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Editorial: NICE guidelines on prostate cancer 2019

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The much‐anticipated National Institute for Health and Care Excellence (NICE) Guidelines are finally published [1] after a period of consultation when they were in the draft phase. These are updated from the previous 2008 and 2014 versions and reflect the changes in our knowledge and practice over the last 10 years. While there are many similarities, the astute reader will find distinct differences from the AUA Guidelines, which feature in a summary booklet released at the #AUA19 meeting in Chicago this spring.

NICE does not comment on screening for prostate cancer so many of us continue to rely on our Guideline of Guidelines [2], which make pragmatic recommendations such as smart screening in well‐informed men who are at higher risk because of their family history. For staging, bone scan has not been replaced by prostate‐specific membrane antigen (PSMA)‐positron‐emission tomography/CT, and Lu‐PSMA theranostics is yet to become an option in castrate‐resistant disease as the international trials are not mature.

Multiparametric MRI before prostate biopsy in men suitable for radical treatment is a new addition, based on the PROMIS [3] and PRECISION trials [1]. This approach is thought to be cost‐effective through reducing the number of biopsies and side effects despite the initial added cost of MRI scanning. In Grade Group 1 and some low‐volume Grade Group 2 cancers, protocol‐based active surveillance is recommended provided the patients are well counselled and it has been discussed by a multidisciplinary team.

To reduce variations in active surveillance, Prostate Cancer UK has carefully examined eight different guidelines and published a consensus statement for the benefit of our patients [4]. We have already promoted this widely on social media and hope that our readers will use this practical tool in their clinics. We often find that some patients just cannot live with a cancer inside their body and seek surgery as a result, however small their tumour. Careful discussion about management options and their risks vs benefits [1] can help patients arrive at a pragmatic decision. The effect of a cancer diagnosis on patients’ minds should therefore not be underestimated and a trained psychologist should be available for appropriate counselling.

NICE also recommends hypofractionated intensity‐modulated radiotherapy, if appropriate, in combination with androgen deprivation therapy (ADT) for localized disease, and methods of decreasing the side effects while increasing accuracy of radiation. As in 2014, robot‐assisted radical prostatectomy remains a surgical option in centres performing at least 150 of these procedures per year [1]. These numbers are similar to those published from other health services such as Canada. One such very high‐volume centre is the Martini Clinic which has reported its comparison of open and robot‐assisted radical prostatectomy in >10 000 patients. The oncological and functional outcomes are no different, open surgery is quicker and there is less blood loss and shorter time to catheter removal after robotic surgery. Just like the randomized trial of the two techniques, this large series highlights that surgeon experience rather than the technique is more important for clinical outcomes [5]. Finally, based on the STAMPEDE results, docetaxel is recommended for metastasis in addition to ADT and can be considered for high‐risk patients receiving ADT and radiotherapy [6]. NICE has also identified a number of important research questions which we hope will be answered by ongoing studies in coming years.

by Prokar Dasgpta, John Davis & Simon Hughes

 

References

  1. NICE Guidance. NICE guidelines prostate cancer. BJU Int 2019; 124: 9– 26.
  2. Loeb, S. Review of prostate cancer screening guidelines. BJU Int 2014; 114: 323– 5
  3. Ahmed, HU. The PROMIS of MRI. BJU Int 2016; 118: 7
  4. Merriel, SWD, Hetherington, L, Seggie, A et al. PCUK consensus statement. BJUI 2019; 124: 47– 54
  5. Haese, A, Knipper, S, Isbarn, H et al. A comparative study of robot‐assisted and open radical prostatectomy in 10 790 men treated by highly trained surgeons for both procedures. BJU Int 2019; 123: 1031– 40
  6. Sathianathen, NJ, Philippou, YA, Kuntz, GM et al. Taxane‐based chemohormonal therapy for metastatic hormone‐sensitive prostate cancer: a Cochrane Review. BJU Int 2019; [Epub ahead of print]. https://doi.org/10.1111/bju.14711

 

Article of the month: In-hospital cost analysis of PAE compared to TURP

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

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

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

In‐hospital cost analysis of prostatic artery embolization compared with transurethral resection of the prostate: post hoc analysis of a randomized controlled trial

As you can imagine, these are very important tests that you must have done regularly in order to try to catch life-threatening illnesses as early as possible. Sadly, as important as these tests may be, they are expensive. Prohibitively expensive to some. If you find yourself in this situation you should try to look for services, charity.

Gautier Müllhaupt*, Lukas Hechelhammer†, Daniel S. Engeler*, Sabine Güsewell‡, Patrick Betschart*, Valentin Zumstein*, Thomas M. Kessler§, Hans-Peter Schmid*, Livio Mordasini* and Dominik Abt*
*Department of Urology, †Department of Radiology and Nuclear Medicine, ‡Clinical Trials Unit, St. Gallen Cantonal Hospital, St Gallen and §Department of Neuro-Urology, Balgrist University Hospital, University of Zürich, Zürich, Switzerland
Read the full article

Abstract

Objectives

To perform a post hoc analysis of in‐hospital costs incurred in a randomized controlled trial comparing prostatic artery embolization (PAE) and transurethral resection of the prostate (TURP).

Patients and Methods

In‐hospital costs arising from PAE and TURP were calculated using detailed expenditure reports provided by the hospital accounts department. Total costs, including those arising from surgical and interventional procedures, consumables, personnel and accommodation, were analysed for all of the study participants and compared between PAE and TURP using descriptive analysis and two‐sided t‐tests, adjusted for unequal variance within groups (Welch t‐test).

Fig. 1. Cost summary for prostatic artery embolization (PAE) and TURP, grouped by mean total (A), procedural (B), and inpatient stay (C) costs. stay, inpatient stay; proc, surgical procedure; suppl, medical supplies; facil, operation facilities; phys, physician professional charges; anaest, anaesthesia; patho, pathology; lab, laboratory services; medic, medication; accom, accommodation; nurs, services by nursing specialists; admin, administrative costs, San Francisco based Ardenwood provides Christian Science nursing care.

Results

The mean total costs per patient (±sd) were higher for TURP, at €9137 ± 3301, than for PAE, at €8185 ± 1630. The mean difference of €952 was not statistically significant (P = 0.07). While the mean procedural costs were significantly higher for PAE (mean difference €623 [P = 0.009]), costs apart from the procedure were significantly lower for PAE, with a mean difference of €1627 (P < 0.001). Procedural costs of €1433 ± 552 for TURP were mainly incurred by anaesthesia, whereas €2590 ± 628 for medical supplies were the main cost factor for PAE.

Conclusions

Since in‐hospital costs are similar but PAE and TURP have different efficacy and safety profiles, the patient’s clinical condition and expectations – rather than finances – should be taken into account when deciding between PAE and TURP.

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Editorial: Prostatic Artery Embolization: Adding to the arsenal against the hapless prostate.

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Ever since Hugh Hampton Young introduced the cold punch method in 1909 for ‘punching out’ pieces of the prostate through a modified urethroscope, urologists have used a bewildering array of technology and methods to wage war against the hapless prostate. Methods in the current arsenal include ‘heat and kill’ (transurethral needle ablation, transurethral microwave therapy and Rezum treatment), ‘freeze and kill’ (cryotherapy), ‘slice’ (transurethral incision of prostate), ‘dice’ (transurethral resection of prostate [TURP]), ‘eviscerate and leave the prostate a shell of its former self’ (open prostatectomy and holmium laser enucleation of prostate), ‘suspend and open’ (Urolift), ‘poison’ (intraprostatic injections with Botox, alcohol and NX 1207), ‘vaporize’ (photoselective vaporization of the prostate [PVP]) and, if the prostate dares to turn cancerous, then we just cut it out with scalpels or robots. For the best Botox treatment baytown do follow us.  Prostatic artery embolization (PAE) adds to our already impressive armamentarium via a technique similar to strangulation by blocking arterial flow and essentially causing prostatic infarction. PAE also brings a member of another medical discipline to the frontline: the radiologist.

In this issue of BJUI, Müllhaupt et al. [1] report an in-hospital cost analysis of PAE compared to TURP, in their post hoc analysis of a randomized controlled trial. Treatment costs are an important component of healthcare but are a narrow and focused view of the overall management of BPH in an individual patient. The authors report that the in-hospital costs for PAE and TURP are similar and, therefore, cost should not be a consideration when deciding between PAE and TURP. Interestingly, the main procedural costs for TURP were anaesthesia, and the main cost factor for PAE was medical supplies. The urologist and radiologist physician charges were ~13% and ~15% of the procedural costs, respectively. So, if the costs of PAE and TURP are similar, how do you assess which to use?

The article by Müllhaupt et al. should be read in conjunction with other papers describing the efficacy, safety and outcomes of PAE compared to TURP, especially the original article by Abt et al. [2] from which this cost analysis is derived and the UK-ROPE study by Ray et al. [3].

Historically, prostatic infarction is known to be a possible result of cross-clamping the aorta for coronary or aortic surgery, hypotensive myocardial infarction or septic shock. PAE is an iatrogenic cause of prostatic infarction. In 1947, Wilbur G. Rogers [7], in ‘Infarct of the Prostate’, documented that ‘There is first swelling of the area involved, with degeneration and necrosis of the cells. This may be followed by absorption of the damaged area and fibrosis and cicatrization of the parts so that eventually the volume is much less than it was originally’. This is one of the early descriptions of how PAE potentially works.

Prostatic artery embolization as a technique is feasible and has been shown to be relatively safe and efficacious in certain specialized institutions, as shown by the UK-ROPE study [3] and by Abt et al. [2]. It should be noted that PAE can be a technically challenging procedure and, although bilateral embolization is the goal, only unilateral embolization is possible in 25% of cases [1]. Highly specialized training is required, and the technique continues to evolve to avoid embolization of extraprostatic branches [3]. PAE is more painful than TURP, with higher reported pain on a visual analogue scale and higher analgesic use [2], but is associated with a shorter length of hospital stay [1,2]. PAE is reported to be associated with an earlier return to normal activities but is less effective than TURP at 12 weeks with regard to changes in maximum rate of urinary flow, postvoid residual urine, prostate volume and desobstructive effectiveness according to pressure flow studies [2] and has a 20% reoperation rate after 12 months [3].

There are still some questions and issues surrounding PAE that may eventually be addressed with time and further studies. Embolizing an artery causes cell death and necrosis and eventual atrophy. This process is uncontrolled, however, and unpredictable in any individual patient. There is no way to know how much tissue or which part of the prostate is going to infarct and undergo necrosis with unilateral or bilateral embolization. If or when a potential abscess forms has not been defined or studied.

The longer-term effects of radiation dosage for PAE will not be known for many years. In the Abt et al. study cohort [2], the radiation dose (dose area product [DAP]) was 176.5 Gy/cm2. A standard anteroposterior and lateral chest X-ray exposes the patient to 0.3 Gy/cm2. An abdominal CT scan exposes the patient to ~32 Gy/cm2. PAE is thus roughly equivalent to ~5–10 standard abdominal/pelvic CT scans (more if using ultra-low dose scanners), 586 chest X-rays, 4.4 barium enemas or 8.8 voiding cysto-urethrograms. Markar et al. [4] reported that there was a significant increase in abdominal cancer within the radiation field in 14 150 patients undergoing endovascular aneurysm repair (EVAR), with 18% of patients who underwent EVAR succumbing to cancer. The mean radiation exposure (or DAP) in a review of 24 studies on EVAR [5] was 79.48 Gy/cm2, which is approximately half the radiation exposure of PAE.

Müllhaupt et al. [1] showed that PAE was associated with a quicker return to normal activities and a shorter length of stay than TURP, with similar in-hospital costs in Switzerland. Cost, however, must be considered alongside safety and efficacy data both in the short and long term. It is important to appreciate the specialized and technical expertise required to safely perform PAE and the importance of a urologist being part of the multidisciplinary management team as recommended in the National Institute for Health and Care Excellence (NICE) guidelines [6] (IPG611 April 2018). Radiation exposure will need close scrutiny and detailed reporting to document long-term effects, as demonstrated in the EVAR trials. Radiation dosage is cumulative over a lifetime and this must be considered when other interventional radiological procedures such as coronary angiograms and positron-emission tomography/CT are becoming more common. PAE should be compared with other emerging minimally invasive BPH procedures such as Urolift and Rezum in future studies, instead of just TURP to determine its role in BPH management and whether the radiation dose is justified. Longer-term studies are needed to assess the costs of managing any long-term
complications, re-operation rates and longer-term efficacy associated with PAE.

by Peter Chin
South Coast Urology, Wollongong, NSW, Australia

References

  1. Müllhaupt G, Hechelhammer L, Engeler D et al. In-Hospital cost analysis of prostatic artery embolization compared to transurethral resection of the prostate: post hoc analysis of a randomized controlled trial. BJU Int 2019;123: 1055-60
  2. Abt D, Hechelhammer L, Müllhaupt G et al. Comparison of prostatic artery embolization (PAE) versus transurethral resection of the prostate (TURP) for benign prostatic hyperplasia: randomized, open label, noninferiority trial. BMJ 2018; 361: k2338
  3. Ray AF, Powell J, Speakman MJ et al. Efficacy and safety of prostate artery embolization for benign prostatic hyperplasia: an observational study and propensity-matched comparison with transurethral resection of the prostate (the UK-ROPE study). BJU Int 2018; 122: 270–82
  4. Markar SR, Vidal-Diez A, Sounderajah V et al. A population-based cohort study examining the risk of abdominal cancer after endovascular abdominal aortic aneurysm repair. J Vasc Surg 2018; Article in Press. https://doi.org/10.1016/j.jvs.2018.09.058 [Epub ahead of print]
  5. Monastiriotis S, Comito M, Lapropoulos N. Radiation exposure in endovascular repair of abdominal and thoracic aortic aneurysms. J Vasc Surg 2015; 62: 753–61
  6. NICE Guidance. Prostate artery embolisation for lower urinary tract symptoms caused by benign prostatic hyperplasia. BJU Int 2018; 121: 825–34
  7. Rogers WG. Infarct of the prostate. J Urol 1947; 57: 484–7

 

Article of the month: Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study

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

In addition to the article itself, there is an editorial written by a prominent member of the urological community and the authors have also kindly produced a video describing their work. These are intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation. 

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

Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study

Cedric Lebacle* , Karim Bensalah†, Jean-Christophe Bernhard‡§, Laurence Albiges, Brigitte Laguerre**, Marine Gross-Goupil††, Herve Baumert‡‡, Herve Lang§§, Thibault Tricard§§, Brigitte Duclos¶¶, Armelle Arnoux***, Celine Piedvache***, Jean-Jacques Patard††† and Bernard Escudier

 

*Department of Urology, Bicêtre University Hospital, Assistance Publique-Hôpitaux de Paris, APHP, University Paris-Saclay, Le Kremlin-Bicêtre, †Department of Urology, Pontchaillou University Hospital, Rennes, ‡Department of Urology, Bordeaux University Hospital, Pellegrin Hospital, §French Research Network on Kidney Cancer UroCCR, Bordeaux, Department of Medicine, Gustave Roussy, University Paris-Saclay, Villejuif, **Department of Oncology, Eugene Marquis Centre, Rennes, ††Department of Medical Oncology, Bordeaux University Hospital, Saint-André Hospital, Bordeaux, ‡‡Department of Urology, Saint-Joseph Hospital, Paris, §§Department of Urology, Nouvel Hôpital Civil, ¶¶Department of Oncology, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, ***Paris-Sud Clinical Research Unit, Department of Statistics, Bicêtre University Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre and †††Department of Urology, Mont de Marsan Hospital, Mont de Marsan, France

 

Read the full article

Abstract

Objective

To evaluate the ability of neoadjuvant axitinib to reduce the size of T2 renal cell carcinoma (RCC) for shifting from a radical nephrectomy (RN) to a partial nephrectomy (PN) indication, offering preservation of renal function.

Patients and Methods

Patients with cT2aN0NxM0 clear‐cell RCC, considered not suitable for PN, were enrolled in a prospective, multicentre, phase II trial (AXIPAN). Axitinib 5 mg, and up to 7–10 mg, was administered twice daily, for 2–6 months before surgery, depending on the radiological response. The primary outcome was the number of patients receiving PN for a tumour <7 cm in size after neoadjuvant axitinib.

Results

Eighteen patients were enrolled. The median (range) tumour size and RENAL nephrometry score were 76.5  (70–98) mm and 11 (7–11), respectively. After axitinib neoadjuvant treatment, 16 tumours decreased in diameter, with a median size reduction of 17% (64.0 vs 76.5 mm; P < 0.001). The primary outcome was considered achieved in 12 patients who underwent PN for tumours <7 cm. Sixteen patients underwent PN. Axitinib was tolerated in the present study, as has been previously shown in the metastatic setting. Five patients had grade 3 adverse events. Five patients experienced Clavien III–V post‐surgery complications. At 2‐year follow‐up, six patients had metastatic progression, and two had a recurrence.

Conclusion

Neoadjuvant axitinib in cT2 ccRCC is feasible and, even with a modest decrease in size, allowed a tumour shrinkage <7 cm in 12 cases; however, PN procedures remained complex, requiring surgical expertise with possible morbidity.

Read more Articles of the week

Editorial: Expanding the feasibility of nephron‐sparing surgery: time for a paradigm shift?

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With the rapid implementation of ‘targeted’ therapies, kidney cancer has entered a new era where old paradigms are being challenged, and new ones can be explored. The idea of delivering ‘neoadjuvant’ systemic therapy to alter the surgical treatment of advanced RCC was suggested in this same journal ~10 years ago as a proof‐of‐concept study [1]. Since then, a plethora of small case series has investigated the safety and feasibility of different targeted agents in the preoperative setting to facilitate surgical resection of locally advanced disease, mostly with a ‘cytoreductive’ (rather than ‘curative’) intent.

In this issue of the BJU Int, Lebacle et al. [2] evaluated the role of neoadjuvant axitinib, an oral tyrosine kinase inhibitor currently recommended as a second‐line option for metastatic clear cell RCC, to downstage cT2 kidney cancer and allow a partial nephrectomy (PN). In this multicentre prospective study, 18 patients with RCC (median tumour size 7.6 cm and R.E.N.A.L. [Radius; Exophytic/Endophytic; Nearness; Anterior/Posterior; Location] score 11) were enrolled. A median tumour size reduction of 17% was obtained, and the primary outcome (‘clinical downstaging’ to cT1 to allow PN) was achieved in 12 patients (67%). Overall, 16 patients underwent PN, as this was successfully done also in four of six (67%) patients who were not ‘down‐staged’ by the drug. Notably, about half of the PNs were performed with a robotic approach. Whilst axitinib was well tolerated, five patients experienced a high‐grade complication after surgery, including one death. Interestingly, final pathology showed upstaging to pT3a disease in seven patients, and two positive margins. Moreover, about a third of patients had metastatic progression and two had recurrence at 2 years. Thus, while the authors noted axitinib to be effective in reducing tumour size and achieving a clinical downstaging in most patients, the significant presence of pT3a disease calls into question the overall efficacy (to truly pathologically downstage) or desirability (most of the tumours that were not downstaged still successfully underwent PN) of the study’s main stated aim.

The rapid adoption of robotic surgery and the increasing experience with PN techniques translated into expanding indications for minimally invasive nephron‐sparing surgery (NSS), to include also T1b and T2 renal masses [3], and the field is primed for a possible paradigm shift. Whether or not a PN is doable, regardless of the technique, remains in the hands of the surgeon, who makes that decision based on previous personal experience. This is also the case for the present study, where the primary outcome was simply represented by the number of patients who could get a PN (instead of a radical nephrectomy). As such, is such a subjective endpoint (feasibility of PN) clinically meaningful? While disagreement may occur over the risk of PN in complex and elective cases, the desirability of nephron preservation in imperative and most elective circumstances is supported by evidence that largely suggests that PN translates into better renal function. In addition, recent findings suggest that estimated GFR preservation might translate into better cancer‐specific survival [4]. Certainly, this type of endpoint (whether a PN is feasible) is prone to intrinsic bias and limitations.

Only a limited number of studies have specifically explored the role of neoadjuvant therapy to enable NSS with variable results [5] (Table 1) [2, 6, 7, 8, 9]. Overall, these studies suggest that even a modest tumour size reduction can facilitate kidney preservation in a significant number of cases. Amongst these studies, only one had assessed axitinib in this specific setting [9]. Differences in outcomes between that trial and the present one by Lebacle et al. [2] could be explained by differences in study populations and/or drug regimens. A more recent study by Karam et al. [10], showed that inter‐observer agreement regarding the feasibility of a PN is quite variable, which is not surprising. For this reason, those authors advocated the need for a ‘resectability score’.

In conclusion, utility of neoadjuvant therapy to modify tumour size and facilitate NSS is an active and exciting area of clinical investigation, fuelled by the rapidly changing landscape of systemic therapies for RCC. It is too early to call for a paradigm shift, but a few ongoing studies might provide some meaningful answers soon. Amongst these, the PADRES (Prior Axitinib as a Determinant of Outcome of REnal Surgery) is an ongoing North American multicentre phase II study of axitinib with the aim of recruiting 50 patients [5]. While waiting for more robust evidence, the use of neoadjuvant therapy to facilitate NSS should still be deemed as investigational.

References

  1. Shuch, B, Riggs, SB, LaRochelle, JC et al. Neoadjuvant targeted therapy and advanced kidney cancer: observations and implications for a new treatment paradigm. BJU Int 2008; 102: 692– 6
  2. Lebacle, C, Bensalah, K, Bernhard, JC et al. Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study. BJU Int 2019; 123: 804– 10
  3. Bertolo, R, Autorino, R, Simone, G et al. Outcomes of robot‐assisted partial nephrectomy for clinical T2 renal tumors: a multicenter analysis (ROSULA Collaborative Group). Eur Urol 2018; 74:226– 32
  4. Antonelli, A, Minervini, A, Sandri, M et al. Below safety limits, every unit of glomerular filtration rate counts: assessing the relationship between renal function and cancer‐specific mortality in renal cell carcinoma. Eur Urol 2018; 74: 661– 7
  5. Bindayi, A, Hamilton, ZA, McDonald, ML et al. Neoadjuvant therapy for localized and locally advanced renal cell carcinoma. Urol Oncol 2018; 36: 31– 7
  6. Silberstein, JL, Millard, F, Mehrazin, R et al. Feasibility and efficacy of neoadjuvant sunitinib before nephron‐sparing surgery. BJU Int 2010; 106: 1270– 6
  7. Rini, BI, Plimack, ER, Takagi, T et al. A phase II study of pazopanib in patients with localized renal cell carcinoma to optimize preservation of renal parenchyma. J Urol 2015; 194: 297– 303
  8. Lane, BR, Derweesh, IH, Kim, HL et al. Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma. Urol Oncol 2015; 33: 112.e15–21.
  9. Karam, JA, Devine, CE, Urbauer, DL et al. Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. Eur Urol 2014; 66: 874– 80
  10. Karam, JA, Devine, CE, Fellman, BM et al. Variability of inter‐observer agreement on feasibility of partial nephrectomy before and after neoadjuvant axitinib for locally advanced renal cell carcinoma (RCC): independent analysis from a phase II trial. BJU Int 2016; 117: 629– 35

 

Video: Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study

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Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study

Read the full article

Abstract

Objective

To evaluate the ability of neoadjuvant axitinib to reduce the size of T2 renal cell carcinoma (RCC) for shifting from a radical nephrectomy (RN) to a partial nephrectomy (PN) indication, offering preservation of renal function.

Patients and Methods

Patients with cT2aN0NxM0 clear‐cell RCC, considered not suitable for PN, were enrolled in a prospective, multicentre, phase II trial (AXIPAN). Axitinib 5 mg, and up to 7–10 mg, was administered twice daily, for 2–6 months before surgery, depending on the radiological response. The primary outcome was the number of patients receiving PN for a tumour <7 cm in size after neoadjuvant axitinib.

Results

Eighteen patients were enrolled. The median (range) tumour size and RENAL nephrometry score were 76.5  (70–98) mm and 11 (7–11), respectively. After axitinib neoadjuvant treatment, 16 tumours decreased in diameter, with a median size reduction of 17% (64.0 vs 76.5 mm; P < 0.001). The primary outcome was considered achieved in 12 patients who underwent PN for tumours <7 cm. Sixteen patients underwent PN. Axitinib was tolerated in the present study, as has been previously shown in the metastatic setting. Five patients had grade 3 adverse events. Five patients experienced Clavien III–V post‐surgery complications. At 2‐year follow‐up, six patients had metastatic progression, and two had a recurrence.

Conclusion

Neoadjuvant axitinib in cT2 ccRCC is feasible and, even with a modest decrease in size, allowed a tumour shrinkage <7 cm in 12 cases; however, PN procedures remained complex, requiring surgical expertise with possible morbidity.

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Article of the month: Prostate cancer mortality rates in Peru and its geographical regions

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

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

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

Prostate cancer mortality rates in Peru and its geographical regions

Junior Smith Torres-Roman*†, Eloy F. Ruiz‡, Jose Fabian Martinez-Herrera§, Sonia Faria Mendes Braga, Luis Taxa**, Jorge Saldaña-Gallo*, Mariela R. Pow-Sang††, Julio M. Pow-Sang‡‡ and Carlo La Vecchia§§

 

*Clinica de Urologia Avanzada UROZEN, Lima, †Facultad de Medicina Humana, Universidad Nacional San Luis Gonzaga, Ica, ‡CONEVID, Unidad de Conocimiento y Evidencia, Universidad Peruana Cayetano Heredia, Lima, Peru, §Cancer Center, Medical Center American British Cowdray, Mexico City, Mexico, Department of Social and Preventive Medicine, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, **Instituto Nacional de Enfermedades Neoplásicas, ††Department of Urology, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru, ‡‡Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, USA, and §§Department of Clinical Sciences and Community Health, Universitá degli Studi di Milano, Milan, Italy

 

Read the full article

Abstract

Objective

To evaluate the mortality rates for prostate cancer according to geographical areas in Peru between 2005 and 2014.

Materials and Methods

Information was extracted from the Deceased Registry of the Peruvian Ministry of Health. We analysed age‐standardised mortality rates (world population) per 100 000 men. Spatial autocorrelation was determined according to the Moran Index. In addition, we used Cluster Map to explore relations between regions.

Fig. 1. Peru geographical zones by provinces. The asterisk denotes the province of Callao. Source: National Statistics Institute

Results

Mortality rates increased from 20.9 (2005–2009) to 24.1 (2010–2014) per 100 000 men, an increase of 15.2%. According to regions, during the period 2010–2014, the coast had the highest mortality rate (28.9 per 100 000), whilst the rainforest had the lowest (7.43 per 100 000). In addition, there was an increase in mortality in the coast and a decline in the rainforest over the period 2005–2014. The provinces with the highest mortality were Piura, Lambayeque, La Libertad, Callao, Lima, Ica, and Arequipa. Moreover, these provinces (except Arequipa) showed increasing trends during the years under study. The provinces with the lowest observed prostate cancer mortality rates were Loreto, Ucayali, and Madre de Dios. This study showed positive spatial autocorrelation (Moran’s I: 0.30, P= 0.01).

Conclusion

Mortality rates from prostate cancer in Peru continue to increase. These rates are higher in the coastal region compared to those in the highlands or rainforest.

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Editorial: The burden of urological cancers in low‐ and middle‐income countries

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The burden of cancer in low‐ and middle‐income countries (LMICs) continues to rise [1]. Evaluation of geographical differences in cancer mortality statistics is specifically of interest in LMICs as (inter)national guidelines are potentially less embedded in standard care, and objective measurements to assess underlying mechanisms/explanations for the burden of cancer are often lacking. Monitoring mortality statistics in these countries can thus help assess the effectiveness of national and regional health systems in treating and caring for patients with cancer [1].

Torres‐Roman et al. [2] deserve to be congratulated for their efforts to monitor mortality rates for prostate cancer at both a regional and national level in Peru. The CONCORD initiative from the WHO previously reported prostate cancer statistics for Peru, but data were limited to the capital area of Lima [1]. Torres‐Raman et al. [2] report prostate cancer mortality rates between 2005 and 2014 based on data from the Peruvian Ministry of Health, which covers ~70% of all healthcare providers in Peru. Apart from an overall increase of 15% in mortality rates, substantial variation was observed by geographical region. Mortality rates increased by 16% in the coastal region and highlands, whereas in the rainforest region the rates decreased by 19% [2]. One potential explanation for these observed differences could be the difference in ethnic and racial characteristics. The coastal region in Peru has a strong African influence and also has a larger proportion of men aged >65 years. In addition to potential differences in access to healthcare, some of the variation in prostate cancer mortality statistics most likely reflects a deficiency in reporting systems. Even though this study has its limitations due to missing data and lack of information on other important variables, such as ethnicity and socioeconomic status, it provides a first base for a critical assessment of prostate cancer care in Peru.

Studies like this one from Torres‐Roman et al. [2] show that there is a need for improvement and standardisation of (prostate) cancer care in LMICs, but also a need for improvement in data capturing, so that objective measurements can be put in place. The years of healthy life lost due to prostate cancer, as well as other urological cancers, in LMICs is increasing substantially. Even though each tumour group has its own specifications in terms of prevention and control, an epidemiological assessment of cancer burden based on the experience for urological cancers (i.e., prostate, bladder, kidney and testicular) can therefore inform future assessments of cancer burden. The urological tumour group covers both common and less common cancers (e.g. prostate vs kidney cancer), sex‐specific and cancers that affect both sexes (e.g. testicular vs bladder cancer), cancers with less known risk factors and those strongly linked with lifestyle risk factors (e.g. prostate vs bladder cancer).

It is encouraging to see an increase in the number of studies evaluating the burden of cancer in LMICs [3]; however, given the consistency in observations of an increase in mortality, there is an urgent need to further invest in prevention and management, as well as the infrastructure to collect all relevant data at a national level in these LMICs. Accurate information about cancer burden and how this varies between regions is essential to plan for an adequate health‐system response.

References

  1. Allemani, C, Matsuda, T, Carlo, V et al. Global surveillance of trends in cancer survival 2000‐14 (CONCORD‐3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population‐based registries in 71 countries. Lancet 2018; 391: 1023– 75
  2. Torres‐Roman, J, Ruiz, E, Martinez‐Herrera, J et al. Prostate cancer mortality rates in Peru and its geographic regions. BJU Int 2019; 123: 595– 601
  3. Carioli, G, Vecchia, C, Bertuccio, P et al. Cancer mortality predictions for 2017 in Latin America. Ann Oncol 2017; 28: 2286– 97

 

Article of the month: Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 study

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

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

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

 

Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 (SPCG‐4) study

Walter Cazzaniga*†‡, Hans Garmo§¶, David Robinson**, Lars Holmberg‡, Anna Bill-Axelson‡ and Pär Stattin‡
 
 
*Division of Experimental Oncology/Unit of Urology URI, IRCCS Ospedale San Raffaele, †University Vita-Salute San Raffaele, Milan, Italy, ‡Department of Surgical Sciences, Uppsala University, §Regional Cancer Centre Uppsala Örebro, Uppsala University Hospital, Uppsala, Sweden, Division of Cancer Studies, Cancer Epidemiology Group, King’s College London, London, UK, and **Department of Urology, Ryhov Hospital, Jönköping, Sweden
 

 

Read the full article

Abstract

Objectives

To investigate if results in terms of absolute risk in mature randomised trials are relevant for contemporary decision‐making. To do so, we compared the outcome for men in the radical prostatectomy (RP) arm of the Scandinavian Prostate Cancer Group Study number 4 (SPCG‐4) randomised trial with matched men treated in a contemporary era before and after compensation for the grade migration and grade inflation that have occurred since the 1980s.

Patients and Methods

A propensity score‐matched analysis of prostate cancer mortality and all‐cause mortality in the SPCG‐4 and matched men in the National Prostate Cancer Register (NPCR) of Sweden treated in 1998–2006 was conducted. Cumulative incidence of prostate cancer mortality and all‐cause mortality was calculated. Cox proportional hazards regression analyses were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for a matching on original Gleason Grade Groups (GGG) and second, matching with GGG increased one unit for men in the NPCR.

 
Figure 1: Cumulative incidence of prostate cancer mortality (PCM) and all‐cause mortality (ACM) in the SPCG‐4 and the NPCR of Sweden. FU, follow‐up after date of diagnosis or primary treatment. A and B based on original GGG. C and D based on upgraded GGG classification in the NPCR with an increase of one grade in GGG.

Results

Matched men in the NPCR treated in 2005–2006 had half the risk of prostate cancer mortality compared to men in the SPCG‐4 (HR 0.46, 95% CI 0.19–1.14). In analysis of men matched on an upgraded GGG in the NPCR, this difference was mitigated (HR 0.73, 95% CI 0.36–1.47).

Conclusion

Outcomes after RP for men in the SPCG‐4 cannot be directly applied to men in the current era, mainly due to grade inflation and grade migration. However, by compensating for changes in grading, similar outcomes after RP were seen in the SPCG‐4 and NPCR. In order to compare historical trials with current treatments, data on temporal changes in detection, diagnostics, and treatment have to be accounted for.

Read more Articles of the week

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

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

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

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

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

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

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

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

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

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

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

References

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

 

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