SUO 2023: Bladder Cancer Debate for MIBC: Trimodality Therapy/Radiotherapy after Complete Clinical Response

(UroToday.com) The 2023 SUO annual meeting included a session on the management of complete clinical response following neoadjuvant systemic therapy for muscle invasive bladder cancer, featuring a presentation by Dr. Adam Feldman discussing trimodality therapy/radiotherapy if there is complete clinical response.

Dr. Feldman noted that the current standard of care for muscle invasive bladder cancer for cisplatin eligible patients is either neoadjuvant chemotherapy + radical cystectomy or trimodality therapy (maximal TUR combined with chemoradiation). There are several reasons for considering trimodality therapy:

• Morbidity and short and long term complication risk of radical cystectomy is relatively high
• Many muscle invasive bladder cancer patients in the United States are undertreated
• It is an option in our guidelines and patient education informational literature
• Oncologic outcomes in appropriately selected patients are similar to surgery
• Quality of life implications for our patients from organ preservation

Unfortunately, data from the RAZOR trial showed no difference for open versus robotic cystectomy, as did data from the iROC trial.¹ However, robotic cystectomy in the iROC trial showed fewer wound and thromboembolic complications with robotic surgery, but the overall complication rates were similar between the open and robotic arms. Additionally, cystectomy may be associated with renal insufficiency, with 72% of patients having a decrease in eGFR by 10 years, ~56% of patients having new onset Stage 3 CKD, and 3.5% progressing to hemodialysis.

At Massachusetts General Hospital (MGH), Dr. Feldman says that they have excellent long-term results with trimodality therapy that are comparable to radical cystectomy: among cT2 disease, 5-year DSS is 74% and 10-year DSS is 66%.² Among patients treated in a contemporary setting (2005-2013), salvage cystectomy rates are only 15%.²

How does trimodality therapy compare to radical cystectomy? Since the UK SPARE trial failed to accrue, we rely on population level data and multi-institutional experiences. Williams et al. used the SEER-Medicare data and propensity score matching to show that patients who underwent trimodal therapy had significantly decreased overall survival (HR 1.49, 95% CI, 1.31-1.69) and cancer-specific survival (HR 1.55; 95% CI, 1.32-1.83):³

No differences in costs at 30 days were observed between trimodal therapy ($15,233 in 2002 vs $18,743 in 2011) and radical cystectomy ($17,990 in 2002 vs $21,738 in 2011). However, median total costs were significantly higher with trimodal therapy than with radical cystectomy at 90 days ($80,174 vs $69,181; median difference, $8,964) and at 180 days ($179,891 vs $107,017; median difference, $63,771). Dr. Feldman notes that one of the key limitations of the SEER-Medicare study was that patients who were unfit for surgery were not able to be excluded. In other population level studies using the NCDB and Veteran Affairs data, there has been no difference in cancer-specific and overall survival.

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 muscle invasive bladder cancer urothelial carcinoma of the bladder. 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 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 vs 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 distant failure-free survival (5-year: 78 vs 82%, p = 0.14):

There was also no difference in regional failure-free survival (5-year: 96 vs 95%, p = 0.33):

However, there was a benefit for trimodality therapy for cancer specific survival (5-year: 85% vs 78%, p = 0.02):

Additionally, trimodality also favored overall survival (5-year: 78% vs 66%, p < 0.001):

With regards to local recurrences after trimodality therapy, based on a pooled MGH and RTOG analysis, this suggests 25%-36% of patients have NMIBC and 13%-14% have muscle invasive bladder recurrence. Based on the MGH experience, Dr. Feldman notes that 13.5% of patients have a salvage radical cystectomy for recurrence while on surveillance with 5- and 10-year disease free survival rates after salvage cystectomy of 64% and 55%, respectively.

For patients that have a complete clinical response after neoadjuvant chemotherapy, we have to be careful that these patients actually have T0 disease. The TUR accuracy after neoadjuvant chemotherapy was assessed in the Systematic Endoscopic Evaluation Trial at the Fox Chase Cancer Center, whereby a biopsy of visible tumor, the tumor bed, and random biopsies were performed prior to radical cystectomy [5]. Among 61 patients enrolled in the trial, 38 (62.3%) received neoadjuvant chemotherapy. On Systematic Endoscopic Evaluation, 31 (50.8%) patients demonstrated no visual nor biopsy-based evidence of disease (seeT0), yet 16/31 (51.6%) harbored residual disease (>pT0), including 8 (8/31, 25.8%) with residual ≥pT2 disease upon radical cystectomy. The negative predictive value of Systematic Endoscopic Evaluation predicting a pT0 bladder was 48.4% (CI 30.2-66.9), below the prespecified hypothesis.

In combined work from MSKCC and Columbia University, Mazza et al. assessed 148 patients who were cT0 after neoadjuvant chemotherapy that was elective for surveillance.⁶ Among these patients, 11% had muscle invasive bladder cancer recurrence, 37% had NMIBC recurrence, and 27 patients (18%) ultimately underwent a salvage radical cystectomy. The 5-year disease specific survival for these patients was 90%. Pooled data in this disease space is poor quality, suggesting:

• Mean bladder recurrence rate: 43% (65% NMIBC, 35% muscle invasive)
• Mean bladder preservation rate: 73%
• 5-year overall survival: 64-89%

For patients that receive radiotherapy after complete clinical response, the mean bladder recurrence rate is 15% (24% NMIBC, 43% muscle invasive, and 33% that is undeterminable), with a mean bladder preservation rate of 74%, and 4 year overall survival rate of 79%. We know from the BC2001 trial that patients undergoing chemoradiation should be receiving radiosensitizing chemotherapy based on disease free and overall survival benefit:⁷
With regards to potential biomarkers in this disease space, Dr. Feldman highlighted the RETAIN I trial, which is a phase II multi-institutional, non-inferiority trial to evaluate a risk-adapted approach to treatment of muscle invasive bladder cancer. Pre-chemotherapy, the primary tumor is sequenced for ATM, ERCC2, FANCC, or RB1, then the patient is treated with 3 cycles of neoadjuvant aMVAC followed by a restaging TURBT and the following post-chemotherapy options:
The primary endpoint of the trial is metastasis free survival at 2 years. An update on RETAIN was presented at GU ASCO 2023 by Dr. Daniel Geynisman. From 4 academic centers, 102 patients were enrolled over 33 months, with the ITT cohort ultimately being 71 patients. The median age was 70 years (IQR: 47-83), 74% were male, 92% Caucasian, 81% were ECOG PS 0, and 79% had cT2 disease. Overall, 90% completed 3 cycles of MVAC with 17% grade 3-4 TRAEs. Among the 37 patients who were mutation negative, most went on to cystectomy, though two did opt for active surveillance, six for chemoradiation, and three for BCG. 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%). The 2-year MFS for the ITT patients was 72% (lower bound exact 1-sided 95% CI = 62%). Unfortunately, this did not meet predefined cutoff for significance, thus the trial could not declare the risk-adapted approach 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). Dr. Feldman notes that RETAIN 2 is adding nivolumab to the neoadjuvant regimen.

 Another trial in this disease space is the Alliance A031701 phase II trial, which has accrued 172 patients of which 24% have a DDR gene alteration. Of note, this trial allows for residual CIS and BCG, radiotherapy, or radical cystectomy as definitive therapy. The trial schema for this trial is as follows:
Is trimodality therapy better after neoadjuvant chemotherapy? Dr. Feldman notes that based on data from the NCDB and from their MGH experience, the answer is no given no difference in cumulative incidence of distant metastasis, disease specific survival, and overall survival:

Dr. Feldman emphasizes that for those who want to keep their bladder, it is important to try and get it right from the start. For 1/3 of muscle invasive bladder cancer patients who are candidates for trimodality therapy, help them make the right choice from the start and avoid additional potential toxicity from neoadjuvant chemotherapy on top of radiosensitizing chemotherapy.

Finally, what about quality of life and radiation cystitis? Toxicity in the RTOG trimodality trials is generally reasonable, with no grade 4 or 5 events and a grade 3 GU toxicity event rate of 5.7%. Additionally, in BC2001, among 360 patients treated with radiation versus trimodality therapy, the grade 3-4 late GU event rate was 3.3%.⁷ In work presented at the 2023 AUA by Egan et al. looking at local bladder complications and radiation cystitis among 271 patients, the majority of events were insignificant, but there is an occasional need for intervention:

Dr. Feldman concluded his presentation discussing trimodality therapy/radiotherapy if there is complete clinical response in the setting of muscle invasive bladder cancer emphasizing that radical cystectomy is the standard of care. However, for patients who refuse cystectomy, chemoradiation allows the patient to keep their bladder, lower the risk of recurrence, and lower the need for salvage cystectomy. Ultimately, this is likely a goldilocks dilemma: radical cystectomy is likely too much, observation is likely not enough, and trimodality therapy may be just right.

Presented by: Adam S. Feldman, MD, MPH Massachusetts General Hospital, Boston, MA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 Society of Urologic Oncology (SUO) Annual Meeting, Washington, D.C., Tues, Nov 28 – Fri, Dec 1, 2023.

References:

1. 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, randomized, phase 3, non-inferiority trial. Lancet 2018 Jun 23;391(10139):2525-2536.
2. Giancalone NJ, Shipley WU, Clayman RH, et al. Long-term outcomes after bladder-preserving tri-modality therapy for patients with muscle invasive bladder cancer: An updated analysis of the Massachusetts General Hospital. Eur Urol 2017 Jun;71(6):952-960.
3. Williams SB, Shan Y, Jazzar U, et al. Comparing survival outcomes and costs associated with radical cystectomy and trimodal therapy for older adults with muscle-invasive bladder cancer. JAMA Surg. 2018 Oct 1;153(10):881-889.
4. 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.
5. Zibelman M, Ashgar AM, Parker DC, et al. Cystoscopy and systematic bladder tissue sampling in predicting pT0 bladder cancer: A prospective trial.  J Urol. 2021 Jun;205(6):1605-1611.
6. Mazza P, Moran GW, Li G, et al. Conservative management following complete clinical response to neoadjuvant chemotherapy of muscle invasive bladder cancer: Contemporary Outcomes of a multi-institutional cohort study. J Urol 2018;200;1005-1013.
7. 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.