SIU 2019

Athens, Greece (Urotoday.com) Dr. Laurence Klotz presented on how to reduce scientific error and ensuring innovation. The history of science is a history of irresponsible dreams, obstinacy, and error. But science is one of the very few human activities – perhaps the only one – in which errors are systematically criticized and often corrected. In science, we often learn from our mistakes and can speak clearly and sensibly about making progress.¹

The scientific error may occur in the execution or analysis of an experiment. There are several types, which include:

1. Human error or mistakes in data collection
2. Systematic error, or flaws in experimental design
3. Random error, caused by environmental conditions or other unpredictable factors

It is important, especially in medical science, to mention the missing subgroup effect. At times, the effect of a drug or intervention may be seen only when applying it to a specific group of patients. Sometimes it is not easy to identify this important subgroup where the researched intervention has the greatest effect.

It is also important to be aware of false conclusions. Studies dubbed as statistically significant and statistically non-significant may not be necessarily contradictory.  Such designations may cause genuine effects to be dismissed.

Another important concept is the relationship between the p-value threshold, power and the false positive rate (Figure 1). As the p-value threshold is lower, the false positive rate is significantly lower at the same power.²

Other important types of manipulating data to achieve a p-value of less than 0.05 include:

1. P-hacking – an analysis run in multiple ways. But only those that produce statistically significant findings are reported
2. HARKing (Hypothesis After Results are Known) – data mining without an a priori hypothesis

The important steps in the scientific method that should be adhered to include:

1. Definition of a research question
2. Gathering of information and resources
3. Formation of an explanatory hypothesis
4. Hypothesis testing by performing an experiment and collecting data in a reproducible manner
5. Data analysis
6. Data interpretation and drawing conclusions that serve as a starting point for new hypothesis
7. Publication of results
8. Reproduce the results – frequently done by other scientists

Figure 1 - The relationship between the p-value threshold, power, and the false positive rate



The problem with a lot of scientific research data today is that there are no attempts to reproduce the data. In one survey  - 55% of researchers tried and failed to reproduce published results,³ with less than 30% of them publishing their failure, and 44% of them reporting difficulty in publishing their contradictory results. Unfortunately, to date, there is no mechanism that exists to confirm reproducibility, and this is a serious problem. Part of this is the low incentive that exists to replicate research.

Dr. Klotz suggested a solution to this which has been gaining momentum. This is the reproducibility project. Its goal is to identify key studies in the literature and reproduce them. The top 50 cited cancer biology studies from 2010-2012 have been chosen to be reproduced in a rapid and cost-effective manner, by expert independent labs. A budget of 1.3 million dollars has been allocated to this. Labs from 400+ research institutions with 75 of the top 100 US research universities have been involved in this project. So far, they have reported a replication effort success for two out of every five cancer papers.⁴

In the urology field, the Movemeber Foundation for Prostate Cancer has supported a pilot study to assess the reproducibility of research findings with implications for prostate cancer patients, aiming to replicate four major landmark studies.

Concluding his talk, Dr. Klotz summarized how to reduce scientific error in the future:

1. Recognize the key role of error in the scientific method
2. Maintain and foster a scientific tradition of scrupulous adherence to truth and objectivity
3. Enhance awareness of pitfalls of human investment in established paradigms
4. Recognize the risk of statistical error, particularly type 2 errors (underpowered studies, missing subgroup) and the hazard of a p-value of less than 0.05
5. Support reproducibility studies for key research findings
6. Be aware of the high prevalence of scientific misconduct

Presented by: Laurence Klotz, MD, FRCS(C), Professor of Surgery, University of Toronto, Toronto, Canada, Chairman of the World Uro-Oncology Federation, former Chief of Urology, Sunnybrook Health Sciences Centre, former President of the Urological Research Society and the Canadian Urological Association

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New-York, USA @GoldbergHanan at the 39th Congress of the Société Internationale d'Urologie, SIU 2019, #SIUWorld #SIU2019, October 17-20, 2019, Athens, Greece  

References:

1. Popper K. Conjectures and Refutations: The growth of scientific knowledge. 1963.
2. Benjamin DJ, Berger JO, Johannesson M, et al. Redefine statistical significance. Nature Human Behaviour 2018; 2(1): 6-10.
3. Mobley A, Linder SK, Braeuer R, Ellis LM, Zwelling L. A Survey on Data Reproducibility in Cancer Research Provides Insights into Our Limited Ability to Translate Findings from the Laboratory to the Clinic. PloS one 2013; 8(5): e63221.
4. Kaiser J. Mixed results from cancer replications unsettle field. Science (New York, NY) 2017; 355(6322): 234-5.

Athens, Greece (Urotoday.com) Oncofid-P-B is a conjugate of paclitaxel and Hyaluronic acid (HA) for the treatment of non-muscle-invasive bladder cancer (NMIBC) by intravesical instillation.

This conjugate confers tumor-targeted activity, improves paclitaxel solubility, reduces paclitaxel toxicity, and confers mucoadhesive properties.

A phase 1 study with multiple escalating doses (150-750 mg for 6 weeks) in 16 BCG refractory carcinoma in situ (CIS) patients showed a complete response rate of 60%. Later, a phase two study (600 mg for 6 weeks + maintenance) in 60 Ta G1-G2 patients demonstrated a 45% complete response rate with disease-free survival of 15.7 months. The drug demonstrated excellent efficacy and safety in all preliminary trials.

The presented study was an open-label, multicenter, multinational, phase 1 study to evaluate the safety and efficacy of this drug in 20 patients with CIS +/- Ta/T1 who were unresponsive or intolerant to BCG and unwilling or unfit to undergo radical cystectomy.

A total of 12 consecutive weekly instillations (intensive phase) were given and followed by 12 monthly installations (maintenance phase). The primary endpoint was the overall safety profile. The secondary endpoints included efficacy, compliance, rate of discontinuation, and systemic absorption. Complete response was defined as a negative cystoscopy including biopsy of the urothelium and negative e cytology.

A total of 21 patients were approached, but 20 were ultimately analyzed. 16 were male, and the mean age was 72.8 years, with all patients being Caucasian. 17 patients had pure CIS and 4 had CIS + Ta.

During the intensive phase, 7 mid-moderate (G1-G2) drug-associated adverse effects including hematuria, proteinuria, nausea, and urticaria were reported. There were no withdrawals resulting from the drug during treatment.

A total of 15/20 patients (75%) reached a complete response rate at the end of the intensive phase. None of the non-responders developed disease progression.

Dr. Rodolfo Hurle concluded that Oncofid-P-B has an excellent safety profile even after a prolonged treatment schedule. The efficacy data is quite favorable. This study shows a potential new therapeutic option in BCG unresponsive CIS patients which deserves further clinical evaluation.

Presented by: Rodolfo Hurle, MD, Department of Urology, Istituto Clinico Humanitas IRCCS, Clinical and Research Hospital, Milan, Italy

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New-York, USA @GoldbergHanan at the 39th Congress of the Société Internationale d'Urologie, SIU 2019, #SIUWorld #SIU2019, October 17-20, 2019, Athens, Greece  

Athens, Greece (Urotoday.com) Dr. Ashish Kamat gave a brief overview of enhanced recovery after surgery (ERAS) in patients undergoing radical cystectomy and provided some data on the comparison of robotic and open radical cystectomy.

In the past, before the implementation of the ERAS pathway, surgery was planned “as soon as possible,” with no training or conditioning of the patient. All patients underwent bowel preparation (both mechanical and antibiotic). Additionally, all patients were instructed not to eat anything before the night of surgery, and patients were put on a clear fluid diet 1-2 days before surgery. At the beginning of surgery all patients received compensatory overhydration, with aggressive hydration during the case. Following the surgery, a nasogastric tube was placed, and the patient was not allowed to eat anything until flatus. Lastly, opioid analgesia was given on a standard basis, limiting mental acuity and mobility. In this type of traditional care, the average stay in the US after radical cystectomy was 10 days, and even more than that in Europe and Asia. Importantly, the complication rate was approximately 60% with a hospital readmission rate of 30%.

The framework of the ERAS pathway designed to improve all aspects of the procedure and improve patient recovery and outcomes is outlined in a summarized manner in Figure 1. This framework entails actions that should be implemented in the preoperative, operative, and postoperative settings. The ERAS pathway originally came from colorectal surgeries showing significant improvement in patient recovery and outcomes.¹ This enhanced recovery pathway has been implemented successfully in patients undergoing radical cystectomy and has been steadily gaining popularity around the world.

In the last part of this talk, Dr. Kamat moved on to discuss the trials comparing robotic and open standard radical cystectomy. The landmark trial published by Bochner et al. in the New England Journal of Medicine² demonstrated that with robotic cystectomy there is 181 cc less amount of blood loss (500 cc vs. 681 cc, p=0.027). In another landmark trial, published in the Lancet, the RAZOR trial,³ robotic cystectomy was compared to open cystectomy as well. In this trial the estimated blood loss difference was more significant, 300 cc vs. 700 cc, p<0.001 (robotic vs. open). The length of hospital stay was lower in the robotic cases by one day (6 vs. 7 days, p=0.02), and the operation time was longer (428 vs. 361 minutes, p=0.005).

A major limitation precluding the adoption of robotic cystectomy in more centers is its high cost. A cost-effectiveness modeling study of robotic vs open radical cystectomy for bladder cancer showed that in the 90-day model, the cost of robotic cystectomy was 3,761 Euro higher than an open radical cystectomy.⁴ It was found that for robotic cystectomy to save costs it would need to meet the following conditions:

1. The length of hospital stay should be 4 days or less
2. The operating time should be limited to 175 minutes or less,
3. The robotic equipment costs cannot go over 281 Euro.⁴

Figure 1 – Framework of enhanced recovery after surgery:



Presented by: Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research at MD Anderson Cancer Center in Houston, Texas. Dr. Kamat serves as; President of International Bladder Cancer Group, Co-President of International Bladder Cancer Network, and Associate Cancer Center Director. Dr. Kamat served as the Program Director, of the MD Anderson Urologic Oncology Fellowship from 2005-2016.

Written By: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New-York, USA @GoldbergHanan at the 39th Congress of the Société Internationale d'Urologie, SIU 2019, #SIUWorld #SIU2019, October 17-20, 2019, Athens, Greece  

References:

1. Gustafsson UO, Scott MJ, Hubner M, et al. Guidelines for Perioperative Care in Elective Colorectal Surgery: Enhanced Recovery After Surgery (ERAS((R))) Society Recommendations: 2018. World journal of surgery 2019; 43(3): 659-95.
2. Bochner BH, Sjoberg DD, Laudone VP. A randomized trial of robot-assisted laparoscopic radical cystectomy. The New England journal of medicine 2014; 371(4): 389-90.
3. Parekh DJ, Reis IM, Castle EP, et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial. Lancet (London, England) 2018; 391(10139): 2525-36.
4. Michels CTJ, Wijburg CJ, Leijte E, Witjes JA, Rovers MM, Grutters JPC. A cost-effectiveness modeling study of robot-assisted (RARC) versus open radical cystectomy (ORC) for bladder cancer to inform future research. Eur Urol Focus 2018.

Athens, Greece (Urotoday.com) Dr. Badrinath Konety presented on intravesical therapy for non-muscle invasive bladder cancer (NMIBC). The current risk-based therapy entails:

• Low risk – surveillance or mitomycin
• Intermediate risk – mitomycin or BCG
• High risk – BCG (and mitomycin as a second choice)

15 years after treatment, 37%, 27% and 34% of patients with high-risk superficial bladder cancer have been shown to be alive with no evidence of disease, dead of other causes, and dead of disease, respectively.¹

BCG therapy does not always work, and there are several definitions of disease recurrence following BCG therapy:¹

1. BCG failure is defined as recurrence after adequate BCG treatment
2. BCG Relapse is defined as recurrence after a tumor-free period:

• Early if it is less than 1 year
• Late if it is more than 2 years

3. BCG Refractory – no tumor-free interval on BCG treatment after induction
4. BCG intolerant – Unable to tolerate BCG induction

In the next part of his talk, Dr. Konety discussed the various additional options for the intravesical treatment of NMIBC.

He began describing the Hyperthermic intravesical chemotherapy (HIVEC) option, which uses mitomycin. It is given at 43 degrees Celsius intravesically for 60 minutes by “Combat Medical”. In a study assessing 40 NMIBC intermediate-risk patients, 24 received this therapy at a neoadjuvant setting (before transurethral resection of bladder tumor [TURBT] for a duration of 8 weeks), and 16 patients received it at the adjuvant setting post-TURBT every week for 4 weeks and then every 6 months).²

The results demonstrated 62% and 33% complete and partial response, respectively, at the neoadjuvant setting and a 21% recurrence rate at 4 years. For the adjuvant setting – 12.5% recurrence rate at 2 years.²

Another more novel option is the Synergo device. In this option, before administering the instillation itself the bladder is heated, instead of the intravesical instillation being heated (Mitomycin). In a study assessing 190 intermediate- and high-risk patients in 11 centers, patients received 1-year maintenance therapy with either the Synergo device or standard intravesical BCG instillations.³ The study was closed early and, in the intention to treat analysis no difference was seen with the Synergo device compared to BCG. However, there was a significant difference in the per-protocol analysis, showing a lower recurrence rate for Synergo.³ The overall adverse event rate was lower with BCG.

Another option is Valrubicin. In a nonrandomized study including 90 patients, the complete response rate was 21% with a 7% durable response at 30-month median follow-up.⁴ Overall this drug was well-tolerated, and it has been FDA approved only for BCG refractory carcinoma in situ (CIS).⁴

The combination of gemcitabine and docetaxel was discussed next. In a study of 45 patients, of which 41/45 had previous BCG therapy, 62% had reported symptoms, and 16% had treatment alteration, with 10 patients undergoing radical cystectomy.⁵

There are several other early phase studies assessing novel medications. These include:

1. CG0070, a GMCSF expressing adenovirus, showing a 49% cure durable for 10 months^6,7
2. Photodynamic therapy with hexaminolevulinate (HAL) – a phase 1 study with 12 patients has been done. A total of 45% of the patients were recurrence-free at 12 months.⁸
3. Nadofaragene firadenovec (Adstiladrin®)- (rAd-interferon-alpha/Syn3; nadofaragene firadenovec), a new drug given at two dose levels, with early results showing a 35% recurrence-free survival at one year, and 41% recurrence-free-survival in patients treated with more than 3 courses of BCG⁹
4. Vicinium (VISTA trial) – a phase 3 study (NCT02449239) assessing Vicinium, which is an EpCAM antibody + pseudomonas toxin A. It seems that over 95% of bladder cancer patients express EpCAM in their bladder. In this study, the newly studied drug resulted in a 39% complete response rate for 273 days, with an adverse event rate of 46% - mostly being dysuria, hematuria and urinary tract infection¹⁰
5. Other ongoing studies include those investigating the efficacy of ALT 803 (IL-15 super antagonist), Imiquimod (TMX-101), and Vaccinia virus

In the last section of the talk, Dr. Konety discussed some of the work being done involving immunotherapy in the setting of NMIBC (Figure 1). In the Keynote-057, high-risk NMIBC patients with papillary or with CIS +/- papillary disease, unresponsive to BCG, who declined or cannot undergo cystectomy were treated with pembrolizumab. Initial results at the 3-month time point showed a complete response rate of 40.2% (Figure 2).

Figure 2 – KEYNOTE 057 trial design:

Dr. Konety concluded his talk giving his personal view on how to treat NMIBC patients:

• High risk with good performance status – offer radical cystectomy
• High risk with poor performance status or not agreeable to cystectomy – offer salvage therapy or trials
• Intermediate risk – salvage chemotherapy and trials, and later radical cystectomy
• Low risk – chemotherapy, BCG and then salvage or repeated fulguration

Presented by: Badrinath Konety, MD, MBA, CEO of the University of Minnesota Physicians, Vice Dean for Clinical Affairs at the University of Minnesota Medical School. Professor, Department of Urology, Director, Institute for Prostate and Urologic Cancers, Minnesota, United States

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New-York, USA @GoldbergHanan at the 39th Congress of the Société Internationale d'Urologie, SIU 2019, #SIUWorld #SIU2019, October 17-20, 2019, Athens, Greece  

References:

1. Steinberg RL, Thomas LJ, Mott SL, O'Donnell MA. Bacillus Calmette-Guérin (BCG) Treatment Failures with Non-Muscle Invasive Bladder Cancer: A Data-Driven Definition for BCG Unresponsive Disease. Bladder Cancer 2016; 2(2): 215-24.
2. Sousa A, Pineiro I, Rodriguez S, et al. Recirculant hyperthermic IntraVEsical chemotherapy (HIVEC) in intermediate-high-risk non-muscle-invasive bladder cancer. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 2016; 32(4): 374-80.
3. Arends TJ, Nativ O, Maffezzini M, et al. Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guerin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non-Muscle-invasive Bladder Cancer. Eur Urol 2016; 69(6): 1046-52.
4. Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. The Journal of urology 2000; 163(3): 761-7.
5. Steinberg RL, Thomas LJ, O'Donnell MA, Nepple KG. Sequential Intravesical Gemcitabine and Docetaxel for the Salvage Treatment of Non-Muscle Invasive Bladder Cancer. Bladder Cancer 2015; 1(1): 65-72.
6. Dinney CP, Fisher MB, Navai N, et al. Phase I trial of intravesical recombinant adenovirus mediated interferon-alpha2b formulated in Syn3 for Bacillus Calmette-Guerin failures in nonmuscle invasive bladder cancer. The Journal of urology 2013; 190(3): 850-6.
7. Burke JM, Lamm DL, Meng MV, et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. The Journal of urology 2012; 188(6): 2391-7.
8. Bader MJ, Stepp H, Beyer W, et al. Photodynamic therapy of bladder cancer - a phase I study using hexaminolevulinate (HAL). Urologic oncology 2013; 31(7): 1178-83.
9. Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd–IFNα/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin–Refractory or Relapsed Non–Muscle-Invasive Bladder Cancer: A Phase II Randomized Study. Journal of Clinical Oncology 2017; 35(30): 3410-6.
10. Dickstein R, Wu N, Cowan B, et al. LBA27 PHASE 3 STUDY OF VICINIUM IN BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER: INITIAL RESULTS. Journal of Urology 2018; 199(4S): e1167-e.

Athens, Greece (Urotoday.com) In this talk, Dr. Tilki reviewed several prognostic biomarkers in the setting of localized prostate cancer management. 

The currently available prognostic biomarkers include: 

• Oncotype Dx (GPS) 
• Prolaris 
• Decipher 
• Decipher Biopsy 

Athens, Greece (UroToday.com) The objective of this talk given by Dr. Derya Tilki was to review the diagnostic biomarkers in the pre-biopsy setting of prostate cancer and to describe their cost-effectiveness. The ideal biomarkers in the pre-biopsy setting should be able to increase the probability of achieving a positive biopsy. Unfortunately, the positive predictive value of the most used biomarker to date for prostate cancer (PSA), is very low (25-40%) when it is in the range of 4-10 ng/ml.¹ Approximately 65-75% and 10-35% of initial and repeat biopsies in the PSA range of 4-10 ng/ml are negative.² The ideal biomarker will reduce over-detection and the number of unnecessary biopsies, as biopsies have significant adverse events (infection, bleeding), and are associated with pain.³

Currently, available prostate cancer biomarkers in the pre-biopsy setting can be divided into two groups:

1. Biomarkers used to ascertain who to initially biopsy (PHI, 4K score, Select MDX, MiPS, ExoDx prostate Intelliscore)
2. Biomarkers used to ascertain when to re-biopsy (PCA3, and ConfirmMDx)

According to the European Association of Urology (EAU) guidelines, to avoid unnecessary biopsies, it is recommended to use risk calculators and additional biomarkers, or imaging.

Dr. Tilki described the important available biomarkers to date. The first biomarkers that were discussed were the PHI and the 4K score. The PHI combines three PSA sub-forms (total PSA, free PSA, and [-2]proPSA) into a single score. It is indicated in men with a PSA of between 2-10 ng/ml and normal digital rectal examination (DRE).⁴ The PHI score has been shown to correlate with the percentage of a positive biopsy.

The 4K score combines four prostate-specific kallikrein assay results (total PSA, free PSA, intact PSA, and hk2) with age and prior biopsy status. The 4K score gives the percentage risk of having aggressive prostate cancer, and it has been shown to predict the probability of distant metastasis within 20 years.⁵

In a comparison of 4k to PHI, both similarly improved discrimination when predicting prostate cancer and high-grade prostate cancer. Both are simple blood tests that can reduce the number of unnecessary biopsies compared with screening with PSA only.⁶ Usage of the 4K score in a hypothetical cohort of 100,000 men suspected of having prostate cancer, can result in an average net savings of 169 million dollars (1694 USD per patient), during the first year after the first urologist visit⁷ (Figure 1).

Figure 1 – Hypothetical decision model to predict cost-effectiveness of the 4K score:



Dr. Tilki moved on to discuss the SelectMDx biomarker. This is a non-invasive urine assay aimed to improve patient selection for initial biopsy. It is a two-gene risk score combining HOXC6 and DLX1 mRNA expression levels with clinical risk factors, which include:

1. PSA density
2. DRE
3. PSA
4. Age
5. History of prostate biopsy
6. Family history

This biomarker can detect high-grade clinically significant prostate cancer. It has an area under the curve (AUC) of 0.89 for detecting clinically significant cancer, and it is highly correlated with Gleason score as well, with a negative predictive value of 98% for aggressive cancer. Various cost-effectiveness studies of SelectMDx have been done, demonstrating its ability to significantly save money.⁸ There has been some data showing the potential role of this biomarker to select patients for multiparametric MRI.¹

Next, the MI-prostate score was discussed. This score consists of:

1. PCA3 mRNA urine test
2. Total PSA in the blood
3. TMPRSS2-ERG mRNA in the urine

It can predict the presence of overall and high-grade prostate cancer on initial and repeat biopsy.⁹ It has been shown to have an AUC of 0.772 for the detection of prostate cancer.¹⁰

ExoDX prostate (Intelliscore) was discussed next. This urine biomarker utilized exosomes, which are small, double-lipid membrane vesicles that are secreted from cells. This is a urinary exosome gene expression assay that predicts the presence of high-grade prostate cancer for men older than 50 with a PSA of 2-10 ng/ml, referred for an initial biopsy. It gives a score between 0-100 by combining the relative weighted expressions of three gene signatures. A score>15.6 is associated with an increased likelihood of high-grade prostate cancer on a subsequent biopsy. It has an AUC of 0.77 and has been validated in a large multicenter study.¹¹

The next two biomarkers discussed were those used to ascertain when to perform a prostate biopsy. She began with the PCA3 urine test, which is analyzed by RT-PCR and is an assay commercially used today for aiding the diagnosis of prostate cancer. This has been used especially in patients with a previous negative prostate biopsy. PCA3 has been shown to be higher in men with a positive rather than a negative prostate biopsy.¹² It has been officially recommended for men at a higher risk of prostate cancer, with a previous negative needle biopsy.

ConfirmMDx is also used to ascertain when to perform a prostate biopsy. ConfirmMDx detects a field-effect or halo associated with the presence of cancer at the DNA level (Figure 2). It detects epigenetic changes and is performed on the residual tissue from previous negative biopsies (up to 30 months old). It helps to distinguish patients who have a true-negative biopsy from those who may have occult cancer. The test helps find men who may benefit from a mpMRI or another biopsy and early detection. It has 90% and 96% negative predictive value for the detection of any cancer and significant prostate cancer, respectively.

In a cost-effectiveness analysis, it has been shown to reduce 1106 unnecessary biopsies for a health plan with 1 million members, with more than 588 USD saved per patient, and more than 530,000 USD saved annually per 1 million members.¹³

Figure 2 – ConfirmMDx biomarker principle:



With this large array of available biomarkers, it is extremely difficult to choose which biomarker to use. Unfortunately, high quality direct comparative studies to aid in the decision process are lacking.

The 4M study is a multicenter prospective study by the Dutch Cancer Foundation. The study will compare multiparametric MRI, various biomarkers and risk calculators in ~ 600 men with a PSA>=3 ng/ml. Recruitment and analysis have been completed and the much-awaited results are expected 2020.

Presented by: Derya Tilki, MD, Attending Urologist, Martini-Clinic Prostate Cancer Center, Hamburg, Germany

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New-York, USA @GoldbergHanan at the 39th Congress of the Société Internationale d'Urologie, SIU 2019, #SIUWorld #SIU2019, October 17-20, 2019, Athens, Greece

References:

1. Hendriks RJ, van Oort IM, Schalken JA. Blood-based and urinary prostate cancer biomarkers: a review and comparison of novel biomarkers for detection and treatment decisions. Prostate cancer and prostatic diseases 2017; 20(1): 12-9.
2. Heidenreich A, Aus G, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2008; 53(1): 68-80.
3. Loeb S, Vellekoop A, Ahmed HU, et al. Systematic review of complications of prostate biopsy. Eur Urol 2013; 64(6): 876-92.
4. Catalona WJ, Partin AW, Sanda MG, et al. A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. The Journal of urology 2011; 185(5): 1650-5.
5. Stattin P, Vickers AJ, Sjoberg DD, et al. Improving the Specificity of Screening for Lethal Prostate Cancer Using Prostate-specific Antigen and a Panel of Kallikrein Markers: A Nested Case-Control Study. Eur Urol 2015; 68(2): 207-13.
6. Nordstrom T, Vickers A, Assel M, Lilja H, Gronberg H, Eklund M. Comparison Between the Four-kallikrein Panel and Prostate Health Index for Predicting Prostate Cancer. Eur Urol 2015; 68(1): 139-46.
7. Voigt JD, Dong Y, Linder V, Zappala S. Use of the 4Kscore test to predict the risk of aggressive prostate cancer prior to prostate biopsy: Overall cost savings and improved quality of care to the us healthcare system. Rev Urol 2017; 19(1): 1-10.
8. Govers TM, Caba L, Resnick MJ. Cost-Effectiveness of Urinary Biomarker Panel in Prostate Cancer Risk Assessment. The Journal of urology 2018; 200(6): 1221-6.
9. Sanda MG, Feng Z, Howard DH, et al. Association Between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer. JAMA oncology 2017; 3(8): 1085-93.
10. Tomlins SA, Day JR, Lonigro RJ, et al. Urine TMPRSS2:ERG Plus PCA3 for Individualized Prostate Cancer Risk Assessment. Eur Urol 2016; 70(1): 45-53.
11. McKiernan J, Donovan MJ, O’Neill V, et al. A Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer at Initial Biopsy. JAMA oncology 2016; 2(7): 882-9.
12. de la Taille A, Irani J, Graefen M, et al. Clinical evaluation of the PCA3 assay in guiding initial biopsy decisions. The Journal of urology 2011; 185(6): 2119-25.
13. Aubry W, Lieberthal R, Willis A, Bagley G, Willis SM, 3rd, Layton A. Budget impact model: epigenetic assay can help avoid unnecessary repeated prostate biopsies and reduce healthcare spending. American health & drug benefits 2013; 6(1): 15-24.

Athens, Greece (UroToday.com) Dr. Laurence Klotz initiated this session on prostate cancer screening. According to Dr. Klotz, there are several problems with the current paradigm with PSA and systematic biopsy:

1. PSA thresholds are too confusing for primary care physicians with no consensus at sight
2. Overdiagnosis of insignificant cancer is a real problem
3. Pathologic miss of significant cancer and misattribution of grade
4. Biopsy complications
5. Discomfort as patients dislike biopsies

PSA with all its resulting controversy and the fact that different societies and organizations have conflicting recommendations regarding its use (Figure 1), is still here to stay. It has had a greater impact on cancer detection, staging, prognosis, and monitoring than any other biomarker had had in any cancer (Figure 2). It is more accessible, ubiquitous, quantitative, reproducible, and accurate than any other cancer biomarker. There is also compelling evidence regarding its role as a screening tool. An important factor to consider is the PSA level in midlife which can predict the lifetime risk of prostate cancer metastases/death with profound accuracy.

Figure 1 – PSA recommendation by various groups around the world:



Figure 2 – Incidence of prostate and breast cancer metastatic diagnosis in the US 1975-2012:



After the US preventative services task force (USPSTF) recommendation in 2012 against prostate cancer screening with PSA, data have shown a steady increase in the incidence of metastatic prostate cancer in the US (Figure 3).

Figure 3 – Increasing incidence of metastatic prostate cancer in the US (2004-2013):¹



Clearly, the incidence of advanced prostate cancer disease at diagnosis is increasing since 2010. There is also no comparable improvement in countries without prevalent PSA testing. Properly performed large randomized trials show a 21-44% mortality reduction (29-56% among men screened) (Figure 4). The number need to screen with PSA is 293 per one death that can be avoided. The number needed to treat at 14 years is 12 (this is likely to even further decrease with longer follow-up). When comparing this to mammography, the number needed to screen is 111-235 at age 50-70, and the number needed to treat is between 10-14, and in colonoscopy, the number needed to screen is 850.

Figure 4- Results of the key prospective randomized screening trials:



PSA done at midlife can predict the risk of metastases and prostate cancer-specific death. In a large study by Vickers et al. assessing 21,277 men aged 33-50, it was shown that the probability of metastases developing in 20-25 years in men with a PSA of less than 1.1 ng/ml is approximately 0.2%.² Another important study by Halpern et al. evaluated the value of digital rectal examination (DRE) in the detection of significant prostate cancer.³ In a large cohort of 35,350 men in the screening arm of the PLCO study, it was shown that DRE made a difference only when the PSA level was above 3.0 ng/ml (23% vs. 13.7%). Thus the authors supported the restriction of DRE to men with PSA > 3.0 ng/ml as a reflex test to improve specificity.³

Dr. Klotz gave a possible solution to performing “informed PSA screening.” This entails:

1. 1^st test at ~age 45. If it is less than 1 then repeat every 5 years, with only 2-3 tests between the ages of 55-65.
2. Screening above age 70 is probably not recommended.
3. Incorporate additional blood/urine biomarkers
4. Utilization of active surveillance for most low-risk disease
5. There is an emerging role for MRI to perhaps replace the biopsy at specific settings

Another option is to use a lower PSA cutoff of 1.5 ng/ml as has been suggested by Dr. Crawford⁴ (Figure 5).

Dr. Klotz moved on to describe what the available options are when faced with an elevated PSA. This is basically choosing between performing a multiparametric MRI and using another biomarker. Table 1 demonstrates the differences between these two options. The problem with newly found biomarkers is the cost and the analytical expertise that is required for their interpretation⁵ (Figure 6).

Dr. Klotz concluded his talk suggesting rehabilitation for PSA testing. The patient needs good information which is difficult for the physician to convey in the typical average clinic visit. That is why a good patient brochure is required. It is important to restrict testing to those who will benefit and restrict the biopsy to those with a compelling reason. Active surveillance should be utilized for low-risk patients. Lastly, the treatment morbidity should be reduced by treating patients at centers of excellence and exploring the option of focal therapy for properly selected patients.

Figure 5: Approach to shared care in prostate cancer diagnosis using a PSA cutoff of 1.5 ng/ml:⁴





Table 1 – Multiparametric MRI or biomarker? What to use when faced with an elevated PSA?

Figure 6 – The cost and complexity of liquid biomarker diagnostics:




Presented by: Laurence Klotz, MD, FRCSC, Professor, Department of Surgery, University of Toronto, Toronto, Canada

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New-York, USA @GoldbergHanan at the 39th Congress of the Société Internationale d'Urologie, SIU 2019, #SIUWorld #SIU2019, October 17-20, 2019, Athens, Greece

References:

1. Weiner AB, Matulewicz RS, Eggener SE, Schaeffer EM. Increasing incidence of metastatic prostate cancer in the United States (2004-2013). Prostate cancer and prostatic diseases 2016; 19(4): 395-7.
2. Vickers AJ, Ulmert D, Sjoberg DD, et al. Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40-55 and long term risk of metastasis: case-control study. BMJ : British Medical Journal 2013; 346: f2023.
3. Halpern JA, Oromendia C, Shoag JE, et al. Use of Digital Rectal Examination as an Adjunct to Prostate Specific Antigen in the Detection of Clinically Significant Prostate Cancer. The Journal of urology 2018; 199(4): 947-53.
4. Crawford ED, Rosenberg MT, Partin AW, et al. An Approach Using PSA Levels of 1.5 ng/mL as the Cutoff for Prostate Cancer Screening in Primary Care. Urology 2016; 96: 116-20.
5. Neuhaus J, Yang B. Liquid Biopsy Potential Biomarkers in Prostate Cancer. Diagnostics (Basel) 2018; 8(4): 68.

Athens, Greece (UroToday.com) Dr. Renu Eapen gave an overview of the role of PET- prostate-specific membrane antigen (PSMA) in prostate cancer and gave a preview of what is to come in the near future of PET diagnostics, and the evolving field of theranostics.

Athens, Greece (UroToday.com) Dr. Eoin MacCraith continued the PET imaging session with a nice overview of the use of PET-FDG in renal cell carcinoma (RCC) and urothelial cancers. PET is beneficial in diagnostics, staging, prognostics, and assessing therapeutic response, but it is currently not recommended for routine use.

Athens, Greece (UroToday.com) Dr. Roland Seiler presented after Dr. Andrea Necchi, supporting the role of chemotherapy in the neoadjuvant setting of treating muscle invasive bladder cancer (MIBC), as opposed to immunotherapy.

Athens, Greece (UroToday.com) Dr. Andrea Necchi began the debate in this session supporting the role of immunotherapy over chemotherapy as neoadjuvant therapy for muscle-invasive bladder cancer (MIBC).

According to the EAU guidelines, neoadjuvant immunotherapy to patients should only be given in the setting of a clinical trial, while chemotherapy is recommended as the standard of care, being the only suggested option of neoadjuvant chemotherapy.

Athens, Greece (UroToday.com)  In this debate, Dr. Renu Eapen recommended against the current use of urinary biomarkers in the management of bladder cancer. According to her, there has been a plethora of research and studies on potential urinary biomarkers that can be used in the treatment of bladder cancer. However, to date, none of the markers have been commonly adopted.