Trimodal Therapy in the Treatment of Muscle-Invasive Bladder Cancer

Article information

J Urol Oncol. 2024;22(3):256-267

Publication date (electronic) : 2024 November 30

doi : https://doi.org/10.22465/juo.244801000050

Yongsoo Jo, Hyeong Dong Yuk

Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Corresponding author: Hyeong Dong Yuk Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea Email: armenia8@snu.ac.kr

Received 2024 September 20; Revised 2024 October 28; Accepted 2024 November 15.

Abstract

INTRODUCTION

Bladder cancer is the 10th most commonly diagnosed cancer worldwide and the 13th leading cause of cancer-related deaths. Each year, more than 573,000 new cases of bladder cancer and approximately 212,000 bladder cancer-related deaths occur [1]. In South Korea, it is also the 10th most common cancer, and the 10th leading cause of cancer-related deaths in men, with approximately 1,770 new cases and 780 bladder cancer-related deaths reported annually [2]. Radical cystectomy (RC) with bilateral pelvic lymph node dissection following neoadjuvant chemotherapy is the standard treatment for muscle-invasive bladder cancer (MIBC) [3]. However, despite the standardization of surgical treatment after chemotherapy, it significantly affects patients’ quality of life due to relevant morbidity and functional impairment [4,5]. It has been reported that 31%–64% of patients who undergo RC experience complications. Additionally, approximately 15% of patients develop grade 3 or higher complications, and the mortality rate is reported to be around 1.5%–2.7% [6,7].

Recently, there has been increasing interest in bladder preservation therapy, which aims to minimize complications and improve quality of life (QoL) while maintaining oncological outcomes comparable to standard treatments. Trimodal therapy (TMT), consisting of transurethral resection of bladder tumor (TURBT), chemotherapy, and radiation therapy (RT), is the most extensively studied and utilized bladder-preserving approach. Reports indicate that TMT achieves oncological outcomes similar to standard treatments, with a 10-year overall survival (OS) rate of approximately 30% and a 10-year disease-specific survival rate of around 50% [8,9].

There is growing evidence supporting the oncological outcomes and safety of TMT, showing its potential to achieve tumor control while preserving bladder function, thus maintaining patients’ QoL [10-12]. Currently, several guidelines recommend TMT as a treatment option for select patients with MIBC [13,14].

This review explores the evolution of TMT, its clinical efficacy, its role in comparison with RC, and future directions.

METHODS

We conducted a nonsystematic literature search on PubMed in October 2024 using the following keywords: “muscle invasive bladder cancer,” “bladder preservation,” “trimodal therapy,” “chemoradiotherapy,” and “radiation therapy.” We searched for papers published in English between 2000 and 2024. Among these, original articles, reviews, and editorials written in English were selected, organized, and cited.

TRANSURETHRAL RESECTION OF THE BLADDER TUMOR IN TMT

The goal of TURBT is to maintain bladder integrity while removing as much of the visible tumor as possible. The extent of tumor resection during TURBT is a crucial predictor of TMT success. Although there are no definitive comparative studies on the efficacy of complete TURBT, a subgroup analysis of MIBC patients enrolled in Radiation Therapy Oncology Group (RTOG) bladder-sparing protocols at Massachusetts General Hospital, who received platinum-based chemotherapy and RT, found that visibly complete bladder tumor resection predicted a better response to bladder preservation therapy in terms of complete response (CR) and survival outcomes. It was reported that 79% of patients achieved CR after induction therapy when complete resection was achieved, with a 22% higher rate of local control compared to patients without complete TURBT [15].

However, results from prominent phase III clinical trials, such as the BC2001 and BCON studies, demonstrated high local control rates despite a high proportion of patients with incomplete resections in both trials. This suggests that complete TURBT is not an essential prerequisite for the success of TMT [16,17].

CHEMOTHERAPY IN TMT

Chemotherapy in TMT is administered alongside RT to act as a radiosensitizer, enhancing the effects of radiation. It also aims to improve local control by eliminating micrometastases in conjunction with RT.

Although various chemotherapeutic agents have been used in combination with RT, there are few studies that have specifically analyzed the efficacy of chemotherapy combined with RT. Only a few randomized controlled trials (RCTs) have compared chemoradiotherapy with radiotherapy alone.

Platinum-based chemotherapy, such as the combination of cisplatin with 5-fluorouracil (FU) or paclitaxel, is widely accepted. An analysis of 6 prospective studies conducted by the RTOG on MIBC patients treated with TMT showed that using platinum-based chemotherapy as part of TMT resulted in a 72% CR, a 5-year survival rate of 57%, and a 10-year survival rate of 36% (Table 1) [18].

Table 1.

Bladder-sparing approaches in trimodal therapy: RTOG/NRG oncology clinical trials

Another regimen using the combination of 5-FU and mitomycin C demonstrated a 5-year survival rate of 48%–53% and a 2-year disease-free survival rate of 67%–70% [17,19].

A different regimen involves low-dose gemcitabine monotherapy. In a phase II randomized trial, treatment with low-dose gemcitabine administered once daily alongside radiotherapy showed promising outcomes, with a 3-year cancer-specific survival (CSS) rate of 82% and an OS rate of 75%, comparable to treatment with cisplatin and 5-FU given alongside twice-daily radiotherapy [20].

In a RCT comparing cisplatin with FU to gemcitabine, the CR rates were 29% versus 25%, and the 3-year distant metastasis-free survival rates were 77.8% versus 84%, showing similar outcomes, with fewer grade 3 or higher adverse events observed with gemcitabine [21].

RADIOTHERAPY IN TMT

The goals of radiotherapy in the treatment of MIBC are threefold: bladder preservation, maintaining QoL and body structure, and achieving oncologic outcomes similar to surgery while avoiding surgery. The standard radiation regimen involves administering an initial dose of 40–45 Gy of external beam radiation therapy to the bladder and pelvic lymph nodes, followed by an additional boost of 10–15 Gy to the bladder and 10 Gy to the tumor, resulting in a total dose of 54 Gy to the bladder and 64–66 Gy to the tumor [22]. Based on whether a cystoscopy and biopsy are performed before the additional boost, there are split regimens [23] and continuous regimens [17]. In the split regimen, after the initial radiotherapy, a cystoscopy and biopsy are performed, and the additional boost is given if there is no evidence of residual cancer. In the continuous regimen, the entire dose of radiation is administered first, followed by a cystoscopy evaluation 1–3 months later. While there is no difference in survival rates and toxicity between the 2 methods, the continuous regimen has been reported to have a higher CR rate (hazard ratio [HR], 0.51) [24].

In TMT, chemoradiation is used rather than radiotherapy alone. The BC2001 trial randomized patients with T2–T4aN0M0 bladder cancer to RT or chemoradiation, and also compared standard whole-bladder radiotherapy with reduced high-dose-volume radiotherapy. The trial demonstrated a clear survival benefit of chemoradiation over radiotherapy alone, with improvements in locoregional control (HR, 0.61) and invasive locoregional control (HR, 0.55). Since the BC2001 trial in 2001, radiotherapy techniques have advanced significantly. Modern radiotherapy is faster due to hypofractionation, more adaptive, with reduced toxicity, and more intense due to increased doses. With the advent of cone-beam computed tomography (CT) and planning CT, image-guided radiotherapy has improved target coverage, enabling adaptive radiotherapy that enhances control rates while reducing toxicity to the target and surrounding organs.

The RAIDER trial, a phase II randomized trial, compared standard/control whole-bladder single-plan radiotherapy (WBRT), standard-dose adaptive tumor-focused radiotherapy (SART), and dose-escalated adaptive tumor-focused radiotherapy (DART) in cT2–T4aN0M0 unifocal MIBC patients. Toxicity was similar across the 3 groups, with no grade 3 or higher adverse events in the 32-fraction group, and one case in each group in the 20-fraction regimen. At 3 months, overall local control rates were 99%, with similar outcomes across the groups. DART showed favorable results compared to WBRT and SART in terms of 2-year event-free rates (84% vs. 80%) and bladder-intact event-free survival (72% vs. 66%).

There is ongoing debate regarding the optimal method of radiotherapy. Some argue that partial bladder radiation can preserve normal tissue, reduce toxicity, and yield similar outcomes to whole-bladder radiation, while others believe it may miss microscopic tumors not visible on imaging or cystoscopy. The BC2001 trial compared whole-bladder irradiation to partial bladder irradiation and found no significant difference in local recurrence (39% vs. 36%) and similar treatment toxicity (13%) [25]. A meta-analysis of patients from the BC2001 and BCON trials reported that a 55-Gy hypofractionated schedule in 20 fractions provided better invasive locoregional control (HR, 0.72) and similar toxicity compared to a 64-Gy schedule in 32 fractions, leading to suggestions that a 55-Gy schedule in 20 fractions should be adopted as the standard for bladder preservation [10]. Another controversial area in radiotherapy is the extent of lymph node coverage. RTOG trials include pelvic lymph node irradiation, whereas European trials such as BC2001 and BCON did not, with no significant increase in nodal recurrence [16,17]. A study of 2,104 patients from the US National Cancer Database who underwent TURBT and chemoradiotherapy found no difference in OS between the group that received bladder-only irradiation and the group that included pelvic lymph node irradiation [26].

PATIENT POPULATION FOR TMT

Not all patients are suitable candidates for bladder preservation therapy, and appropriate patient selection is crucial for the success of TMT. In clinical practice, patients who undergo RT may include those with significant comorbidities, elderly patients with high morbidity, those in poor overall health who are unable to undergo surgery, or patients who could undergo surgery but opt for TMT. The most suitable candidates for TMT are those with good bladder function and the ability to tolerate chemoradiation. A retrospective analysis from 2005 to 2017 conducted at 3 academic institutions in the United States and Canada compared TMT with RC in patients with solitary tumors smaller than 7 cm, no bilateral hydronephrosis, and no CIS. The 5-year metastasis-free survival was identical at 75%, and there was no difference in disease-free survival or CSS between the 2 groups [9].

Although there are no unified or standardized criteria for patient selection for TMT, several guidelines suggest that appropriate candidates include those with T2–T4aN0M0 disease, urothelial or small cell histology, good bladder function, absence of CIS, absence of bilateral hydronephrosis, and no metastasis (Table 2).

Table 2.

Patient eligibility criteria for trimodal therapy recommended by NCCN, EAU, AUA, ASCO, ASTRO, SUO, and ESMO guidelines

Limited T2–T3 disease, patients with organ-confined (T2) or locally advanced but nonmetastatic (T3) MIBC are typically the best candidates. Advanced-stage disease or extensive local invasion (T4) may limit the efficacy of TMT and make surgical intervention more necessary. Absence of carcinoma in situ (CIS), the presence of CIS may lead to a higher risk of recurrence after bladder-sparing approaches. Patients without CIS generally fare better with TMT. Good bladder function, patients should have good baseline bladder function and no significant bladder symptoms, as TMT aims to preserve bladder function. Poor bladder function could lead to unacceptable QoL outcomes posttreatment. Absence of bilateral hydronephrosis, bilateral hydronephrosis is often a marker of advanced disease and poor prognosis, and such patients may not benefit as much from bladder preservation strategies. No evidence of distant metastasis (N0M0), TMT is intended for localized disease. The presence of nodal or distant metastasis would usually warrant systemic therapies rather than local control approaches like TMT. General good health, patients need to be fit enough to undergo both chemotherapy and radiation. Significant comorbidities or poor performance status may make patients more suitable for RC rather than TMT. Additional criteria mentioned in various studies include unifocal, solitary tumors with a maximum diameter of less than 7 cm, and no residual tumor after TURBT, which have been associated with favorable outcomes. Patients with large primary tumors, squamous cell carcinoma or adenocarcinoma, extensive CIS, bilateral hydronephrosis, poor bladder function, low bladder capacity, multifocal tumors, or severe lower urinary tract symptoms are at higher risk for recurrence and metastasis, and RC is recommended in these cases. Furthermore, previous pelvic radiation, small bladder capacity (<100 mL), and radiation hypersensitivity syndrome are considered relative contraindications to radiotherapy, making TMT challenging for these patients. However, incomplete resection after TURBT, unilateral hydronephrosis, or the presence of peritumoral CIS (not extensive) are not contraindications to TMT.

FOLLOW-UP

Recurrence after TMT can occur up to 10 years posttreatment, with the highest recurrence rates in the first 2–3 years. While local recurrence is more common, distant metastasis cannot be ruled out, so long-term follow-up is necessary to monitor both local and systemic recurrence.

Although guidelines vary, cystoscopy and chest and abdominal CT are generally recommended. The EAU guidelines [27] suggest performing cystoscopy every 3–6 months for the first 5 years, with chest and abdominal CT every 3–4 months during the first 2 years and every 6 months thereafter until the fifth year. The American Urological Association (AUA) guidelines [28] recommend cystoscopy every 3 months in the first year, every 4–6 months in the second year, and every 6–12 months thereafter. Additionally, cross-sectional imaging of the abdomen and pelvis, as well as chest imaging, is advised every 6 months for the first 2 years. However, there is insufficient evidence to confirm that following these schedules improves survival outcomes [29].

ONCOLOGIC OUTCOME OF TMT

Multiple studies report OS and CSS outcomes following TMT, with 5-year CSS ranging from 50%–82% and 5-year OS ranging from 36%–74% (Table 3). A long-term analysis of prospective studies, including 5 phase II studies (RTOG 8802, 9506, 9706, 9906, and 0233) and one phase III study (RTOG 8903), reported a 5-year CSS of 71% and OS of 57%, while the 10-year CSS was 65% and OS was 36% (Table 1) [18].

Table 3.

Clinical outcomes of trimodal therapy in recent studies

Although different radiosensitizers were used, the 2 prospective phase III trials, BC2001 [30] and BCON [31], both reported similar results, with 5-year OS of 49% and 10-year OS of 30%.

In a US National Cancer Database observational study analyzing 1,257 patients who underwent TMT and 11,586 patients who underwent RC, the median OS was 40 months for TMT and 43 months for RC, showing similar outcomes. However, TMT was associated with worse long-term survival (HR, 1.37) [32]. The SPARE trial, which ended due to incomplete patient accrual, found that locoregional recurrence-free survival was superior in the RC group compared to the TMT group, and that non–muscle-invasive recurrences were more common after RT than MIBC [33].

In retrospective analyses, patients with cT3b or less, no hydronephrosis, no lymphovascular invasion (LVI) in TURBT specimens, and no palpable mass on bimanual examination who underwent RC showed a 5-year OS of 64.8% and a 5-year CSS of 83.5%, which were relatively better than TMT outcomes [34].

A population-based study using data from the SEER (Surveillance, Epidemiology, and End Results)-Medicare database from 2002–2011 found that patients who underwent TMT had worse OS (HR, 1.54) and CSS (HR, 1.51) compared to RC [35]. A study analyzing data from the US National Cancer Database on 32,300 bladder cancer patients found that 5-year OS was 48% for RC and 30% for TMT, with RC showing relatively superior survival outcomes [36].

A meta-analysis of 57 related studies found that 75.3% of patients achieved CR after TMT, and 5-year OS, CSS, and RFS after CR were 66.9%, 78.3%, and 52.5%, respectively. There was no statistically significant difference in 10-year OS (35.1% vs. 30.9%, p=0.32) or CSS (50.9% vs. 57.8%, p=0.26) between TMT and RC [8].

There are few RCT directly comparing TMT and RC, and differences in patient populations, chemotherapy regimens, and the use of neoadjuvant or adjuvant chemotherapy make direct comparisons difficult. Differences in outcomes between the 2 treatments may result from these confounding variables.

RECURRENCE OF TMT

The CR rate following TMT is approximately 60%–80%, but 10%–40% of patients who achieve CR will experience local recurrence [1,8,11,17]. The recurrence rates for muscle-invasive recurrences at 5 and 10 years were 13% and 14%, respectively, while the recurrence rates for non–muscle-invasive recurrences were 31% and 36%, respectively [18]. A retrospective analysis of data from 2005 to 2017 at 3 academic institutions in the United States and Canada found that most recurrences after TMT were local, with muscle-invasive recurrences occurring in 11% of cases and non–muscle-invasive recurrences in 20%. Recurrence of muscle-invasive disease tends to occur more frequently within the first 2–3 years after TMT [9]. However, there have been reports of late recurrences occurring beyond 5 years, with another study reporting that the median time to recurrence was less than 2 years, though late recurrence rates of up to 8% have been observed even up to 10 years [37].

SALVAGE RADICAL CYSTECTOMY

After TMT, patients are reassessed 2–3 months later. If no residual tumor is found, follow-up continues; if residual tumor is detected or invasive recurrence occurs after CR, salvage RC (SRC) is considered [38]. The ESMO (European Society for Medical Oncology) guidelines recommend early SRC for patients with T1 disease, tumors >3 cm, CIS, or LVI after TMT [39].

A retrospective analysis from 2005 to 2017 at 3 academic institutions in the United States and Canada reported an SRC rate of 30% after TMT [9]. The RTOG trials showed an SRC rate of 21% after TMT [18]. However, with more advanced radiation techniques and a more limited patient population, SRC rates have dropped below 15% [40]. In the BC2001 trial, the SRC rate after TMT was 22% [30], while in the BCON trial it was 8.3% [31].

For patients who did not achieve CR or experienced recurrence after CR, the 5-year CSS and OS following SRC were approximately 60% and 45%, respectively [11,18,41,42]. Studies comparing SRC after TMT to primary RC have shown no significant difference in perioperative mortality or grade 3 or higher complication rates [42-44]. Additionally, studies comparing early SRC in patients who failed to achieve CR with delayed SRC after MIBC recurrence have found that early SRC was associated with more cardiovascular complications, while delayed SRC was more likely to result in wound healing complications.

QUALITY OF LIFE

Patients undergoing RC and urinary diversion may experience diminished sexual and urinary function, as well as psychological and emotional impacts on body image due to the presence of external stomas, leading to a decreased QoL [45]. The goal of TMT is to maintain QoL by avoiding RC and urinary diversion, but there have been no prospective studies directly comparing QoL between the 2 treatment methods.

Retrospective studies have shown that QoL at 5 years post-TMT was relatively better compared to RC (p=0.001), with TMT patients showing better sexual function, physical, social, and occupational role functioning, and better body image. However, there was no significant difference in urinary symptom scores between the 2 groups, with both experiencing diminished function [5].

Urodynamic studies evaluating bladder function in long-term TMT survivors found that 75% had normally functioning bladders, although most patients showed reduced bladder compliance [46].

CURRENT AND FUTURE DIRECTIONS

Bladder-sparing approaches like TMT are expected to increase in the future. However, there is a need for more research and consensus to better apply TMT in patients with invasive bladder cancer.

Currently, there is a lack of consensus on the standardization of TMT protocols. Differences exist between studies regarding radiotherapy target volumes and fractionation schemes. Common chemotherapy regimens include cisplatin-based combinations, single-agent gemcitabine, and 5-FU with mitomycin C, but there is no agreement on which regimens to use or how to administer them. Additionally, more research is needed to understand the role and efficacy of neoadjuvant and adjuvant chemotherapy in TMT.

There is also a lack of long-term data beyond 15 years following TMT, and standardized guidelines for follow-up and management of recurrences or progression after TMT are lacking across institutions.

Recent research has focused on biomarkers that may predict responses to TMT, though none are yet validated for clinical use [47]. Some biomarkers, such as MRE11, which is associated with DNA-damage signaling, and immune-related markers like interferon-gamma expression, have shown promise as predictors of response to radiotherapy [48,49]. HER2 (human epidermal growth factor receptor 2) overexpression has been associated with reduced CR rates, and ERCC2 mutations have been linked to increased sensitivity to cisplatin and radiation [47]. Biomarker development could help improve patient selection for TMT and allow for more personalized treatment approaches in MIBC. For example, patients with high biomarker expression predicting a good response could be directed to TMT, while those with low expression could be considered for RC [50].

In 2012, a Japanese center proposed a modified bladder preservation approach, adding partial cystectomy and pelvic lymph node dissection after TMT in cases where no MIBC remained in the trigone or bladder neck [51]. In a 2019 study of 107 patients treated with this approach, the 5-year OS and CSS were 93% and 91%, respectively, with a local recurrence rate of 18%, MIBC recurrence rate of 4%, and satisfactory bladder function and QoL [52]. These promising results suggest that such modifications to TMT could further improve outcomes, and additional research is warranted.

The recent development of immune checkpoint inhibitors targeting PD-1 (programmed death-1) and PD-L1 (programmed death ligand-1) has brought significant advances in the treatment of bladder cancer. Preclinical studies have shown that combining immune checkpoint inhibitors with TMT can enhance tumor suppression and abscopal antitumor effects [53].

In human studies, the ANZUP-1502 trial involved 28 patients with cT2–T4aN0M0 MIBC who were treated with weekly cisplatin and pembrolizumab as part of TMT. The CR rate at 24 weeks was 88%, with a 2-year distant metastasis-free survival rate of 78% and locoregional progression-free survival (PFS) of 87%, and the median OS was 39 months [54].

The DUART trial, involving patients who were ineligible for surgery and cisplatin, examined the use of durvalumab combined with radiotherapy. The median PFS was 21.8 months, and the median OS was 30.8 months [55]. Additionally, numerous studies are currently ongoing (Table 4). These results suggest that immune checkpoint inhibitors combined with TMT may not only expand the range of suitable patients for current TMT but also present a promising option for future bladder-sparing therapies.

Table 4.

Current research on trimodal therapy combined with immune checkpoint inhibitors in bladder cancer

CONCLUSIONS

TMT has been shown to provide oncologic outcomes similar to RC in selected patients while improving QoL. With ongoing advancements in immunotherapy, biomarkers, and radiotherapy techniques, the use of TMT is expected to increase. Standardization of TMT protocols and long-term evaluations of oncologic outcomes, toxicity, and QoL will be necessary to ensure proper patient selection and successful results.

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