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Embracing Trimodal Therapy as a Viable Alternative to Radical Cystectomy

For years, the standard treatment for muscle-invasive bladder cancer (MIBC) was radical cystectomy (RC), preceded by neoadjuvant cisplatin-based chemotherapy (NAC), if tolerable. Currently, the National Comprehensive Cancer Center (NCCN) has two category 1 recommendations for patients with cT2-T4aN0 MIBC: NAC followed by cystectomy, and trimodal therapy (TMT).1

Trimodal therapy consists of maximal transurethral resection of bladder tumor (TURBT) followed by concurrent chemoradiotherapy and ongoing surveillance. Optimal candidates for TMT have low-volume T2-T4a urothelial carcinoma of the bladder with no CIS, no unilateral hydronephrosis, and good bladder and lower urinary tract function. TMT was historically reserved for medically inoperable patients, due to the perception that it might be inferior to RC in preventing cancer recurrence and progression. A key barrier to wider adoption of TMT was the lack of prospective randomized studies providing a head-to-head comparison with RC. Phase 3 trials were attempted, but they closed early due to inadequate accrual. The inability to accrue was likely due to both lack of equipoise on the part of the surgeons and patients being unwilling to be randomly assigned to undergo surgery versus no surgery.

Recently, however, we have seen mounting interest in bladder-preserving strategies for treating MIBC in appropriately selected patients. The Radiation Therapy Oncology Group (RTOG) has been evaluating TMT for bladder cancer since the 1980s, and when looking at their combined data from six trials (one phase 3; five phase 1/2 or 2),2-7 the data show that TMT is associated with similar outcomes to cystectomy. In a pooled study of 468 patients from these trials, 5-year overall survival and disease-specific survival were 57% and 71%, respectively, similar to studies of cystectomy in patients with similarly staged MIBC.8 In addition, the BC2001 study was a multicenter phase 3 trial in which 360 patients with MIBC were randomly assigned to undergo radiotherapy with or without synchronous chemotherapy with fluorouracil and mitomycin C. Chemoradiotherapy significantly improved 2-year locoregional disease-free survival (67% versus 54% in the radiotherapy group) without significantly increasing grade 3/4 adverse events during follow-up.9 In a subsequent study of long-term outcomes from this trial, the benefit of adding chemotherapy to radiotherapy was maintained over 10 years.10 Moreover, when retrospectively comparing TMT with RC, long-term follow-up studies, decision analyses, and meta-analyses have linked TMT with improved body image and better quality of life and functioning across social, cognitive, sexual, and bowel domains.11-15

More recently, we saw the publication of a landmark study that employed propensity score matching, a sophisticated way to analyze retrospective data that emulates a clinical trial by creating treatment groups whose baseline characteristics resemble those produced by randomization.16,17 Published in Lancet Oncology in 2023, the study included data from 722 patients with clinical stage T2-T4N0M0 MIBC. All patients were considered suitable for either TMT or RC—they had solitary tumors measuring under 7 cm, no extensive or multifocal CIS, and no bilateral hydronephrosis.16 In all, 440 patients underwent RC, and 282 received TMT. After propensity score matching, the two groups were similar in terms of age, sex, presence of hydronephrosis, and receipt of neoadjuvant or adjuvant chemotherapy. Strikingly, 5-year metastasis-free survival, disease-free survival, and cancer-specific survival were similar between the two groups, while TMT was associated with better overall survival (hazard ratio, 0.75; 95% CI 0.58 to 0.97), in part due to a 2.5% rate of perioperative mortality in the RC group. Additionally, this study showed a modern salvage cystectomy rate of only 13% after TMT.

This innovative study certainly helps demonstrate the equivalence of TMT to RC for carefully selected patients with MIBC. However, multidisciplinary input is crucial for treatment selection, and urologists, radiologists, medical oncologists, and radiation oncologists should all weigh in. Together, clinicians should consider tumor stage, grade, size, location, amenability to complete resection, response to neoadjuvant therapy (if administered), performance status, ability to tolerate surgery, and patient preferences. Imaging prior to TURBT is very useful to more precisely determine tumor extent and involvement and help guide treatment decisions and planning.1 Contrast-enhanced CT with delayed-phase CT urography helps assess the upper tracts, and the use of cross-sectional CT aids in estimating tumor volume, borders, and extent of transmural involvement. When feasible, MRI provides optimal resolution for assessing the tumor and bladder wall as well as nearby structures for local staging. Taking the time to fully inform patients of the known risks and benefits of bladder-preservation strategies and RC is essential to support shared decision-making.

Chemoradiotherapy has been shown to increase PD-L1 expression in bladder cancer.18 With the success of immunotherapy in treating various stages of bladder cancer,19 the question of whether immunotherapy can improve TMT outcomes becomes important. To this end, the randomized, multicenter, phase 3 SWOG/NRG1806 trial is comparing TMT with or without the addition of a PD-L1 inhibitor, atezolizumab, in patients with MIBC.19,20 The study has completed its target enrollment of 475 patients, making it by far the largest randomized trial of TMT to date. The primary study outcome is bladder-intact event-free survival, and secondary outcomes include overall survival, complete and partial pathologic response, metastasis-free survival, cancer-specific survival, rates of salvage cystectomy, rates of adverse events, quality-of-life measures, and patient-reported measures. Primary results, which are expected in 2024, will significantly advance our understanding of the role of immunotherapy as part of bladder-preserving strategies in MIBC. SWOG/NRG1806 accrued quickly compared with previously attempted MIBC trials, which probably reflects the growth in acceptance of TMT by patients and practitioners.

We also are seeing mounting interest in bladder preservation strategies for patients with node-positive bladder cancer, a subgroup that typically was not considered for bladder preservation in the past. A recent multicenter retrospective study of 287 patients with cN+ M0 MIBC found no difference in survival outcomes between recipients of chemotherapy and RC and recipients of radical-dose radiation therapy with chemotherapy.21 In both groups, 2-year overall survival was 56%, underscoring that clinically node-positive bladder cancer generally carries a relatively poor prognosis, and that patients should be counseled carefully and realistically to help them share fully in treatment decisions before they proceed to radical surgery. While patients with cN1-3M0 MIBC previously would not have been considered candidates for TMT, NCCN guidelines now include TMT as a treatment option (in some cases with neoadjuvant chemotherapy).1

Antibody-drug conjugates also are becoming an area of interest. These have proven to be highly effective in metastatic bladder cancer, and they are of interest in earlier-stage patients with non-metastatic disease. In one recent preclinical study, the antibody-drug conjugates (ADCs) enfortumab vedotin and sacituzumab govitecan showed synergistic tumor cell killing when combined with radiation therapy in in vitro clinical models.22 We can expect to see clinical trials of ADCs as part of trimodality therapy in the future.

For earlier-stage (non-muscle invasive) bladder cancer (NMIBC), data on TMT are not sufficiently robust to make a recommendation. The phase 2 RTOG 0926 trial posted encouraging results, although the study was small (n=37).23 This trial did show a rate of freedom from cystectomy at 3 years of 88% and has turned attention to TMT in patients with NMIBC whose next treatment option is cystectomy.

We also lack optimal data on TMT for the management of variant histology MIBC. In a single-center retrospective study of 303 patients with MIBC who underwent TMT at Massachusetts General Hospital, a multivariable analysis found no significant differences in survival outcomes between patients with pure urothelial carcinoma and those with variant histologies.24 More data are needed. In addition, the role of neoadjuvant chemotherapy in variant histology MIBCs remains unclear and probably varies according to tumor histology and definitive treatment. Thus far, retrospective multicenter studies and meta-analyses have produced mixed results on the efficacy of neoadjuvant chemotherapy when used in variant histology MIBC of different subtypes (i.e., squamous cell carcinoma, micropapillary, sarcomatoid, etc.).25-27

In summary, we are seeing growing interest in TMT as a bladder-preserving treatment strategy in MIBC. Despite the lack of randomized prospective data comparing it to RC, we now have a fairly robust body of evidence that TMT in carefully selected patients can help conserve health-related quality of life while producing equivalent outcomes to RC. Good candidates for TMT have clinical T2-T4a disease, no bilateral hydronephrosis, no extensive CIS, no multifocal disease, good bladder function, a maximal TURBT, and the ability to tolerate chemoradiotherapy. While current TMT protocols appear to be associated with a lower risk of cancer recurrence than historic approaches, patients still need to be willing and able to undergo regular cystoscopic surveillance after TMT ends. This Center includes a wealth of resources on TMT for clinicians, while the Bladder Cancer Advocacy Network (BCAN) is a wonderful resource for patients seeking more information on bladder cancer treatment strategies, including bladder-preserving strategies.28

Written by: Leslie Ballas, MD, Department of Radiation Oncology, Cedars Sinai Medical Center, Los Angeles, California

References:

  1. National Comprehensive Cancer Center. NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 2.2024—March 27, 2024. Accessed April 2, 2024. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
  2. Tester W, Caplan R, Heaney J, et al. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: Results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996;14:119–126. doi: 10.1200/JCO.1996.14.1.119
  3. Shipley WU, Winter KA, Kaufman DS, et al. 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;16:3576–3583. doi: 10.1200/JCO.1998.16.11.3576
  4. Kaufman DS, Winter KA, Shipley WU, et al. The initial results in muscle-invading bladder cancer of RTOG 95-06: Phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist. 2000;5:471–476. doi: 10.1634/theoncologist.5-6-471
  5. Hagan MP, Winter KA, Kaufman DS, et al. RTOG 97-06: Initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003;57:665–672. doi: 10.1016/s0360-3016(03)00718-1
  6. Kaufman DS, Winter KA, Shipley WU, et al. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009;73:833–837. doi: 10.1016/j.urology.2008.09.036
  7. Mitin T, Hunt D, Shipley WU, et al. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): A randomised multicentre phase 2 trial. Lancet Oncol. 2013;14:863–872. doi: 10.1016/S1470-2045(13)70255-9
  8. Mak RH, Hunt D, Shipley WU, et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014;32(34):3801-3809. doi: 10.1200/JCO.2014.57.5548
  9. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012;366(16):1477-1488. doi:10.1056/NEJMoa1106106
  10. Hall E, Hussain SA, Porta N, et al. Chemoradiotherapy in muscle-invasive bladder cancer: 10-yr follow-up of the phase 3 randomised controlled BC2001 trial. Eur Urol. 2022;82(3):273-279. doi: 10.1016/j.eururo.2022.04.017
  11. Mak KS, Smith AB, Eidelman A, Clayman R, et al. Quality of life in long-term survivors of muscle-invasive bladder cancer. Int J Radiat Oncol Biol Phys. 2016;96(5):1028-1036. doi: 10.1016/j.ijrobp.2016.08.023
  12. Giacalone 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 experience. Eur Urol. 2017;71(6):952-960. doi: 10.1016/j.eururo.2016.12.020
  13. Royce TJ, Feldman AS, Mossanen M, et al. Comparative effectiveness of bladder-preserving tri-modality therapy versus radical cystectomy for muscle-invasive bladder cancer. Clin Genitourin Cancer. 2019;17(1):23-31.e3. doi: 10.1016/j.clgc.2018.09.023
  14. Ditonno F, Veccia A, Montanaro F, et al. Trimodal therapy vs radical cystectomy in patients with muscle-invasive bladder cancer: a systematic review and meta-analysis of comparative studies. BJU Int. Published online April 15, 2024. doi: 10.1111/bju.16366
  15. Mitin T, George A, Zietman AL, et al. Long-term outcomes among patients who achieve complete or near-complete responses after the induction phase of bladder-preserving combined-modality therapy for muscle-invasive bladder cancer: a pooled analysis of NRG Oncology/RTOG 9906 and 0233. Int J Radiat Oncol Biol Phys. 2016; 94:67–74. doi: 10.1016/j.ijrobp.2015.09.030
  16. 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;24(6):669-81. doi: 10.1016/S1470-2045(23)00170-5
  17. Shin JI, Grams ME. Trial emulation methods. Am J Kidney Dis. 2024;83(2):264-267. doi: 10.1053/j.ajkd.2023.07.024
  18. Singh P, Tangen C, Efsathiou JA, et al. INTACT: Phase III randomized trial of concurrent chemoradiotherapy with or without atezolizumab in localized muscle invasive bladder cancer—SWOG/NRG1806. J Clin Oncol. 2020;38:6_suppl. doi: 10.1200/JCO.2020.38.6_suppl.TPS58
  19. Lopez-Beltran A, Cimadamore A, Blanca A, et al. Immune checkpoint inhibitors for the treatment of bladder cancer. Cancers (Basel). 2021 Jan 3;13(1):131. doi: 10.3390/cancers13010131.
  20. Southwest Oncology Research Group. Phase III randomized trial of concurrent chemoradiotherapy with or without atezolizumab in localized muscle invasive bladder cancer. Accessed April 26, 2024. https://www.swog.org/clinical-trials/s1806
  21. Swinton M, Mariam NBG, Tan JL, et al. Bladder-sparing treatment with radical dose radiotherapy is an effective alternative to radical cystectomy in patients with clinically node-positive nonmetastatic bladder cancer. J Clin Oncol. 2023;41(27):4406-4415. doi: 10.1200/JCO.23.00725
  22. D’Andrea V, Zhou Y, Shanmugan SP, et al. Activity of antibody-drug conjugates (ADCs) with radiation in preclinical bladder cancer models. J Clin Oncol. 2024;42(4_suppl). doi: 10.1200/JCO.2024.42.4_suppl.66
  23. Dahl DM, Rodgers J, Shipley WU, et al. NRG Oncology/RTOG 0926: Phase II protocol for patients with stage T1 bladder cancer to evaluate selective bladder preserving treatment by radiation therapy concurrent with radiosensitizing chemotherapy following a thorough transurethral surgical re-staging. Int J Radiat Oncol Biol Phys. 2021; 111(3S):S133-S134. doi: 10.1016/j.ijrobp.2021.07.302
  24. Krasnow RE, Drumm M, Roberts HJ, et al. Clinical Outcomes of Patients with Histologic Variants of Urothelial Cancer Treated with Trimodality Bladder-sparing Therapy. Eur Urol. 2017;72(1):54-60. doi: 10.1016/j.eururo.2016.12.002
  25. Chakiryan NH, Jiang DD, Gillis KA, et al. Pathological downstaging and survival outcomes associated with neoadjuvant chemotherapy for variant histology muscle invasive bladder cancer. J Urol. 2021;206(4):924-932. doi: 10.1097/JU.0000000000001855
  26. Alvarez-Maestro M, Chierigo F, Mantica G, et al. The effect of neoadjuvant chemotherapy among patients undergoing radical cystectomy for variant histology bladder cancer: A systematic review. Arab J Urol. 2021 Nov 7;20(1):1-13. doi: 10.1080/2090598X.2021.1994230.
  27. Cooke I, Abou Heidar N, Mahmood AW, et al. The role of neoadjuvant chemotherapy for patients with variant histology muscle invasive bladder cancer undergoing robotic cystectomy: Data from the International Robotic Cystectomy Consortium. Urol Oncol. 2024;42(4):117.e17-117.e25. doi: 10.1016/j.urolonc.2024.01.002
  28. Bladder Cancer Advocacy Network. What is bladder preservation therapy? Updated May 23, 2023. https://bcan.org/bladder-preservation/