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Editorial: RC & VTE – Are We Doing Enough?

Using a large comprehensive population-based cohort from Canada, Doiron et al. [1] present an in-depth analysis of risk factors and timing of venous thromboembolism (VTE) after radical cystectomy (RC) for bladder cancer. This report reiterates what is already known, which is that VTE after RC occurs at a non-negligible rate (5.4%) and most VTEs occur after hospital discharge (55%). VTE is an established complication in patients undergoing major oncological surgery, with some guidelines recommending 4 weeks of VTE prophylaxis after major pelvic surgery. This significant incidence of VTE after discharge highlights the potential impact of extended VTE prophylaxis for up to 28 days. Level I evidence for such practice was published more than a decade ago [2]. Yet, the uptake of these data remains low, at least in urological oncology. A recent survey-based study of pelvic cancer centres from the UK showed that only two-thirds of centres use post-discharge prophylaxis [3]. Using highly granular data, Doiron et al. [1] provide a detailed timeline of VTE occurrence after RC. They found that among patients who were diagnosed with VTE after discharge, >60% of these events occurred at ≤4 weeks of discharge. Unfortunately, there were no data on whether VTE prophylaxis was used in the study population.

The authors identified greater surgeon volume and increased length of hospital stay as risk factors for postoperative VTE, while accounting for important disease-related covariates. As mentioned by the authors, surgeon volume is most likely a surrogate for another unmeasured confounder. Higher volume surgeons, who often practice in large/academic institutions, may have increased case complexity with patients at higher risk for VTE. Additionally, such institutions may be more prone to perform diagnostic testing in high-risk patients and identify VTEs that would have otherwise gone unnoticed. A report from France found that the rate of VTE after RC was 24% in a cohort of patients who all underwent complete lower limb ultrasound, yet the vast majority (92%) were asymptomatic [4]. In other words, if you are looking for a VTE, you are more likely to find one. However, the clinical relevance of these VTEs remains unclear.

As shown from prior studies, length of stay was also found to be a risk factor for VTEs. Why does an increase in length of stay lead to a higher rate of VTE? One explanation is that patients who stay in the hospital longer are more likely to be immobilised for longer. This may explain why patients undergoing RC have higher rates of VTE than those undergoing other urological oncology procedures. However, immobilisation is a difficult variable to define or to measure. If longer immobilisation leads to increased VTE incidence, recently implemented enhanced recovery after surgery (ERAS) protocols that lead to earlier mobilisation would be expected to be associated with fewer VTEs. It is important to mention that other previously associated factors with VTE, including operative time and body mass index, which may be related to immobilisation time are not recorded in this study.

The use of neoadjuvant chemotherapy (NACT) for muscle-invasive bladder cancer has been shown to improve overall survival and is being increasingly used in RC patients. This study examined NACT as a risk factor but did not find an association. Notably, they were limited by the few patients who had received NACT. The use of chemotherapy in patients with cancer is a well-recognised risk factor for VTE [5]. It will be important in the future to continue to examine the incidence of VTE in NACT patients as this population grows.

Taken together, patients undergoing major cancer surgery have a significant risk of postoperative VTE, with evidence showing that rates of VTE are increasing over time [6]. Although guidelines for VTE prophylaxis are not uniform, this study’s findings [1] that most VTEs occur after discharge is a reason for urological surgeons to strongly consider extended VTE prophylaxis in this high-risk population.

Nawar Hanna and Jacqueline M. Speed

 

Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Womens Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

 

References

 

 

2 Bergqvist D, Agnelli G, Cohen AT et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. Engl J Med 2002; 346: 97580

 

3 Pridgeon S, Allchorne P, Turner B, Peters J, Green J. Venous thromboembolism (VTE) prophylaxis and urological pelvic cancer surgery: a UK national audit. BJU Int 2015; 115: 2239

 

 

5 Blom JW, Vanderschoot JPM, Oostindier MJ, Osanto S, van der Meer FJM, Rosendaal FR. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. J Thromb Haemost 2006; 4: 52935

 

6 Trinh VQ, Karakiewicz PI, Sammon J et al. Venous thromboembolism after major cancer surgery: temporal trends and patterns of care. JAMA Surg 2014; 149: 439

 

Société Internationale d’Urologie : Buenos Aires 2016


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Hola como estas? The 36th SIU congress was held in Buenos Aires, Argentina 20-24th October. Their motto: ‘we bring urologists together’ was certainly fulfilled as reflected by the warm atmosphere and international mix of speakers and attendees. The scientific programme included plenary sessions, debates, hands on instructional courses, trainee Q&A sessions and symposiums.

The location and facilities at the Hilton were first class. A large exhibition hall allowed for interaction with industry. The use of the pool bar hosted by the SIU innovators group was a particular highlight.

The conference app was easy to use and the conference hashtag #SIU16 and a #selfie challenge were promoted.  The selfie prize of a trip to SIU Portugal was won by Argentine resident Dr. Jose Nolazco with over 300 likes!

siu1Thursday

The conference kicked off with varied and interesting sessions on a range of urology, which included sub-section meetings such as societies of the Middle East, Africa, Asia, and Argentina; plus the 2nd SIU nurses educational symposium. The most popular meeting (in numbers attending and discussions after) was the World Urological Oncology Federation Symposium (WUOF). A delegate from South Africa told me that he appreciated the summary of new research and highlighting the areas of change, especially in a field when advances can occur quickly, for example PMSA-PET which may be able to give more information on metastatic prostate cancer than MRI. Arnaud Villiers vs Robert Reiter debated the issue of focused vs radical therapy to an intermediate, solitary lesion in the prostate. Reiter argued NOT for focal therapy on the basis of the imperfections of the MRI.

The MRI-TRUS fusion course, hosted by SIU Innovators division and with MIMS from industry present, championed MRI as a primary diagnostic test to investigate prostate cancer. Boris Hadaslick quoted (PROMIS trial) that TRUS biopsy without MRI had a 50% chance of finding cancer: ‘like flipping a coin’. He emphasised that targeted plus systematic biopsy sampling was best practice and highlighted the fusion software systems can improve cancer diagnosis. However cognitive fusion can be as good.

Speakers enthusiastic about advances in urology described high costs that had to be justified to their healthcare system like PSMA-PET and immunotherapy for bladder cancer. Yet these costs would be impossible for other delegates to take back to their home countries. Indeed the most innovative speakers presented their cost-saving techniques in the ‘SANTU’ session; the opening remarks of ‘how can you drive a Ferrari if you don’t have paved roads?’ was particularly levelling. One speaker, Mohammed Lezrek, stood out as being particularly creative, which he says is as a result of necessity, he showed videos using rubber from syringes or saline bag ports to fix the bungs on his endoscopes in Morocco (https://m.youtube.com/user/lezrekmohamed). These are issues I wouldn’t even think to know how to fix, being fortunate enough to work in the NHS. Other speakers in the same session described using generic, mass produced Ureteric stents that were a fraction of the price, another described treating a condition common to him in Indonesia of penile dermatosclerosis caused by penile injections of oil obtained as easily as ‘getting a haircut’ with the low cost surgical technique of scrotal flap. There was also a symposium on Urology in the Developing World, which included the best-titled talk: ‘the hunt for the perfect penis’ given by Ms Rampersad. She is the only surgeon performing hypospadias repair in Trinidad and Tobago, at an incidence of 2.7 per 1000 live births and recommended that specialist surgery be performed by those who are keen and performing larger volumes.

The Endourology Society Symposium was a popular session with standing room only. There were lessons on the possibilities, but also the limitations of flexible ureteroscopy, including an impromptu debate on use of access sheath and a case of stone clearance in a patient with HSK. A Canadian audience member spoke of his difficulty in justifying the use of flexi URS to managers in view of longer operation time compared to PCNL due to OR pressure. Michael Grasso captivated the audience with his experience in using flexible URS for diagnosis and treating upper tract TCC. In his series this meant less nephrectomies, no dialysis and better palliation. He even does LA flexi URS in selected patients! An important message on the dangers of IntraRenal pressure was presented by Palle Osther, which can occur even at an irrigation height of 40cm. He highlighted that whilst papers are championing the use of Flexi URS in more complex cases this means more time in the renal pelvis with the added risk of complications. He quoted Hippocrates ‘do no harm’. Grasso and Olivier Traxer explained their methods of stringent use of irrigation via piston controlled syringe and limiting operation time to an hour.

siu2My personal highlight was the presentation of videos by Mr René Sotelo on ‘getting out of sticky situations’ (SIU innovators symposium). An expert panel described similar mistakes to the ones shown on the videos and added what they would do if faced with the problem, leading to a fruitful and rich discussion. He showed tachycardia inducing, faint provoking videos of bleeding from upper and lower tract minimally invasive surgery. Advice such as stay calm, phone a friend, increase the pneumo, ‘suture fast’ was useful and practical. One case showed a rectal perforation at cystectomy where the attending/junior had been asked to place a swab (on stick) into the vagina, but it became apparent once the swab was on show and the vagina was intact that the swab had been misplaced into the rectum, thus highlighting the need to know your anatomy! An amazing image of a Ureteric stent that had been accidentally placed in the atrium was shown; but we were told the next step should not be to call an endourologist!

siu3In the opening ceremony we were welcomed by Argentine tango dancers, the Minister of Health: a qualified doctor with degree in public health, and some Argentine hospitality of wine and typical foods. Friendly and collegiate atmosphere is what the Secretary of the SIU promised us, and friendly banter was present during the day. The first Brexit joke came when Mr Chris Parker started to explain to one presenter of the World Oncology federation why the UK was not included in the observation of deterioration of prostate cancer outcomes during the 2008 world recession, to which the presenter replied that it was only European countries in the paper. There was a mix of cheers and boos from the audience. However UK prostate cancer research, such as the PROMIS trial and the Emberton team studies were frequently quoted, as well as other British papers, with high esteem as corner stones of cancer research and advancing patient care.

 

Day 2 Friday

There was an early start for many who attended one of four optional instructional courses: each covered a different theme. I attended ‘management of priapism’ in view of its direct relevance to potential situations I may find myself in as an on call registrar. UCLH Consultants Asif Muneer and Guilio Garaffa hosted and gave clear information on acute management and surgical shunt techniques, plus imaging for more difficult cases, such as CT to exclude intra-abdominal cause of refractory priapism. The take home message was to consider early implantation of penile prosthesis if priapism lasts >72 hours. This was shown clearly on operative videos of prosthesis surgery at 3 weeks compared to 6 m; where the latter had penile fibrosis increasing surgical difficulty.

The first plenary session covered new advances in testicular cancer and another debate of focal therapy in intermediate prostate cancer. Scott Eggener presented a polished and compelling argument on why focal therapy could be the future, but Markus Graefen described his reluctance to accept it based on the research, limitations in MRI, and need for follow that is similar to active surveillance; but perhaps patient choice will drive us to make a conclusion. Fernando Secin described the low uptake of Active Surveillance within Argentina. This may be due to costs (both AS costs and costs lost by not operating) and lack of protocols; however, those clinicians who had undergone oncological training and worked in Academic centres were more likely to recommend AS.

Description of how Ebola affected our African colleagues and sadly mortality due to HSW highlights the breadth of education and world issues covered by the SIU congress. Winner of the SIU Astellas European Foundation Award, Dr John M Barry, described how five transplantation principles can be applied to urology. This included using life expectancy calculations, not age, in making decisions (he used his own Charlson comorbidity score to illustrate the point that it can be improperly used); he suggested using a quality of life grid and that practice guidelines, from numerous organisations use different grading systems thus he calls for unified, world scientific language.

I was invited to attend a ‘quick fire session for trainees’ where I met five experts and discussed career questions such as fellowships, choosing urology specialties and engaging with academia, which includes networking that we can practice during the conference. The experts were super friendly and one attendee was thrilled to meet Olivier Traxor who is his endourological hero.

Other sessions included the first session on ‘Professionalism in urology’ and included information on using Twitter and working with industry without compromising or influencing patient care by always practising evidence-based medicine. However, many researchers have ties to industry. Several tweets were shared during this session, for example:


Another session popular with trainees was ‘how to write a paper’ hosted by the World Journal of Urology.

Dan Wood from UCLH, UK chaired the session for congenital reconstruction, which included how to set up a service by Miss Claire Taylor; she emphasised the need to define the service you want to provide, decide which paediatric hospital you want to work with and having an excellent MDT and clinical specialist nurse, of which she is fortunate to have Winnie Nugent who works to bridge the gap between child and adult services.

The ‘Surgical Demo, session on Laparoscopy was well attended and the audience watched excellent videos from Karim Touijer on lap prostatectomy and Gonzalo Vitagliano on lap nephrectomy. The videos were clear and narration highlighted the relevant steps and anatomy. They emphasised the need to gain a mentor to reduce the learning curve and not attempt to set up a lap service solo. There was also an ‘encyclopaedic’ style Surgical Masters session of all types of prostate surgery for BPH that included surgical videos and tips/tricks.

 

Saturday

Many attended the sessions with a sore head on Saturday morning following the SIU Night party held at La Rural, a National Historic Landmark located in the Palermo district of Buenos Aires. It was inaugurated in the late 1800s in order to support and promote agricultural issues in Argentina. We were treated to typical foods: empanadas, freshly barbequed meats and sausages, breads and of course home grown wine. Entertainment was provided by Argentinian tango dancers and Argentine Gaucho dancers whose finale ended with Bolleadoras a dance that made hearts pound from the open male shirts, fast rhythm and the whirling ropes. Additionally, there was a photo booth for traditional Argentine dress, football snooker and a mechanical bull; luckily the only injury was an Australian trainee’s trousers.

siu4 siu5

The morning’s plenary session ‘Shifting sands – new technologies in stone disease’ covered a range of topics including retrograde intrarenal surgery by Mr Traxer. Mr Jorge Guitierrez highlighted the dangers of sepsis in stone disease; one key message included stopping stone surgery (including PCNL) when there was purulent urine. The panel agreed that 1-2cm stones fall in a grey area in the guidelines as to which treatment is the best. The majority of the panel favoured flexible ureteroscopy; but admitted that a patient’s ability to afford PCNL vs flexi URS and the surgeon’s skills and availability of equipment was what often governed practice rather than choice. Mariano Gonzalez described stone disease affecting pregnant women and the challenges of treating; interestingly he suggested that a low dose CT in the 2nd and 3rd trimester can be considered safe. Pradeep Rao informed us of the changing PCNL sizes and how the smaller ‘seeing needle scope’ at 4.8F enabled him to remove the stone in an infant less than one years old. Norberto Bernardo shared his experience with managing stones in complex patients, such as a case with severe scoliosis and another in a HSK. Mr Traxor made a plea that stents be used for the shortest time to reduce patient morbidity, i.e. as soon as they have been placed make a plan for ureteroscopy to enable stone treatment and removal.

The use of mesh for vaginal prolapse was debated by Nissrine Nakia (pro) and Paulo Palma (con). Palma highlighted the anatomy of the pelvic floor and the importance of identifying the level of deformity, which should then be used to select the right patients and select the correct procedure. The counter argument from Nakia started with a campaign slogan P.R.O.M.E.S.H in keeping with the ongoing US presidential debate. She stated that whilst the FDA did raise concerns regarding re-operation rates, there are now more modern meshes and are subjected to rigorous testing, plus experience has been gained regarding placement of mesh, post-mesh cystoscopy and use of oestrogen cream, which have all improved patient outcomes.


The European and Asian societies both presented in the plenary sessions. The EUA lecture, given by Arnulf Stenzl, described ongoing changes on how to improve TURBT, which included better training for juniors, including simulation, better visualisation (photo dynamic diagnosis) and the use of ‘bloc’ dissection with hybridknife to enable whole tumour removal in once piece, which can aid histological analysis.

Mr Foo from Singapore presented the UAA lecture on the subject of ‘holistic approach’ to care of BPH. Additionally that perhaps the Intro vesicular prostatic protrusion (IPP) tells us more about the likelihood of obstruction and when surgery would make the most difference.

Three parallel plenary sessions provided learning in the fields of spinal cord injury, paediatric urology and urological histology. The histology speakers had a tough job describing their field to us surgeons! The plenary session ‘SIU-ICD joint consultation on urological management of Spinal cord injury patients’ was well attended and covered the anatomy, surgical and non -surgical options, urodynamics and bladder emptying options. Speakers emphasised the need for Long-term follow-up, including upper tract imaging, blood tests (U&Es) and QOL questionnaires of which there are several. Each presenter clearly stated their recommendation and the level of evidence to support it. Tweets from this session included a commitment to reduce urine culture and treatment of UTI on asymptotic patients.


‘Ageing and urology’ session complemented the holistic theme as an expert panel discussed optimisation of elderly patients and the difficult decision making process of offering surgery in patients with frailty, high risk GA and delirium and co-morbidities. One panellist said it was about making a judgement that if the patient will appreciate the change and it will add to their QOL then age is not a barrier to operating; however, teamwork with anaesthetists and geriatrics is key to optimisation.

Each day a ‘Surgical Demo’ session’ ran, Saturday’s was on stones which was, like many stone sessions, full; Perhaps highlighting the enthusiasm towards Endourology. Pictured is Mr Guitierrez describing correct ureteroscopic hand manoeuvres and his ‘painting’ technique to dust stones. Additionally Mr Lojanapiwat from Thailand presented his operative experience in subcostal access for upper pole stones.

Throughout the afternoon were moderated poster sessions; from reducing laparoscopic camera fogging to comparison of traditional vs western medicine. These accepted abstracts were presented by urologists who were at varying stages of their careers. Presentations reflected high standards of research and a culmination of hard work. After watching some of the poster presentations I joined the urethral reconstruction ‘surgical tips’ session, which drew the biggest audience. The presentations offered high-quality operative pictures and complimentary radiology pictures showing the complexity of some of these strictures. Daniela Andrich from UCLH presented their experience of post-traumatic strictures and emphasised that the mechanism of injury correlates to the stricture pattern. Furthermore that partial ureteric injuries are probably under reported as they heal with the catheter in situ, sited by the trauma/orthopaedic team.

 

Sunday

The sun shone brightly on the last day of the conference and whilst many In the city were enjoying their Sunday lie in or preparing for church, conference delegates made their way to the last four early morning instructional courses. I attended ‘surviving prostate cancer’ chaired by Prof Mundy, which covered the aftermath of treatment for prostate cancer: fistulae, strictures, incontinence. Interestingly as our colleagues in General Surgery change techniques it provides new challenges relating to recto-vesical fistulae. It was recommended that MRIs should include sagittal views to best define the fistula anatomy. Prof Mundy described the difficulty that radiotherapy creates by scarring the tissues, which makes these patients more at risk of post-operative complications. This means it’s imperative to properly assess people prior to radiotherapy, including a cystoscopy to assess the bladder (and if applicable the post-prostatectomy anastomosis). Then consent the patient thoroughly prior to radiotherapy so that they’re aware of the more difficult surgery they face, should it be required.

The plenary session started with four speakers describing the emerging role of immunotherapy and specifically in cancers of the prostate, bladder and kidney. The research presented gave optimism of improving treatments for these cancers and that trials are ongoing and concluding. Fred Saad described how access to tissue can try to develop precision medicine; mutations specific to that tumour and patient could be assessed and tested in the laboratory so that treatment can be targeted and avoid treatments that don’t work.

A fierce debate regarding the role of varicocele surgery in the era of assisted reproduction ended in favour of offering surgery. Robert Brannigan presenting the ‘yes’ argument argued that varicocelectomy needs to be synergistic to assisted contraception, especially if time is of the essence in relation to maternal age. He gave evidence that varicocelectomy improves sperm quality for assisted conception and sees changes 3 months post-surgery. Alex Pastusak said he’d rather be ‘successful than lucky’ and was in favour of assisted contraception as the evidence for varicocelectomy, even the meta-analysis papers, has limitations so casts doubt on validity of available studies.

Rene Sotelo presented his endoscopic techniques for fistula repair, which included lap or robotic surgery within the bladder to remove the tract, create a plane between the bladder and surrounding tissues, place omentum or fascia between and then close the defect. We quickly moved from advanced techniques to trying to establish the basic technique with the next speaker. Alain Houlgate described his experience of establishing an endourological teaching programme between France and Senegal, which cumulates in a diploma.

Abstract prize winner Henry Woo presented his work on the International journal club #urojc where each month newly published articles are sent out to twitter followers and discussion generated. Unsurprisingly he was congratulated via twitter:


The last plenaries of the conference prior to further poster sessions included uroradiology, systemic cancer therapies and surgical demo on robotic cystectomy. The radiology session highlighted the advances in PSMA PET for prostate cancer recurrence but that TRUS still had a role.


siu13River Plate Urological Meeting: representatives from the RSM – Urological section, UK, met with representatives from the Hospital Británicos in Rosario and Buenos Aires, Argentina and Montevideo, Uruguay. This is the first time these groups have met with the aim of collaboration and training. The day included presentations from the hospitals’ urology trainees, in English, on a range of topics and were marked as per the RSM marking criteria. The winning presentation was on ‘laparoscopic nephrectomy for living kidney donors’ and 2nd place for a presentation on ‘history of circumcision’. We had a tour of the hospital and were then welcomed into the British Embassy, to meet the Ambassador who is supportive of the relationships that are forming as a result of this meeting.

 

Concluding remarks

Overall the SIU was well organised, navigable and the incredible range of urology was well represented by experts in their field. The conference delegates were friendly, approachable and our host Buenos Aires warm and welcoming. Friendships and collaborations will undoubtedly continue beyond this congress.

The SIU Night was a particular highlight, showcasing the Argentine spirit in one evening for those who weren’t staying long in the country. The programme used varied formats and operative videos shown were generally of good quality. The presentations were of good calibre and the research presented both new and established. Reference was often made to EAU and AUA guidelines and international papers from a range of journals, in particular BJUI, Eur Urol and J Urol. The meeting of minds is certainly healthy to urological progress and exchanging ideas is key to innovation and improvement within our specialty across the world. There is so much we can learn from each other.

Adios SIU 2016! and ‘Até logo’ SIU 2017 Portugal!

 

Sophie Rintoul-Hoad is a urology trainee in the South Thames Deanery, currently working at King’s College hospital. She attended the SIU 2016 conference in Buenos Aires and then saw some of Argentina’s highlights, including a few days at El Venado Estancia playing polo and learning how to be a gaucho!

 

 

Article of the Week: Complications and QoL in patients undergoing CU with single stoma or IC after RC

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

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

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video discussing the paper.

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

Complications and quality of life in elderly patients with several comorbidities undergoing cutaneous ureterostomy with single stoma or ileal conduit after radical cystectomy

Nicola Longo*, Ciro Imbimbo*, Ferdinando Fusco*, Vincenzo Ficarra, Francesco Mangiapia*, Giuseppe Di Lorenzo, Massimiliano Creta§, Vittorio Imperatore§ and Vincenzo Mirone*

 

*Department of Neurosciences, Sciences of Reproduction and Odontostomatology, University Federico II of Naples, Naples, Urology Department, University of Udine, Udine, Oncology Department, University Federico II of Naples, and §Urology Unit, Buon Consiglio Fatebenefratelli Hospital, Naples, Italy

 

Read the full article

Objectives

To compare peri-operative outcomes and quality of life (QoL) in a series of elderly patients with high comorbidity status who underwent single stoma cutaneous ureterostomy (CU) or ileal conduit (IC) after radical cystectomy (RC).

Patients and Methods

The clinical records of patients aged >75 years with an American Society of Anesthesiologists (ASA) score >2 who underwent RC at a single institution between March 2009 and March 2014 were retrospectively analysed. After RC, all patients included in the study received an IC urinary diversion or a CU with single stoma urinary diversion. Preoperative clinical characteristics as well as intra- and postoperative outcomes were evaluated and compared between the two groups. In addition, the Bladder Cancer Index (BCI) was used to assess QoL.

aotw-oct-5-results

Results

A total of 70 patients were included in the final comparative analyses. Of these, 35 underwent IC diversion and 35 CU single stoma diversion. The two groups were similar with regard to age, gender, ASA score, type of indication and pathological features. Operating times (P < 0.001), estimated blood loss (P < 0.001), need for intensive care unit stay (P = 0.01), time to drain removal (P < 0.001) and length of hospital stay (P < 0.001) were significantly higher in patients undergoing IC diversion. The number of patients with intra- (P = 0.04) and early postoperative (P = 0.02) complications was also significantly higher among those undergoing IC diversion. Interestingly, the mean BCI scores were overlapping in the two groups.

Conclusions

The present results show that CU with a single stoma can represent a valid alternative to IC in elderly patients with relevant comorbidities, reducing peri-operative complications without a significant impairment of QoL.

Read more articles of the week

Editorial: Cutaneous Ureterostomy: ‘Back to the Future’

An increasingly ageing and frail population undergoing cystectomy and urinary diversion has rekindled interest in urinary diversions with a lower risk of peri-operative complications, such as cutaneous ureterostomy (CU).

The study in this issue of BJUI by Longo et al. [1] compares complications and quality of life in elderly patients with high comorbidities (American Society of Anesthesiologists [ASA] physical status score 3–4 and Charlson Comorbidity Index [CCI] ~5) receiving either an ileal conduit (IC) or a CU with a single stoma. Although the IC group had longer surgery, greater intra-operative blood loss, a higher number of patients needing intensive care monitoring, a longer time to drain removal and a longer hospital stay, as well as a higher number of intra- and early postoperative complications, the intensive care unit length of stay and quality of life did not differ.

Complication rates are high for cystectomy and urinary diversion, especially in the frail elderly population with comorbidities [2]. Most studies are retrospective and the reported complication rates differ largely. Few centres have compared IC with CU and, probably as a result of selection biases, the results vary [3, 4]. Obvious advantages of CU are the reduced length of surgery and the lack of a bowel anastomosis, and peritoneal lesions can be minimized or omitted, thus reducing the risk of postoperative ileus (POI), a common complication after urinary diversion. These advantages were confirmed in the present study, with prolonged POI observed in 25.7% in the IC group vs 5.7% in the CU group and the duration of surgery being 226 min in the IC group vs 150 min in the CU group. Interestingly, there was no difference in major complications classified as Clavien–Dindo grades III–IV, with the exception of urinary leakage from the uretero-ileal anastomosis (14.2%).

Somewhat surprisingly, 42.8% of patients with IC required a blood transfusion compared with 17.1% with UC. The main blood loss usually takes place during cystectomy, whereas blood loss during urinary diversion is minimal [5]. The authors explain this through bleeding from the mesenteric vessels associated with isolating a bowel segment for IC, an occurrence not commonly observed in our experience or in other published reports. Overall the transfusion rate seems high, but this is highly dependent on the preoperative haemoglobin level/anaemia and the haemoglobin level set for transfusion, which differs between centres.

One of the main problems with CU is ureteric obstruction, especially of the left ureter. The rationale behind this is the more extensive mobilization of the left ureter to enable its transfer to the right side, which can result in ischaemic lesions of the distal ureter. Stenosis and kinking of the ureters when passing through the abdominal wall can also lead to obstruction. For these reasons, many patients have long-term ureteric stents. In the present study, the ureteric stents were changed every month. Foreign bodies in the urinary tract can cause problems such as upper urinary tract infections, stent encrustation and nephrolithiasis [3]. To reduce these problems, meticulous care of the CU and frequent changes of the silicone JJ stent with antibiotic prophylaxis are generally recommended. A cost assessment would be of interest to determine the long-term cost of regular stent changes compared with the management of a higher rate of peri-operative complications in patients receiving an IC. Tubeless approaches have been described, and one study reported less ureteric obstruction with deferred stent removal after surgery [6].

The Bladder Cancer Index score as a measure of quality of life did not differ between groups. Quality of life questionnaires assessing urinary diversion have inherent problems. When comparing leakage (frequency of leakage) and control (amount of leakage) in a patient with an IC or a CU, it is not surprising that there is no difference. However, the need for regular hospital visits to change the stents, which can be bothersome for patients, especially the frail and dependent elderly or those with problems travelling, because of the need to transport the necessary aides (stoma bags, pads, catheters), are rarely addressed in questionnaires.

Cutaneous ureterostomy, which is being rediscovered, belongs in the armamentarium of every surgeon performing cystectomy. However, each type of urinary diversion has its pros and cons, and careful selection is necessary to balance benefits against risks in an effort to offer the best individual option to the older and frail patient.

Read the full article

 

Fiona C. Burkhard* and Patrick Y. Wuethrich

 

*Department of Urology, University Hospital Bern, Inselspital Anna Seiler-Haus, Bern, Switzerland and Department of Anaesthesiology and Pain Medicine, University Hospital Bern, Bern, Switzerland

 

References

 

Immunotherapy in urological malignancies: can you take your knowledge to the next level?

bju13648-fig-0001In this month’s issue of the BJUI, we highlight the evolving era of immunotherapy in solid tumour therapy. As urological surgeons, we spend a large portion of our time working with anatomy, instruments, and robots – things we can see, touch, and control. Immunotherapy is a different conversation – cartoon pathways, process blockades, molecular expression levels, combination therapies, and treatment resistance. Curing a patient with a successful operation is a major draw to our field, but we know our limitations when faced with lethal variant prostate cancer, and high-grade/high-stage bladder and kidney cancers in particular. Systemic therapies have been around for decades and are part of our guidelines – so why all the excitement over immunotherapy?

Our highlighted articles are a review from Mataraza and Gotwals [1] and a comment from Elhage et al. [2]. I urge you to start with the review article [1] and give it a full line-by-line read. You may need to pull out pen and paper, and practice spelling and pronouncing a number of new compounds. They may sound as awkward as abiraterone did the first time you heard of it years ago but will eventually become familiar and attached to yet another catchy trade name from pharma. Here is a quick list/homework assignment: ipilimumab, nivolumab, pembrolizumab, pidilizumab, atezolizumab. Another 20 or more are in development. Challenge yourself to write out their pathways, and you may re-learn a thing or two about familiar agents like sipuleucel-T, interferon α, and interleukin 2.

A major theme in both articles is the experience with immunotherapy in advanced melanoma. The enticing message is that a cohort of patients with metastatic melanoma treated with ipilimumab survived 3 years and the Kaplan–Meier curves plateau out to 10 years. This observation sparks different possible futures such as immune ‘memory’, durable response, and ultimately the word we like to use in surgery – cure.

The picture in urological cancers is not entirely as rosy as the melanoma Kaplan–Meier curve. Multiple trials are highlighted by our review with familiar themes of single agent trials, combination immunotherapies, and combined immunotherapy plus anti-angiogenesis agents. Many trials enrol heavily pre-treated populations with limited remaining options. Many endpoints still observe responses followed by resistance patterns. An important theme to follow is the coupling of biomarkers that link expression to treatment response (i.e. predictive vs prognostic), and the USA Food and Drug Administration (FDA) has approved such a biomarker for nivolumab response. However, even this story line is perplexing, as drug response is not always linked to the marker, and immune cell expression may be ‘inducible and dynamic’ [1].

Last step – re-read the review and comment articles and see if you can write down some key agenda items for future immunotherapy. How are checkpoint inhibitors different from vaccines? How do we generate a durable immune response? What is the ‘abscopal effect’? What are three major areas of research and development in immunotherapy?

If you can spend the time on these articles and ponder these challenging questions, you will move up to the next level of understanding and enjoy a greater appreciation of the next abstract you hear at a major meeting. In closing, I am reminded of the oft-repeated words from the hit television show Game of Thrones (based on the novels of George R.R. Martin) from the House Stark: ‘Winter is Coming’. In urological oncology, ‘Immunotherapy is Coming’, so be prepared!

 

John W. Davis

BJUI Associate Editor Urological Oncology

 

References

1 Mataraza JM, Gotwals P. Recent advances in immuno-oncology and its application to urological cancers. BJU Int 2016; 118: 50614

 

2 Elhage O, Galustian C , Dasgupta P. Immune checkpoint blockade treatment for urological cancers? BJU Int 2016; 118: 498505

 

Article of the Week: Impact of Re-TUR on BCG-Treated T1 HG/G3 Bladder Cancer

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

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

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Francesca Pisano and Paolo Gontero, discussing their paper.

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

The impact of re-transurethral resection on clinical outcomes in a large multicentre cohort of patients with T1 high-grade/Grade 3 bladder cancer treated with bacille Calmette–Guerin

Paolo Gontero1, Richard Sylvester2, Francesca Pisano1, Steven Joniau3, Marco Oderda1, Vincenzo Serretta4,Stephane Larre5, Savino Di Stasi6, Bas Van Rhijn7, Alfred J.Witjes8, Anne J. Grotenhuis8, Renzo Colombo9, Alberto Briganti9, Marek Babjuk10, Viktor Soukup10, Per-Uno Malmstrom11, Jacques Irani12, Nuria Malats13, Jack Baniel14, RoyMano14, Tommaso Cai15, Eugene K. Cha16, Peter Ardelt17, John Vakarakis18, Riccardo Bartoletti19, Guido Dalbagni20, Shahrokh F. Shariat16, Evanguelos Xylinas16, Robert J.Karnes21 and Joan Palou22

 

1Urology Clinic, Citta della Salute e della Scienza di Torino, University of Studies of Turin, Turin ,4Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, 6Policlinico Tor Vergata-University of Rome, Rome, 9Dipartimento di Urologia, Universita Vita-Salute. Ospedale S. Raffaele, Milan, 15Department of Urology, SantaChiara Hospital, Trento, 19Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy, 2Formerly Department of Biostatistics, EORTC Headquarters, Brussels, 3Oncologic and Reconstructive Urology, Department of Urology, University Hospitals Leuven, Leuven, Belgium, 5Department of Surgical Science, John Radcliffe Hospital, University of Oxford, Oxford, UK, 7Department of Urology, Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, 8Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, 10Department of Urology, Motol Hospital, University of Praha, Praha, Czech Republic, 11Department of Urology, Academic Hospital, Uppsala University, Uppsala, Sweden, 12Department of Urology, Centre Hospitalier Universitaire La Miletrie, University of Poitiers, Poitiers, France, 13Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, 22Department of Urology, Fundacio Puigvert, University of Barcelona, Barcelona, Spain, 14Department of Urology, Rabin Medical Centre, Tel Aviv, Israel, 16Department of Urology, Weill Medical College of Cornell University in New York City, 20Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, 21Department of Urology, Mayo Clinic, Rochester, MN, USA, 17Facharzt fur Urologie, Abteilung fur Urologie. Chirurgische Universitats klinik, Freiburg, Germany, and 18Department of Urology, Sismanoglio Hospital, University of Athens, Athens, Greece

 

Read the full article

Objectives

To determine if a re-transurethral resection (TUR), in the presence or absence of muscle at the first TUR in patients with T1-high grade (HG)/Grade 3 (G3) bladder cancer, makes a difference in recurrence, progression, cancer specific (CSS) and overall survival (OS).

Patients and methods

In a large retrospective multicentre cohort of 2451 patients with T1-HG/G3 initially treated with bacille Calmette–Guérin, 935 (38%) had a re-TUR. According to the presence or absence of muscle in the specimen of the primary TUR, patients were divided in four groups: group 1 (no muscle, no re-TUR), group 2 (no muscle, re-TUR), group 3 (muscle, no re-TUR) and group 4 (muscle, re-TUR). Clinical outcomes were compared across the four groups.

JUlAOTW4Results

Results

Re-TUR had a positive impact on recurrence, progression, CSS and OS only if muscle was not present in the primary TUR specimen. Adjusting for the most important prognostic factors, re-TUR in the absence of muscle had a borderline significant effect on time to recurrence [hazard ratio (HR) 0.67, P = 0.08], progression (HR 0.46, P = 0.06), CSS (HR 0.31, P = 0.07) and OS (HR 0.48, P = 0.05). Re-TUR in the presence of muscle in the primary TUR specimen did not improve the outcome for any of the endpoints.

Conclusions

Our retrospective analysis suggests that re-TUR may not be necessary in patients with T1-HG/G3, if muscle is present in the specimen of the primary TUR.

Read more articles of the week

Editorial: Time to re-evaluate and refine re-TUR in bladder cancer?

In this issue of BJUI, Gontero et al. [1] present data from a large multi-centre study that should allow us to re-evaluate and refine the indications for re-transurethral resection (TUR) in bladder cancer.

Herr [2] first described this procedure in 1999 and for the past 16 years the indications have remained largely unchanged and are summarised in the latest European Association of Urology guidelines on non-muscle-invasive bladder cancer (NMIBC) [3]:

  • After incomplete initial TUR of bladder tumour (TURBT).
  • If there is no muscle in the specimen after initial resection.
  • In all T1 tumours.
  • In all Grade 3 tumours except primary carcinoma in situ.

In a multi-centre retrospective study of 2 451 patients with high-grade (HG)/Grade 3 (G3) T1 NMIBC treated with BCG, Gontero et al. [1]examined 935 patients who had re-TUR (38% of the total, itself a low figure). Patients were divided into four groups according to the presence or absence of detrusor muscle in the first TURBT specimen:

  • No muscle, no re-TUR
  • No muscle, re-TUR
  • Muscle, no re-TUR
  • Muscle, re-TUR

The authors found that re-TUR only had a positive impact on recurrence, progression, cancer-specific and overall survival, if detrusor muscle was not present in the original specimen. Importantly, in the presence of detrusor muscle in the original specimen, re-TUR did not improve outcomes. The authors conclude that re-TUR may be unnecessary in HG/G3 T1 patients if detrusor muscle is present at the first TURBT.

These findings are important for two reasons: firstly, Herr’s [2] paper was the first to draw attention to the finding that TURBT, a routine urological procedure, was often carried out inadequately. In recent years, the importance of carrying out a high-quality TURBT has been increasingly recognised [4], whilst the presence of detrusor muscle in the TURBT specimen has been shown to be a good measure of the technical quality of a TURBT [5]. This paper [1] further reinforces the importance of obtaining detrusor muscle in the first TURBT. Indeed, as failure to do so results in the patient having to have a second operation and delays their treatment, perhaps we should start to think of a failure to obtain detrusor muscle at the first TURBT in much the same way as positive margin rates are used as a measure of the quality of radical prostatectomy and by inference, the skill of the surgeon.

Secondly, re-TUR arguably serves one overarching purpose: to identify patients with muscle-invasive bladder cancer (MIBC) who have been under-staged by an inadequate first TURBT and who without a re-TUR would be inadequately treated.

Although a secondary role of re-TUR is to identify patients with residual NMIBC, which has some prognostic value, in practice it rarely changes the patient’s management in this setting, which is intravesical therapy usually with BCG. However, in many healthcare systems the timely organisation of a re-TUR within the recommended 6 weeks is challenging and there is usually a further delay of at least 2 weeks until the pathology is reviewed and a patient with NMIBC can finally commence treatment. In this context, it is not surprising that a recent paper in BJUI showed that the interval to re-TUR was a predictor of recurrence and progression and that a re-TUR after 7 weeks was associated with a much worse outcome [6]. It therefore seems logical to reserve re-TUR only for those patients who truly need it, so that limited resources are focused on ensuring that they receive their operation in a timely manner, ideally within 2–4 weeks. If adopted into day-to-day urological practice, the findings by Gontero et al. [1] will allow many patients with HG/G3 T1 and detrusor muscle in the first TURBT specimen to avoid a re-TUR and start intravesical therapy without further delay. Pragmatically, the same should apply to patients with HG/G3 Ta with detrusor muscle in the specimen. On the other hand, HG/G3 T1 patients without detrusor muscle should be fast-tracked for re-TUR as soon as is practicable and certainly no later than 6 weeks.

The article [1] does have some shortcomings. The study design excludes patients with MIBC, so we do not know by comparison how many patients with MIBC were under-staged at the initial TUR based on subsequent re-TUR but as the authors point out, their conclusions would hold true even in this group, as it is very unlikely that one would miss MIBC if there was adequate detrusor muscle in the pathology specimen.

In conclusion, we should consider refining the indications for re-TUR to improve the utilisation of healthcare resources and ensure that for those that need it, a re-TUR is carried promptly whilst for those that do not, essential intravesical treatment is not delayed.

Read the full article
A. Hugh Mostad, Consultant Urologist and Honorary
Senior Lecturer The Royal Surrey County Hospital, Guildford, Surrey, UK

 

References

 

Video: Impact of Re-TUR on BCG-Treated T1 HG/G3 Bladder Cancer

The impact of re-transurethral resection on clinical outcomes in a large multicentre cohort of patients with T1 high-grade/Grade 3 bladder cancer treated with bacille Calmette–Guerin

Paolo Gontero1, Richard Sylvester2, Francesca Pisano1, Steven Joniau3, Marco Oderda1, Vincenzo Serretta4,Stephane Larre5, Savino Di Stasi6, Bas Van Rhijn7, Alfred J.Witjes8, Anne J. Grotenhuis8, Renzo Colombo9, Alberto Briganti9, Marek Babjuk10, Viktor Soukup10, Per-Uno Malmstrom11, Jacques Irani12, Nuria Malats13, Jack Baniel14, RoyMano14, Tommaso Cai15, Eugene K. Cha16, Peter Ardelt17, John Vakarakis18, Riccardo Bartoletti19, Guido Dalbagni20, Shahrokh F. Shariat16, Evanguelos Xylinas16, Robert J.Karnes21 and Joan Palou22

 

1Urology Clinic, Citta della Salute e della Scienza di Torino, University of Studies of Turin, Turin ,4Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, 6Policlinico Tor Vergata-University of Rome, Rome, 9Dipartimento di Urologia, Universita Vita-Salute. Ospedale S. Raffaele, Milan, 15Department of Urology, SantaChiara Hospital, Trento, 19Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy, 2Formerly Department of Biostatistics, EORTC Headquarters, Brussels, 3Oncologic and Reconstructive Urology, Department of Urology, University Hospitals Leuven, Leuven, Belgium, 5Department of Surgical Science, John Radcliffe Hospital, University of Oxford, Oxford, UK, 7Department of Urology, Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, 8Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, 10Department of Urology, Motol Hospital, University of Praha, Praha, Czech Republic, 11Department of Urology, Academic Hospital, Uppsala University, Uppsala, Sweden, 12Department of Urology, Centre Hospitalier Universitaire La Miletrie, University of Poitiers, Poitiers, France, 13Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, 22Department of Urology, Fundacio Puigvert, University of Barcelona, Barcelona, Spain, 14Department of Urology, Rabin Medical Centre, Tel Aviv, Israel, 16Department of Urology, Weill Medical College of Cornell University in New York City, 20Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, 21Department of Urology, Mayo Clinic, Rochester, MN, USA, 17Facharzt fur Urologie, Abteilung fur Urologie. Chirurgische Universitats klinik, Freiburg, Germany, and 18Department of Urology, Sismanoglio Hospital, University of Athens, Athens, Greece

 

Read the full article

Objectives

To determine if a re-transurethral resection (TUR), in the presence or absence of muscle at the first TUR in patients with T1-high grade (HG)/Grade 3 (G3) bladder cancer, makes a difference in recurrence, progression, cancer specific (CSS) and overall survival (OS).

Patients and methods

In a large retrospective multicentre cohort of 2451 patients with T1-HG/G3 initially treated with bacille Calmette–Guérin, 935 (38%) had a re-TUR. According to the presence or absence of muscle in the specimen of the primary TUR, patients were divided in four groups: group 1 (no muscle, no re-TUR), group 2 (no muscle, re-TUR), group 3 (muscle, no re-TUR) and group 4 (muscle, re-TUR). Clinical outcomes were compared across the four groups.

JUlAOTW4Results

Results

Re-TUR had a positive impact on recurrence, progression, CSS and OS only if muscle was not present in the primary TUR specimen. Adjusting for the most important prognostic factors, re-TUR in the absence of muscle had a borderline significant effect on time to recurrence [hazard ratio (HR) 0.67, P = 0.08], progression (HR 0.46, P = 0.06), CSS (HR 0.31, P = 0.07) and OS (HR 0.48, P = 0.05). Re-TUR in the presence of muscle in the primary TUR specimen did not improve the outcome for any of the endpoints.

Conclusions

Our retrospective analysis suggests that re-TUR may not be necessary in patients with T1-HG/G3, if muscle is present in the specimen of the primary TUR.

Read more articles of the week

Article of the Month: Further Evidence that Bladder Cancer Patients should Stop Smoking

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. Smoking in a daily basis can affect your lungs, make sure to improve your indoor air quality just by checking out the latest blaux portable ac reviews.

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

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

Trends in the risk of second primary cancer among bladder cancer survivors: a population-based cohort of 10 047 patients

Joris Muller*,, Pascale Grosclaude, Benedicte Lapotre-Ledoux§,Anne-Sophie Woronoff§,**, Anne-Valerie Guizard§,††, Simona Bara§,‡‡, Marc Colonna§,§§Xavier Troussard§,¶¶, Veronique Bouvier§,***, Brigitte Tretarre§,†††, Michel Velten*,,§,‡‡‡ and Jeremie Jegu*,
*Bas-Rhin Cancer Registry, EA 3430, FMTS, University of Strasbourg, Department of Public Health, University Hospital of Strasbourg, Strasbourg, Tarn Cancer Registry, Albi, §
Francim: Reseau francais des registres des cancers, Toulouse, Somme Cancer Registry, Department of Hygiene and Public Health, University Hospital of Amiens, Amiens, **Doubs and Belfort Territory Cancer Registry, University Hospital of Besancon, Besancon, ††Calvados General Cancer Registry, Cancers & Preventions, U 1086 Inserm, Francois Baclesse Centre, Caen, ‡‡Manche Cancer Registry, Cotentin Hospital, Cherbourg-Octeville, §§Isere Cancer Registry, University Hospital of Grenoble, Grenoble, ¶¶Basse-Normandie Haematological Malignancies Cancer Registry, University Hospital of Caen, ***Calvados Digestive Cancer Registry, Cancers & Preventions, U 1086 Inserm, Francois Baclesse Centre, Caen, †††Herault Cancer Registry, Research Center, Montpellier , and ‡‡‡Department of Epidemiology and Biostatistics, Paul Strauss Center, Strasbourg, France
Read the full article

Objectives

To determine whether the risk of second primary cancer (SPC) among patients with bladder cancer (BCa) has changed over past years.

Materials and Methods

Data from 10 French population-based cancer registries were used to establish a cohort of 10 047 patients diagnosed with a first invasive (≥T1) BCa between 1989 and 2004 and followed up until 2007. An SPC was defined as the first subsequent primary cancer occurring at least 2 months after a BCa diagnosis. Standardized incidence ratios (SIRs) of metachronous SPC were calculated. Multivariate Poisson regression models were used to assess the direct effect of the year of BCa diagnosis on the risk of SPC.

JulAOTW1Results

Results

The risk of new malignancy among BCa survivors was 60% higher than in the general population (SIR 1.60, 95% confidence interval [CI] 1.51–1.68). Male patients presented a high risk of SPC of the lung (SIR 3.12), head and neck (SIR 2.19) and prostate (SIR 1.54). In multivariate analyses adjusted for gender, age at diagnosis and follow-up, a significant increase in the risk of SPC of the lung was observed over the calendar year of BCa diagnosis (P for linear trend 0.010), with an SIR increasing by 3.7% for each year (95% CI 0.9–6.6%); however, no particular trend was observed regarding the risk of SPC of the head and neck (P = 0.596) or the prostate (P = 0.518).

Conclusions

As the risk of SPC of the lung increased between 1989 and 2004, this study contributes more evidence to support the promotion of tobacco smoking cessation interventions among patients with BCa.

Read more articles of the week

Editorial: Analysis of Genetics to Identify Susceptibility to Secondary Malignancies in Patients with BCa

A study by Muller et al. [1] evaluated a cohort of 10 047 patients diagnosed with a first invasive (≥T1) bladder cancer and found that independent of gender and age, the risk of subsequent lung cancer was increased. This is not surprising considering the strong association of both bladder and lung cancer with tobacco, which is the main risk factor for both malignancies. While the authors limited their analysis to patients with invasive disease, the same association of bladder and lung cancer probably holds true for patients with non-invasive disease. An important question this raises is whether urologists should be more proactive in screening for lung cancer in their patients with bladder cancer. While chest radiographs are commonly used to monitor patients who undergo cystectomy, they are not routinely used for patients with non-invasive disease. Furthermore, the recommendations for screening for lung cancer based on the National Lung Cancer Screening Trial (NLST) involve use of low-dose chest CT, which is rarely done routinely by urologists [2]. In the Muller et al. [1] study, despite the large cohort and median follow-up of 3.1 years, there were still only 295 cases of lung cancer. This was three-times the expected incidence but overall a low rate.

One interesting consideration is whether use of genetic factors may be useful to identify which patients might be at higher risk at baseline for subsequent secondary cancers. Currently, single nucleotide polymorphism (SNP) analysis is not used clinically in screening but other genetic abnormalities such as BRCA (BReast Cancer gene) mutations and Lynch syndrome have been used to identify secondary malignancies. However, identifying individuals at higher risk of developing cancer may inform clinicians and allow for a more targeted screening strategy, even in patients of increased baseline risk.

The USA National Cancer Institute performed genome-wide association studies (GWAS) for 49 492 patients with cancer and 34 131 controls to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers [3]. They calculated that at least 24% and 7% of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Only four pairs of cancers had marginally statistically significant correlations including bladder and lung.

While tobacco is the major cause of lung cancer, only ≈10% of smokers develop lung cancer in their lifetime indicating there is significant individual variation in susceptibility to lung cancer. The International Lung Cancer Consortium pooled genotype data for SNPs at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 patients with lung cancer and 14 954 control subjects [4]. Associations between 15q25 and the risk of lung cancer were replicated in White ever-smokers (rs16969968) but there was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, they confirmed statistically significant associations in Whites for both rs2736100 and rs402710 and identified similar associations in Asians. Zhang et al. [5] undertook a gene–smoking interaction analysis in a GWAS of lung cancer in Han Chinese population of 5 408 subjects (2 331 patients and 3 077 controls) using a two-phase designed case-control study. They identified two SNPs associated with lung cancer and smoking, including one with a synergistic interaction (rs4589502) and one with an antagonistic interaction (rs131629).

There have also been several studies evaluating SNPs and risk of bladder cancer. A study of 1 595 patients and 1 760 controls, stratified for smoking habits, found that different SNP combinations were relevant in smokers and non-smokers [6]. In smokers, polymorphisms involved in detoxification of cigarette smoke carcinogens were most relevant (GSTM1 [glutathione S-transferase μ1], rs11892031), in contrast to those in non-smokers where MYC (v-myc avian myelocytomatosis viral oncogene homolog) and APOBEC3A (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A) near polymorphisms (rs9642880, rs1014971) were the most influential. A study of genome-wide interaction of smoking and bladder cancer risk based on data from 3 002 patients and 4 411 controls with validation in a separate dataset identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use [7]. These studies of genetic polymorphisms add evidence regarding the impact of gene–environment interactions, which influence the detrimental effects of tobacco on risk of bladder cancer.

There are other genetic polymorphisms that have been found to increase risk of tobacco-related malignancies. A study of polymorphisms inNAT2 (N-acetyltransferase 2 [arylamine N-acetyltransferase]), GSTM1, NAT1, GSTT1 (GST θ1), GSTM3, and GSTP1 (GST π1) in 1 150 patients with bladder cancer and 1 149 controls found that compared with NAT2 rapid or intermediate acetylators, NAT2 slow acetylators had an increased overall risk of bladder cancer (odds ratio 1.4, 95% CI 1.2–1.7), which was stronger for cigarette smokers than for never smokers. No significant associations were found with the other polymorphisms [8]. The overall association for GSTM1 was also robust (P < 0.001) but was not modified by smoking status (P = 0.86).

While it may be too early to apply GWAS to all patients who smoke, a trial focusing on those with other tobacco-related malignancies may identify cohorts where screening for other malignancies is not only effective but also practical.

Read the full article
Yair Lotan, Professor of Urology
Department of Urology, UT Southwestern Medical Center at Dallas, Dallas, TX, USA

 

References

 

 

2 National Lung Screening Trial Research Team, Aberle DR, Adams AM et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365: 395409

 

3 Sampson JN, Wheeler WA, Yeager M et al. Analysis of heritability and shared heritability based on genome-wide association studies for thirteen cancer types. J Natl Cancer Inst 2015; 107: pii: djv279. doi: 10.1093/jnci/djv279

 

 

5 Zhang R, Chu M, Zhao Y et al. A genome-wide gene-environment interaction analysis for tobacco smoke and lung cancer susceptibility. Carcinogenesis 2014; 35: 152835

 

6 Schwender H, Selinski S, Blaszkewicz M et al. Distinct SNP combinations confer susceptibility to urinary bladder cancer in smokers and non-smokers. PLoS One 2012; 7: e51880

 

7 Figueroa JD, Han SS, Garcia-Closas M et al. Genome-wide interaction study of smoking and bladder cancer risk. Carcinogenesis 2014; 35: 173744

 

 

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