Tag: Article of the Week

Posts

Article of the Month: MEAL Study – Effects of Diet in PCa Patients on AS

March 28, 2018/by admin Z.9

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

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

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

Men’s Eating and Living (MEAL) study (CALGB 70807 [Alliance]): recruitment feasibility and baseline demographics of a randomized trial of diet in men on active surveillance for prostate cancer

J. Kellogg Parsons*†‡ , John P. Pierce§, James Mohler¶, Electra Paskett**, Sin-Ho Jung††, Michael J. Morris‡‡, Eric Small§§, Olwen Hahn¶¶, Peter Humphrey***, John Taylor††† and James Marshall†††

*Division of Urologic Oncology, UC San Diego Moores Comprehensive Cancer Center, La Jolla, CA, USA, †Department of Urology, UC San Diego Health System, La Jolla, CA, USA, ‡VA San Diego Healthcare System, La Jolla, CA, USA, §Department of Family Medicine and Public Health and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA, ¶Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA, **Department of Medicine, College of Medicine, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA, ††Alliance Statistics and Data Center, Duke University, Durham, NC, USA, ‡‡Memorial Sloan Kettering Cancer Center, New York, NY, USA, §§UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA, ¶¶Alliance Central Protocol Operations, University of Chicago, Chicago, IL, USA, ***Department of Pathology, Yale University Medical School, New Haven, CT, USA, and †††Department of Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, NY, USA J. Protocol Operations, University of Chicago, Chicago, IL, USA, ***Department of Pathology, Yale University Medical School, New Haven, CT, USA, and †††Department of Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, NY, USA

Read the full article

Abstract

Objective

To assess the most recommended books on keto and the feasibility of performing national, randomized trials of dietary interventions for localized prostate cancer.

Methods

The Men’s Eating and Living (MEAL) study (CALGB 70807 [Alliance]) is a phase III clinical trial testing the efficacy of a high‐vegetable diet to prevent progression in patients with prostate cancer on active surveillance (AS). Participants were randomized to a validated diet counselling intervention or to a control condition. Chi‐squared and Kruskal–Wallis analyses were used to assess between‐group differences at baseline.

Results

Between 2011 and 2015, 478 (103%) of a targeted 464 patients were randomized at 91 study sites. At baseline, the mean (sd) age was 64 (6) years and mean (sd) PSA concentration was 4.9 (2.1) ng/mL. Fifty‐six (12%) participants were African‐American, 17 (4%) were Hispanic/Latino, and 16 (3%) were Asian‐American. There were no significant between‐group differences for age (P = 0.98), race/ethnicity (P = 0.52), geographic region (P = 0.60), time since prostate cancer diagnosis (P = 0.85), PSA concentration (P = 0.96), clinical stage (T1c or T2a; P = 0.27), or Gleason sum (Gleason 6 or 3+4 = 7; P = 0.76). In a pre‐planned analysis, the baseline prostate biopsy samples of the first 50 participants underwent central pathology review to confirm eligibility, with an expectation that <10% would become ineligible. One of 50 participants (2%) became ineligible.

Conclusion

The MEAL study shows the feasibility of implementing national, multi‐institutional phase III clinical trials of diet for prostate cancer and of testing interventions to prevent disease progression in AS.

Read more articles of the week

Editorial: PCa Prevention – Proof is Elusive

March 28, 2018/by Laurence Klotz

Prevention is so much better than cure because it saves the labor of being sick. Thomas Adams, 1618

Inferior doctors treat the full blown disease; mediocre doctors treat the disease before evident; superior doctors prevent disease. Nai Ching, 1^st Chinese Medical Text, 2600 BC.

Enthusiasm for prevention is hundreds, even thousands of years old. In the field of prostate cancer, profound differences in the regional variation of prostate cancer around the world (highest in Americans and Scandinavians, lowest in Asians) despite the similar incidence of histologic occult prostate cancer, and shifts in the incidence in mortality amongst immigrant populations moving from low to high prostate cancer regions, led to a firm belief that clinical disease was preventable. This belief was supported by the known long initiation phase for prostate cancer, providing an opportunity over decades for diet and micronutrient intake to influence the likelihood of disease progression.

In addition, many epidemiologic studies pointed to the benefits of fruits and vegetable intake high in Vitamin E, Selenium, Beta Carotene, Lycopene, and other micronutrients, and a diet low in animal fat.

However, recently several pivotal studies have taken the bloom off the rose of prevention. In particular, the SELECT study demonstrated a 17% increased rate of prostate cancer in men on Vitamin E, and an increase in DM in men on Selenium (1). The study was resoundingly negative. In addition, both high intake of multivitamins, and high dairy and calcium intake, have been associated with an increased risk of fatal prostate cancer (2). Folic acid intake results in an increased incidence of prostate cancer. Despite the positive PCPC and Reduce trials, the 5 ARIs were not approved for prevention by the FDA due to concerns about an increased risk of high grade prostate cancer, despite the reduction in positive biopsies in men on the drug (mostly due to a decrease in low grade cancer).

Further, studies of the association between dietary intake of fruits and vegetables and PCa are inconsistent. For example, one large study of 130,544 men found no significant association between fruit or vegetable intake, including cruciferous vegetables, and prostate cancer. (3) Another study showed dietary modification, reducing fat and increasing fruits, vegetables, and fiber, had no impact on PSA. (4).

And yet, despite the negative intervention studies, a lingering spark of hope exists that the many positive population, epidemiologic, and pre- clinical studies supporting dietary prevention will be vindicated. The study in the current issue of BJU Int on the MEAL study is therefore a laudable and ambitious initiative (5). Remarkably, 478 men have been randomized to validated dietary counseling intervention vs no intervention. This paper reports the initial demographics and eligibility data. It is undoubtedly the first of many publications that will arise from this important trial.

Will this study prove its’ ambitious goal, to demonstrate that prostate cancer progression can be influenced by dietary modification? While the initiative is laudable, I suspect the hurdles are insurmountable given the sample size and conceptual basis for the study. The study is being performed in men on active surveillance, and the primary end point will be the risk of disease ‘progression’. The study references the Redeem study, which showed a 44% reduction in disease ‘progression’ with dutasteride compared to placebo (6).

What we have learned since the Redeem study was initiated more than a decade ago was that the major limitation of conservative management in men diagnosed with low grade prostate cancer on systematic biopsy is not disease progression as it is usually defined (ie, developing worse disease over time); it is grade misattribution, based on sampling and pathologic miss of co-existent higher grade cancer (7). Higher grade cancer is present in about 30% of men with Gleason 6 cancer on systematic biopsy. Finding this on subsequent systematic biopsy is largely a matter of luck, location of the cancer, and biopsy strategy and number. In contrast, true grade progression (from Gleason pattern 3 to pattern 4 or 5) is uncommon, estimated to occur in only 1-2% of patients per year (8). The adoption of MRI and targeted biopsy into the surveillance algorithm has reduced the misattribution problem. Thus, the true ‘event rate’ (exclusive of misattribution) is likely to be in the 15% range at 10 years. A study with the power to detect a 20% relative difference in these events, ie a 3% absolute difference, would require more than a thousand patients followed for 10 years.

In the Redeem study, the reduction in ‘progression’ was entirely related to a decrease in the volume of low grade cancer. Indeed, the rate of upgrading was 13% in both arms in Redeem. Therefore the decrease in progression in that study likely reflected the cytoreduction effect of 5 ARIs, and not a real biological effect on cancer progression.

Thus, to be meaningful, prevention studies in men on surveillance should identify, at the very least, a real reduction in grade progression, based on state of the art evaluation at baseline with MRI and targeted biopsies as warranted, and long term follow up. A decrease in the rate of volume progression of Gleason 6, a major end point of this study, is not meaningful. In the study as described, which does not explicitly incorporate MRI, an imbalance in the number of patients having off protocol MRI and targeted biopsies between the two arms could significantly bias the outcome.

A further problem with long term studies of dietary intervention relates to the well-known methodological limitations in this area—ensuring long term compliance, recall bias of food intake, and contamination of the control arm.

Nonetheless, the authors deserve strong congratulations for pursuing this major initiative. We will follow the course of this study with interest.

Dr. Laurence Klotz C.M.

Division of Urology, Sunnybrook Health Sciences Centre, 2075 Bayview Ave. #MG408

Toronto, Ontario M4N 3M5

Read the full article

References

Klein EA, Thompson IM Jr, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011
Lawson KA, Wright ME, Subar A, et al.: Multivitamin use and risk of prostate cancer in the National Institutes of Health-AARP Diet and Health Study. J Natl Cancer Inst 99 (10): 754-64, 2007
Key TJ, Allen N, Appleby P, et al.: Fruits and vegetables and prostate cancer: no association among 1104 cases in a prospective study of 130544 men in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 109 (1): 119-24, 2004
Shike M, Latkany L, Riedel E, et al.: Lack of effect of a low-fat, high-fruit, -vegetable, and -fiber diet on serum prostate-specific antigen of men without prostate cancer: results from a randomized trial. J Clin Oncol 20 (17): 3592-8, 2002.
BJU-2016-1793.R2 – The Men’s Eating and Living (MEAL) Study (CALGB 70807 [Alliance]): Recruitment Feasibility and Baseline Demographics of a Randomized Trial of Diet in Men on Active Surveillance for Prostate Cancer
Fleshner NE, Lucia MS, Egerdie B, et al. Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. 2012;379(9821):1103-1111.
Cooperberg MR, Carroll PR, Klotz L: Active surveillance for prostate cancer: progress and promise. J Clin Oncol 29 (27): 3669-76, 2011. [PubMed]
Lurdes Y.T. Inoue, Bruce J. Trock, Alan W. Partin, H. Ballentine Carter, Ruth Etzioni Modeling Grade Progression In An Active Surveillance Study Stat Med. Author manuscript; available in PMC 2015 Mar 15. Published in final edited form as: Stat Med. 2014 Mar 15; 33(6): 930–939.

Article of the Week: Chitosan membranes applied on the prostatic neurovascular bundles after nerve‐sparing robot‐assisted radical prostatectomy: a phase II study

March 21, 2018/by admin Z.9

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.

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

Chitosan membranes applied on the prostatic neurovascular bundles after nerve‐sparing robot‐assisted radical prostatectomy: a phase II study

Francesco Porpiglia* , Riccardo Bertolo*, Cristian Fiori*, Matteo Manfredi*, Sabrina De Cillis* and Stefano Geuna†

*Division of Urology, Department of Oncology, and †Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy

Read the full article

Abstract

Objective

To evaluate the feasibility and the safety of applying chitosan membrane (ChiMe) on the neurovascular bundles (NVBs) after nerve‐sparing robot‐assisted radical prostatectomy (NS‐RARP). The secondary aim of the study was to report preliminary data and in particular potency recovery data.

Patients and Methods

This was a single‐centre, single‐arm prospective study, enrolling all patients with localised prostate cancer scheduled for RARP with five‐item version of the International Index of Erectile Function scores of >17, from July 2015 to September 2016. All patients underwent NS‐RARP with ChiMe applied on the NVBs. The demographics, perioperative, postoperative and complications data were evaluated. Potency recovery data were evaluated in particular and any sign/symptom of local allergy/intolerance to the ChiMe was recorded and evaluated.

Results

In all, 140 patients underwent NS‐RARP with ChiMe applied on the NVBs. Applying the ChiMe was easy in almost all the cases, and did not compromise the safety of the procedure. None of the patients reported signs of intolerance/allergy attributable to the ChiMe and potency recovery data were encouraging.

Conclusion

In our experience, ChiMe applied on the NVBs after NS‐RARP was feasible and safe, without compromising the duration, difficulty or complication rate of the ‘standard’ procedure. No patients had signs of intolerance/allergy attributable to the ChiMe and potency recovery data were encouraging. A comparative cohort would have added value to the study. The present paper was performed before Conformité Européene (CE)‐mark achievement.

Read more articles of the week

Editorial: Nerve wrapping with biomaterials during radical prostatectomy to improve potency recovery

March 21, 2018/by Vipul Patel

Radical prostatectomy is one of the standard treatment options for localized prostate cancer. The functional outcomes of radical prostatectomy are steadily improving along with better understanding of the surgical anatomy involved. Technological and technical advancements have helped improve continence outcomes significantly. High‐volume centres have consistently reported continence rates of >95% 1; however, potency recovery is the major limiting factor in achieving trifecta, even with full nerve‐sparing. Neuropraxia secondary to surgical dissection is one of the factors delaying potency recovery. We were the first to introduce the concept of protecting the neurovascular bundle using a wrap. In 2015, we first published our work on dehydrated human amnion‐chorion membrane (dHACM) nerve wrapping, a potential means of improving functional outcomes after radical prostatectomy 2.

Clinical applications of biomaterials are increasingly being explored. Their biological and physiochemical properties influence their role in peripheral nervous system regenerative therapy 3. Amniotic membrane graft has multiple growth factors including epidermal growth factor, vascular endothelial growth factor and anti‐inflammatory chemokines and cytokines including interleukin (IL)‐1, IL‐10 and IL‐1ra. In vitro and in vivo studies have reported that dHACM minimizes the surgical trauma‐induced inflammation and peri‐neural adhesions. These membranes are commercially available in various sizes for clinical use.

Porpiglia et al. 4 have reported their work on chitosan membrane application on the prostatic neurovascular bundle. Their phase II study is a step towards finding an ideal biomaterial favouring peripheral nerve healing. Chitosan is another potential biomaterial made of glucosamine and N‐acetyl glucosamine polymer which are natural components of mammalian tissues 5. Chitosan is hypoallergenic and only transiently stimulates the immune system and ultimately becomes bio‐tolerated and metabolized. It is not possible to develop specific antibodies against it because there are no proteins and lipids in its structure. Chitosan has inherent antimicrobial activity as its positive loads destabilize the membrane integrity of microorganisms. The inherent haemostatic and antimicrobial action of chitosan favour its application in wound healing. Chitosan has been extensively researched as a carrier molecule for biologically active particles and a scaffold in tissue engineering. Porpiglia et al. 4 have reported the safety and feasibility of its application for neurovascular bundle wrap during radical prostatectomy. In their non‐comparative study, they observed 96.4% continence and 68.6% potency recovery within 6 months. Comparative clinical trials are recommended to study its advantages in both partial and full nerve‐sparing settings. Membranes were manufactured from chitosan solution and sterilized for the purposes of the study. Pending approval by the regulators, study in other centres using chitosan membrane may be challenging.

The urological community has long been searching for ways to optimize functional outcomes after radical prostatectomy. Even for an ideal candidate with full nerve‐sparing, potency recovery is not assured. Several technical and technological modifications are being explored to address this concern. Bio-materials hold potential, and further exploration is warranted in the form of multicentre and randomized trials.

Hariharan Palayapalayam Ganapathi, Fikret Onol, Travis Rogers and Vipul Patel

Global Robotics Institute at Florida Hospital, University of Central Florida College of Medicine, Celebration, FL, USA

Read the full article

References

1 Patel VR, Abdul‐Muhsin HM, Schatloff O et al.Critical review of ‘pentafecta’ outcomes after robot‐assisted laparoscopic prostatectomy in high‐volume centres. BJU Int2011; 108: 1007–17
Google Scholar

2 Patel VR, Samavedi S, Bates AS et al.Dehydrated Human Amnion/Chorion membrane allograft nerve wrap around the prostatic neurovascular bundle accelerates early return to continence and potency following robot‐assisted radical prostatectomy: propensity score‐matched analysis. Eur Urol2015; 67: 977–80
Google Scholar

3 Dalamagkas K, Tsintou M, Seifalian A. Advances in peripheral nervous system regenerative therapeutic strategies: a biomaterials approach. Mater Sci Eng C Mater Biol Appl2016; 65: 425–32
Google Scholar

4 Porpiglia F, Bertolo R, Fiori C, Manfredi M, De Cillis S, Geuna S. Chitosan membranes applied on the prostatic neurovascular bundles after nerve‐sparing robot‐assisted radical prostatectomy: a phase II study. BJU Int2018; 121: 473–9
Google Scholar

5 Rodríguez‐Vázquez M, Vega‐Ruiz B, Ramos‐Zúñiga R, Saldaña‐Koppel DA, Quiñones‐Olvera LF. Chitosan and its potential use as a scaffold for tissue engineering in regenerative medicine. Biomed Res Int2015; 2015: 821279
Google Scholar

Video: Chitosan membranes applied on the prostatic neurovascular bundles after nerve‐sparing robot‐assisted radical prostatectomy: a phase II study

March 21, 2018/by admin Z.9

Chitosan membranes applied on the prostatic neurovascular bundles after nerve‐sparing robot‐assisted radical prostatectomy: a phase II study

Read the full article

Abstract

Objective

Patients and Methods

Results

Conclusion

View more videos

Article of the Week: Prospective randomised non-inferiority trial of PD placement vs ND placement after RARP

March 14, 2018/by admin Z.9

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

Prospective randomised non-inferiority trial of pelvic drain placement vs no pelvic drain placement after robot-assisted radical prostatectomy

Avinash Chenam* , Bertram Yuh*, Ali Zhumkhawala*, Nora Ruel†, William Chu*, Clayton Lau*, Kevin Chan*, Timothy Wilson* and Jonathan Yamzon*

*Department of Surgery, Division of Urology and Urologic Oncology , and †Department of Biostatistics, City of Hope National Medical Center, Duarte, CA, USA

Read the full article

Abstract

Objective

To determine if eliminating the prophylactic placement of a pelvic drain (PD) after robot-assisted radical prostatectomy (RARP) affects the incidence of early (90-day) postoperative adverse events.

Patients and Methods

In this parallel-group, blinded, non-inferiority trial, we randomised patients planning to undergo RARP to one of two arms: no drain placement (ND) or PD placement. Patients with demonstrable intraoperative leakage upon bladder irrigation were excluded. Randomisation sequence was determined a priori using a computer algorithm, and included a stratified design with respect to low vs intermediate/high D’Amico risk classifications. Surgeons remained blinded to the randomisation arm until final eligibility was verified at the end of the RARP. The primary endpoint was overall incidence of 90-day complications which, based on our standard treatment using PD retrospectively, was estimated at 13%. The non-inferiority margin was set at 10%, and the planned sample size was 312. An interim analysis was planned and conducted when one-third of the planned accrual and follow-up was completed, to rule out futility if the delta margin was in excess of 0.1389.

Results

From 2012 to 2016, 189 patients were accrued to the study, with 92 patients allocated to the ND group and 97 to the PD group. Due to lower than expected accrual rates, accrual to the study was halted by regulatory entities, and we did not reach the intended accrual goal. The ND and PD groups were comparable for median PSA level (6.2 vs 5.8 ng/mL, P = 0.5), clinical stage (P = 0.8), D’Amico risk classification (P = 0.4), median lymph nodes dissected (17 vs 18, P = 0.2), and proportion of patients receiving an extended pelvic lymph node dissection (70.7% vs 79.4%, P = 0.3). Incidence of 90-day overall and major (Clavien–Dindo grade >III) complications in the ND group (17.4% and 5.4%, respectively) was not inferior to the PD group (26.8% and 5.2%, respectively; P < 0.001 and P = 0.007 for difference of proportions <10%, respectively). Symptomatic lymphocoele rates (2.2% in the ND group, 4.1% in the PD group) were comparable between the two arms (P = 0.7).

Conclusions

Incidence of adverse events in the ND group was not inferior to the group who received a PD. In properly selected patients, PD placement after RARP can be safely withheld without significant additional morbidity.

Read more articles of the week

Editorial: To drain or not to drain after RARP? That is the question

March 14, 2018/1 Comment/by Ben Challacombe

In the current issue of BJUI, the article by Chenam et al. [1] from the City of Hope Hospital clarifies an important surgical issue that most major uro-oncology centres face every day, but it also raises several other important surgical issues. The objective of the study was to determine if eliminating the routine placement of a pelvic drain after robot-assisted radical prostatectomy (RARP) affects the incidence of early (90-day) postoperative adverse events. RARP has become the new ‘gold standard’ approach for the surgical treatment of localized prostate cancer, and now comprises the majority of radical prostatectomies performed in the USA and the UK, with >80% of cases using this technique [2].

In this parallel-group, blinded, non-inferiority trial, patients who were planned to undergo RARP were randomized to one of two arms: no drain placement or pelvic drain placement. The primary endpoint was incidence of 90-day complications which, based on standard treatment using pelvic drain retrospectively, was estimated at 13%. The non-inferiority margin was set at 10%, and the planned sample size was 312. Despite stopping short of the intended number of patients to reach the accrual goal, it was impressive to read that the study was still well conducted, with robust statistical evidence that the no drain placement group was not inferior to the pelvic drain group. As a result, the authors conclude that pelvic drain can be safely omitted based on a clinical decision according to the surgeon’s discretion.

It has previously been demonstrated that the need for pelvic drain placement in RARP may be significantly less than in open prostatectomy techniques [3], and the concept of omitting the drain was initially presented more than 10 years ago [4]. But in any radical prostatectomy the rationale for placing a pelvic drain is potentially complex. Firstly, an anastomotic urine leak and subsequent urinoma or urinary peritonitis are the key historical concerns. The current reliable continuous running anastomosis now routinely possible with the robotic approach is far superior to the five to seven interrupted sutures inserted with the open or laparoscopic techniques, and hence the integrity is far more robust. Anastomotic leak rate is therefore generally very low at ~0.5–1% [2], and other non-randomized studies have previously shown that omission of pelvic drains is potentially safe [5].

Secondly, a drain may also assist with drainage of lymphatic leak after pelvic lymphadenectomy, preventing symptomatic lymphocele. The incidence of symptomatic lymphocele is ~2.5% in those undergoing RARP and extended pelvic lymph node dissection, as most lymphoceles are asymptomatic, but those that present late may be more at risk of infection in people with diabetes [6]. Another aspect that a small randomized controlled trial will not evaluate is the impact of the very occasional disaster, such as significant anastomotic disruption by a pelvic haematoma or a postoperative haemorrhage, and how that might be adverted by prior placement of a pelvic drain.

One of the few relevant problems with small randomized controlled trials in single centres is generalizability; results potentially only relate to very similar patient populations, i.e. those treated at high-volume and experienced centres, and cannot necessarily be extrapolated to other situations, such as RARPs performed by surgeons early on their learning curve or by those on fellowship/training programmes, or complex cases such as salvage RARP or when the anastomosis is technically challenging. This may include cases with significant bladder neck reconstruction, RARPs performed after TURP, or even cases with patients on steroids or other immunosuppressants. How necessary a pelvic drain is to the rapidly emerging Retzius-sparing RARPs remains to be seen, but judicious placement initially during the learning curve at least seems very sensible. Thus it would be wrong to conclude from the present study that pelvic drains are never indicated, as the authors also specify. Perhaps future larger studies may indicate more clearly those populations which do require pelvic drains in the form of an algorithm or decision-making tool.

It is clear that, as the emphasis shifts to enhanced recovery in the RARP population, pelvic drain placement may delay discharge and have a negative impact on the patient, such as increased anxiety and potential morbidity. In a public healthcare system such as the NHS, in which length of stay is an important cost variable, the present study empowers urologists to dispense with drains in the majority of cases. We believe the study was very well conducted and raises an important and a controversial topic. Overall, as we are all so much more familiar with standard RARP, it seems the time has come to omit the routine pelvic drain.

Salma Ghanem, Benjamin Namdarian and Ben Challacombe

Urology Centre, Guy’s Hospital, London, UK

Read the full article

References

1 Chenam A, Yuh B, Zhumkhawala A et al. Prospective randomized non-inferiority trial of pelvic drain placement vs no pelvic drain placement after robot-assisted radical prostatectomy. BJU Int 2018; 121: 358–65

2 BAUS UK Radical Prostatectomy Audit 2016. Available at: https:// www.baus.org.uk/_userfiles/pages/files/Publications/Audit/Radical% 20Prostatectomy%202016%20final%20analysis.pdf. Accessed November 2017

3 Danuser H, Di Pierro GB, Stucki P, Mattei A. Extended pelvic lymphadenectomy and various radical prostatectomy techniques: is pelvic drainage necessary? BJU Int 2013; 111: 963–9

4 Sharma S, Kim HL, Mohler JL. Routine pelvic drainage not required after open or robotic radical prostatectomy. Urology 2007; 69: 330–3

5 Musser JE, Assel M, Guglielmetti GB et al. Impact of routine use of surgical drains on incidence of complications with robot-assisted radical prostatectomy. J Endourol 2014;28:1333–7

6 Keskin MS, Argun OB, Obek C et al. The incidence and sequela of lymphocele formation after robot-assisted extended pelvic lymph node dissection. BJU Int 2016; 118: 127–31

Article of the Week: Natural history of ‘second’ biochemical failure after SRT for PCa

March 7, 2018/by admin Z.9

If you only have time to read one article this month, it should be this one.Follow us rothwelldouglas for more articles like this one.

Natural history of ‘second’ biochemical failure after salvage radiation therapy for prostate cancer: a multi-institution study

Vasu Tumati*, William C. Jackson†, Ahmed E. Abugharib†, Ganesh Raj‡, Claus Roehrborn‡, Yair Lotan‡ ,Kevin Courtney§, Aditya Bagrodia‡, Jeffrey C. Gahan‡, Zachary S. Zumsteg**, Michael R. Folkert*, Aaron M. Laine*, Raquibul Hannan*, Daniel E. Spratt† and Neil B. Desai*

Departments of *Radiation Oncology, ‡Urology, §Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA, Department of †Radiation Oncology, University of Michigan, Ann Arbor, MI, USA, and **Department of Radiation Oncology Cedars-Sinai Medical Center, Los Angeles, CA, USA

Read the full article

Abstract

Objectives

To describe the natural history of prostate cancer in men who experience a second biochemical recurrence (BCR) after salvage radiotherapy (SRT) after prostatectomy.

Patients and Methods

After undergoing SRT at one of two institutions between 1986 and 2013, 286 patients experienced a second BCR, defined as two rises in prostate-specific antigen (PSA) of ≥0.2 ng/mL above nadir. Event rates for distant metastasis (DM) or freedom from DM (FFDM), castration-resistant prostate cancer (CRPC), prostate cancer-specific survival (PCSS), and overall survival (OS) were estimated using the Kaplan–Meier method. Cox regression was used for comparative analyses.

Results

At a median of 6.1 years after second BCR, DM, CRPC, PCSS and OS rates were 41%, 27%, 83% and 73%, respectively. On multivariable analysis, interval to second BCR <1 year (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.71–4.14; P < 0.001], Gleason score 8–10 (HR 1.65, 95% CI 1.07–2.54; P = 0.022), and concurrent ADT during SRT (HR 1.76, 95% CI 1.08–2.88; P = 0.024) were associated with FFDM, while PCSS was associated with interval to second BCR <1 year (HR 3.00, 95% CI 1.69–5.32; P < 0.001) and concurrent ADT during SRT (HR 2.15, CI 1.13–4.08; P = 0.019). These risk factors were used to stratify patients into three groups, with 6-year FFDM rates of 71%, 59% and 33%, and PCSS rates of 89%, 79%, and 65%, respectively.

Conclusion

Following second BCR after SRT, clinical progression is enriched in a subgroup of patients with prostate cancer, while others remain without DM for long intervals. Stratifying patients into risk groups using prognostic factors may aid counselling and future trial design.

Read more articles of the week

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

March 7, 2018/by Felix Couture

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

Read the full article

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

February 28, 2018/by admin Z.9

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

Read the full article

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
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.

Read more articles of the week