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AUA 2023

AUA 2023: Optimal Management of cN+ Muscle Invasive Bladder Cancer

(UroToday.com) The 2023 AUA annual meeting included the Bladder Cancer Forum, featuring a debate discussing the optimal management of clinical N+ muscle invasive bladder cancer. Dr. Neema Navai started by highlighting a case of a 61 year old, very active and healthy female (BMI 21), with no prior smoking history or secondhand exposure or family history of cancer. She had four years of irritative voiding symptoms and 3 months of gross hematuria. Her GFR was 63 mL/min/1.73 m2, and she had no hearing loss or CHF. A CT scan demonstrated cT3bN2 (short axis 1.9 cm left obturator and 1.5 cm right hypogastric lymph node) cM0 bladder cancer:


Images.jpg

Dr. Navai then polled the audience with the question “How would you proceed?”:

  • 76%: Primary cisplatin-based chemotherapy followed by local consolidation (radical cystectomy or radiotherapy +/- chemotherapy) if a complete or partial response +/- adjuvant immunotherapy
  • 22%: Primary cisplatin-based chemotherapy followed by local consolidation (radical cystectomy or radiotherapy +/- chemotherapy) regardless of response +/- adjuvant immunotherapy
  • 0%: Primary cisplatin-based chemotherapy followed by maintenance immunotherapy and local consolidation in select circumstances
  • 0%: Primary cisplatin-based chemotherapy followed by observation and local consolidation (cystectomy versus radiotherapy) or treatment (ie. BCG for high grade NMIBC) for late, local only, relapsed disease
  • 3%: Clinical trial

Dr. Petros Grivas then took the position of primary cisplatin-based chemotherapy followed by switch maintenance avelumab (with the potential for local consolidation later in carefully selected circumstances). Dr. Grivas started by highlighting that at the University of Washington they have a multidisciplinary bladder cancer clinic that has a weekly conference to discuss these challenging cases. Ultimately, systemic disease requires early systemic therapy. cN2 is most likely a systemic disease state with distant micro-metastasis present, even if not visible with conventional scans. In his opinion, cause of death is the presence of micro-metastatic disease, which needs to be controlled with systemic therapy. Furthermore, consolidation radical cystectomy with lymphadenectomy is associated with notable morbidity, a mortality risk and has a major impact on quality of life. Secondary to wound healing, systemic therapy cannot be given, thus leaving the patient at high risk of losing disease control, and clinical complete response is not durable after chemotherapy with a very short PFS.

Dr. Grivas highlighted work from Necchi et al that suggests a lack of effectiveness of post-chemotherapy lymphadenectomy in bladder cancer with clinical evidence of metastatic pelvic or retroperitoneal lymph nodes.1 In this study, 242 (46.4%) patients received post-chemotherapy lymphadenectomy and 280 (53.6%) observation after chemotherapy. There were 177 (33.9%) and 345 (66.1%) patients with either retroperitoneal or pelvic lymphadenopathy only, respectively. Double robust estimation-adjusted comparison was not significant for improved OS for post-chemotherapy lymphadenectomy (HR 0.86, 95% CI 0.56-1.31, p=0.479), confirmed by matched analysis (HR 0.91, 95% CI 0.60-1.36, p=0.628). The following shows propensity score-adjusted overall survival curves according to the study group (post-chemotherapy lymphadenectomy: green line; no post-chemotherapy lymphadenectomy: red line) and extent of lymph node metastases (pelvic lymph nodes: thick line; retroperitoneal lymph nodes: thin line), without (A) and with a 3-month landmark (B):

survival prob.jpg

Dr. Grivas then discussed the JAVELIN Bladder 100 trial.2 Patients were eligible for this trial if they had unresectable locally advanced or metastatic urothelial carcinoma that had not progressed with 4-6 cycles of first-line gemcitabine plus cisplatin or carboplatin. Patients were then randomized to receive maintenance avelumab plus best supportive care or best supportive care alone within 4-10 weeks. The trial design for JAVELIN Bladder 100 is as follows:

javelin 100 study design

Long term follow-up of this trial shows prolonged overall survival (HR 0.76, 95% CI 0.63-0.92) and progression free survival (HR 0.54, 95% CI 0.46-0.65) with avelumab + best supportive care versus best supportive care alone:

comparisons.jpg

Additionally, the benefits of the use of avelumab maintenance therapy were seen in patients with a complete response (HR 0.72, 95% CI 0.48-1.08), an initial partial response (HR 0.70, 95% ci 0.54-0.91), or initially stable disease (HR 0.84, 95% CI 0.60-1.19).

overall survival comparisons

When subgroups were stratified by number of cycles, patients receiving avelumab plus best supportive care had survival benefit across all cycles, with statistically significant improved survival if they received six cycles of chemotherapy (HR 0.66, 95% CI 0.47-0.92):

further relationships

Furthermore, the addition of avelumab first-line maintenance to best supportive care had a relatively minimal effect on quality of life.3 As follows is the Kaplan-Meier analysis of time to deterioration in FBISI-18 DRS-P score in the overall population:

survival overtime

Dr. Grivas concluded his presentation by highlighting two abstracts suggesting that real world evidence supports first line switch maintenance avelumab:

  1. In an Italian population, avelumab showed clinical benefit with a manageable safety profile with a median OS of not reached, 1-year OS rate of 69.2% (95% CI 64.8%-73.7%), and median PFS of 8.1 months (95% CI 6.1-10.4)
  2. AVENANCE demonstrated the activity and acceptable safety profile of avelumab in a large cohort (n = 593) from a heterogeneous real world population. The 1-year OS rate was 65.4%, median OS was 20.7% (95% CI 17.1 – NE), and median PFS was 5.7 months (95% CI 5.3-7.0). In this population, there were no new safety concerns.

Dr. Max Kates then made the argument for local consolidation in patients with cN+ muscle invasive bladder cancer. For this particular patient, Dr. Kates makes several assumptions:

  1. There has been a thorough discussion of goals of care
  2. She is 61, very active, and wants long-term cancer control. In his mind, based on cT3bN2, she will receive 6 cycles of neoadjuvant chemotherapy, and if she has a partial or complete response she will go for radical cystectomy with extended pelvic lymph node dissection, and if she has persistent T2-T4 or N+ she will get adjuvant nivolumab.

Dr. Kates notes that in the past, our role for cystectomy was to use it some of the time in high risk NMIBC and for the majority of patients with muscle invasive bladder cancer, whereas the current paradigm looks more like the following:

progression to MIBC

Dr. Kates then highlighted a phase 2 trial design of dose dense MVAC +/- durvalumab in patients with lymph node positive bladder cancer:

phase 2

According to Dr. Kates, there are two arguments for omitting cystectomy, as posed by Dr. Grivas:

  • Argument #1: Consolidative cystectomy is under treatment and will not affect outcomes of this “systemic disease”. His response is that if a patient has N+ disease, extended pelvic lymph node dissection may be curative and can be reinforced with adjuvant nivolumab. The combination of radical cystectomy + nivolumab for N+ disease is associated with an improved DFS
  • Argument #2: Consolidative cystectomy is over treatment. The patient is cured and does not need a cystectomy. His response is that neoadjuvant chemotherapy followed by surveillance for T2N0 patients with complete response is associated with frequent local and systemic recurrences, so why should this be different for T3N2 patients?

For argument #1, if we have a typical cystectomy population with clinical N0 disease, how many will have pathologic N+ disease. Data from the 2003 Grossman et al. SWOG S8710 trial with long term follow-up, showed that among 115 patients who had radical cystectomy with negative surgical margins, compared with T0 patients, those with residual Ta, T1, or CIS appeared to have worse OS (p = 0.054).4,5 Lymph node-positive disease was found to be associated with worse OS than lymph node-negative disease (p = 0.0005), and patients with lymph node-negative disease (ie, those with <10 lymph nodes removed) appeared to have inferior OS compared with those with 10+ lymph nodes removed (p = 0.079).

 Dr. Kates then highlighted CheckMate-274, a phase 3, multicenter, double-blind, randomized (1:1), controlled trial, of muscle-invasive urothelial carcinoma who had undergone radical surgery to receive either nivolumab or placebo every 2 weeks for up to 1 year.6 The primary endpoint was disease free survival. In this trial, ~46% of patients enrolled were N1-3 disease, with a 12 month DFS benefit of 62.8% for nivolumab compared to 46.6% for placebo. This is further highlighted in the following forest plot subgroup analysis:

nodal status

This data suggests the largest hazard ratio for N+ disease and confirms that aggressive management of N+ bladder cancer with neoadjuvant chemotherapy + nivolumab is associated with long term cancer control in some patients.

For argument #2, Dr. Kates highlighted the RETAIN trial, which was presented at GU ASCO 2023. RETAIN was a single-arm, phase II, non-inferiority trial to evaluate a risk-adapted approach for muscle invasive disease. Eligible patients included those with cT2-T3N0M0 urothelial carcinoma who underwent neoadjuvant chemotherapy with accelerated MVAC. Pre-chemotherapy TURBT specimens were sequenced for mutations in ATM, ERCC2, FANCC or RB1. Patients with ≥ 1 mutation and no clinical evidence of disease by restaging TURBT, urine cytology and imaging post-neoadjuvant chemotherapy began pre-defined active surveillance and the remaining patients underwent bladder-directed therapy. The trial design is as follows:

sequencing flow2

In the ITT population, 33 (46%) had a relevant mutation and 26 (37%) began active surveillance. With a median follow-up of 41 months, 47 patients (66%) are metastasis-free (CI 54%-77%) and the 2-year MFS for the ITT patients was 72% (lower bound exact 1-sided 95% CI=62%). This did not meet the predefined cutoff for significance, thus the trial could not declare the risk-adapted approach as non-inferior. On post hoc analysis, the 2-year MFS was 76.9% in the AS group and 70.5% in the remaining patients (no significant difference). According to Dr. Kates, this data suggests that avoiding cystectomy, even in cT0N0 patients after neoadjuvant chemotherapy will miss persistent bladder cancer and nodal disease. If it is not standard of care for clinical N0 patients, it certainly should not be standard of care for clinical N+ patients.

Dr. Kates concluded his portion of the presentation in favor of local control with the following take-home messages:

  • For patients with cN+ disease, a good response to induction chemotherapy should be consolidated with aggressive local control (cystectomy + extended pelvic lymph node dissection)
  • With the addition of adjuvant nivolumab, these patients have the opportunity for long-term cancer control

Dr. Navai then highlighted that this particular patient underwent 6 cycles of dose dense MVAC, had a clinical complete response on imaging, and repeat cystoscopy demonstrated cT0 disease with a normal examination under anesthesia. After an extensive discussion, she underwent a robotic radical cystectomy with pathology ypT2aypN0R0 with 23 negative lymph nodes. The pathologist noted foamy histiocytes consistent with treated prior disease in the obturator nodes, but no viable disease. She is 4 years without evidence of disease and continues on surveillance. To conclude the session, Dr. Navai re-polled the audience “How would you proceed?”:

  • 89%: Primary cisplatin-based chemotherapy followed by local consolidation (radical cystectomy or radiotherapy +/- chemotherapy) if a complete or partial response +/- adjuvant immunotherapy
  • 7%: Primary cisplatin-based chemotherapy followed by local consolidation (radical cystectomy or radiotherapy +/- chemotherapy) regardless of response +/- adjuvant immunotherapy
  • 4%: Primary cisplatin-based chemotherapy followed by maintenance immunotherapy and local consolidation in select circumstances
  • 0%: Primary cisplatin-based chemotherapy followed by observation and local consolidation (cystectomy versus radiotherapy) or treatment (ie. BCG for high grade NMIBC) for late, local only, relapsed disease
  • 0%: Clinical trial

Moderator: Neema Navai, MD Anderson Cancer Center, Houston, TX

Debater: Petros Grivas, University of Washington, Seattle, WA

Debater: Max Kates, Johns Hopkins University, Baltimore, MD

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 American Urological Association (AUA) Annual Meeting, Chicago, IL, April 27 – May 1, 2023

References:

  1. Necchi A, Mariani L, Lo Vullo, et al. Lack of effectiveness of post-chemotherapy lymphadenectomy in bladder cancer with clinical evidence of metastatic pelvic or retroperitoneal lymph nodes only: A propensity score-based analysis. Eur Urol Focus 2019;5(2):242-249.
  2. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2020 Sept 24;383(13):1218-1230.
  3. Grivas P, Kopyltsov E, Su PJ, et al. Patient-reported outcomes from JAVELIN Bladder 100: Avelumab first-line maintenance plus best supportive care versus best supportive care alone for advanced urothelial carcinoma. Eur Urol 2022;83(4):320-328.
  4. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9):859-866.
  5. Sonpavde G, Goldman BH, Speights VO, et al. Quality of pathologic response and surgery correlate with survival for patients with completely resected bladder cancer after neoadjuvant chemotherapy. Cancer 2009;115(18):4104-4109.
  6. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114.