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Editorial: Unveiling the surgical risk associated with neoadjuvant chemotherapy in bladder cancer

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In this issue of BJU International, Johnson et al. [1] examine the association between neoadjuvant chemotherapy (NAC) for bladder cancer and 30-day morbidity related to radical cystectomy (RC). Level 1 evidence supports use of cisplatin-based NAC for bladder cancer; a meta-analysis of 11 randomised trials including 3005 patients who received NAC found a 5% absolute increase in 5-year overall survival and a 9% absolute increase in 5-year disease-free survival compared with RC alone [2]. Despite this, recent studies have reported underutilisation of NAC at ≈20% [3], with several reasons proposed for this ‘non-compliance’ to guidelines. A 2013 National Cancer Data Base (NCDB) analysis found that increasing age, lower patient income, and treatment at a non-academic institution (P < 0.01) negatively influenced the receipt of NAC, while higher clinical stage and fewer comorbid conditions were associated with higher likelihood of receiving NAC (P < 0.01) [3].

Another relevant concern is that NAC may increase perioperative complications for RC given the toxicities associated with chemotherapy, advanced age and often high rates of renal and cardiac comorbidities among potential candidates [4]. Credit should be given to Millikan et al. [5] for first negating this fear in 2001 with a randomised trial comparing NAC vs adjuvant chemotherapy in patients with bladder cancer; this study did not find any increase in perioperative morbidity.

The present analysis by Johnson et al. [1] further debunks this misconception in contemporary practice (2005–2011), drawing on the American College of Surgeons National Surgical Quality Improvement Program (NSQIP), which prospectively collects a sample of risk-adjusted validated surgical patient data from >450 participating USA hospitals. The authors show that NAC was not an independent predictor of complications, reoperation, wound infection or dehiscence. The robustness of these findings is reinforced by the shorter adjusted length of stay among patients receiving NAC. Given that scant data exists on this topic, the authors contribute a valuable paper that substantially adds to the literature.

Despite its strengths, the study should be interpreted in light of notable limitations that the authors acknowledge. Many crucial variables are not tracked by the NSQIP and therefore cannot be accounted for, including type of chemotherapy regimen, delay between chemotherapy and surgery, surgical technique (open, laparoscopic, robotic), surgical quality (margins, extent of lymphadenectomy), clinical/pathological stage of bladder cancer, and hospital/surgeon volume. Besides, because RC is a morbid procedure with a mean length of stay of 11 days, 30-day complication rates do not capture its true morbidity as well as 90-day rates. In particular, several common complications, such as postoperative ileus or small bowel obstruction, tend to occur later during the postoperative recovery period. As such, chances are that the event rate is biased downward by the short-term duration of data capture by the NSQIP. This study also cannot fully examine the association of NAC with certain subtypes of complications, including gastrointestinal or bleeding complications, especially when other investigators examining robotic RC have reported a conflicting increase in perioperative complications associated with NAC [6] driven by a 27% rate of gastrointestinal complications, which are not tracked by the NSQIP. Of note, unadjusted rates of transfusion and bleeding events were both higher in the NAC group in the present study.

One of the relevant and heartening observations of the report is the gradual increase in the use of NAC over the study period from 4% of eligible patients to 11%, close to the NCDB estimates of 7.6% in 2006 to 20.9% in 2010 (P < 0.01) [3]. Interestingly, there was an increased probability of any complication in the most recent time period (odds ratio 0.47 for 2005–2009 relative to 2010–2011 in the primary multivariate model, P < 0.001). A plausible explanation is that as physicians have heeded the message to increase usage of NAC, treatment has expanded into a wider population with more comorbidities and therefore a greater propensity for complications. It would have been of interest to address this point by restricting the analyses to the most recent data to see if NAC does indeed predict perioperative complications in the most recent period from 2010 to 2011.

Finally, given the lack of detail available in the NSQIP, other relevant questions could not be addressed. Among them it would be relevant to know if complication rates vary between standard MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) and newer chemotherapy regimens such as dose dense MVAC (DD-MVAC) or gemcitabine plus cisplatin (GC). Similarly, the role of the delay or the elapsed time between chemotherapy and surgery on complications might be helpful in future trial planning.

Additional work still needs to be done to identify prognostic factors for both perioperative complications and long-term outcomes after NAC, so that this valuable therapy can be appropriately provided to the correct patients. Indeed, given the lack of randomised controlled trial data investigating less toxic regimens than MVAC, perhaps NAC is underused because clinicians and patients are underserved by the available data. The authors should be commended for their efforts in deconstructing possible barriers to increased uptake of NAC, a therapy known to confer survival benefits for our patients with bladder cancer.

Joaquim Bellmunt,*† Jeffrey J.Leow‡ and William Martin-Doyle§
*Bladder Cancer Center, Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, USA; †University Hospital Del Mar-IMIM, Barcelona, Spain; ‡Brigham and Women’s Hospital, Division of Urology and Center for Surgery and Public Health, Boston, MA, USA; §University of Massachusetts Medical School, Worcester, MA, USA

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References

  1. Johnson DC, Nielsen ME, Matthews J et al. Neoadjuvant chemotherapy for bladder cancer does not increase risk of perioperative morbidity. BJU Int 2014; 114: 221–228
  2. Bellmunt J, Orsola A, Wiegel T et al. Bladder cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. ESMO Guidelines Working Group. Ann Oncol 2011; 22 (Suppl. 6): 45–49
  3. Zaid HB, Patel SG, Stimson CJ et al. Trends in the utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer: results from the National Cancer Database. Urology 2014; 83: 75–80
  4. Meeks JJ, Bellmunt J, Bochner BH et al. A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol 2012; 62: 523–533
  5. Millikan R, Dinney C, Swanson D et al. Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. J Clin Oncol 2001; 19: 4005–4013
  6. Johar RS, Hayn MH, Stegemann AP et al. Complications after robot-assisted radical cystectomy: results from the International Robotic Cystectomy Consortium. Eur Urol 2013; 64: 52–57
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Social Media and Twitter from a Resident’s Perspective

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“Happy Twitterversary! You’ve just turned 1”

Really? As I stared bleary eyed, post-call at the email in my inbox I couldn’t believe what an ingenious idea such an email was (how many of us remember the day we started using Twitter?) and that another year as a resident (albeit on Twitter) was behind me.

No question I was a “slow adapter” to social media, in particular Twitter – it was too reactionary, I was too busy, it would take up too much time. I can’t remember how or why I was persuaded, but curiosity led to me to create a Twitter account in the middle of the night while waiting to put up a ureteral stent. Immediately my perception and the time frame in which I obtained information completely changed. I started adding accounts for sports and news outlets and…..urologists and urology journals. Who knew?!

Over the past year, I’ve become more comfortable and engaged with Twitter. As a resident, there are a number of opportunities and a few challenges associated with navigating and managing a successful and educational Twitter experience.

Opportunities:

1) World-wide collaborations with leaders in the field who may otherwise be “less accessible” – as a resident, this may be THE most important aspect of Twitter. For those of us pursuing fellowship, building research connections, etc., being able to have access to and follow program directors and leaders in urology is invaluable.

2) Centralization for notifications of publications that are recently in press – as an aspiring urologic oncologist and academician, this is very helpful. BJU International (@BJUIjournal), the Journal of Urology (@JUrology), European Urology (@EUplatinum), Urology Match (@UrologyMatch) and UroToday.com (@urotoday) are personally a few of the most active and informative accounts I follow.

3) Connected at meetings – the ability to be “everywhere”! Getting updates from multiple concurrent sessions has changed the way I attend meetings. AUA 2014 this past year in Orlando was my first meeting on Twitter – to be able to keep up to date on concurrent sessions while contributing to the session I was attending, enhanced and broadened my learning experience.

Drs. Tim Averch, Benjamin Davies, Stacy Loeb, Brian Stork , Henry Woo, Matt Cooperberg, Declan Murphy (Not pictured, Dr. Christopher Bayne). American Urological Association Social Media Committee – See more at: https://www.drbrianstork.com/blog/medical-student-perspective-aua14/

 

 

4) Quick hit knowledge “tidbits” – what immediately comes to mind is the evolution of the International Urology Journal Club. This has been very useful and has changed the social media landscape for international, real-time, educational discussions.

Like everything with being a resident, Twitter takes time. However, whether we are walking to a meeting, waiting in the OR, riding the elevator, there are opportunities throughout the day to stay involved and engaged. While I may occasionally miss out on discussions, such as the 48 hours of Urology Journal Club (which may just happen to correspond with a call week), one can always use hashtags (ie. #urojc) to go back and catch up on the banter and knowledge shared.

Personally, I have yet to encounter my attendings expressing concern about what I’m Tweeting or how I’m engaging in social media. To my knowledge, residents are not receiving any formal training or best practice training in social media during residency.  As Twitter continues to evolve and the field of Urology continues to lead the medical foray into Twitter, a resident “social media ethics seminar” may be something the AUA considers during the national meeting. Perhaps this may be held in conjunction with the Twitter training sessions at the AUA Resource Center and may take into consideration the recent Engaging Responsibly with Social Media: the BJUI Guidelines and the EAU Recommendations. As importantly, medical students interested in Urology should be aware of their online profiles displayed on social networking websites, considering that program directors are increasingly utilizing this avenue to further evaluate residency applicants.

Until then, we may all consider sticking to the advice of ESPN Radio personality Colin Cowherd “Social media: Don’t do it after a cocktail or in your underwear.”

 

Zach Klaassen is a Resident in the Department of Surgery, Section of Urology Georgia Regents University – Medical College of Georgia Augusta, USA. @zklaassen_md

 

What’s the diagnosis?

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Image from Autorino R et al. BJU Int 2014; 113: 762–768. doi: 10.1111/bju.12455

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Editorial: Pushing the robot-assisted prostatectomy envelope – to the safety limits? Better outcomes

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The present article by Lim et al. [1] describing the new technique for robot-assisted radical prostatectomy is provocative. It really does highlight the dramatic improvement in outcomes of prostate cancer surgery for men over the last 25 years. What used to be a 3-week hospital stay with a 50% incontinence rate and a 100% impotence rate [2, 3] now becomes a day case with a high likelihood of excellent urinary control early after surgery and a fair potential for potency preservation. Twenty-five years ago men who underwent radical prostatectomy were truly brave patients.

Lim et al. report a single series by the senior author of 50 cases performed using the so-called Retzius preservation technique. Their cohort of 50 patients treated this way was compared with a retrospective cohort of the surgeon’s patients. The patients had lower-risk disease and patients who had seminal vesicle invasion or extracapsular extension noted preoperatively, presumably on MRI, were excluded from the series. The authors report a shorter operating time and an earlier return to urinary continence in the first 6 months after surgery.

I guess where surgeons are now taking us is to an attempt to remove the prostate from the hammock of neurovascular, muscular and fascial tissue surrounding it, without disturbing the anatomy [4]. If this can be achieved then radical prostatectomy with minimal morbidity is a very compelling choice for the primary treatment of prostate cancer.

The authors’ hypothesis is that preservation of the levator fascia, puboprostatic ligaments and detrusor apron will fix the bladder somewhat like a sling would, with support at the bladder neck during increased intra-abdominal pressure.

It should be noted, however, that the present paper represents a single series of patients selected after a long learning curve by a very experienced surgeon. These excellent outcomes may simply reflect the fact that the surgeon is now extremely technically capable. It is contentious to assume that a propensity score matching of a retrospective cohort would represent a true comparator to contemporary outcomes. These excellent outcomes probably reflect technical improvements achievable with more risky and innovative surgery – after many cases. The authors should be congratulated on pushing the envelope to achieve even better outcomes for patients undergoing this operation, but the exclusion of patients with high-risk disease is probably the major negative aspect of their report. It has become increasingly obvious that patients with high-risk disease are those who benefit most from radical prostatectomy surgery. Surgery for patients with very-low-risk disease (Gleason 6) is probably unnecessary. Nevertheless, with continued insights such as those provided by these surgeons, we may be able to increase the range of patients to whom Retzius-sparing surgery in higher risk cohorts can be offered.

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Anthony J. Costello
Department of Urology, Royal Melbourne Hospital, Parkville, Victoria, Australia

References

  1. Lim SK, Kim KH, Shin T-Y et al. Retzius-sparing Robot-assisted Laparoscopic Radical Prostatectomy – combining the best of retropubic and perineal approaches. BJU Int 2014; 114: 236–244
  2. Wein AJ, Kavousi LR, Novick AC, Partin AW, Peters CA. Campbell-Walsh Urology, 10th edn. Saint Louis, MO: Saunders, 2011: 5688
  3. Catalona WJ, Carvalhal GF, Mager DE, Smith DS. Potency, continence and complication rates in 1,870 consecutive radical retropubic prostatectomies. J Urol 1999; 162: 433–438
  4. Costello AJ, Brooks M, Cole OJ. Anatomical studies of the neurovascular bundle and cavernosal nerves. BJU Int 2004; 94: 1071–1076
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Picture Quiz

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This image is taken from Ramos et al. assessing the validity of dry laboratory exercises for robotic training.

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Do we really need to show a survival benefit to justify ePLND in prostate cancer?

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Whilst extended pelvic lymphadenectomy has become part of standard care in select patients undergoing radical prostatectomy at some centres, it is not universally accepted or performed and remains controversial, so why is this? The most common reasons cited for not performing a node dissection, or at least an extended node dissection, include lack of proven therapeutic benefit and the increased operative time and risk of complications. But do we really need to show a survival benefit to accept the role of extended pelvic lymphadenectomy for patients undergoing radical prostatectomy? It would take a randomised trial run over at least a decade, thousands of patients and untold cost to prove or disprove. Although randomised trials can be invaluable in assessing some aspects of medical or surgical care, they are not always appropriate or even desirable for surgical outcomes as O’Brien et al eloquently illustrated. What’s more, results from RCTs in surgery can be misleading – consider the Prostate Cancer Intervention Versus Observation Trial, in which overall survival at a median follow-up of 10 years was approximately 50% in both arms. This is equivalent to the overall survival in the observation arm of Messing’s trial, in which virtually no patients died of non-prostate cancer causes and contrasts starkly with the current life expectancy of 65 year old males in Australia of 20 years. Patients in PIVOT weren’t living long enough to die from prostate cancer!

There is no doubt that for accurate nodal staging, an extended lymphadenectomy is currently the gold standard, as reflected in the EAU guidelines on prostate cancer. Two very elegant trials in recent years assessed the performance of similar templates in terms of staging accuracy and concluded that a modified extended template struck the right balance between accuracy and risk of complications. Joniau et al, showed in a prospective cohort of 74 patients, around half of whom were lymph node positive, a modified extended template including the pre-sacral nodes had a staging accuracy of 97% and removed 88% of positive nodes. Omitting the pre-sacral nodes accurately staged 94% of patients and removed 76% of positive nodes. Mattei et al concluded that their modified ePLND removed approximately 75% of “sentinel” nodes in a prospective series of 34 node negative patients. Whether a “modified” ePLND or “plain” ePLND is performed, the staging accuracy is significantly better than a “standard” PLND, which omits the nodes around the internal iliac vessels and according to Joniau et al would accurately stage 76% of patients and remove only 29% of positive nodes. A “limited” node dissection, removing only the tissue within the obturator fossa performed even worse, staging 47% and removing just 15% of positive nodes.

 From Mattei et al European Urology 2008, 53:118-125

But what is the real value in accurate nodal staging? Does it change patient management? The Messing trial showed that node positive patients who received adjuvant hormone therapy had improved CSS and OS compared to node positive patients observed until clinical progression. The study, however, has limited application to current real life patient management. Whilst patients with high volume nodal disease are likely to benefit from adjuvant hormone therapy, some patients with node positive disease, particularly those with micro-metastatic disease, will not suffer biochemical progression let alone clinical progression and therefore may not warrant ADT. Furthermore, most patients will be commenced on hormone therapy according to specific PSA criteria long before clinical progression. Despite these apparent weaknesses, the CSS and OS are remarkably similar to many retrospective series of node positive patients outside trials and managed in “real life”. Bader and Schumacher presented series of 92 and 122 node positive patients respectively, none of who received adjuvant hormone therapy. Ten year CSS for both of these series was approximately 60% and 10-yr OS in the Schumacher cohort was 53%, almost identical to the 10-yr OS in the Messing trial. Conversely, a number of retrospective series of node positive patients in which all, or almost all patients received AHT, 10-yr CSS ranged between 74-86% and 10-yr OS was 60 – 67%. These outcomes are similar to the AHT arm in Messing’s trial, in which 10-yr CSS was 85% and 10-yr OS was 75%. This is far from compelling evidence in favour of AHT in node positive patients, but it is certainly food for thought.

Rather than treat all node positive patients equally, however, we should be more sophisticated in our approach. Briganti and Schumacher have shown that patients with 1 or 2 positive lymph nodes have better 10-yr CSS than patients with 3 or more positive nodes whether they receive adjuvant hormone therapy or not. In Schumacher’s series, 10-yr CSS was 72-79% for patients with 1 and 2 positive nodes, versus 33% for patients with 3 or more positive nodes, without AHT. In Briganti’s series, 10-yr CSS for patients with 3 or more positive nodes was 73% and they were almost twice as likely to die from prostate cancer than those with fewer than 3 nodes positive. All patients received AHT. Perhaps then, we should consider patients with higher volume nodal disease on extended pelvic lymphadenectomy for immediate adjuvant hormone therapy, whilst those with micro-metastatic disease may be suitable for observation until predetermined PSA criteria are reached.

Beyond the staging benefit, Jindong et al recently published a prospective, randomised trial showing a BCR free survival benefit for patients undergoing extended versus standard pelvic lymphadenectomy. With a median follow-up of just over 6 years, intermediate risk patients undergoing ePLND had a 12% absolute reduction in biochemical recurrence (73.1% v 85.7%) and high risk patients more than 20% (51.1% v 71.4%) compared to those undergoing a standard node dissection. This may eventually translate into a survival benefit, or at least a clinical progression benefit, but in this cohort of patients, a reduction in biochemical recurrence means a reduction in the numbers requiring salvage radiation therapy and salvage androgen deprivation and the consequent side-effects and complications of these treatments.

It is clear the complication rate following ePLND is higher than with sPLND or no node dissection, but a recent review revealed the difference is accounted for by an increase in the incidence of symptomatic lymphoceles, most of which resolve with conservative management. Ureteric, nerve and major vascular injuries are rare. This would appear to be a much more acceptable complication profile than that following salvage radiotherapy, or androgen deprivation. Although uncommon, membranous urethral stricture following salvage radiation often confers debilitating and enduring morbidity. Continence and potency rates also suffer, not to mention bowel toxicity. A 20% absolute reduction in biochemical recurrence may also swing the pendulum away from adjuvant radiation in high risk disease, benefiting even more patients.

Proving a survival benefit with level 1 evidence is the holy grail of medical and surgical trials, but it is not the only outcome to consider. Biochemical recurrence following radical prostatectomy carries significant psychological burden and salvage therapies can carry significant morbidity. Disease recurrence is most common in the high risk population and there is now level 1 evidence of a real benefit to these patients when ePLND is included as part of their surgical care.

 

Dr Philip E Dundee

Epworth Prostate Centre and The Royal Melbourne Hospital

T: @phildundee

 

What’s the diagnosis?

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This image from Carthon et al. shows a patient with penile cancer.

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What’s the diagnosis?

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Two different prostate pathologies are shown. Images from Korkes et al. BJUI 2014; 113: 822–829. doi: 10.1111/bju.12339

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Staring Into The Abyss

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I was surprised at the referral in the first place, but baffled after seeing the patient in the flesh. It was someone else’s clinic, and the note read that this 94 year-old man on androgen deprivation for asymptomatic low volume metastatic prostate cancer for many years had a climbing PSA. About 8. Please discuss combined androgen blockade with him. I began the talk about how combined blockade has a pretty weak benefit at the best of times, and that in a 94 year-old it almost certainly would not make him live any longer. He was asymptomatic, so he would not feel any better, and he may have a worsening of his side effects. I wrapped it up by telling him he was old enough to make his own decisions about his treatment, and if he didn’t want another pill to take, he could certainly say no. He said yes. I clarified the points about limited or no benefit, and possible exacerbation of side effects. He said if it would give him a few more years, he’d take it. I told him it wouldn’t. He wanted it anyway. I could not promise the treatment would not make him live any longer, and that was good enough for him. At the end of the consultation he was well counseled, and had made his decision. You might think of an 80 year-old you have seen who seemed more like a 60-year old, and think I was being unfair to the man, but I can confirm he was a 94 year-old who seemed very much to be 94.

I tend to assume that when people get to a certain age, they have come to terms with a few things, including death. This is not always the case, and I think running from death is becoming more popular. While research confirms that doctors have few illusions about treatment leading up to their own demise, and plan to refuse much of it, laypeople are hungry for all the invasive treatment they can get. As doctors, we don’t always help with this. We have pills and procedures that make statistically significant improvements in cancer specific survival, and what cancer sufferer would say no to that? We spend a lot more time studying how to hold failing anatomy together than we do learning to let entropy take its course. We have treatments that hint at immortality, nobody needs to die of Condition X anymore, now that we have Drug Y. What if this patient in front of us is the one in a hundred that has a durable remission? What if we kill them through inaction? What about the guilt-ridden estranged son who wants “Everything Done”?

Popular media have kept up a sustained and determined campaign for cardiovascular resuscitation in particular. Having an intelligent, sensitive, pragmatic talk to a family about not resuscitating the palliative patient due to the invasive, undignified nature of resuscitation for a virtually negligible chance of durable success is not as convincing as James Bond being defibrillated in his Aston Martin.

 

What is the definition of “good survivor” if not continuing to drink, gamble, and assassinate day zero post-resuscitation? Sadly, days or weeks of vegetative decline is much more common.

So what of the 94 year-old, who has already outlasted his cohort’s life expectancy by over 20 years? Who lived through two world wars, the rise and fall of the Soviet Communist state, the invention of Rock ‘n’ Roll, space flight, and electric foot spas? Objectively, he made an informed decision about his health care, prioritizing his values and concluding that the chance of increased quantity, however tiny, trumped quality. I can’t help think that in reality he kidded himself that he was beating death once again. He had evaded those cruel icy fingers, and secretly maybe thought he could live to a hundred and fifty. If he was my Grandpa, maybe I could have talked to him about embracing the end as a part of the natural cycle; not fearing, but accepting. But then, I was just his doctor.

Jim Duthie is a Urological Surgeon/Robotic Surgeon. Interested in Human Factors Engineering, training & error, and making people better through electronic means. Tauranga, New Zealand. @Jamesduthie1

 

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