Conferences

BCANTT 2020: High-Risk Non-Muscle Invasive BCG Unresponsive Bladder Cancer: Molecular Subtypes

(UroToday.com) Woonyoung Choi, PhD, from the Johns Hopkins Greenberg Bladder Cancer Institute, presented on the association of molecular subtypes and Bacillus Calmette-Guerin (BCG) responses. She used the consensus subtype classification (CSC) and found no association between responders/no responders using the CSC.

BCANTT 2020: High-Risk Non-Muscle Invasive BCG Unresponsive Bladder Cancer: Immune Response to BCG

(UroToday.com) Max Kates, MD, Johns Hopkins Greenberg Bladder Cancer Institute, presented mechanisms of bacillus calmette-guerin (BCG) in bladder cancer. T cell expansion is a driving force in immune cell recruitment. The immune checkpoint and BCG response has showed PDL1 expression is relatively high among patients with carcinoma in situ (CIS). Colonization of PDL1 and CD8 among BCG responders has been shown with a void of CD4+ cells. CD4 T cells recognize the antigen which then stimulates CD8 cells to kill tumor cells. However, cancers can silent CD8 cells to avoid tumor death. What is the role of PD1/PDL1 monotherapy and combination therapy in BCG unresponsive disease? Dr. Kates has observed certain post/pre gene expression among paired BCG unresponsive samples differ which may have evidence of adaptive resistance mediated through PD-L1 checkpoint.

Presented by: Max Kates, MD, Director, Bladder Cancer Program, Assistant Professor of Urology, Johns Hopkins Greenberg Bladder Cancer Institute 

Written by: Stephen B. Williams, MD, Medical Director for High-Value Care; Chief of Urology, Professor, Director of Urologic Oncology, Director Urologic Research, The University of Texas Medical Branch at Galveston, TX at the 2020 Virtual Bladder Cancer Advocacy Network Think Tank 2020

BCANTT 2020: Phase 3 Trial of Nadofaragene Firadenovec for High-Risk, BCG Unresponsive, Non-Muscle Invasive Bladder Cancer

(UroToday.com) Colin Dinney, MD, of the MD Anderson Cancer Center, discussed Nadofaragene firadenovec. He reported the initial results of 30% complete response (CR) which prompted a phase III trial for bacillus Calmette-Guerin (BCG) unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC). A total of 157 patients were evaluated for safety with 151 patients for efficacy. At 3mo 53% had CR and 24% had CR at 12 mo. Patients with carcinoma in situ (CIS) versus no CIS CR at 12mo was 46% and 60%, respectively. A total of 8 (5%) patients progressed to ≥T2 disease, however, they observed 65% cystectomy free survival at 2 years. Toxicity was minimal and overall administration well tolerated.

NadofarageneFiradenovec_PhaseIII.png


Presented by: Colin Dinney, MD, Chairman, Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX

Written by: Stephen B. Williams, MD, Medical Director for High-Value Care; Chief of Urology, Professor, Director of Urologic Oncology, Director Urologic Research, The University of Texas Medical Branch at Galveston, TX at the 2020 Virtual Bladder Cancer Advocacy Network Think Tank 2020.

Related Content:
Read: BCANTT 2020: Non-Muscle Invasive BCG Unresponsive Bladder Cancer
Watch: Results of the SUO CTC Phase III Nadofaragene Firadenovec Trial for BCG Unresponsive NMIBC - Colin Dinney

BCANTT 2020: High-Risk Non-Muscle Invasive BCG Unresponsive Bladder Cancer: A Patient Perspective

(UroToday.com) Karen Saches, Bladder Cancer Advocacy Network (BCAN) patient advocate, shared the patient perspective in the management of bacillus calmette-guerin (BCG) unresponsive high-risk non-muscle invasive bladder cancer (NMIBC).

BCANTT 2020: High-Risk Non-Muscle Invasive BCG Unresponsive Bladder Cancer: Vicineum

(UroToday.com) Rian Dickstein, MD, from Chesapeake Urology, presented on vicineum in bacillus calmette-guerin (BCG) unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC). Vicineum is a recombinant fusion protein antibody linked to a variant of pseudomonas exotoxin A (ETA) which is administered intravesically for 2 hours twice weekly with induction x 6wks and maintenance weekly for 6 weeks. The phase III trial data in high-risk BCG unresponsive NMIBC was discussed: Cohort 1= Carcinoma in situ (CIS) refractor, Cohort 2= CIS papillary tumors, Cohort 3= no CIS. At 3 months there was 40% CR with CIS with 39% CR at 15 months. At 3 months, 71% recurrence-free survival (RFS) was observed, and 50% probability RFS at 12 months. Toxicity minimal with 4% had Grade 3/4 toxicity. A planned confirmatory trial is underway. Another concentration trial is also underway.

Presented by: Rian Dickstein, MD, Chesapeake Urology, University of Maryland Medical System, Hanover, Maryland 

Written by: Stephen B. Williams, MD, Medical Director for High-Value Care; Chief of Urology, Professor, Director of Urologic Oncology, Director Urologic Research, The University of Texas Medical Branch at Galveston, TX at the 2020 Virtual Bladder Cancer Advocacy Network Think Tank 2020

BCANTT 2020: BCG Unresponsive High-Risk Non-Muscle-Invasive Bladder Cancer

(UroToday.com) Peter Black, MD, of Vancouver Prostate Center and the University of British Columbia, presented a thorough discussion regarding bacillus calmette-guerin (BCG) unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC). The consensus definition which was established and used by the Food and Drug Administration (FDA) which are important for clinical trials but also translational scientists which can more accurately determine which patients are BCG unresponsive. This is important as radical cystectomy is the guideline recommendation for BCG unresponsive disease. Bladder sparing treatments have been limited and recently investigated agents have and are being tested in clinical trials. He presented retrospective data regarding gemcitabine/docetaxel for BCG-unresponsive disease. Against this backdrop, he discussed recent clinical trials and future direction. 

BCGUnresponsiveNMIBC.png

BCGUnresponsiveNMIBC_Relapse_T1.png



Presented by: Peter Black, MD, Vancouver Prostate Center and the University of British Columbia, Vancouver, British Columbia, Canada

Written by: Stephen B. Williams, MD, Medical Director for High-Value Care; Chief of Urology, Professor, Director of Urologic Oncology, Director Urologic Research, The University of Texas Medical Branch at Galveston, TX at the 2020 Virtual Bladder Cancer Advocacy Network Think Tank 2020

Related Content: 
Read: BCANTT 2020: Non-Muscle Invasive BCG Unresponsive Bladder Cancer
Watch: A Debate on The Management of BCG Unresponsive - Cystectomy Ineligible Bladder Cancer Patient: Pembrolizumab Vs. Nadofaragene Firadenovec - Arjun Balar & Peter Black

BCANTT 2020: High-Risk Non-Muscle Invasive BCG Unresponsive Bladder Cancer: Pembrolizumab

(UroToday.com) Arjun Balar, MD, New York University Langone Health, presented a discussion regarding pembrolizumab in high-risk bacillus calmette-guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC). Keynote-057 focused on BCG unresponsive disease among patients with carcinoma in situ (CIS) with/without HGTa or T1 and the other arm HGTa or any T1 without CIS.

BCANTT 2020: Non-Muscle Invasive BCG Unresponsive Bladder Cancer

(UroToday.com) Drs. Colin Dinney, MD Anderson Cancer Center, and Peter Black, the University of British Columbia, started the meeting with a discussion regarding the history of bladder cancer research and Bladder Cancer Advocacy  Network (BCAN). In particular, they discussed the advances in understanding the biology of the disease including recent advances regarding bacillus calmette-guerin (BCG) and BCG unresponsive disease including recent clinical trials.

SUO - AUA 2020 Summer Webcast: Three Papers in the Past Year that Have Changed My Practice: Kidney Cancer

(UroToday.com) The Society of Urologic Oncology (SUO) held a virtual meeting on Saturday, July 18, 2020 in place of the usual meeting held at the American Urological Association (AUA) annual meeting. This virtual meeting was divided into sessions on bladder cancer, kidney cancer, and prostate cancer. In the session on prostate cancer, Sarah Psutka, MD, presented three papers in kidney cancer which most significantly changed her practice in the past year.

EAU 2020: Frailty and Cognitive Assessment in Patients Diagnosed with Muscle-Invasive Bladder Cancer

(UroToday.com) Radical cystectomy with or without neoadjuvant chemotherapy is considered the standard treatment for localized muscle-invasive bladder cancer. Radical cystectomy is a major abdominal surgery that has a high morbidity rate, with perioperative complications being around 50% to 70%.

EAU 2020: The New Testis Cancer Biomarker miRNA 371: Ready for Prime Time?

(UroToday.com) As part of a plenary presentation at the European Association of Urology (EAU) Virtual 2020 meeting assessing “Testis cancer and surgical andrology,” Robert Hamilton, MD, MPH, FRCSC, examined whether miRNA-371 is ready for “prime time” as a testis cancer biomarker.

He began by giving an overview of the landscape of testis cancer in which better biomarkers would aid patient care. These run the gamut from diagnosis and early staging to the provision of chemotherapy and post-chemotherapy retroperitoneal lymph node dissection (RPLND), as well as to reduce the burden of imaging.

DIagnosis-Imaging_EAU2020.png

MicroRNA (also called miRNA) are small, single-stranded non-coding RNA fragments. They interact with messenger RNA (mRNA) to influence post-transcription gene expression through translational repression and mRNA degradation. They have been studied as biomarkers in a range of human conditions, including many cancers. This is because miRNA expression is dysregulated in the cancer process with amplification and deletion of miRNA genes; aberrant transcriptional control; epigenetic changes; and altered biogenesis. As suggested by both amplification and deletion leading to carcinogenesis, miRNA may function as either oncogenes or tumor suppressors.

In 2006, Voorhoeve and colleagues were the first to report that miR-371-373 cluster was highly expressed in testis cancer. Subsequent work demonstrated that both the miR-371 cluster and the miR-302 cluster were overexpressed in testis cancer regardless of tumor type (non-seminomatous germ cell tumor (NSGCT) or seminoma), NSGCT subtype, pre- or post-pubertal disease, and anatomic site (gonadal vs. extra-gonadal tumor).

Beyond implication in the relevant biologic processes, miRNA have characteristics which make them well suited as biomarkers: these are detectable in the bloodstream, stable due to their resistance to degradation, and have a short half-life. With a half-life in the range of 3-7 hours, levels fall to 2.6% of pre-orchiectomy levels within 24 hours of surgery. This half-life is much shorter than traditionally utilized biomarkers such as human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP), which have half-lives of 36 hours and 5-7 days, respectively.

Expression24Hours_EAU2020.png

In germ cell tumors (GCTs), two clusters of miRNA are overexpressed:

  1. The miR-371-373 cluster including: miR-371a-3p, miR-372a-3p, miR-373a-3p
  2. The miR-302 cluster including: miR-367, miR-302a, miR-302b, miR-302c, miR-302d

Assessing the miR-371 cluster, analysis of miR-371a-3p performed as well in terms of area under the curve (AUC) for the receiver operating characteristic (ROC) curve as a panel of all four miRNA combined (AUC 0.93, 95% confidence interval 0.87 to 0.98).

A recent review article highlighted the main studies of micro-RNAs in germ cell tumors demonstrating very high sensitivity and generally very high levels of specificity as well.

Table2_SummaryMainStudies_miRNA_EAU2020.png

Across the board, the area under the curve (AUC) of the miRNA derived risk prediction models is between 0.87 to 0.97. Thus, we can conclude the miR-371a-3p is very good at detecting when GCT is present, compared to when it was not.

Assessing patients who received chemotherapy and subsequent post-chemotherapy RPLND, Dr. Hamilton discussed a study from his group led by Dr. Ricardo Leao which assessed levels of miR-371a-3p, miR-373-30, and miR-367-3p following orchiectomy but before chemotherapy and following chemotherapy but before RPLND. They compared these levels to clinical characteristics, conventional tumor marks, and PC-RPLND pathology. Expression of miR-371A-3p demonstrated significant differences for patients with viable GCT at PC-RPLND compared to teratoma or fibrosis/necrosis.

miR371a-3p_AUC0.87_EAU2020.png

The authors then assessed whether serum miR-371a-30 could be useful in guiding treatment decisions. For example, among patients with 1-3cm masses, the authors used the miRNA assay to predict pathology: among 18 patients with a negative miR-371A-3p assay, 8 had teratoma, 10 had necrosis/fibrosis, and none had viable GCT while among 21 with a positive miRNA assay, 6 had viable GCT, 5 had teratoma, and 10 had necrosis/fibrosis. These data suggest that miR-371a-3p can exclude viable disease in patients following chemotherapy. However, teratoma remains a surgical disease so it is less clear whether this can accurately guide treatment.


miR-371a-3p_VIableGCT.png
Dr. Hamilton then highlighted data from Dr. Lafin and colleagues who assessed the association between miR-371a-3p and viable germ cell tumor in patients undergoing RPLND, without prior chemotherapy.

Dr. Hamilton then highlighted ongoing prospective trials including:

  1. SWOG S182: a prospective observational cohort study to assess miR-371a-3p for outcome prediction in patients with newly diagnosed germ cell tumors. The primary objective of this study is to correlate miR-371 expression with relapse in clinical stage I and IIa disease. Patients will be assessed prior to orchiectomy, post-orchiectomy, and every 3 months for 2 years. The goal is to accrue 1200 patients over 24 months with trial activation occurring very recently, in June 1, 2020.
  2. AGCT1521: minimizing toxicity for low and standard risk pediatric, adolescent, and young adult germ cell tumor patients. In patients with clinical stage IA/B seminoma or NSGCT, a secondary outcome of this study is to assess the utility of found miRNA, including miR-371-373 and miR-302. Samples are collected prior to orchiectomy and then monthly for 3 months followed by every 3 months for 1 year and every 6 months for another year.

Despite this clinical promise, Dr. Hamilton highlighted limitations of miR-371a-3p including a lack of agreed-upon assay methodology, lack of agreed-upon cut-offs for normal levels, and questions about how to manage patients with teratoma.

Interestingly, tissue-based miRNA assay has found elevated less of miR-375 in teratomas. Thus, if this is validated in serum, the combined use of this with miR-371a-3p may allow for a more comprehensive assessment. However, there are concerns about the reliability of miR-375 to discriminate teratoma.

Presented by: Robert J. Hamilton, MD, MPH, FRCSC, Division of Urology, University of Toronto, Toronto, Canda  

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Nashville, TN, USA, Twitter: @WallisCJD, at the Virtual 2020 EAU Annual Meeting #EAU20, July 17-19, 2020

EAU 2020: Open vs. Minimally Invasive Partial Nephrectomy: What is the Evidence?

(UroToday.com) The European Association of Urology (EAU) Virtual 2020 meeting featured a session on controversies in renal cancer. As part of this session, Maria Carmen Mir Maresma, MD, from Barcelona discussed the evidence for open versus minimally invasive partial nephrectomy. The purpose of partial nephrectomy is to provide negative surgical margins, to maximize renal function preservation, and to perform the procedure with low perioperative morbidity. The adoption of the robotic-assisted approach has increased the number of minimally invasive partial nephrectomies: in 2013 in the United States, 64.1% of partial nephrectomies were performed robotically, 4.8% laparoscopically, and 31.1% open, compared to 2004 when 79.8% of partial nephrectomies were performed open.

Since 2004, Dr. Mir Maresma notes that there have been 1,450 PubMed citations referencing robotic partial nephrectomy. However, many of these studies are (i) by highly skilled surgeons reporting their single-center experience, (ii) for proctoring/intuitive surgery, (iii) published in journals with minimal impact factor, (iv) include no randomized studies, (v) have no few comparative studies, and (vi) no there are adjustments or if there are they are rarely applied.

There are several factors related to partial nephrectomy including pre-surgical, surgical, and post-surgical factors. These are summarized in the following figure:

PartialNephrectomy_SurgicalFactors_EAU2020.png

In a study by Dagenais et al.they estimated the relative contributions of patient and surgeon characteristics with regards to key outcomes after partial nephrectomy. Among 1,461 patients, there was significant between-surgeon variability in operative time, estimated blood loss, ischemia time, excisional volume loss, length of stay, positive margins, Clavien complications, and 30-d readmission rate (all p<0.001), but not chronic kidney disease upstaging (p=0.47) or percentage preservation of glomerular filtration rate (p=0.49). Patient factors explained 82% of the variability in excisional volume loss and 0-32% of the variability in the remainder of outcomes. As such, even after adjusting for patient characteristics, there is significant between-surgeon variability in outcomes after partial nephrectomy.

With regards to tumor complexity, several metrics have been reported over the last decade. These include the RENAL score, PADUA score, adhesive perinephric fat Mayo score, and contact surface area. These scoring systems are part of standard reporting of complexity prediction of surgical complications.

There are several resection techniques for patients undergoing partial nephrectomy, including resection (traditional partial nephrectomy), enucleoresection, and simple enucleation. The implications of resection technique are essentially minimal, as surgical margin rates for enucleation (5%) are comparable to enucleoresection (10%), and traditional resection (2%). However, the resection technique and surgical approach are predictors of major complications and acute kidney injury.

The surgical factors impacting partial nephrectomy, stratified by an open versus robotic approach, can be summarized as follows:

PartialNephrectomy_Table_EAU2020.png

Additionally, the host factors impacting partial nephrectomy are as follows:

HostFactors_PartialNephrectomy_EAU2020.png

Dr. Mir Maresma concluded with the following take-home messages from her presentation:

  • Oncologic outcomes are similar between open partial nephrectomy and minimally invasive partial nephrectomy
  • Renal functional outcomes seem to be slightly better with robotic partial nephrectomy
  • There is a large variability of procedures and standardization (resection, surgeon, operative volume, etc)
Presented by: Maria Carmen Mir Maresma, MD, Fundacion IVO, Barcelona, Spain

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, GA, USA, Twitter: @zklaassen_md, at the Virtual 2020 EAU Annual Meeting #EAU20, July 17-19, 2020

References:

  1. Dagenais J, Bertolo R, Garisto J, et al. Variability in Partial Nephrectomy Outcomes: Does Your Surgeon Matter? Eur Urol 2019 Apr;75(4):628-634.

EAU 2020: Treatment of Recurrent Lymph Node Metastatic Prostate Cancer - Radiation Is the Best Option

(UroToday.com) The European Association of Urology (EAU) Virtual 2020 meeting included a prostate cancer session highlighting a debate regarding the optimal treatment of recurrent lymph node metastatic prostate cancer. Piet Ost, MD, PhD, from Ghent, Belgium, discussed the utility of radiation for these patients.

EAU 2020: How to Best Approach the Large Renal Mass: Tips and Tricks

(UroToday.com) As part of the 2020 European Association of Urology (EAU) Virtual Meeting, a session on controversies in renal cancer surgery featured a presentation by Dr. Tim O’Brien discussing the optimal approach to large renal masses. As follows are 10 tips and tricks from Dr. O’Brien for managing large renal masses:

EAU 2020: Five Things I Wish I Would Have Known Earlier in My Career: Lessons from the Mentors - Bladder Cancer

Dr. Mark Soloway gave a talk on areas for improvement in bladder cancer, from his significant experience spanning a 50-year time period as a urologist-oncologist, working in many centers across the United States.

EAU 2020: Robotic RPLND is Safe and Feasible

(Urotoday.com) As part of a plenary presentation at the European Association of Urology (EAU) Virtual Annual Meeting assessing “Testis cancer and surgical andrology,” Andreas Hiester, MD, argued for the role of robotic-assisted retroperitoneal lymph node dissection (RPLND).

EAU 2020: Controversies in Renal Cancer Surgery: Organ Preservation: Do the Benefits Outweigh Additional Risks? – Pro: Minimally Invasive Nephrectomy

(UroToday.com)  To discuss the role of minimally invasive nephrectomy, Abdullah Canda, MD, provided this perspective as part of the controversies in renal cancer surgery organ preservation debate at the European Association of Urology (EAU) Virtual 2020 meeting.

EAU 2020: Open RPLND is Still the Gold Standard

(UroToday.com) As part of a plenary presentation at the European Urologic Association Virtual Annual Meeting assessing “Testis cancer and surgical andrology,” David Nicol, MBBS, FRACS, defended the position that open retroperitoneal lymph node dissection (RPLND) remains the gold standard.

Dr. Nicol began by highlighting the definition of the gold standard which, according to the Collins English Dictionary, as “the supreme example of something against which others are judged or measured.”

EAU 2020: Was Twitter Right? Can We Use SoMe to Better Educate Patients?

(UroToday.com) As part of a plenary presentation at the European Association of Urology (EAU) Virtual Annual Meeting assessing “Testis Cancer and Surgical Andrology”, Juan Luis Vásquez, MD, PhD, highlighted the role of social media, both in urology and more generally.

EAU 2020: How to Manage Testicular Microlithiasis and Carcinoma in Situ

(UroToday.com) As part of a plenary presentation at the European Association of Urology (EAU) Virtual 2020 meeting assessing “Testis cancer and surgical andrology,” Marij Dinkelman-Smit, PhD, outlined an approach to testicular microlithiasis and germ-cell neoplasia in situ (GCNIS).

Dr. Dinkelman-Smit began by highlighting that cure rates for testicular cancer are high following orchiectomy with or without adjuvant therapy as indicated. This paradigm is well established; however, the role of screening of the contralateral testicle with identification of testicular microlithiasis or GCNIS is fraught with significant uncertainty regarding optimal treatment with options including surveillance, orchiectomy, radiotherapy, and chemotherapy. Thus, it leaves open the question of whether we should actively pursue the diagnosis of GCNIS, to offer preventative therapy, with the hopes of improving already high rates of cure.

Dr. Dinkelman-Smit then transitioned to an overview of testicular microlithiasis, which are calcium deposits within the seminiferous tubules, comprising hydroxyapatite core with concentric rings of cellular debris, glycoprotein, and collagen. The etiology is somewhat uncertain but hypothesized mechanisms including inflammation, defective phagocytosis by Sertoli cells, immune response, nanoparticles, or rapid cell turn over. However, she highlighted that testicular microlithiasis are not a precursor lesion for testicular cancer, not are they a causal factor for the development of testicular cancer.
TesticularMicrolithiasis_EAU2020.png

Dr. Dinkelman-Smit highlighted that testicular microlithiasis is a common finding on scrotal ultrasound, present in 2.4-5.6% of asymptomatic men and up to 15% of symptomatic men. Testicular microlithiasis has been associated with testicular cancer, particularly among infertile men in observational cohort. However, there are significant issues with the heterogeneity of the data and shared risk factors.

She recommended a treatment approach driven by reassurance. As with all men, monthly self-examination should be recommended for men with microlithiasis. Ultrasound follow-up, in her estimation, is cost-ineffective. In particularly high-risk patients, biopsy may be considered to exclude GCNIS and cancer.

Transitioning to a discussion of GCNIS, Dr. Dinkelman-Smit highlighted that, unlike testicular microlithiasis, GCNIS may be a precursor lesion to testicular cancer as germ cell tumors are diagnosed in 50% of patients with GCNIS within 5 years and 70% within 7 years. This is an immunohistochemical diagnosis on the basis of testicular biopsy.

GCNIS may be diagnosed adjacent to existing testicular tumors, contralateral to known testicular tumors, and among patients undergoing testicular biopsy for other reasons.

GCNIS_Foci_EAU2020.png

Treatment options for patients with GCNIS include preventative orchiectomy, radiotherapy, surveillance, or chemotherapy. Each of these options has strengths and weaknesses, on the basis of a balance of oncologic control and impairment in testicular function.

OptionsTreatment_EAU2020.png

In patients who opt for chemotherapy, repeat biopsy to prove resolution of GCNIS is recommended with radiotherapy for those with persistent disease.

Presented by: Marij Dinkelman-Smit, PhD, Erasmus University Medical Center, Rotterdam, The Netherlands 

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Nashville, TN, USA, Twitter: @WallisCJD, at the Virtual 2020 EAU Annual Meeting #EAU20, July 17-19, 2020