ASTRO 2024: Bladder Preservation - A Modern Choice for Patients

(UroToday.com) The 2024 American Society for Radiation Oncology (ASTRO) annual meeting held in Washington D.C. was host to the session Presidential Symposium: Innovations in Genitourinary Cancers: Session II - Bladder Preservation - A Modern Choice for Patients. Dr. Leslie Ballas opened this session with a talk titled: Bladder Preservation - A Modern Choice for Patients.

Dr. Ballas began by highlighting how bladder cancer treatment has changed very little over the last 40 years, cystectomy has remained the standard of care, and despite other organ sites moving on to organ-preservation strategies, bladder cancer has not followed the same path. For decades pioneering work has led to the idea of bladder preservation despite resistance from the scientific community. Multiple trials have attempted to incorporate radiation therapy (RT) into the treatment algorithm for muscle-invasive bladder cancer (MIBC), starting with the RTOG 85-12 study in 1985 paving the way for numerous bladder preservation trials.¹ A detailed timeline of MIBC bladder cancer treatment is shown below:

The difficult part of bladder preservation was changing the mindset and paradigm that muscle-invasive bladder cancer (MIBC) must be treated exclusively with surgery. Historically, the gold standard treatment for MIBC was radical cystectomy. However, the concept of organ preservation using trimodality therapy (TMT), which consists of maximal transurethral resection of the bladder tumor (mTURBT) followed by chemoradiation, has been established as a viable alternative to surgical bladder removal.

Despite the lack of direct head-to-head randomized comparisons between TMT and radical cystectomy, the Radiation Therapy Oncology Group (RTOG)/NRG has been at the forefront of integrating radiation therapy into bladder preservation for years, but most typically for patients who were not fit for cystectomy initially. Prospective data have shown that TMT can yield similar long-term clinical outcomes to cystectomy series, with comparable safety and tolerability across multiple prospective trials, especially with contemporary radiation therapy techniques and chemotherapy combinations.

Several chemotherapy combinations have been assessed in the TMT setting, most of which are cisplatin-based regimens (such as 5-FU/cisplatin, MCV/cisplatin, and Taxol/cisplatin, followed by gemcitabine/cisplatin). In the RTOG 05-24 trial, patients whose tumors showed HER2/neu overexpression were additionally treated with trastuzumab and paclitaxel. The complete response rate (CR) ranged between 66-88%, and the 3- and 5-year overall survival rates were comparable to previously published data on radical cystectomy. A detailed list of RTOG trials addressing TMT for MIBC is shown below:

Dr. Ballas discussed the 10-year follow-up results of the BC2001 trial, the largest randomized controlled trial (n=458) for bladder-sparing treatment in muscle-invasive bladder cancer (MIBC). This phase 3 trial utilized a 2 × 2 factorial design, randomizing patients with MIBC cT2-T4aN0M0 to receive either radiotherapy (RT, n=178) or chemoradiotherapy (CRT, n=182) and further randomizing them to standard whole-bladder radiotherapy (n=108) or reduced high-dose-volume radiotherapy (n=111). The chemoradiotherapy combination demonstrated improved locoregional control (HR 0.61, p=0.004), invasive locoregional control (HR 0.55, p=0.006), and bladder cancer-specific survival (BCSS), with a benefit lasting over two years with time-varying effects. Moreover, TMT reduced the salvage cystectomy rate (14% in CRT vs. 22% in RT, p=0.034). However, there was no statistically significant difference in disease-free survival (DFS), metastasis-free survival (MFS), or overall survival (OS).³ Furthermore, there was no significant difference in health-related quality of life (HRQoL) with the addition of chemotherapy.

Despite the lack of head-to-head direct comparison between patients treated with radical cystectomy vs. TMT. A multi-institutional propensity score-matched comparison of radical cystectomy versus trimodality therapy (TMT) for muscle-invasive bladder cancer (MIBC) was conducted at three university centers in the USA and Canada with high-volume bladder cancer surgeons and expert radiation oncologists. This retrospective analysis included patients with cT2-T3/4aN0M0 urothelial MIBC treated between 2005 and 2017. All patients had solitary tumors less than 7 cm, no or unilateral hydronephrosis, and no multifocal carcinoma in situ (CIS).⁴

The 3:1 matched cohort comprised 1,116 patients (834 treated with radical cystectomy and 282 with TMT). The median follow-up was 4.38 years for radical cystectomy and 4.88 years for TMT. The 5-year metastasis-free survival was 74% for radical cystectomy and 75% for TMT with inverse probability of treatment weighting (IPTW). Similarly, the 5-year disease-free survival was 73% for radical cystectomy and 74% for TMT.

Notably, overall survival (OS) favored TMT (IPTW: 66% vs. 73%; hazard ratio 0.70 [95% CI 0.53-0.92]; p=0.010). There were no differences in cancer-specific survival between patients who received salvage cystectomy and those who did not undergo salvage cystectomy (p=0.69). Salvage cystectomy was performed in 38 (13%) of the TMT-treated patients.

In a recent study by Brück et al., the investigators identified all patients with nonmetastatic MIBC in the population-based Netherlands Cancer Registry and compared 2-year disease-free survival (DFS) in patients treated with TMT versus radical cystectomy (RC). A total of 1,432 patients were included in this analysis, of whom 1,101 underwent RC and 331 underwent TMT, with a median follow-up of 39 months. The IPTW-adjusted 2-year DFS was 61.5% with TMT versus 55.3% with RC. The adjusted 2-year overall survival (OS) for patients treated with TMT versus RC was 74% versus 66%, respectively. There was no statistically significant difference in the 2-year DFS or OS between patients treated with TMT and RC, strengthening the evidence that both can be offered as standard-of-care approaches for MIBC.⁵

The latest recommendations from the NCCN guidelines for muscle-invasive bladder cancer (MIBC). The panel now recommends bladder preservation with concurrent chemoradiotherapy and maximal transurethral resection of the bladder tumor (TURBT) as a primary treatment option for patients with stage II (cT2N0) and stage IIIA (cT3N0, cT4N0, cT1-cT4N1) disease. As a result, radical cystectomy is no longer the sole standard of care for the treatment of MIBC.⁶

With the impressive success of TMT, Dr. Ballas raised the question of whether we should consider expanding TMT to other areas of the disease spectrum, such as non-muscle invasive bladder cancer (NMIBC) or metastatic bladder cancer.

Data from the RTOG 0926 phase II trial was highlighted in this context. This trial included patients with recurrent high-grade NMIBC who otherwise candidates for radical cystectomy were. The protocol involved maximal TURBT followed by chemoradiotherapy, which consisted of 61.2 Gy delivered in 34 fractions, along with radio sensitizing cisplatin or mitomycin/5-FU chemotherapy. The results of the study were promising, showing that at 3 years, 88% of patients were free from undergoing cystectomy, and the 5-year overall survival rate was 53%. This trial underscores the potential for TMT to serve as a bladder-preserving option in select patients with high-grade NMIBC, offering an alternative to radical cystectomy and contributing to the expanding role of TMT in bladder cancer management.

In the metastatic bladder cancer setting, a retrospective analysis examined patients who received first-line therapy for metastatic urothelial bladder cancer and were progression-free after treatment. These patients had no more than five residual metastases and were subsequently treated with definitive radiotherapy (>45 Gy) to the bladder and remaining metastases. This "consolidative" group was compared to a control group that did not receive radiotherapy and was under observation. The landmark analysis at 6 months revealed that radiotherapy was associated with improved overall survival (OS), with a hazard ratio (HR) of 0.48 (p = 0.026), indicating a significant survival benefit for those receiving RT compared to those who did not. This finding suggests that consolidative radiotherapy may play an important role in improving outcomes for selected patients with metastatic bladder cancer who achieve initial disease control after first-line therapy. The potential for RT to extend survival in this patient population highlights the need for further investigation into the role of radiotherapy as part of a multimodal treatment approach.

Dr Ballas mentioned to date, there are questions that need to be addressed such as:

• TMT in combination with immunotherapy
• Neoadjuvant chemotherapy + TMT
• How important really is a maximal TURBT?

The SWOG/NRG 1806 study, also known as INTACT, is a Phase III randomized trial investigating the effectiveness of concurrent chemoradiotherapy with or without atezolizumab in patients with localized MIBC. The primary endpoint of the study is bladder intact event-free survival (BIEFS). Impressively, the trial enrolled 485 patients over a period of just under five years, achieving a recruitment rate of up to 12 patients per month, even during the pandemic. This speaks to the commitment of the participating centers and the urgent need for effective treatment options in this patient population. The design of the trial is detailed below, and results are eagerly awaited in the coming years.

Another question that is important to address is the role of neoadjuvant chemotherapy with TMT. This is based on data (SWOG 8710) showing that neoadjuvant chemotherapy followed by radical cystectomy improved OS. Recently, that paradigm was updated by Dr. Powles presented the results of the highly anticipated NIAGARA trial This Phase III, randomized, open-label, multicenter, international trial evaluated the efficacy of perioperative immune checkpoint inhibitor durvalumab in combination with neoadjuvant chemotherapy (NAC), revealed promising outcomes, with 82.2% of patients in the durvalumab arm alive at 24 months, compared to 75.2% in the chemotherapy-only arm. There was a statistically significant survival advantage for the combination therapy.¹⁰

So why is it different with TMT, and why NAC prior to TMT is not part of the classic treatment paradigm? This question was addressed with the RTOG 89-03 study in 1998 assessed the efficacy of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy in patients with MIBC treated with TMT. The investigators found no difference in the 5-year overall survival rate (48% vs. 49%) between the MCV group and the TMT-only group. Thus, they concluded that two cycles of MCV neoadjuvant chemotherapy did not show an increase in survival over TMT alone and the addition of MCV was associated with significant treatment-related toxicity that led to early termination of the study.

However, the RTOG 89-03 trial used different RT techniques and different chemotherapy than what is used today, so this has allowed us to revisit this question. Moreover, a study involving 785 patients with MIBC (cT2-4aN0-2M0) who underwent RT across 10 academic centers in Canada utilized inverse probability of treatment weighting (IPTW) to balance covariates between those who received NAC before RT and those who did not. Notably, patients who progressed or die during NAC were not included in the analysis and this may have skewed the results of this trial toward the NAC group. The results indicated that NAC was significantly associated with improved CSS and OS However, a sensitivity analysis detailed in supplementary table 3 of the study revealed that among patients undergoing TMT only, NAC no longer demonstrated a benefit in OS, with a hazard ratio of 0.82 (95% CI 0.54–1.25, p=0.4).¹²

In a retrospective study evaluating 757 patients with nonmetastatic MIBC who underwent radiotherapy (RT) across the same 10 Canadian institutions, researchers analyzed survival outcomes based on the completeness of transurethral resection of bladder tumor (TURBT). Of these patients, 484 had complete TURBT, while 259 had incomplete TURBT. The adjusted survival analyses indicated no significant differences in 5-year overall survival (OS) (48% vs. 52%, p = 0.8), cancer-specific survival (CSS) (64% vs. 61%, p = 0.7), or metastasis-free survival (MFS) (43% vs. 46%, p = 0.8) between the two groups.¹³

Dr. Ballas concluded her presentation by highlighting the exciting advancements in bladder cancer treatment occurring in the past two years. Notably, the SWOG/NRG 1806 trial, the largest randomized trial on bladder preservation has completed accrual, and the AMBASSADOR study has reported improved disease-free survival with adjuvant pembrolizumab following radical cystectomy. The NIAGARA trial has shown increased overall survival with perioperative durvalumab combined with gemcitabine and cisplatin and has changed the paradigm for treatment in the perioperative setting; the EV-301 trial demonstrated that antibody drug conjugates (ADCs) enfortumab vedotin in combination with pembrolizumab enhances progression-free survival compared to chemotherapy in locally advanced or metastatic urothelial carcinoma.

All of these have set the stage for the opening of two NRG randomized trials evaluating trimodality therapy (TMT)—one in the non-muscle invasive bladder cancer (NMIBC) setting and another in the muscle-invasive bladder cancer (MIBC) setting. Additionally, a SWOG trial is being conducted to investigate the use of radiotherapy following neoadjuvant therapy.

These developments underscore a promising future for bladder cancer treatment, offering hope for improved patient outcomes. For more details, you can explore the latest clinical trial results and ongoing research updates in oncological journals and clinical trial registries.

This presentation was concluded with the following key take-home messages:

• Cystectomy is no longer the sole gold standard in the treatment of MIBC.
• Trimodality therapy offers oncologic outcomes that are equivalent to those of radical cystectomy for appropriately selected patients.
• Now is the time to enhance outcomes for a broader range of patients through expanded inclusion criteria and increased research efforts focused on other disease settings.
• The drivers of change that have influenced the mentality of physicians treating bladder cancer include clinical trials, clinical practice guidelines, and the individuals behind these initiatives.

Presented by: Leslie Ballas, MD, FASTRO, Radiation Oncologist at Cedars Sinai Los Angeles, CA, United States of America.

Written by: Julian Chavarriaga, MD – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @chavarriagaj on Twitter during the 2024 American Society for Radiation Oncology (ASTRO) annual meeting held in Washington D.C., between the 29^th of September and the 2^nd of October.

1. Tester W, Porter A, Asbell S, Coughlin C, Heaney J, Krall J, Martz K, Venner P, Hammond E. Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12. Int J Radiat Oncol Biol Phys. 1993 Apr 2;25(5):783-90. doi: 10.1016/0360-3016(93)90306-g. PMID: 8478228.
2. Michaelson MD, Hu C, Pham HT, Dahl DM, Lee-Wu C, Swanson GP, Vuky J, Lee RJ, Souhami L, Chang B, George A, Sandler H, Shipley W. A Phase 1/2 Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation After Transurethral Surgery for Noncystectomy Candidates With Muscle-Invasive Bladder Cancer (Trial NRG Oncology RTOG 0524). Int J Radiat Oncol Biol Phys. 2017 Apr 1;97(5):995-1001. doi: 10.1016/j.ijrobp.2016.12.018. Epub 2016 Dec 19. PMID: 28333021; PMCID: PMC5536836.
3. Hall E, Hussain SA, Porta N, Lewis R, Crundwell M, Jenkins P, Rawlings C, Tremlett J, Sreenivasan T, Wallace J, Syndikus I, Sheehan D, Lydon A, Huddart R, James N; BC2001 Investigators. Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial. Eur Urol. 2022 Sep;82(3):273-279. doi: 10.1016/j.eururo.2022.04.017. Epub 2022 May 14. PMID: 35577644.
4. Zlotta AR, Ballas LK, Niemierko A, Lajkosz K, Kuk C, Miranda G, Drumm M, Mari A, Thio E, Fleshner NE, Kulkarni GS, Jewett MAS, Bristow RG, Catton C, Berlin A, Sridhar SS, Schuckman A, Feldman AS, Wszolek M, Dahl DM, Lee RJ, Saylor PJ, Michaelson MD, Miyamoto DT, Zietman A, Shipley W, Chung P, Daneshmand S, Efstathiou JA. 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. doi: 10.1016/S1470-2045(23)00170-5. Epub 2023 May 12. PMID: 37187202.
5. Brück K, Meijer RP, Boormans JL, Kiemeney LA, Witjes JA, van Hoogstraten LMC, van der Heijden MS, Donders AR, Franckena M, Uyl de Groot CA, Leliveld AM, Aben KKH, Hulshof MCCM. Disease-Free Survival of Patients With Muscle-Invasive Bladder Cancer Treated With Radical Cystectomy Versus Bladder-Preserving Therapy: A Nationwide Study. Int J Radiat Oncol Biol Phys. 2024 Jan 1;118(1):41-49. doi: 10.1016/j.ijrobp.2023.07.027. Epub 2023 Jul 28. PMID: 37517601.
6. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Muscle invasive bladder cancer V.4.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed [September 29, 2024]. To view the most recent and complete version of the guideline, go online to NCCN.org.
7. Dahl DM, Rodgers JP, Shipley WU, Michaelson MD, Wu CL, Parker W, Jani AB, Cury FL, Hudes RS, Michalski JM, Hartford AC, Song D, Citrin DE, Karrison TG, Sandler HM, Feng FY, Efstathiou JA. Bladder-Preserving Trimodality Treatment for High-Grade T1 Bladder Cancer: Results From Phase II Protocol NRG Oncology/RTOG 0926. J Clin Oncol. 2024 Sep 3:JCO2302510. doi: 10.1200/JCO.23.02510. Epub ahead of print. PMID: 39226514.
8. Aboudaram A, Chaltiel L, Pouessel D, Graff-Cailleaud P, Benziane-Ouaritini N, Sargos P, Schick U, Créhange G, Cohen-Jonathan Moyal E, Chevreau C, Khalifa J. Consolidative Radiotherapy for Metastatic Urothelial Bladder Cancer Patients with No Progression and with No More than Five Residual Metastatic Lesions Following First-Line Systemic Therapy: A Retrospective Analysis. Cancers (Basel). 2023 Feb 11;15(4):1161. doi: 10.3390/cancers15041161. PMID: 36831503; PMCID: PMC9954747.
9. Parminder Singh et al.,INTACT: Phase III randomized trial of concurrent chemoradiotherapy with or without atezolizumab in localized muscle invasive bladder cancer—SWOG/NRG1806.. JCO 38, TPS586-TPS586(2020) DOI:10.1200/JCO.2020.38.6_suppl.TPS586
10. Powles, Thomas, et al. "Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer." The New England journal of medicine (2024): 1-14.
11. Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. doi: 10.1200/JCO.1998.16.11.3576. PMID: 9817278.
12. Kool R, Dragomir A, Kulkarni GS, Marcq G, Breau RH, Kim M, Busca I, Abdi H, Dawidek M, Uy M, Fervaha G, Cury FL, Alimohamed N, Izawa J, Jeldres C, Rendon R, Shayegan B, Siemens R, Black PC, Kassouf W. Benefit of Neoadjuvant Cisplatin-based Chemotherapy for Invasive Bladder Cancer Patients Treated with Radiation-based Therapy in a Real-world Setting: An Inverse Probability Treatment Weighted Analysis. Eur Urol Oncol. 2024 Feb 6:S2588-9311(24)00040-3. doi: 10.1016/j.euo.2024.01.014. Epub ahead of print. PMID: 38326142.
13. Avolio PP, Kool R, Shayegan B, Marcq G, Black PC, Breau RH, Kim M, Busca I, Abdi H, Dawidek M, Uy M, Fervaha G, Cury FL, Sanchez-Salas R, Alimohamed N, Izawa J, Jeldres C, Rendon R, Siemens R, Kulkarni GS, Kassouf W. Effect of Complete Transurethral Resection on Oncologic Outcomes After Radiation Therapy for Muscle-Invasive Bladder Cancer. Int J Radiat Oncol Biol Phys. 2024 Aug 24:S0360-3016(24)03292-9. doi: 10.1016/j.ijrobp.2024.08.036. Epub ahead of print. PMID: 39186955.