The session began with a debate-style format discussion of the role of urinary markers in the surveillance of NMIBC. A poll of the audience demonstrated that 85% of the audience members do not use additional markers besides cytology in intermediate-risk NMIBC. Several FDA-approved urinary markers (CxBladder, UroVysion, ImmunoCyt, NMP22, etc.) demonstrate sensitivity of 60-70% but specificity lower than urinary cytology.1 Dr. Kelly Bree argued for utilizing urinary markers in intermediate risk by alternating markers and spacing out the frequency of cystoscopy to reduce frequency of cystoscopy without compromising oncologic outcomes. Dr. Kamal Pohar highlighted that current trials fall short of guidance, but a future randomized trial led by Dr. Florian Schroeck looking to answer this question, will be helpful. In higher-risk patients, a singular biomarker has not outperformed cystoscopy with cytology and there was agreement that one should not be used in place of a visual assessment.
Dr. Badrinath Konety and Dr. Jeremy Teoh continued the session discussing optimal TURBT technique and whether all HG NMIBC requires re-resection. An audience poll demonstrated that 29% recommended all receive re-TUR, 55% for T1 only, and 16% for none. The discussion centered on the presence of muscle in the specimen, visual completeness of resection, and utilizing the en-bloc resection technique. Dr. Konety highlighted a large systematic review which demonstrated that in patients with Ta disease, 0-8% were upstaged and with T1 disease 0-32% were upstaged.2 While en-bloc could be an effective methodology, it is feasible for tumors <3cm and is not universally adopted. While this is an evolving debate, at present there is still significant data to continue performing re-TUR.
The following session centered on the management of recurrent LG intermediate-risk bladder tumors. Dr. Sarah Psutka focused on de-escalation, given high recurrence rates, up to 80% at 5 years. Additionally, >95% of these recurrences are low-grade and costly, with perioperative risks and financial toxicity.3 She focused on options for management including in-office fulguration and chemoablative options without resection, highlighting improved benefits and low oncologic risks. Dr. Param Mariappan focused on the evidence heterogeneity, with up to 20% of tumors thought to be LG on visual inspection representing HG disease, high rates of surveillance failure and recurrences with chemoablation, and advocating for a nuanced approach focused on patient quality of life and symptoms.4
Very high-risk NMIBC with variant histology was addressed by Dr. Paolo Gontero and Dr. Michael Cookson, with the latter advocating for a thoughtful approach with proper staging, repeat resection, and vigilant surveillance when bladder sparing options are selected. Dr. Gontero highlighted the low-quality evidence available in variant histology and that conservative measures should prevail with early cystectomy, especially for plasmacytoid variants.5
Next, we discussed BCG unresponsive disease with Drs. Sima Porten and Roger Li. Dr. Porten presented data to suggest that one line of therapy after being BCG unresponsive is reasonable, however significant delay to cystectomy can demonstrate worse oncologic outcomes. Dr. Li argued for repeat intravesical options, especially when clinical factors allow, and suggested focusing on the durability of subsequent intravesical treatments. This is an evolving area that was featured at the 2023 IBCG Forum.
Drs. Seth Lerner and Sia Daneshmand discussed the findings of S1011 and the LEA trials, describing standard template of lymph node dissection in radical cystectomy. Dr. Lerner described increased mortality risk for extended lymph node dissection with no benefit in overall survival. He suggested reasons to possibly explain these findings: very meticulous standard dissection, high use of neoadjuvant chemotherapy, use of adjuvant chemotherapy, and predominant T2-T4a disease/N0-2 inclusion.6 Dr. Daneshmand discussed the retrospective data demonstrating the benefit of extended PLND of 5% in 5-year RFS, highlighting that the number needed to treat may not have been reached in powering the RCTs and that there are still select cases in which it has a role.7
The next session focused on the use of biomarkers and imaging to avoid local consolidation of MIBC after neoadjuvant chemotherapy or immunotherapy. The audience poll suggested that 75% of members did not think that markers can help patients avoid consolidative therapy. Dr. Petros Grivas presented data for future molecular biomarkers which could help select patients who have a higher chance of achieving complete response with systemic therapy and avoid radical surgery/radiation. He highlighted the use of mpMRI and ctDNA data to help predict clinical complete response in patients but agreed that this is nascent work which is exciting but perhaps not yet ready for prime time.
Finally, the session concluded with a discussion of recently reported clinical trials, highlighting paradigm-shifting data for metastatic urothelial carcinoma with enfortumab+pembrolizumab. In the EV-302 trial comparing EV+P to cisplatin-based chemotherapy, overall survival for EV+P nearly doubled, 31 months versus 16 months for chemotherapy (HR 0.47), a significant mortality reduction for patients who received EV+P. Furthermore, they discussed patients who achieved complete responses. In the trial, around 29% of patients achieved complete radiographic response in the arm of EV+pembrolizumab. If patients have a complete response, that is sustained, this presents a clinical challenge as the data is unclear on de-escalation protocols. Lastly, there will certainly be questions of sequencing as EV+pembrolizumab moves earlier in the treatment line and how this will impact response to further lines of therapy.
The session was lively, prompted excellent debate and engagement, and highlighted areas for further exploration. The IBCG retreat will be held on August 22- 24, 2024 in Houston, Texas, and will focus on establishing recommendations for intermediate-risk NMIBC as well as sequencing of therapy in MIBC.
Written by: Bogdana Schmidt, MD, MPH, Assistant Professor Urologic Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah
References:
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- Seth P. Lerner et al. SWOG S1011: A phase III surgical trial to evaluate the benefit of a standard versus an extended lymphadenectomy performed at time of radical cystectomy for muscle-invasive urothelial cancer.JCO 41, 4508-4508(2023).DOI:10.1200/JCO.2023.41.16_suppl.4508
- Tarin TV, Power NE, Ehdaie B, et al. Lymph node-positive bladder cancer treated with radical cystectomy and lymphadenectomy: effect of the level of node positivity. Eur Urol 2012;61:1025-30. 10.1016/j.eururo.2012.01.049