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Editorial: Are historical studies relevant in the setting of grade migration?

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While randomized controlled trials are the ‘gold standard’ for comparative effectiveness research, it is important that they be taken in context of their limitations. This is especially true in surgical trials for prostate cancer. For one, factors such as blinding and allocation concealment are often impossible in surgery, and surgeon skill may have a large impact [1]. What is more, it can take over a decade before interventions yield detectable differences in prostate cancer survival. Consequently, shifts in diagnosis and management may make historical clinical trial findings less useful for contemporary patients. For example, the landmark Scandinavian Prostate Cancer Group Study number 4 (SPCG‐4) showed a survival benefit for men treated with radical prostatectomy rather than observation during the 1989–1999 time period [2] but management in the study differed from contemporary practice as, in the 1990s, strict ‘active surveillance’ protocols did not exist.

In addition to shifts in management, men diagnosed with prostate cancer today differ from those diagnosed in previous decades. This was shown by Dalela et al. [3] who compared registry‐based data from the USA with data on patients enrolled in the Prostate Cancer Intervention Versus Observation (PIVOT) trial, and found significant differences between the two cohorts.

In a similar vein, Cazzaniga et al. [4] designed an elegant study to assess the generalizability of the SPCG‐4 to contemporary cohorts of men with prostate cancer. They focused on histological grading and compared the natural history of men in the SPCG‐4 study to men in similar grade categories diagnosed approximately one decade later in Sweden.

The contemporary cohort was made up of men with localized prostate cancer drawn from the Swedish National Prostate Cancer Register (NPCR). Men in the NPCR diagnosed in 2005–2006 had lower prostate cancer‐specific and all‐cause mortality compared to men with similar grade cancer in the SPCG‐4 (hazard ratios 0.46, 95% CI 0.19–1.14, and 0.66, 95% CI 0.46–0.95, respectively). While some of the observed differences in survival may have been attributable to improved treatments, Cazzaniga et al. hypothesized that grade migration was to blame.

As expected, the authors found a shift in Gleason grading, with a decrease in Gleason Grade Group (GGG) 1 disease, corresponding to a historical score of Gleason 3 + 3 = 6, and a concurrent increase in GGG2 and GGG3 disease, corresponding to historical scores of 3 + 4 = 7 and 4 + 3 = 7, respectively. Importantly, these differences in prostate cancer‐specific and all‐cause mortality were mitigated after compensating for grade migration by increasing GGG by one for the NPCR group; in other words, men in the SPCG‐4 treated in the 1990s had similar prostate cancer‐specific and all‐cause mortality to men in a later period with a one‐unit higher GGG.

Grade migration has been a gradual process, which was hastened by the major 2005 International Society of Urological Pathology revision that recategorized some Gleason patterns from 3 to 4. Changes in 2014 further refined these, and the concept of grade groups was introduced by Epstein two years later. Older cases of Gleason score 6 cancer include histological patterns, such as cribriform and poorly formed glands, which today would be considered Gleason pattern 4.

Grade migration was also demonstrated by Danneman et al. [5] who analysed the Gleason scoring of prostate biopsies from the NPCR in Sweden for the period 1998–2011. There was an increasing incidence of low‐risk cancer (cT1 20% in 1998 to 51% in 2011) and a concurrent decrease in high‐risk cancers (cT3 29% to 16%), reflecting earlier detection. With earlier diagnosis from screening, one would expect a shift towards lower grades at diagnosis, but they found the opposite. Among low‐risk tumours (stage cT1 and PSA 4–10 ng/mL) the proportion of Gleason score 7–10 increased from 16% to 40%. Among high‐risk tumours (stage cT3 and PSA 20–50 ng/mL) the proportion of Gleason 7–10 increased from 65% to 94%.

Gleason score reclassification was also addressed by Albertsen et al. [6], who had prostate biopsy slides for the period 1990 to 1992 re‐reviewed by an experienced pathologist in 2002–2004. They found an upward shift in Gleason grading, with 55% of the samples upgraded, 14% downgraded, and 31% unchanged. Comparing matched cohorts of historical vs contemporary patients with prostate cancer, one might erroneously infer better survival. This illusory change in prognosis is known as the ‘Will Rogers phenomenon’.

While randomized trials such as the SPCG‐4 represent one of the highest levels of clinical evidence, it is important to keep in mind that these trials have limitations. Given the interval changes in grading criteria for prostatic adenocarcinoma, predicting clinical outcomes based on historical cohorts is rarely as simple as it may seem. While the fundamental conclusions of the SPGC‐4 remain valid, the finding that Gleason grade did not modify the effect of prostatectomy on survival is now less certain. Physicians should therefore use caution when inferring prognosis based on those results.

Cazzaniga et al. should be congratulated for this important work which will help physicians better counsel patients making decisions based on trials like the SPCG‐4.

References

  1. Trinh QD, Cole AP, Dasgupta P. Weighing the evidence from surgical trials. BJU Int 2017; 119: 659–60
  2. Bill‐Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364: 1708–17
  3. Dalela D, Karabon P, Sammon J et al. Generalizability of the Prostate Cancer Intervention Versus Observation Trial (PIVOT) results to contemporary North American men with prostate cancer. Eur Urol 2017; 71: 511–4
  4. Cazzaniga W, Garmo H, Robinson D, Holmberg L, Bill‐Axelson A, Stattin P. Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 (SPCG‐4) study. BJU Int 2019; 123: 421–8
  5. Danneman D, Drevin L, Robinson D, Stattin P, Egevad LJ. Gleason inflation 1998–2011: a registry study of 97,168 men. BJU Int 2015; 115: 248–55
  6. Albertsen PC, Hanley JA, Barrows GH et al. Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 2005; 97: 1248–53C

 

Article of the week: Does the robot have a role in radical cystectomy?

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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 editorial written by a prominent member of the urological community, and a video prepared by the authors. These are 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, we recommend this one.

Does the robot have a role in radical cystectomy?

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Abstract

Between 2014 and 2015, 3742 radical cystectomies (RCs) were performed in the UK. The majority of these were open RCs (ORCs), and only 25% were performed with robot assistance. These data contrast starkly with the picture in radical prostatectomy (RP), for which most operations are robot assisted (79.4% of the 7673 in 2016). Given that most pelvic surgeons have access to robotic facilities (as shown by the RP trends) and urologists are typically early adopters, one must question why many surgeons have yet to be convinced by robot‐assisted RC (RARC). This question is particularly perplexing given that RC is a more morbid operation than RP and most patients with bladder cancer are considerably less fit than the average man with prostate cancer, and therefore, reductions in morbidity are especially rewarding in this cohort.

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Editorial: Evidence trumps consensus

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We read with great interest the article by Khetrapal et al. [1]. Certain advantages of robotic cystectomy have been shown in retrospective studies and confirmed in the RAZOR trial [2]. Robotic cystectomy has been associated with lower blood loss, lower transfusion rates and a shorter length of stay; however, two randomized trials have shown no difference in complication rates, which was the original reason robotic cystectomy was attempted [2,3]. Khetrapal et al. seem to believe that this was because diversions were performed extracorporeally, and intracorporeal diversion would allow urologists to uncover the true benefit of robotic cystectomy. When the RAZOR trial was being designed (in 2009), intracorporeal diversion was early in development. Even today its use in the USA is restricted to a few centres and the Pasadena consensus statement (2015) acknowledges that only 3% of all diversions were performed intracorporeally [4]. While more commonly performed in Europe, intracorporeal diversions still form the minority of all urinary diversions. To date there are no reliable prospective data to convince us that intracorporeal diversion is superior, and the low quality of available evidence has been acknowledged in the Pasadena statement [4]. The iROC trial is a step in the right direction and we await its results with interest [5].

We agree with the authors that cost analysis is essential in evaluating the exact role of robotic cystectomy. It is also worth factoring in the indirect costs of the two procedures, given that most patients undergoing robotic cystectomy will have a shorter hospital stay and fewer blood transfusions, although robotic cystectomies may take longer to perform. We anticipate that as newer robotic systems are introduced the direct surgical costs may be reduced.

There is no universally accepted learning curve for performing a cystectomy based on prospective studies. Ten cystectomies in the preceding year before enrolment in the RAZOR trial was the lowest number of cystectomies permitted for the surgeon to be eligible to participate [2]. All surgeons were fellowship-trained with high-volume bladder cancer practices, and the majority had performed significantly more than 10 cystectomies. The high quality of surgical surrogates for both approaches that we reported, namely, lymph node yield, positive margins and complication rates, are testament to this. We believe that the authors’ statement that novice surgeons may have operated on trial patients is simply inaccurate. It is largely self-serving to fit the results of the RAZOR trial into their own narrative about their beliefs in the advantages of robotic surgery. The iROC trial requires surgeons to have carried out 30 or more intracorporeal diversions in their entire career, with accredited surgeons being required to perform more than 10 cystectomies per year for the last 2 years as primary surgeon, which does not seem remarkably different from the RAZOR trial criteria for surgeon participation [5].While it is clear that large volumes are associated with better outcomes, the magic number is unclear. The Pasadena Consensus Statement cites the National Institute for Health and Care Excellence (NICE) guidelines in the UK, which mandate a minimum of five cystectomies per year per surgeon as adequate surgical volume [4].

Operating time in RAZOR was defined as the time from patient entry to the time the patient exited the operating theatre [2]. In most instances, the time for positioning and anaesthesia (preparation and induction) before making any incision and the time after closure for extubation and leaving the room is generally ~60–80 min. The Pasadena Consensus statement recommends that experienced surgeons should aim to complete robotic cystectomies within 5–6 h, depending on the type of diversion, basing their recommendation on three available studies [4]. Of those papers, Hayn et al. (overall mean operating time 386 min and mean operating time after 50th case 339 min) and Richards et al. (mean operating time 449 min after 40th case of learning curve) defined operating time in their papers as incision to closure time [6,7]. The paper by Collins et al. does not define operating time; however, the mean operating time for cystectomy with intracorporeal diversion for both surgeons in that study was 438 min, and 87.5% of the cases selected in this study had ≤pT2 disease, suggesting a significant selection bias [8]. This institution is a part of the International Robotic Cystectomy Consortium (IRCC) which defines operating time as incision to closure time, leading us to believe that this was the probably the definition they used [8]. A recent study from the IRCC reported a mean operating time (incision to closure) of 364 min in 2134 patients [9]. All these data suggest that operating times in RAZOR were extremely competitive if not actually faster, once again attesting to the proficiency of the participating surgeons. Khetrapal et al. would have reached a different conclusion about the RAZOR trial results had they accurately interpreted the scientific data from the above-mentioned studies.

The RAZOR trial provided level 1 evidence proving the oncological efficacy of robotic cystectomy and confirming advantages such as reduced blood loss and length of stay [2]. We agree that the true place for robotic cystectomy will be determined once a cost–benefit analysis can be performed, and after we obtain high-level prospective data about intracorporeal diversions. To this end, we look forward to the successful completion of the iROC trial and await its publication. Until such time, we suggest more reliance on high-level evidence than on consensus statements and narratives.

by Vivek Venkatramani and Dipen J. Parekh on behalf of RAZOR trial investigators

References

  1. Khetrapal P, Kelly J, Catto J, Vasdev N. Does the robot have a role in radical cystectomy? BJU Int 2019; 123(3): 380-2.
  2. ParekhDJ, Reis IM, Castle EP et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an openlabel, randomised, phase 3, non-inferiority trial. Lancet 2018; 391: 2525–36
  3. Bochner BH, Dalbagni G, Sjoberg DD et al. Comparing open radical cystectomy and robot-assisted laparoscopic radical cystectomy: a randomized clinical trial. Eur Urol 2015; 67: 1042–50
  4. Wilson TG, Guru K, Rosen RC et al. Best practices in robot-assisted radical cystectomy and urinary reconstruction: recommendations of the Pasadena Consensus Panel. Eur Urol 2015; 67: 363–75
  5. Catto JWF, Khetrapal P, Ambler G et al. Robot-assisted radical cystectomy with intracorporeal urinary diversion versus open radical cystectomy (iROC): protocol for a randomised controlled trial with internal feasibility study. BMJ Open 2018; 8: e020500
  6. Hayn MH, Hussain A, Mansour AM et al. The learning curve of robot- assisted radical cystectomy: results from the international robotic cystectomy consortium. Eur Urol 2010; 58(2): 197–202
  7. Richards KA, Kader K, Pettus JA et al. Does initial learning curve compromise outcomes for robot-assisted radical cystectomy? A critical evaluation of the first 60 cases while establishing a robotics program. J Endourol 2011; 25(9): 1553–8
  8. Collins JW, Tyritzis S, Nyberg T et al. Robot-assisted radical cystectomy (RARC) with intracorporeal neobladder – what is the effect of the learning curve on outcomes? BJU Int 2014; 113(1): 100-7
  9. Hussein AA, May PR, Ahmed YE et al. Development of a patient and institutional-based model for estimation of operative times for robot-assisted radical cystectomy: results from the international robotic cystectomy consortium. BJU Int 2017; 120(5): 695–701

Video: Does the robot have a role in radical cystectomy?

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Does the robot have a role in radical cystectomy

Read the full article

Abstract

Between 2014 and 2015, 3742 radical cystectomies (RCs) were performed in the UK. The majority of these were open RCs (ORCs), and only 25% were performed with robot assistance. These data contrast starkly with the picture in radical prostatectomy (RP), for which most operations are robot assisted (79.4% of the 7673 in 2016). Given that most pelvic surgeons have access to robotic facilities (as shown by the RP trends) and urologists are typically early adopters, one must question why many surgeons have yet to be convinced by robot‐assisted RC (RARC). This question is particularly perplexing given that RC is a more morbid operation than RP and most patients with bladder cancer are considerably less fit than the average man with prostate cancer, and therefore, reductions in morbidity are especially rewarding in this cohort.

View more videos

 

Article of the week: Prognostic evaluation of perinephric fat, renal sinus fat, and renal vein invasion for patients with pathological stage T3a clear‐cell RCC

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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 editorial written by a prominent member of the urological community. These are 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.

Prognostic evaluation of perinephric fat, renal sinus fat, and renal vein invasion for patients with pathological stage T3a clear‐cell renal cell carcinoma

Paras H. Shah*, Timothy D. Lyon*, Christine M. Lohse†, John C. Cheville‡,
Bradley C. Leibovich*, Stephen A. Boorjian* and R. Houston Thompson*
 
*Department of Urology, †Department of Health Sciences Research, and
‡Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA
 

 

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Abstract

Objective

To investigate the prognostic significance of various patterns of extrarenal extension that comprise pathological stage T3a clear‐cell renal cell carcinoma (ccRCC) amongst patients undergoing nephrectomy for non‐metastatic disease.

Patients and Methods

A retrospective review of 563 patients who underwent radical nephrectomy for pathologically confirmed T3aN0/NxM0 ccRCC between 1970 and 2011 was performed. All pathological slides were re‐reviewed by one urological pathologist. Associations of patterns of extrarenal extension (perinephric fat [PF], renal sinus fat [SF], and renal vein [RV], in isolation or in any combination) with disease progression, cancer‐specific mortality (CSM), and all‐cause mortality were evaluated on multivariable analyses.

Fig. 1. Progression-free survival stratified by type of extrarenal extension

Results

Overall, PF invasion, renal SF invasion, and RV tumour thrombus were present in 144 (26%), 51 (9%), and 163 (29%) patients, respectively, with multiple patterns of extrarenal extension identified in 205 (36%) patients. There were no significant differences in survival outcomes for isolated involvement of PF, renal SF, or RV. However, patients with multiple patterns of extrarenal extension were at significantly increased risk of disease progression (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.04–1.65; P = 0.020), CSM (HR 1.64, 95% CI 1.27–2.12; P < 0.001), and all‐cause mortality (HR 1.32, 95% CI 1.08–1.61; P = 0.008).

Conclusions

The presence of multiple patterns of extrarenal extension is associated with a higher risk of disease progression and cancer‐related death after radical nephrectomy compared to isolated involvement of the PF, renal SF, or RV, which carry similar prognostic weight. If validated, these findings may help refine risk stratification of non‐metastatic T3a RCC by distinguishing patients with multiple vs one pattern of extrarenal extension.

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Editorial: Does knowing the risk of relapse in localized renal cell carcinoma matter?

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Shah et al. [1] report a retrospective analysis from the Mayo Clinic investigating the prognostic significance of different patterns of pathological T3a clear‐cell RCC in patients who underwent radical nephrectomy for localized disease. There was no difference in disease progression, cancer‐specific mortality or all‐cause mortality when comparing isolated perinephric fat invasion vs isolated renal sinus fat invasion vs isolated renal vein invasion. Multiple sites of extra‐renal extension compared with one site, however, was independently associated with an increased risk of disease progression (hazard ratio [HR] 1.31, P = 0.02), death from RCC (HR 1.64, P < 0.001) and all‐cause mortality (HR 1.32, P = 0.008) when adjusting for multiple key variables including age, tumour size, grade, presence of coagulative tumour necrosis and sarcomatoid differentiation. The authors incorporated multiple sites of extra‐renal extension vs one site into three RCC prognostic models: SSIGN score, UISS and MSKCC nomogram. After controlling for these three predictive tools independently, multiple sites of extra‐renal disease predicted progression, death from RCC and all‐cause death. These data suggest that risk stratification for pT3aN0MO clear‐cell RCC is improved by differentiating multiple vs one site of extra‐renal extension.

Does an improved ability to predict recurrence and mortality increase the likelihood of cure in high‐risk localized RCC patients in 2018? Unfortunately, the answer is no. Ideally, prognostic models would identify patients at sufficient risk to consider adjuvant therapy, which would increase cure rates by eradicating micro‐metastatic disease with an acceptable toxicity. Regrettably, in RCC management there are no well‐established post‐surgical therapies that improve cure rates. The deficiency of established adjuvant therapies is not attributable to a lack of investigative trials. In the era before vascular endothelial growth factor receptor (VEGFR) targeting, adjuvant vaccines, immunotherapies and other systemic therapies failed to demonstrate improved recurrence‐free (RFS) or overall survival (OS) [2]. The efficacy of VEGFR‐targeted therapies in the metastatic setting re‐energized the hope for adjuvant therapy in patients with high‐risk localized RCC after surgical resection in the past two decades. The results to date have been disappointing. To date, three trials (ASSURE, PROTECT and S‐TRAC) have been completed, comparing oral VEGFR tyrosine kinase inhibitors with placebo in high‐risk localized clear‐cell RCC, with disease‐free survival (DFS) as the primary endpoint [3,4,5]. ASSURE and PROTECT showed no difference in RFS or OS [3,4,5]. S‐TRACT demonstrated an improvement in DFS but not in OS [4]. A pooled analysis of these three trials also failed to demonstrate improved DFS or OS with adjuvant VEGFR‐targeted therapy [6]. Significant side effects with discontinuation of adjuvant therapy occurred in 28–45% of patients as a result of drug‐related toxicity [6]. Trials investigating immune checkpoint inhibitors have yet to be published and, with the established efficacy of these drugs in the metastatic setting, hope still remains for adjuvant therapy in resected high‐risk localized RCC.

If the current literature does not support adjuvant therapy for resected high‐risk RCC, does knowing the risk of relapse alter surveillance? National Comprehensive Cancer Network guidelines for resected stage III RCC recommend chest and abdominal imaging within 3–6 months, along with subsequent chest and abdominal imaging every 3–6 months for 3 years, and then annually up to 5 years. Although the ideal schedule for surveillance imaging is unknown, further characterizing of the risk of relapse in high‐risk localized RCC would not be likely to affect this schedule significantly.

Although knowing the risk of relapse in high‐risk localized RCC does not help management in 2018, there is still a value to enhancing our prognostic tools. For one, our prognostic tools help clinicians counsel patients appropriately about their risk of recurrence. In addition, enhanced prognostic tools will assist in selecting appropriate patients with high‐risk localized RCC for future clinical trials of adjuvant therapy and also help us understand the results when comparing cohorts within and between trials.

References

  1. Shah PH, Lyon TD, Lohse CM. Prognostic evaluation of perinephric fat, renal sinus fat, and renal vein invasion for patients with pathologic stage T3a clear cell renal cell carcinoma. BJU Int 2019; 123: 270–6
  2. Scherr AJO, Lima JPSN, Sasse EC et al. Adjuvant therapy for locally advanced renal cell cancer: a systematic review with meta‐analysis. BMC Cancer 2011; 11: 115–21
  3. Haas N, Manola J, Uzzo R et al. Adjuvant sunitinib or sorafenib for high‐risk, non‐metastatic renal‐cell carcinoma (ECOG‐ACRIN E2805): a double‐blind, placebo‐controlled, randomised, phase 3 trial. Lancet 2016; 387: 2008–16
  4. Ravaud A, Motzer RJ, Pandha HS et al. Adjuvant sunitinib in high‐ risk renal‐cell carcinoma after nephrectomy. N Engl J Med 2016; 375: 2246–54
  5. Motzer RJ, Haas NB, Donskov F et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol 2017; 35: 3916–23
  6. Sun M, Marconi L, Eisen T et al. Adjuvant vascular endothelial growth factore‐targeted therapy in renal cell carcinoma. Eur Urol 2018; 74: 611–20

 

Article of the week: Adjuvant radiation with androgen‐deprivation therapy for men with lymph node metastases after radical prostatectomy

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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 editorial written by a prominent member of the urological community. These are 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.

Adjuvant radiation with androgen‐deprivation therapy for men with lymph node metastases after radical prostatectomy: identifying men who benefit

Mohit Gupta*, Hiten D. Patel*, Zeyad R. Schwen*, Phuoc T. Tran*† and Alan W. Partin*

 

*Department of Urology, James Buchanan Brady Urological Institute, and †Department of Radiation Oncology and Molecular Radiation Sciences and Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA

 

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Abstract

Objectives

To perform a comparative analysis of three current management strategies for patients with lymph node metastases (LNM; pN1) following radical prostatectomy (RP): observation, androgen‐deprivation therapy (ADT), and external beam radiation therapy (EBRT) + ADT.

Patients and Methods

Patients with LNM after RP were identified using the National Cancer Database (2004–2013). Exclusion criteria included any use of radiation therapy or ADT before RP, clinical M1 disease, or incomplete follow‐up data. Patients were categorised according to postoperative management strategy. The primary outcome was overall survival (OS). Kaplan–Meier curves and adjusted multivariable Cox proportional hazards models were employed. Sub‐analyses further evaluated patient risk stratification and time to receipt of adjuvant therapy.

Results

A total of 8 074 patients met the inclusion criteria. Postoperatively, 4 489 (55.6%) received observation, 2 065 (25.6%) ADT, and 1 520 (18.8%) ADT + EBRT. The mean (median; interquartile range) follow‐up was 52.3 (48.0; 28.5–73.5) months. Patients receiving ADT or ADT + EBRT had higher pathological Gleason scores, T‐stage, positive surgical margin rates, and nodal burden. Adjusted multivariable Cox models showed improved OS for ADT + EBRT vs observation (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.64–0.94; P = 0.008) and vs ADT (HR 0.76, 95% CI: 0.63–0.93; P = 0.007). There was no difference in OS for ADT vs observation (HR 1.01, 95% CI: 0.87–1.18; P = 0.88). Findings were similar when restricting adjuvant cohorts for timing of adjuvant therapy. There was no difference in OS between groups for up to 2 549 (31.6%) patients lacking any of the following adverse features: ≥pT3b disease, Gleason score ≥9, three or more positive nodes, or positive surgical margin.

Conclusions

For patients with LNM after RP, the use of adjuvant ADT + EBRT improved OS in the majority of patients, especially those with adverse pathological features. Conversely, adjuvant therapy did not confer significant OS benefit in up to 30% of patients without high‐risk features, who may be managed with observation and forego the morbidity associated with immediate ADT or radiation.

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Editorial: Postoperative radiation and hormonal therapy for men with node‐positive prostate cancer: a new standard?

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The best management strategy for men with pathologically node‐positive (pN+) prostate cancer after radical prostatectomy (RP) has been debated for decades [1]. In the 1990s, the Radiation Therapy and Oncology Group (RTOG) initiated the RTOG 9608 trial to test the impact of radiotherapy (RT) and androgen‐deprivation therapy (ADT) in this setting. However, due to the rise in PSA screening and the practice of treating high‐risk prostate cancer with primary RT, the incidence of pN+ disease fell. Consequently, the trial closed due to poor accrual and the question faded in prominence. Today, both trends have reversed. PSA screening is less common and men with high‐risk prostate cancer are more frequently opting for RP. As such, physicians increasingly face the dilemma of pN+ disease. Guidelines provide little assistance, as they support everything from observation to multimodal treatment with RT and ADT. Patients and providers want to know, is there a standard treatment for all patients, and if not, how should one choose between such disparate options?

To answer these questions, one must start with the little randomised data that exist in this setting. The seminal trial by Messing et al. [1] randomised men with pN+ prostate cancer to ADT or observation with initiation of ADT after the development of symptomatic progression or distant metastases. ADT clearly improved overall survival and prostate cancer‐specific survival. However, critics noted the relatively poor outcomes in the observation group and the small sample size. Later, retrospective studies called the benefit of immediate ADT into question [2].

Against this backdrop, it is interesting that Gupta et al. [3] found the most common management approach in the USA National Cancer Database (NCDB) was observation rather than immediate ADT. Despite the randomised data, the cumulative side‐effects from lifelong ADT in a cohort of patients with no disease‐related symptoms and a median survival of well over 10 years are unappealing. Ultimately, many men do not appear to be willing to endure the diminished quality of life in exchange for a small improvement in quantity of life.

In contrast to the non‐curative nature of ADT, the possibility exists that the combination of postoperative RT and ADT could provide durable disease control, perhaps even without lifelong ADT. The data reported by Gupta et al. [3] in this edition of the BJUI provide support for this paradigm. These data add to a growing body of literature [4] that tells a consistent story with two common themes: (i) postoperative RT with ADT appears to be associated with improved survival in men with pN+ prostate cancer, and (ii) RT appears to convey the largest benefit to men with certain high‐risk pathological features. Should this body of literature lead us to eschew the old standard and advise observation for low‐risk men and RT with ADT for men at higher risk?

Before a new standard is declared, the limitations of retrospective population‐based research must be addressed. The authors performed a sophisticated analysis to reduce the impact of selection bias. However, due to the limitation of the available data, the authors were not able to account for possibly the most important variable: the postoperative PSA. One study showed that men with pN+ disease with a persistent PSA had an 8‐year clinical recurrence rate of 69% vs 12% for those with undetectable PSA [5].

It is likely that men with persistent PSA in the NCDB would have received immediate ADT with or without RT rather than observation. As such, one must be cautious of the similar survival between the observation and ADT group, especially in light of contradictory randomised data. That being said, it is reasonable for some men to conclude that the side‐effects of ADT outweigh the potential benefit, especially those with low‐risk features such as an undetectable postoperative PSA, low Gleason score, and limited lymph node involvement.

As RT with ADT appears superior to either observation or ADT alone, should more men receive RT? Probably. Of the men with high‐risk features, only 22% actually received postoperative RT. Should postoperative RT now be considered the standard for all men? Probably not. Whilst it appears that some men may indeed benefit from RT, the possibility of selection bias driving this result is real. Even if there is a true effect, identifying which patients harbour residual local disease, but do not already have subclinical distant metastatic disease is challenging. RT for all would lead to unnecessary side‐effects for men that would not benefit from the treatment. Ultimately, a randomised trial will be required to establish the benefit of RT and to define subgroups of men that may or may not benefit. Until then, we will continue to rely on excellent work like the accompanying paper from Gupta et al. [3] to identify men who may benefit from postoperative RT and ADT.

References

  1. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node‐positive prostate cancer. N Engl J Med 1999; 341: 1781–8
  2. Wong YN, Freedland S, Egleston B, Hudes G, Schwartz JS, Armstrong K. Role of androgen deprivation therapy for node‐positive prostate cancer. J Clin Oncol 2009; 27: 100–5
  3. Gupta M, Patel HD, Schwen ZR, Tran PT, Partin AW. Adjuvant radiation with androgen deprivation therapy for men with lymph node metastases following radical prostatectomy: identifying men who benefit. BJU Int 2019; 123: 252–60
  4. Abdollah F, Karnes RJ, Suardi N et al. Impact of adjuvant radiotherapy on survival of patients with node‐positive prostate cancer. J Clin Oncol 2014; 32: 3939–47
  5. Bianchi L, Nini A, Bianchi M et al. The role of prostate‐specific antigen persistence after radical prostatectomy for the prediction of clinical progression and cancer‐specific mortality in node‐positive prostate cancer patients. Eur Urol 2016; 69: 1142–8

 

Article of the week: Immediate versus delayed exercise in men initiating ADT

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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 editorial written by a prominent member of the urological community, and a video produced by the authors. These are 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.

Immediate versus delayed exercise in men initiating androgen deprivation: effects on bone density and soft tissue composition

Dennis R. Taaffe*†‡, Daniel A. Galvão*†, Nigel Spry*§¶, David Joseph***, Suzanne K. Chambers*††‡‡§§, Robert A. Gardiner*¶¶***, Dickon Hayne†††‡‡‡, Prue Cormie§§§, David H.K. Shum††¶¶¶and Robert U. Newton*†‡****

 

*Exercise Medicine Research Institute, †School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, ‡School of Human Movement and Nutrition Sciences, University of Queensland, Brisbane, Queensland, §Genesis CancerCare, Joondalup, Faculty of Medicine, University of Western Australia, **Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, ††Menzies Health Institute Queensland, Griffith University, Gold Coast, ‡‡Centre for Research in Cancer, Cancer Council, Queensland, Brisbane, Queensland, §§Prostate Cancer Foundation of Australia, Sydney, New South Wales, ¶¶Department of Urology, Royal Brisbane and Women’s Hospital, ***University of Queensland Centre for Clinical Research, University of Queensland, Brisbane, Queensland, †††UWA Medical School, University of Western Australia, Crawley, ‡‡‡Fiona Stanley Hospital, Murdoch, Western Australia, §§§Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria, Australia, ¶¶¶Neuropsychology and Applied Cognitive Neuroscience Laboratory, Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China, and ****Institute of Human Performance, The University of Hong Kong, Hong Kong, China

 

Read the full article

Abstract

Objectives

To examine whether it is more efficacious to commence exercise medicine in men with prostate cancer at the onset of androgen‐deprivation therapy (ADT) rather than later on during treatment to preserve bone and soft‐tissue composition, as ADT results in adverse effects including: reduced bone mineral density (BMD), loss of muscle mass, and increased fat mass (FM).

Patients and methods

In all, 104 patients with prostate cancer, aged 48–84 years initiating ADT, were randomised to immediate exercise (IMEX, n = 54) or delayed exercise (DEL, n = 50) conditions. The former consisted of 6 months of supervised resistance/aerobic/impact exercise and the latter comprised 6 months of usual care followed by 6 months of the identical exercise programme. Regional and whole body BMD, lean mass (LM), whole body FM and trunk FM, and appendicular skeletal muscle (ASM) were assessed by dual X‐ray absorptiometry, and muscle density by peripheral quantitative computed tomography at baseline, and at 6 and 12 months.

Results

There was a significant time effect (P < 0.001) for whole body, spine and hip BMD with a progressive loss in the IMEX and DEL groups, although lumbar spine BMD was largely preserved in the IMEX group at 6 months compared with the DEL group (−0.4% vs −1.6%). LM, ASM, and muscle density were preserved in the IMEX group at 6 months, declined in the DEL group at 6 months (−1.4% to −2.5%) and then recovered at 12 months after training. FM and trunk FM increased (P < 0.001) over the 12‐month period in the IMEX (7.8% and 4.5%, respectively) and DEL groups (6.5% and 4.3%, respectively).

Conclusions

Commencing exercise at the onset of ADT preserves lumbar spine BMD, muscle mass, and muscle density. To avoid treatment‐related adverse musculoskeletal effects, exercise medicine should be prescribed and commenced at the onset of ADT.

Read more Articles of the week

 

Editorial: Daily exercise is daily medicine

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Memes such as #10000steps, #Fit4LIFE and Apple’s new #CloseYourRings demonstrate the mantra ‘exercise is medicine’, a cornerstone of modern medical advice. Taaffe et al. [1] in this issue of the BJUI discuss the value of exercise medicine – Immediate vs delayed exercise in men initiating androgen deprivation: effects on bone density and soft tissue composition.

Moving from anecdotal observation about exercise to actionable evidence has seen considerable progress recently. In the last 20 years, the biological rationale for the benefits of exercise through mechanisms of physiological adaptation has become better understood [2]. Benefits, comparable to some biopharma breakthroughs, have been demonstrated in cardiovascular, neurobiological and psychological health and disease. This is now equally true in oncology [3]. Researchers at the University of Glasgow in Scotland wanted to seek out out if glycerol could hydrate also as creatine and what would happen if they combined both ingredients. What they found was pretty astonishing! 24 participants were ran through a series of experiments over 7 days where they ingested either creatine or glycerol and where they ingested both glycerol plus creatine at an equivalent time. The researchers discovered the participants who took glycerol and creatine had almost 40% more fluid weight than the participants who only took creatine and nearly 50% more fluid than those that only took glycerol. Some people wonder if this fluid increase will have a “soft” look and therefore the answer is absolute not because the water increase from glycerol is usually within the blood. To be more precise it increases the quantity of plasma in your body. So if you would like to urge that hardcore, skin-tearing pump, combine them both in your pre-workout, shop stairmaster machines.

Since the stoma serves as a channel for the feces to be eliminated in the body, it is vital to maintain skin integrity surrounding it. Stoma skin barrier is being placed to the stoma to keep the ostomy bag kept in place. An ostomy bag is being connected to the barrier to collect body waste. Generally, ostomy procedure is being performed for greater efficiency during waste elimination. Most of these supplies are given as one package when you purchase it in pharmacies or medical stores.

In cancer surgery, it is intuitive that physical activity/exercise increases cardio‐respiratory fitness and the body’s adaption to physiological stress, hence reducing mortality and morbidity in the perioperative period. Buy Athletic Sports Tape Today for the best result in exercise and comfortable exercise.  Less obvious is how this phenomenon offers benefit to quality of life, morbidity, and survival. Recent understanding in biology helps link exercise and systemic fitness to cellular metabolism, immunological response, and mutagenesis. Discoveries in previously overlooked epigenetic, immunological, metabolic, and cell growth pathways; and more research, are leading to the inception of the new fields of metabolic oncology and exercise oncology [4]. There is a growing resource of therapeutic candidates in trials targeting novel metabolic pathways, induced also in exercise, improving cellular metabolic fitness to reduce the Warburg effect and immunosuppressive lactate in the tumour microenvironment [5]. Whether you’re a beginner or a seasoned lifter, there’s a workout plan for your goals. 

Several notable studies have looked at genetics, quantified cardio‐pulmonary measures of fitness, exercise pre‐habilitation/enhanced recovery, and survivorship programmes across many cancers including oesophageal, colorectal, and prostate cancer. The data suggest that exercise improves outcomes after surgery, quality of life, hospital admissions, progression‐free survival, and overall survival [6].

Prostate cancer is a special case often treated with androgen‐deprivation therapy (ADT), yet androgens are an essential factor in maintaining bone mineral density; muscle mass, as well as motivation to exercise/exercise capacity; and sexual health. Hormone chemotherapy compromises the key role of androgens in maintaining musculoskeletal health and fitness at a systemic and cellular level. This poses hazards. Aside from the longer term hope of targeted therapies to maintain exercise capacity with all of its biological adaptations, perhaps we can reduce some of the deleterious effects of ADT with exercise interventions. Together with behavioural, nutritional and pharmacological treatment pathways, we aim to augment the positive effect exercise brings to patients with prostate cancer, and patients with cancer more generally.

As our scientific understanding increases, it is clear that personalised, prescribed exercise pre‐habilitation is likely to become a ‘gold standard’ in oncology care. Many treatments may increase survival, but at a cost of quality of life; physical activity may not only extend life but may also enhance its quality. Pre‐habilitation warrants serious further study if it is to become widely adopted in practice. It is not simply about telling patients to keep active. As per the Silver and Baima [7] definition, it is ‘a process on the cancer continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment, includes physical and psychological assessments that establish a baseline function level, identifies impairments, and provides targeted interventions that improve a patient’s health to reduce the incidence and the severity of current and future impairments’.

References

  1. Taaffe D, Galvão D, Spry N et al. Immediate versus delayed exercise in men initiating androgen deprivation: effects on bone density and soft tissue composition. BJU Int 2019; 123: 261–9
  2. Hojman P, Gehl J, Christensen JF, Pedersen BK. Molecular mechanisms linking exercise to cancer prevention and treatment. Cell Metab 2017; 27: 10–21
  3. Cormie P, Zopf EM, Zhang X, Schmitz KH. The impact of exercise and cancer: systematic review of the impact of exercise on cancer mortality, recurrence and treatment related side effects. Epidemiol Rev 2017; 39: 71–92
  4. Kinnaird A, Michelakis ED. Metabolic modulation of cancer: a new frontier with great translational potential. J Mol Med 2015; 93: 127–42
  5. Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 2011; 10: 671–84
  6. Thomas RJ, Holm M, Al‐Adhami A. Physical activity after cancer: an evidence review of the international literature. Br J Med Pract 2014; 7: 16–22
  7. Silver JK, Baima J. Cancer prehabilitation: an opportunity to decrease treatment‐related morbidity, increase cancer treatment options, and improve physical and psychological health outcomes. Am J Phys Med Rehabil 2013; 92: 715–27

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