivity over the years, problems with older ADT records, new therapies for castration-resistant prostate cancer since 2010), may have significantly influenced outcomes in the sample. We understand that most of these subgroupings, even if theoretically necessary, would probably have made analyses underpowered. Furthermore, as discussed in the paper, it would have been relevant to study PSA doubling time, as it is a well-recognised surrogate for clinical progression and PCSS in primary BCR [5]; maybe similar results could have been expected in second BCR.

Overall, our team thinks that the study led by Tumati et al. [1] reached its primary objective of describing the natural history of second BCR following SRT after RP, whilst providing new, multi-centric data on this poorly explored topic. Moreover, the proposed risk stratification system for FFDM and PCSS after 6 years provides much needed prognostic insight for treatment-resistant disease. In addition, such data can help design future trials assessing new treatment options or novel diagnostic techniques and improve clinical management of second BCR.

Felix Couture * Come Tholomier *† and Kevin C. Zorn
**Section of Urology, Department of Surgery, University of Montreal Health Center (CHUM), Universite de Montreal, Montreal, Quebec, Canada and †Department of Surgery, Division of Urology, McGill University, Health Centre, Montreal, Quebec, Canada

 

 

References

 

1 Tumati V, Jackson WC, Abugharib AE et al. Natural history of ‘second’ biochemical failure after salvage radiation therapy for prostate cancer: a multi-institution study. BJU Int 2018; 121: 366–73.

 

2 Eggener SE, Scardino PT, Walsh PC et al. Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J Urol 2011; 185: 869–75

 

3 Tendulkar RD, Agrawal S, Gao T et al. Contemporary update of a multi-institutional predictive nomogram for salvage radiotherapy after radical prostatectomy. J Clin Oncol 2016; 34: 3648–54

 

4 Wadhwa H, Terris MK, Aronson WJ et al. Long-term oncological outcomes of apical positive surgical margins at radical prostatectomy in the Shared Equal Access Regional Cancer Hospital cohort. Prostate Cancer Prostatic Dis 2016; 19: 423–8

 

5 Freedland SJ, Humphreys EB, Mangold LA et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 2005; 294: 433–9

 

Article of the Month: Comparing survival after RN vs NSS in RCC

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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 month, it should be this one.

Testing the external validity of the EORTC randomized trial 30904 comparing overall survival after radical nephrectomy vs nephron-sparing surgery in contemporary North American patients with renal cell cancer

 

Firas Abdollah, * Sohrab Arora, * Nicolas von Landenberg, †Philipp Gild, ‡Akshay Sood, * Deepansh Dalela, * Quoc-Dien Trinh, §Mani Menon, * and Craig Rogers, *

 

*Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA, †Department of Urology, Marien Hospital Herne, Ruhr-University Bochum, Herne, Germany, ‡Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg,Germany and §Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

 

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The European Organization for Research and Treatment of Cancer (EORTC) randomized trial 30904 reported that for solitary renal masses ≤5 cm, radical nephrectomy (RN) was associated with a higher overall survival (OS; primary endpoint): 81%, compared with 76% for nephron-sparing surgery (NSS) at a median follow-up of 9.3 years (P = 0.03). The difference in cancer-specific mortality, however, was not significant. For histologically proven RCC, and after exclusion of patients with positive surgical margins, NSS was associated with equivalent OS compared with RN [1]. It is noteworthy that the renal function outcomes of the two groups in the trial have been reanalysed, showing that renal function does not decline over time after RN, as was expected [2].

The EORTC 30904 trial had difficulty recruiting and randomizing patients, and was criticized for not meeting the accrual goal of 1300 patients. Additionally, the generalizability of the study findings to ‘real-world’ patients has been questioned. Despite the criticism, and more than 20 retrospective studies [3, 4] showing better OS and cancer-specific survival with NSS, this randomized clinical trial (RCT) remains the only available level 1 evidence on this subject. Notably, no study to date has formally examined the external validity [5] of the trial.

For any RCT to be externally valid, its supposedly randomly selected sample must be representative of the general population seen in clinical practice. In this context, we studied patients with localized RCC treated with NSS or RN within the National Cancer Database (NCDB), in an effort to test the external validity of the EORTC 30904. Our objective was not to compare survival outcomes between the two treatment arms, as this is beyond the scope of examining the external validity of an RCT, and such analysis is already available in literature. Instead, our aim was to ascertain if the trial patients were representative of contemporary patients with RCC in the USA, using the NCDB, which captures ~70% of all incident cancer diagnoses in the USA [6].

We identified patients who met the clinical and pathological inclusion criteria of the EORTC 30904 within the NCDB from 2004 to 2013: histologically confirmed RCC; tumour size ≤5 cm; clinically node-negative, non-metastatic disease; no positive surgical margins; and no pT3/4 disease. After exclusions, there were 90 844 assessable patients within the NCDB, of whom 41 588 (45.78%) underwent RN and 49256 (54.22%) underwent NSS. The demographic characteristics, namely, age, gender (percentage of men), presence of comorbidities (yes/no), histology (clear cell/non-clear cell), Fuhrman grade (1, 2, 3 or 4) and surgical approach (open/robotic/laparoscopic) were then compared with the patients enrolled in the EORTC 30904. The statistical significance of differences in categorical variables was tested using the chi-squared test. Unfortunately, the trial did not provide measures of variance (such as standard deviation, or interquartile range) for continuously coded variables; we were therefore unable to test for the statistical significance of differences in these variables. All analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA), with a P value <0.05 taken to indicate statistical significance.

The median age of the NCDB cohort was 60.0 years, compared with 62.0 years in the EORTC 30904. The median clinical tumour size in the NCDB was 30 mm, similar to the 30-mm tumour size observed in the trial. The percentage of men was 59.4% in the NCDB vs 65.8% in EORTC 30904 trial (P < 0.001). The NCDB cohort was healthier, with 70.03% patients having no comorbidity vs 62.8% in the trial (P < 0.001). The percentage of patients with clear-cell histology was 81.9% in the NCDB vs 62.9% in the trial (P < 0.001). The trial did not report data on race, while the NCDB had 15.6% non-white patients. Finally, the percentage of patients with high-grade disease (Fuhrman grade ≥3) was 21.1% in the NCDB vs 11.2% in the EORTC 30904 (P < 0.001; Table 1). Notably, in the EORTC 30904 trial, there was no central pathology review.

Table 1. Descriptive statistics of 391 clinically and pathologically eligible patients randomized to nephron-sparing surgery (NSS) or radical nephrectomy (RN) in the European Organization for Research and Treatment of Cancer randomized trial 30904 compared with 40 762 patients within the National Cancer Database with similar inclusion/exclusion criteria, who underwent NSS vs RN, between 2004 and 2013
Variable EORTC 30904 trial NCDB P

  1. EORTC 30904, European Organization for Research and Treatment of Cancer randomized trial 30904; IQR, interquartile range; NCDB, National Cancer Database.
Study period 1992–2003 2004–2013 –
Number of patients clinically and pathologically eligible 391 90 844 –
Median (IQR) age, years 62 (not provided) 60 (51–69) –
Median (IQR) clinical tumour size, mm 30 (not provided) 30 (21–40) –
Men, % 65.8 59.44 <0.001
Race Not provided Non-white 15.6% –
Free of comorbid disease, % 62.8 70.03 <0.001
Clear cell histology, % 62.9 81.9 <0.001
Tumour grade, %
1 22.30 18.08 <0.001
2 66.60 60.78
3 10.50 19.63
4 0.70 1.51
Surgical approach (recorded in NCDB since 2010, n = 15 604), %
Open 100 39.4 <0.001
Robotic 0 34.6
Laparoscopic 0 23.5

Several important observations emerge from these results. First, age and tumour size were similar in the EORTC 30904 trial and the NCDB. These two variables are the most important determinants of mortality and stage of disease, respectively, which implies that the trial was able to recruit patients representative of those seen in ‘real-world’ clinical practice.

Second, there was a higher incidence of high-grade disease and clear-cell histology in the NCDB cohort compared with the EORTC 30904 trial. In other words, patients in the NCDB had more aggressive tumours as compared with patients in the trial. Arguably, such patients are better served with RN, which has a higher probability of completely eradicating the tumour. The survival benefit of RN observed in the trial might therefore be even more evident in clinical practice, where a higher proportion of patients harbour unpredictable aggressive disease.

Finally, the EORTC seems to have recruited patients with a higher comorbidity burden than is generally observed in clinical practice. The significance of this finding is controversial. On the one hand, it might be argued that the higher background mortality of the cohort could have masked the potential OS benefit of NSS by offering this treatment method to sicker patients with limited life expectancy [7]. On the other hand, preserving renal function might be even more important in sicker patients, who have the burden of other comorbidities [8].

The present study has some limitations. An inherent limitation of the NCDB is the lack of information on the performance status of patients. Second, the comparison was between two cohorts separated in time. The mode of treatment and thus, patient selection might have changed over time. The NCDB provides information about surgical approach starting in 2010, and indeed open surgery was performed in only 39.4% of the cases compared with 100% in the trial. More than 15% of patients in the NCDB had missing tumour grade compared with 4% in the trial; however, this proportion was equally distributed between patients undergoing RN and PN in the NCDB (data not shown). Despite the limitations, these findings are significant in the context of the recent debate on contemporary guidelines recommending NSS ‘wherever possible’ in patients with a normal contralateral kidney [9].

In conclusion, our results indicate that, although the EORTC 30904 cohort had somewhat different baseline characteristics than ‘real-world’ patients with small renal masses, none of these differences seem to have the potential to significantly alter the outcomes of the trial. The latter should therefore be considered generalizable to contemporary North American patients with renal masses ≤5 cm.

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Editorial: Is overall survival not influenced by PN vs RN?

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In this issue of the BJUI, Abdollah et al. [1] have for the first time tested the external validity of the only randomized clinical trial, 30904, run by the European Organization for the Research and Treatment of Cancer Genito-Urinary Group (EORTC GU) in the early 1990s, comparing cancer-specific survival and overall survival in patients with solitary renal masses of ≤5 cm and stage T1 and T2 in the TNM classification (in use at that time). The trial showed, as expected, that renal function was worse after radical nephrectomy (RN) and that the complication rate was higher after partial nephrectomy (PN) [2]. However, unexpectedly, overall survival after PN was not better than after RN [3], as was suggested or claimed in many non-randomized studies and also in a meta-analysis that included the EORTC 30904 trial as the only randomized clinical trial [4].

Despite a couple of limitations in the randomized trial, and it’s premature closure because of slow accrual, we performed a second analysis looking at the estimated GRF in the vast majority of the included patients and, most importantly, showed that kidney function did not progressively deteriorate after RN when the contralateral kidney was normal, and that only exceptionally did patients developed chronic kidney disease (CKD) necessitating dialysis [5].

Whilst it was anticipated that decreased kidney function should induce cardiovascular disease and increase cardiovascular death, this was separately investigated by Capitanio et al. [6] in a multicentre study where this suggestion was confirmed. However, looking at their Kaplan–Meier curves, it is clear that, although the negative impact on cardiovascular disease should become more and more obvious and accumulate over time, the split of the curves in favor of PN occurred very early after surgery. This indicates that the patients included in these non-randomized studies were different from the start, meaning that those selected for PN were ‘better’ patients who obviously had less cardiovascular disease and therefore had better cardiovascular outcomes. Another study confirmed that both PN and RN impact on cardiovascular disease [7], whilst another meta-analysis showed no difference for cardiovascular outcomes [8]. Obviously patients with preoperative CKD will benefit from nephron-sparing surgery [9], as well as those who have concomitant conditions, e.g. hypertension, diabetes, and a worse Charlson’s Comorbidity Index [10].

The authors, who tested the external validity of the EORTC 30904 trial in contemporary North American patients, need to be congratulated for the effort undertaken to show that the EORTC 30904 cohort was not significantly different from the National Cancer Database cohort in a manner that could influence the reported trial outcomes.

Hein Van Poppel* and Richard Sylvester†
*UZ Leuven – Urology, Leuven, Belgium and †EAU Guidelines Office, Brussels, Belgium

 

Read the full article

 

References

 

1 Rogers C, Abdollah F, Arora S, et al. Testing the external validity of the EORTC randomized trial 30904 comparing overall survival after radical nephrectomy vs nephron-sparing surgery in contemporary North American patients with renal cell cancer. BJU Int 2018; 345–8

 

2 Van Poppel H, Da Pozzo L, Albrecht W et al. A prospective randomized EORTC intergroup phase 3 study comparing the complications of elective nephron-sparing surgery and radical nephrectomy for low-stage renal carcinoma. Eur Urol 2007; 51: 1606–15

 

3 Van Poppel H, Da Pozzo L, Albrecht W et al. A prospective, randomized EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011; 59: 543–52.

 

4 Kim SP, Thompson RH, Boorjian SA et al. Comparative effectiveness for survival and renal function of partial and radical nephrectomy for localized renal tumors: a systematic review and meta-analysis. J Urol 2012; 188: 51–7.

 

5 Scosyrev E, Messing EM, Sylverste R et al. Renal function after nephron- sparing surgery versus radical nephrectomy; results from EORTC randomized trial 30904. Eur Urol 2014; 65: 372–7.

 

6 Capitanio U, Terrone C, Antonelli A et al. Nephron-sparing techniques independently decrease the risk of cardiovascular events relative to radical nephrectomy in patients with a T1a-T1b renal mass and normal preoperative renal function. Eur Urol 2015; 67: 683–9

 

7 Shuch B, Hanley J, Lai J et al. Overall survival advantage with partial nephrectomy: a bias of observational data? Cancer 2013; 15: 2981–9

 

8 Wang Z , Wang G, Xia Q et al. Partial nephrectomy vs radical nephrectomy for renal tumors: a meta-analysis of renal function and cardiovascular outcomes. Urol Oncol 2016; 34: 533. e11-533. e19

 

9 Woldu SL , Weinberg AC, Korets R et al. Who really benefits from nephron-sparing surgery? Urology 2014; 84: 860–7

 

10 Larcher A, Capitanio U, Terrone C et al. Elective nephron sparing surgery decreases other cause mortality relative to radical nephrectomy only in specific subgroups of patients with renal cell carcinoma. J Urol 2016; 196: 1008–13.

 

Video: Centralisation of RC for bladder cancer in England

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Centralisation of radical cystectomies for bladder cancer in England, a decade on from the ‘Improving Outcomes Guidance’: the case for super centralisation

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Abstract

Objective

To analyse the impact of centralisation of radical cystectomy (RC) provision for bladder cancer in England, on postoperative mortality, length of stay (LoS), complications and re-intervention rates, from implementation of centralisation from 2003 until 2014. In 2002, UK policymakers introduced the ‘Improving Outcomes Guidance’ (IOG) for urological cancers after a global cancer surgery commission identified substantial shortcomings in provision of care of RCs. One key recommendation was centralisation of RCs to high-output centres. No study has yet robustly analysed the changes since the introduction of the IOG, to assess a national healthcare system that has mature data on such institutional transformation.

Patients and Methods

RCs performed for bladder cancer in England between 2003/2004 and 2013/2014 were analysed from Hospital Episode Statistics (HES) data. Outcomes including 30-day, 90-day, and 1-year all-cause postoperative mortality; median LoS; complication and re-intervention rates, were calculated. Multivariable statistical analysis was undertaken to describe the relationship between each surgeon and the providers’ annual case volume and mortality.

Results

In all, 15 292 RCs were identified. The percentage of RCs performed in discordance with the IOG guidelines reduced from 65% to 12.4%, corresponding with an improvement in 30-day mortality from 2.7% to 1.5% (P = 0.024). Procedures adhering to the IOG guidelines had better 30-day mortality (2.1% vs 2.9%; P = 0.003) than those that did not, and better 1-year mortality (21.5% vs 25.6%; P < 0.001), LoS (14 vs 16 days; P < 0.001), and re- intervention rates (30.0% vs 33.6%; P < 0.001). Each single extra surgery per centre reduced the odds of death at 30 days by 1.5% (odds ratio [OR] 0.985, 95% confidence interval [CI] 0.977–0.992) and 1% at 1 year (OR 0.990, 95% CI 0.988–0.993), and significantly reduced rates of re-intervention.

Conclusion

Centralisation has been implemented across England since the publication of the IOG guidelines in 2002. The improved outcomes shown, including that a single extra procedure per year per centre can significantly reduce mortality and re-intervention, may serve to offer healthcare planners an evidence base to propose new guidance for further optimisation of surgical provision, and hope for other healthcare systems that such widespread institutional change is achievable and positive.

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Editorial: Examining the role of centralisation of radical cystectomy for bladder cancer

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Despite the high risk of postoperative complications and/or death, radical cystectomy (RC) is currently considered as the standard of care for patients with muscle-invasive bladder cancer (MIBC) without clinical evidence of metastases at initial diagnosis. As an alternative, trimodality bladder-sparing therapy with a potentially more favourable toxicity profile has been developed over recent decades, but definitive surgery may provide better cancer control outcomes, especially in fit individuals. Consequently, efforts have been made recently to improve RC quality by introducing new concepts in the perioperative management of patients with MIBC. For example, the implementation of robot-assisted techniques and enhanced recovery protocols may help to reduce surgical stress and facilitate discharge after early rehabilitation. Nonetheless, such valuable interventions are more likely to be delivered at expert centres in MIBC management.

Interestingly, given that surgical experience mostly comes from surgical volume, numerous studies suggest that there is an inverse relationship between hospital as well as surgeon volume and morbidities for major surgeries including RC. Specifically, a recent meta-analysis showed that high-volume hospitals (odds ratio [OR] 0.55, 95% CI: 0.44–0.69; P < 0.001) and surgeons (OR 0.58, 95% CI: 0.46–0.73; P < 0.001) were significantly associated with a lower risk of death after RC [1]. As a result, centralisation of RC at high-output centres has been advocated worldwide to optimise perioperative management of patients with MIBC and improve short-term outcomes.

In this issue of the BJUI, Afshar et al. [2] eloquently show that such a healthcare policy can be effective at the population level. The authors impressively collected perioperative information on >15 000 RC patients from the Hospital Episode Statistics (HES) dataset in England, where the ‘Improving Outcomes Guidance’ (IOG) programme recommends since 2002 that RC should be performed by surgeons operating at least five cases per year at centres carrying out ≥50 procedures per year. Interestingly, they found that the proportion of RC performed in discordance with IOG guidelines decreased from 60.7% in 2003 to 12.4% in 2013. This resulted in a significant improvement in the overall 30-day crude mortality rate, with a reduction from 2.7% to 1.5% over the 11-year period (P = 0.02). After adjusting for available confounding, RC patients in the non-IOG-compliant group were more likely to die at 30 days (OR 1.41, 95% CI: 1.13–1.76) or 1 year (OR 1.31, 95% CI: 1.21–1.43) as compared to those in the IOG-compliant group. When analysing the incremental effect of hospital volume, each extra RC per year reduced the risk of death at 30 days and 1 year by 1.5% (OR 0.985, 95% CI: 0.977–0.992) and 1% (OR 0.990, 95% CI: 0.988–0.993), respectively. Although there was no significant difference in the odds of postoperative complications between the two groups (OR 0.96, 95% CI: 0.88–1.04), the risk of re-intervention was higher in the non-IOG-compliant group (OR 1.20, 95% CI: 1.12–1.30). It is noteworthy that, as observed for the risk of death, each extra RC decreased the risk of re-intervention (OR 0.99, 95% CI: 0.991–0.995). In conclusion, the findings by Afshar et al. [2] suggest that urologists have embraced centralisation of care for RC patients in England and this is likely to have positively affected the short-term outcomes.

Although, as acknowledged by the authors, many limitations related to the administrative nature of the HES dataset (e.g. missing data or coding errors) may have influenced the aforementioned results, other reports from the USA are consistent with this study. Specifically, it has been estimated that up to 40% of the decline in 30-day mortality after RC from 2000 to 2008 was attributable to centralisation of care [3]. In addition, other RC quality criteria, such as adequate pelvic lymph node dissection at the time of surgery, have improved after similar centralisation in the Netherlands between 2006 and 2012 [4]. As such, centralisation of RC offers many undisputable advantages, but given that travel distance to the treating facility may represent an important barrier for patients with MIBC seeking surgical care, concerns have been raised with regards to potential drawbacks, including increased time to definitive surgery. However, a recent report from the USA showed that, although centralisation of RC has led to a decrease overall access to the treating facilities, the process simultaneously improved access to high-volume centres [5]. It is noteworthy that hospital volume standards for centralisation of RC should not be set too high to avoid unreasonable travel burdens on patients with MIBC [6].

To summarise, centralisation of care is arguably the best way to go, to continue improving quality of RC and its associated short-term outcomes in the near future. Despite inherent limitations, virtually all available evidence, including the study by Afshar et al. [2], converge toward the general concept that RC patients should be managed by experienced urologists operating at expert centres with trained surgical teams.

Thomas Seisen 
Department of Urology, Pitie Salpetriere Hospital, Assistance Publique des Hopitaux de Paris, Paris Sorbonne University, Paris, France

 

Read the full article

 

References

 

1 Goossens-Laan CA, Gooiker GA, van Gijn W et al. A systematic review and meta-analysis of the relationship between hospital/surgeon volume and outcome for radical cystectomy: an update for the ongoing debate. Eur Urol 2011; 59: 775–83

 

2 Afshar M, Goodfellow H, Jackson-Spence F et al. Centralisation of radical cystectomies for bladder cancer in England, a decade on from the ‘Improving Outcomes Guidance’: the case for super centralisation. BJU Int 2018; 121: 217–24 166

 

 3 Finks JF, Osborne NH, Birkmeyer JD. Trends in hospital volume and operative mortality for high-risk surgery. N Engl J Med 2011; 364: 2128–37

 

4 Hermans TJ, Fransen van de Putte EE, Fossion LM et al. Variations in
pelvic lymph node dissection in invasive bladder cancer: a Dutch

 

nationwide population-based study during centralization of care. Urol
Oncol 2016;34:532. e7–532.e12

 

5 Casey MF, Wisnivesky J, Le VH et al. The relationship between centralization of care and geographic barriers to cystectomy for bladder cancer. Bladder Cancer 2016; 2: 319–27

 

6 Birkmeyer JD, Siewers AE, Marth NJ, Goodman DC. Regionalization of high-risk surgery and implications for patient travel times. JAMA 2003; 290: 2703–8

 

Article of the Week: Centralisation of RC for bladder cancer in England

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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.

Centralisation of radical cystectomies for bladder cancer in England, a decade on from the ‘Improving Outcomes Guidance’: the case for super centralisation

Mehran Afshar*, Henry Goodfellow†, Francesca Jackson-Spence‡, Felicity Evison§, John Parkin§, Richard T. Bryan‡, Helen Parsons, Nicholas D. James§‡ and Prashant Patel§‡

 

*St George’s Hospital NHS Trust, London, UK, †The Royal Free London NHS Trust, London, UK, ‡University of Birmingham, Birmingham, UK, §University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK, and Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UK
Read the full article

Abstract

Objective

To analyse the impact of centralisation of radical cystectomy (RC) provision for bladder cancer in England, on postoperative mortality, length of stay (LoS), complications and re-intervention rates, from implementation of centralisation from 2003 until 2014. In 2002, UK policymakers introduced the ‘Improving Outcomes Guidance’ (IOG) for urological cancers after a global cancer surgery commission identified substantial shortcomings in provision of care of RCs. One key recommendation was centralisation of RCs to high-output centres. No study has yet robustly analysed the changes since the introduction of the IOG, to assess a national healthcare system that has mature data on such institutional transformation.

Patients and Methods

RCs performed for bladder cancer in England between 2003/2004 and 2013/2014 were analysed from Hospital Episode Statistics (HES) data. Outcomes including 30-day, 90-day, and 1-year all-cause postoperative mortality; median LoS; complication and re-intervention rates, were calculated. Multivariable statistical analysis was undertaken to describe the relationship between each surgeon and the providers’ annual case volume and mortality.

Results

In all, 15 292 RCs were identified. The percentage of RCs performed in discordance with the IOG guidelines reduced from 65% to 12.4%, corresponding with an improvement in 30-day mortality from 2.7% to 1.5% (P = 0.024). Procedures adhering to the IOG guidelines had better 30-day mortality (2.1% vs 2.9%; P = 0.003) than those that did not, and better 1-year mortality (21.5% vs 25.6%; P < 0.001), LoS (14 vs 16 days; P < 0.001), and re- intervention rates (30.0% vs 33.6%; P < 0.001). Each single extra surgery per centre reduced the odds of death at 30 days by 1.5% (odds ratio [OR] 0.985, 95% confidence interval [CI] 0.977–0.992) and 1% at 1 year (OR 0.990, 95% CI 0.988–0.993), and significantly reduced rates of re-intervention.

Conclusion

Centralisation has been implemented across England since the publication of the IOG guidelines in 2002. The improved outcomes shown, including that a single extra procedure per year per centre can significantly reduce mortality and re-intervention, may serve to offer healthcare planners an evidence base to propose new guidance for further optimisation of surgical provision, and hope for other healthcare systems that such widespread institutional change is achievable and positive.

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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

 

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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

 

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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

 

Video: Association between T2DM, curative treatment and survival in localized PCa

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

Read the full article

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.

View more videos

Article of the Week: Safety and efficacy of 2-weekly cabazitaxel in mCRPC

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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.

Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer

Alice Clement-Zhao* , Marie Auvray*, Hail Aboudagga†, Felix Blanc-Durand*, Antoine Angelergues *, Yann Alexandre Vano*, Florence Mercier‡, Nader El Awadly*, Benjamin Verret*, Constance Thibault* and Stephane Oudard*

 

*Department of Medical Oncology, †Pharmacy Department, Hopital Europeen Georges Pompidou, Paris, and ‡Stat Process Society, Port-Mort, France

 

Read the full article

How to Cite

Clément-Zhao, A., Auvray, M., Aboudagga, H., Blanc-Durand, F., Angelergues, A., Vano, Y. A., Mercier, F., El Awadly, N., Verret, B., Thibault, C. and Oudard, S. (2018), Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer. BJU International, 121: 203–208. doi: 10.1111/bju.13855

Abstract

Objectives

To evaluate the safety and efficacy of a 2-weekly cabazitaxel schedule in patients with metastatic castration-resistant prostate cancer (mCRPC).

Materials and methods

During the period October 2013 to February 2016, 43 patients with mCRPC were treated with cabazitaxel (16 mg/m2, on days 1 and 15 of a 4-week cycle) together with prophylactic granulocyte colony-stimulating factor (G-CSF). The safety profile and efficacy (prostate-specific antigen [PSA] response; biological, clinical or radiological progression-free survival [PFS] and overall survival [OS]) of the treatment were analysed.

Results

All patients had received prior docetaxel and 79.1% abiraterone acetate. At inclusion, 46.5% were aged >70 years and 27.9% had an Eastern Cooperative Oncology Group performance status ≥2. Six patients stopped treatment because of toxicity. Grade ≥3 toxicities were: asthenia (16.3%); neutropenia (11.6%); thrombocytopenia (9.3%); diarrhoea (7%), anaemia (4.7%), febrile neutropenia (4.7%) and haematuria (2.3%). In all, 52.4% achieved a ≥30% PSA response and 40.5% had a ≥50% PSA response. The median OS was 15.2 months.

Conclusion

This prospective pilot study suggests that cabazitaxel 16 mg/m² given 2-weekly has a manageable toxicity profile in docetaxel- and abiraterone acetate-pretreated patients with mCRPC. A prospective phase III trial comparing this regimen with the standard cabazitaxel regimen is planned to confirm these results.

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