What Providers Should Know About Trimodal Therapy for Bladder Cancer

The American Cancer Society (ACS) estimates that in 2022, close to 81,000 new cases of bladder cancer will be diagnosed, and nearly 17,000 patients will experience cancer-related mortality.¹  Approximately 1 out of every 3 or 4 patients with newly diagnosed bladder cancer will present with muscle-invasive disease at diagnosis, with an even smaller subset having locally advanced or metastatic disease at presentation.¹

With 73 years as the average age at diagnosis, most patients with bladder cancer are anticipated to have multiple comorbidities that may increase the morbidity and mortality risk of therapeutic interventions. The gold standard treatment for localized but muscle-invasive bladder cancer (MIBC) is radical cystectomy with pelvic lymphadenectomy; however, the operation has a significant rate of both early and late complications, with an estimated overall complication rate of nearly 60%.²

For patients with muscle-invasive disease at presentation, the ability to enact bladder-sparing therapies provides a viable and attractive alternative treatment modality when compared with the morbidity associated with radical cystectomy. This is true for both relatively healthy patients with unifocal disease seeking bladder preservation and for older patients with multiple medical comorbidities that warrant caution before proceeding with any drastic intervention.

Over the past century, several types of bladder-sparing therapies have been examined in clinical trials, including radical transurethral resection (TUR) with or without chemotherapy or radiation therapy, or chemotherapy, or radiation alone. Collection of these data led to development of the concept of “trimodal” therapy, which comprises complete transurethral resection of bladder tumor (TURBT) along with chemotherapy and radiation.

The aim of this article is to briefly summarize the profile of the ideal patient candidate for trimodal therapy, the conceptual basis behind trimodal therapy, and how outcomes compare to radical cystectomy with urinary diversion, which is the existing gold standard of care.

Ideal Candidates for Trimodal Therapy for Bladder Cancer

Patient selection is a critical decision factor underlying the success and response to trimodal therapy. In most clinical trials that have compared trimodal therapy to other interventions, the presence of extensive carcinoma-in-situ (CIS) or multiple sites of invasive disease within the urinary bladder, have served as exclusion criteria. This stems from well-documented lower rates of complete response (CR) and disease recurrence after completion of therapy.³ Other factors that should preclude patients from consideration as candidates for trimodal therapy include a suspected high clinical stage (>T3) of disease or the presence of hydronephrosis.

The next second critical component of optimizing success in trimodal therapy is the ability for the urologist to perform a visibly complete TURBT. Complete endoscopic resection is essential for ensuring superior rates of CR and overall survival (OS).⁴

Another important factor to consider is the functional state of the pretreatment bladder. Patients with severely decompensated bladders, from bladder outlet obstruction or other etiologies, may be poor candidates for high doses of radiation because radiation will reduce bladder volume and cause other bothersome side effects, such as hematuria.

Patients who should be considered as candidates for trimodal therapy can be broadly classified into 2 groups: good surgical candidates with limited unifocal muscle-invasive disease (ensuring the ability for complete endoscopic resection) and poor surgical candidates who are not fit to undergo radical cystectomy and urinary diversion.

Chemotherapy and Radiation

Although intravenous administration of chemotherapeutic agents has a cytotoxic effect on cancer cells, the primary role of chemotherapy in trimodal therapy is to act as a radio-sensitizing agent, thereby enhancing the utility of radiation therapy and allowing for greater control of tumor cell growth than chemotherapy alone.

The value of combining treatment modalities was well-demonstrated in the BC2001 phase 3 trial published by James et al, in which 360 patients with MIBC were enrolled to undergo radiation treatment with or without chemotherapy.⁵ At the 24-month follow-up, the authors demonstrated that the combined therapy cohort had a higher rate of locoregional disease-free survival (DFS; 67% vs 54% in the radiation-alone arm) and an improved OS rate (48% vs 35% with radiation alone) without a substantial difference in adverse events during follow-up.⁵ Long-term follow-up results from this trial demonstrated lower rates of locoregional DFS and salvage cystectomy in patients receiving chemoradiation.⁶

A variety of chemotherapeutic compounds have been investigated in trials of trimodal therapy, including platinum-based regimens, such as cisplatin and other classes such as mitomycin-C, gemcitabine and 5-fluorouracil (5-FU). The benefit of using the latter compounds lies in the fact that up to 50% of patients with MIBC may be poor candidates for platinum-based chemotherapy owing to its nephrotoxic effects.^3,7

Radiation techniques in trimodal therapy can be broadly classified into 2 major protocol types: split and continuous.⁸ The type of radiation most frequently utilized is external-beam radiation (EBRT). In the split protocol, patients undergo induction chemotherapy and radiation for half the standard course and undergo repeat imaging and cystoscopic evaluation of the bladder to check for treatment response. If, during this evaluation, the patient demonstrates noninvasive disease, then the chemoradiation course is completed; however, evidence of persistent invasive disease would warrant a recommendation of salvage radical cystectomy.

Because of this, patients undergoing split protocols typically are good surgical candidates who wish to retain their urinary bladder but can undergo and likely tolerate radical cystectomy if necessary. In comparison, continuous-course radiation employs a faster schedule of chemotherapy and subsequent radiation delivery in which clinicians will perform a repeat endoscopic and imaging evaluation to evaluate for treatment response, typically within 3 months after completion.

Outcomes of Trimodal Therapy for Bladder Cancer

Oncologic outcomes from trimodal therapy have been demonstrated to be similar to those of patients undergoing radical cystectomy and pelvic lymphadenectomy, with the caveat that careful patient selection is required.

A large meta-analysis including several prospective phase 3 trimodal therapy trials, as well as smaller phase 2 studies, demonstrated promising 5-year cancer-specific survival rates ranging from 50% to 82%, and OS rates ranging from 36% to 74%.⁸ Unfortunately, many patients undergoing trimodal therapy will experience recurrence of invasive disease, and an estimated 30% will require salvage cystectomy, although one recent study reported a lower 13% rate.^8,9

The patients who do complete trimodal therapy without salvage cystectomy reported health-related quality of life (HRQoL) returning to baseline within 6 months of completing therapy.¹⁰ In recent data presented at ASCO 2022, Zlotta and colleagues reported similar 5-year metastasis-free survivals for patients receiving radical cystectomy or trimodal therapy in a matched-cohort retrospective study.⁹

In conclusion, trimodal therapy can be a viable therapeutic alternative for patients with MIBC seeking bladder preservation who have unifocal, lower-stage (T2) disease without evidence of CIS, and stable bladder function prior to trimodal therapy. Learn more about how radical cystectomy compares to trimodality therapy.

Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.

 

References

1. American Cancer Society. Key statistics for bladder cancer. https://www.cancer.org/cancer/bladder-cancer/about/key-statistics.html. Accessed April 25, 2022.
2. Shabsigh A, Korets R, Vora KC, et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol. 2009;55(1):164-174. doi: 1016/j.eururo.2008.07.031
3. Chung P, Guruli G, Kuk C, Mir MC, Alonso EP. Trimodal therapy in muscle invasive bladder cancer management. American Urological Association. AUA Update Series 2021;40; lesson7. https://auau.auanet.org/content/update-series-2021-lesson-7-trimodal-therapy-muscle-invasive-bladder-cancer-management#group-tabs-node-course-default2. Accessed April 25, 2022.
4. Efstathiou JA, Spiegel DY, Shipley WU, et al. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol. 2012;61(4):705-711. doi: 1016/j.eururo.2011.11.010
5. James ND, Hussain SA, Hall E, et al; for the BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012;366(16):1477-1488. doi: 1056/NEJMoa1106106
6. Hall E, Hussain SA, Porta N, et al. BC2001 long-term outcomes: a phase III randomized trial of chemoradiotherapy versus radiotherapy (RT) alone and standard RT versus reduced high-dose volume RT in muscle-invasive bladder cancer. J Clin Oncol. 2017;35(6 suppl); abstract 280. doi: 1200/JCO.2017.35.6_suppl.280
7. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer [published correction appears in N Engl J Med. 2003;349(19):1880]. N Engl J Med. 2003;349(9):859-866. doi: 1056/NEJMoa022148.
8. Ploussard G, Daneshmand S, Efstathiou JA, et al. Critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic review. Eur Urol. 2014;66(1):120-137. doi: 1016/j.eururo.2014.02.038
9. Zlotta AR, Ballas LK, Niemierko A, et al. Multi-institutional matched comparison of radical cystectomy to trimodality therapy for muscle-invasive bladder cancer. J Clin Oncol. 2022;40(6 suppl); abstract 433. doi: 1200/JCO.2022.40.6_suppl.433
10. Huddart RA, Hall E, Lewis R, et al; for the BC2001 Investigators. Patient-reported quality of life outcomes in patients treated for muscle-invasive bladder cancer with radiotherapy ± chemotherapy in the BC2001 phase III randomised controlled trial. Eur Urol. 2020;77(2):260-268. doi: 1016/j.eururo.2019.11.001