ASCO 2024: Bladder-Sparing Treatment Strategies for Localized Urothelial Cancer

(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting featured a session on optimizing treatment for your patient with urothelial cancer, and a presentation by Dr. Brent Rose discussing bladder sparing treatment strategies for localized urothelial cancer. Organ preservation is common in many other cancers, including laryngeal cancer, anal cancer, and rectal cancer.

Bladder cancer is largely a disease of the elderly, often with a long smoking history and among patients with significant comorbidities. Although radical cystectomy is a very effective treatment option, it has substantial peri-operative morbidity and mortality risks, as well as quality of life implications. Dr. Rose started by discussing several cases to set the stage for his presentation. Case #1 was a 83 year old man with COPD and prior myocardial infarction who developed a 7 cm T3N0M0 high grade urothelial cancer involving the right ureteral orifice and associated with hydroureter, s/p incomplete TURBT:
Case #2 was a 65 year old man with a 3 cm unifocal cT2N0 high grade urothelial cancer, with no associated CIS at the left lateral bladder wall that was completely resected on TURBT:
Dr. Rose then discussed the efficacy of chemoradiotherapy for bladder preservation starting with the BC2001 trial.^1-2 This was a phase 3 randomized controlled 2 × 2 factorial trial conducted between 2001 and 2008, among 458 patients with T2-T4a N0M0 muscle invasive bladder cancer. There were 360 patients randomized to radiotherapy (n = 178) or chemoradiotherapy (n = 182), and 218 were randomized to standard whole-bladder radiotherapy (n = 108) or reduced high-dose-volume radiotherapy (n = 111). Chemoradiotherapy improved locoregional control (HR 0.61, 95% CI 0.43-0.86) and invasive locoregional control (HR 0.55, 95% CI 0.36-0.84):

This benefit translated to disease-related outcomes (not statistically significant): disease free survival (HR 0.78, 95% CI 0.60-1.02), metastasis free survival (HR 0.78, 95% CI 0.58-1.05), overall survival (HR 0.88, 95% CI 0.69-1.13), and bladder cancer specific survival (HR 0.79, 95% CI 0.59-1.06):
The 5-year cystectomy rate was 14% (95% CI 9-21%) with chemoradiotherapy versus 22% (95% CI 16-31%) with radiotherapy alone (HR 0.54, 95% CI 0.31-0.95). Importantly, Dr. Rose notes that the Kaplan-Meier survival curves for bladder preservation compared to neoadjuvant chemotherapy followed by radical cystectomy appear similar:
Arguably, the best data outside of a randomized clinical trial, comes from a high-level propensity matched score matched multi-institutional (Toronto, MGH, USC) study assessing radical cystectomy versus trimodality therapy in highly selected patients.⁴ This retrospective analysis included 703 patients with muscle invasive bladder cancer clinical stage T2-T3/4aN0M0. Specifically, there were 421 radical cystectomy patients and 282 trimodality therapy patients who would have been eligible for both trimodality therapy or radical cystectomy (2005-2017). To compare homogeneous cohorts, all patients included in this analysis had solitary tumors <7 cm, no or unilateral hydronephrosis, and no extensive carcinoma in situ. Treatment propensity scores were estimated using logistic regression, and patients were matched 3:1 with replacement and a caliper of 0.25. Covariates included age, sex, clinical T stage (cT2 vs cT3-4), hydronephrosis, (neo)adjuvant chemotherapy, body mass index, smoking history, and ECOG status. Overall survival was estimated with adjusted Cox models, and cancer-specific survival, distant failure-free survival, regional failure-free survival and metastasis-free survival (combined distant and pelvic nodal failure) were estimated with adjusted competing risk models.

The 3:1 matched cohort comprised 1,116 patients (834 radical cystectomy versus 282 trimodality therapy). After matching, age (71.3 vs 71.6 years), cT2 clinical stage (88 vs 90%), presence of hydronephrosis (12 vs 10%), and use of (neo)adjuvant chemotherapy (60 vs 56%) were similar between radical cystectomy and trimodality therapy cohorts. At 5 years, there was no difference in metastasis-free survival (73 vs 78%, p = 0.07):
There was also no difference in regional failure-free survival (5-year: 96 vs 95%, p = 0.33):
To summarize, Dr. Rose notes that there is level one evidence to support the use of chemoradiation for bladder cancer, with invasive locoregional recurrence rates of ~20%, distant metastasis rates of ~40%, and bladder cancer mortality deaths rates of ~40%. Indeed, metastases are the primary cause of cancer death for these patients. The existing data suggests that chemoradiation is an effective treatment for bladder cancer with outcomes that are similar to cystectomy.

With regards to tolerability of chemoradiation, Dr. Rose discussed patient reported outcomes data from the BL2001 trial.⁴ Patients completed the Functional Assessment of Cancer Therapy – Bladder (FACT-BL) questionnaires at baseline, end of treatment, and 6, 12, 24, 36, 48, and 60 months after radiotherapy. Health related quality of life declined at end of treatment, but recovered to baseline at 6 months and remaining similar to baseline subsequently, with no difference between groups:
Patient reported outcomes for urinary control, urinary frequency, diarrhea, and erections are as follows:
Of note, approximately 1/3 of patients have a clinically significant worsening of bladder function:

Taken together, chemoradiation is generally well tolerated, with transient worsening of bladder and bowel function. Approximately 1/3 of patients will experience long-term worsening of bladder function though a significant proportion will note an improvement. Salvage cystectomy for toxicity occurs in ~1-2% of patients.

For patient selection and shared decision making, there are two main patient criteria for bladder sparing options:

1. Fitness for radical cystectomy
2. Likelihood of good outcomes with bladder preservation

Dr. Rose emphasized that assessing patient preference and shared decision making should be the standard of care. Patients undergoing radical cystectomy should be counselled on a perioperative complication rate of 30-60% and a 90-day perioperative mortality rate of ~1.5%. However, this 90-day mortality rate increases with age:

• <70 years of age: 2.0%
• 70-79 years of age: 5.4%
• 80+ years of age: 9.2%

Predictors of a good outcome from bladder preservation are as follows:

• Urothelial histology
• Maximal TURBT
• No hydronephrosis
• Limited CIS
• Unifocal tumors < 6 cm
• Good bladder function at baseline

Revisiting the aforementioned cases, Dr. Rose notes that for Case #1, assessing the two criteria for bladder sparing options is as follows:

1. Fitness for radical cystectomy: poor
2. Likelihood of good outcomes with bladder preservation: poor – large tumor, hydronephrosis, incomplete TURBT

For Case #2:

1. Fitness for radical cystectomy - good
2. Likelihood of good outcomes with bladder preservation: good – small tumor, no hydronephrosis, complete TURBT, no CIS

Standard approaches to treatment may include 64 Gy in 32 fractions or 55 Gy in 20 fractions. A meta-analysis from 2021 assessing BC2001 and BCON trials showed that 55 Gy in 20 fractions improved local control with no difference in toxicity:⁵
At UC San Diego, Dr. Rose and his team’s approach to chemoradiation is to use MMC + 5-FU, with alternatives being weekly cisplatin or twice weekly gemcitabine. Radiotherapy includes 55 Gy in 20 fractions to the whole bladder, being sure to have an empty bladder for reproducibility. Alternatively, 64 Gy in 32 fractions is used when treating the whole pelvis, and partial bladder dose reduction is feasible/needed for organs at risk. Dr. Rose notes that there are several questions remaining with regards to delivery of chemoradiation:

1. Should we be using neoadjuvant chemotherapy?
2. How should we use radiotherapy to the pelvic lymph nodes?
3. Should we incorporate adaptive radiotherapy?
4. Should we use a higher radiotherapy dose or more conformality?

Finally, Dr. Rose discussed novel approaches for bladder preservation. Published in 2023,⁶ Galsky and colleagues assessed gemcitabine + cisplatin + nivolumab as an organ sparing treatment for muscle invasive bladder cancer in a phase 2 trial. This trial included 76 patients that underwent the aforementioned neoadjuvant therapy and those with a clinical complete response were observed without upfront cystectomy or radiotherapy. Overall, 33 patients achieved a clinical complete response (43%, 95% CI 32%, 55%), and 32 of 33 who achieved a clinical complete response opted to forgo immediate cystectomy. The positive predictive value of clinical complete response was 0.97 (95% CI 0.91, 1), meeting the co-primary objective:
Among those patients achieving a clinical complete response, two patients developed metastasis and one patient had bladder cancer mortality. For those achieving a clinical complete response, both metastasis free survival and overall survival were significantly improved compared to those that did not achieve a clinical complete response: 

Moreover 23/33 patients avoided local therapy and 9/33 eventually underwent a radical cystectomy:
Initial results of the RETAIN trial were presented at GU ASCO 2023. RETAIN is a single-arm, phase II, non-inferiority trial to evaluate a risk-adapted approach for muscle invasive bladder cancer. Eligible patients included those with cT2-T3N0M0 urothelial carcinoma who underwent neoadjuvant chemotherapy with accelerated MVAC. Pre-neoadjuvant 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 TUR, urine cytology and imaging post-neoadjuvant chemotherapy began pre-defined active surveillance. The remaining patients underwent bladder-directed therapy. The full trial protocol is as follows:
With a median follow-up of 41 months, 47 patients (66%) were metastasis-free (95% CI 54%-77%). The 2-year metastasis free survival for the intention to treat patients (primary endpoint) was 72% (lower bound exact 1-sided 95% CI: 62%). Unfortunately, this did not meet the predefined cutoff for significance, thus the risk-adapted approach could not be deemed non-inferior. On post hoc analysis, the 2-year metastasis free survival rate was 76.9% in the active surveillance group and 70.5% in the remaining patients (no significant difference). The 2-year overall survival rate was 84.3% and 88.5% in the intention to treat and active surveillance groups, respectively.  

For both of these studies assessing systemic therapy alone, Dr. Rose notes that they show promise, but local recurrence remains significant. In the Galsky et al. phase 2 trial, local recurrences were managed with radical cystectomy and did not lead to metastases, whereas the local recurrences in the RETAIN study were associated with metastases. Thus, should these patients be managed with immunotherapy? Early salvage cystectomy? Importantly, optimal patient selection requires further study: molecular predictors do not currently appear to add predictive power, and bladder MRI may hold promise.

Dr. Rose concluded his presentation discussing bladder sparing treatment strategies for localized urothelial cancer with the following take home messages:

• Bladder preservation with chemoradiation is a safe and effective strategy in selected patients
• Discussion of bladder preservation should be a part of the shared decision making for appropriate patients
• Novel approaches to bladder preservation are exciting and evolving rapidly

Presented by: Brent S. Rose, MD, Oncologist, Associate Professor and the Director of the Division of Radiation Oncology, University of California, San Diego, San Diego, CA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024.

References:

1. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-1488.
2. Hall E, Hussain SA, Porta N, et al. Chemoradiotherapy in Muscle-Invasive Bladder Cancer: 10-year Follow-up of the Phase 3 Randomized Controlled BC2001 Trial. Eur Urol. 2022 Sep;82(3):273-279.
3. Zlotta AR, Ballas LK, Niemierko A, et al. Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: A multi-institutional propensity score matched and weighted analysis. Lancet Oncol. 2023 Jun;24(6):669-681.
4. Huddart RA, Hall E, Lewis R, et al. Patient-reported Quality of Life Outcomes in Patients Treated for Muscle-invasive Bladder Cancer with Radiotherapy +/- Chemotherapy in the BC2001 Phase III Randomized Controlled Trial. Eur Urol. 2020 Feb;77(2):260-268.
5. Choudhury A, Porta N, Hall E, et al. Hypofractionated radiotherapy in locally advanced bladder cancer: an individual patient data meta-analysis of the BC2001 and BCON trials. Lancet Oncol. 2021 Feb;22(2):246-255.
6. Galsky MD, Daneshmand S, Izadmehr S, et al. Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: A phase 2 trial. Nat Med. 2023 Nov;29(11):2825-2834.