Trimodality therapy for bladder cancer: modern management and future directions

Abstract

Purpose of review

This review examines both trimodality therapy (TMT) in the definitive management of bladder cancer as well as the use of adjuvant radiotherapy for bladder cancer with a specific focus on publications from the last 2 years.

Recent findings

TMT is an effective management strategy for muscle invasive bladder cancer with outcomes similar to radical cystectomy. Effectiveness of this strategy exists in variant histologies and can be personalized with use of biomarkers. There is a role for adjuvant radiotherapy in locally advanced bladder cancer, especially in the age of improved imaging and modern radiotherapy techniques.

Summary

This review should provide the reader data necessary to support use of TMT and adjuvant radiation therapy in their clinic.

INTRODUCTION

Inmodern oncology, organ preservation with multimodality therapy is used in multiple diseases including breast, anal, prostate, and head and neck cancer. Although radical cystectomy is the most commonly used treatment for muscle invasive bladder cancer (MIBC), trimodality therapy (TMT) offers comparable oncologic outcomes while preserving the native bladder in more than 70% of patients. [1] In this review, we discuss the role of radiation therapy in bladder preservation as well as adjuvant radiation therapy (ART) following radical cystectomy.

TRIMODALITY THERAPY

TMT consists of maximal transurethral resection of bladder tumor (TURBT) followed by external beam radiotherapy (EBRT) with concurrent chemotherapy. The majority of TMT patients achieve a clinical complete response (cCR) (70-80%), avoiding salvage radical cystectomy, while offering long-term survival rates comparable to those in contemporary radical cystectomy series [2-6]. Giacalone et al. [7■■] found a cCR rate of 88%, bladder intact disease-specific survival (DSS) in 75%, and 5-year overall survival (OS) of 84% in patients treated in the modern era. A group in Madrid reported similar results with long-term follow-up of prospectively enrolled patients [8]. The 10-year cancer-specific mortality and OS rates were 76.3 and 43.2%, respectively, with 10-year bladder preservation rate of 79%. Patients with small tumors, complete TURBT, no hydronephrosis, and a functional bladder are ideal for bladder preservation.

Many patients with MIBC have age-related comorbidities, such as renal function impairment, and cardiovascular or respiratory disease, which disqualify them from surgery or chemotherapy. However, there was an OS benefit in adding chemotherapy to radiation therapy in patients older than 80 years of age on a propensity score analysis of National Cancer Database (NCDB) (56 versus 42% at 2 years, P<0.001) [9]. In addition, one propensity analysis of protocol-enrolled patients found that TMT has similar outcomes (DSS 61.2 versus 68.6% at 5 years) and tolerability in patients older than 75 compared with younger patients [10].

Two recently completed phase II studies suggest alternative chemosensitization regimens. Radiation therapy oncology group (RTOG) 0524 was a multiinstitutional phase I/II trial of daily radiation therapy with weekly paclitaxel, in those not suitable for radical cystectomy, with the addition of trastuzumab for those with Her2/Neu overexpression [11■]. The cCR at 12 weeks after the completion of radiation therapy was 61.5% in Her2/Neu-positive patients and 62.5% in Her2/Neu-negative patients. Acute toxicity was comparable to prior RTOG studies, but survival data were not reported. Coen et al. have recently reported the results of RTOG 0712, a phase II trial comparing fluorouracil (5-FU) and cisplatin with radiation twice a day or gemcitabine and daily radiation [12■]. Distant metastasis-free survival was similar at 3 years between 5-FU/cisplatin and gemcitabine (78 versus 84%, respectively, P=0.73) with comparable cCR rate (88 versus 78%, respectively). The combined bladder intact and distant metastasis-free survival at 3 years was 67 versus 72% with no difference in grade 3 or greater toxicity (64 versus 55%, P=0.45).

Established by RTOG 9506 and RTOG 0233, the TMT standard utilizes twice-a-day radiation in contrast to the recent RTOG trials. A pooled analysis of these trials demonstrated excellent long-term disease control and bladder preservation in patients that achieved a complete or near-complete response after TMT [13■]. Though the efficacy and toxicity observed in the daily radiation arms of RTOG 0524 and RTOG 0712 were favorable, a direct comparison of the effect of radiation fractionation cannot be made given different chemotherapy regimens. Nevertheless, daily radiation is more convenient for patients and better suited to routine clinical schedules.

There are no randomized control trials (RCTs) comparing patients treated with TMT with those receiving radical cystectomy. Without completed RCTs, the best data comparing TMT to radical cystectomy come from retrospective studies and a systematic review and metaanalysis. A recent retrospective study used propensity scores to match 56 patients who received full TMT (maximal TURBT, EBRT with concomitant chemotherapy) with those who received radical cystectomy at the Princess Margaret Hospital [14■■]. In this carefully screened group of patients with MIBC, the investigators found no significant difference in OS (64.3 versus 70.7%, P=0.84) with 5-year disease free survival (DFS) (73.2 versus 76.6%, P=0.49). About 10.7% of patients who underwent TMT required salvage cystectomy with no cystectomy required for toxicity. However, a limitation of this study is the relatively small patient size, which may limit the power of the analysis.

Several studies have attempted to compare radical cystectomy with TMT using the NCDB. However, TMT is not directly coded and thus investigators must attempt to infer which patients received TMT. In one retrospective NCDB analysis, Cahn et al. observed an OS advantage for radical cystectomy compared with TMT but defined TMT loosely as undergoing any radiation therapy with use of chemotherapy within 3 months of radiation therapy [15■]. This can erroneously include patients who undergo some form of radiation with recurrence that requires chemo within 3 months. Additionally, it can include patients who get subtherapeutic radiation doses. Also, the authors did not take into account upstaging of patients from clinical stage to pathologic stage [16].

Another NCDB study performed a matched pair analysis using clinical staging [17]. TMT was defined as a radiation therapy dose greater than 55Gy with chemotherapy delivered within 14 days of radiation, and a median radiation therapy dose of 64.8 Gy. Lin et al. [17] found similar OS between radical cystectomy and TMT with 3- and 5-year OS of 52.1 and 40.0% for radical cystectomy versus 53.3 and 33.2% for TMT, which was confirmed after propensity score matching. In addition, a radiation dose at least 60Gy resulted in better OS than 55Gy. The authors also found that 28.6% of the radical cystectomy patients had lower clinical stage compared with a higher pathologic stage. By including patients treated with an adequate radiation dose and analyzing by clinical stage, Lin et al. did not demonstrate inferior overall survival with TMT compared with radical cystectomy.

Vashistha et al. performed a metaanalysis of 19 retrospective studies with more than 12 000 patients comparing radical cystectomy and combined modality therapy [18■]. The authors found no difference in OS, DDS, or progression free survival at 5 or 10 years. Two of five prospective studies reported a near-10% perioperative mortality rate in the radical cystectomy arms. As both TMT and radical cystectomy seem to have similar survival outcomes, Royce et al. performed a comparative effectiveness analysis of TMT and radical cystectomy for MIBC using a Markov model [19]. The endpoint of interest was quality-adjusted life years (QALYs). When they limited the model to contemporary cohorts of patients, TMT had an incremental gain of 1.61 QALYs. This further supports that in the properly selected patients, TMT is an important option for patients, providing better quality of life.

Elderly patients may be more suitable for TMT compared with surgery. A recent surveillance, epidemiology, and end results-medicare study suggested that TMT was associated with significantly decreased OS and cancer specific survival (CSS) at increased costs when compared with radical cystectomy [20]. Again, TMT was broadly defined as radiation therapy and chemotherapy without radical cystectomy and the median number of treatment fractions was 18, far less than the 30 or more required for TMT. In a retrospective database from 28 institutions, Boustani et al. found that TMT was an acceptable alternative in patients older than 80, with a median OS of 1.99 versus 1.97 years for surgery (P=0.73) [21].

Better selection of patients can help predict tumors that are more radioresensitive and will more likely to successfully achieve bladder preservation. About 10–53% of bladder cancer is either histologic variants of urothelial cell carcinoma or variant histologies. Krasnow et al. compared TMT outcomes between urothelial cell cancer patients and those with variant histologies. Of the 303 patients included, 22% had variant histologies [22]. They found no difference in complete response rate, salvage cystectomy rate, DSS, or OS.

Molecular biomarkers should be considered in addition to standard clinopathologic criteria to determine the best candidates for TMT. Bladder tumors often have alterations in DNA repair pathways, like MRE11 and ERCC1/2, that are linked to sensitivity chemotherapy and radiation, which may improve response to TMT. Choudhury et al. showed that low MRE11 expression is predictive of worse CSS in patients undergoing radiotherapy, but not predictive for patients undergoing cystectomy [23]. Others found that high expression of ERCC1/2 protein was associated with improved cancer-specific survival outcomes and recurrence rates [24,25]. After comparing mutations in three immunohistochemistry-based subtypes (urobasal [Uro], genomically unstable, and squamous cell cancer-like [SCCL]), a genomic database analysis found that SCCL tumors have high rates of RB1 mutation, whereas genomically unstable tumors have high rates of ERCC2 mutations [24].

Tanaka et al. retrospectively analyzed a preoperative chemoradiation (CRT) prior to partial cystectomy or radical cystectomy [26■]. They found that MIBC has variable CRT sensitivity depending on its subtype. Genomically unstable and SCCL cancers showed significantly more favorable CRT responses compared with Uro cancer, despite being considered more clinically aggressive. Future directions include using molecular subtyping to selecting for patients who are likely to benefit from neoadjuvant CRT and identify patients who may benefit risk adaptive radiation prescriptions for bladder preservation.

ADJUVANT RADIOTHERAPY

Local-regional recurrence (LRR) for patients with at least pT3 disease after radical cystectomy is a significant problem as salvage therapies for local-regional failure are rarely successful and may lead to distant metastasis. With routine and better surveillance imaging with computed tomography (CT) and MRI, we know that pelvic recurrences in locally advanced bladder cancer are more common than previously suspected, and chemotherapy alone has not been shown to reduce the risk of LRR [27-30]. A retrospective study by Reddy et al. found that LRR was as high as 31% in patients with pathologic T4 and node-positive disease, which was not affected by treatment factors including extent of lymph node dissection or perioperative chemotherapy [31■]. Out of the patients who experienced LRR, 34% experienced LRR without distant metastasis. Other studies support this finding, with a metaanalysis of randomized controlled trials with or without platinum-based chemotherapy following local therapy (usually radical cystectomy) demonstrating that 26% of patients had local recurrence as a first event with or without synchronous distant failure [32].

ART can improve local control and may prevent subsequent development of distant disease, leading to improved DFS and OS. ART is most commonly used in patients with positive surgical margins or pT4 disease; yet, oncologists have not historically embraced ART, primarily because of concern for gastrointestinal toxicity from radiotherapy [33]. The best data come from the Egypt, reported initially by Zaghloul et al. in 1992 [34]. Patients who received radical cystectomy for MIBC were randomized to observation, ART using 1.25Gy three times daily to a total dose of 37.5Gy or ART using 2Gy per fraction daily to 50Gy using two-dimensional radiation therapy techniques. Patients receiving the ART regimens had improved 5-year local control (87 and 93 versus 50%, P<0.0001) and improved 5-year DFS (49 and 44 versus 25%, P<0.0001). However, given majority of patients had SCC (67%) and higher incidence of late radiation enteritis (36%), this regimen was not routinely adopted outside of Egypt.

A second Egyptian phase III study enrolled patients radical cystectomy with negative surgical margins that had at least pT3b disease, high-grade or involved lymph nodes, and randomized them to either adjuvant sequential sandwich chemotherapy and radiation therapy (ACRT) versus adjuvant chemotherapy [35■■]. In patients who received ACRT, 2-year local recurrence-free survival was improved (LRFS) (96 versus 69%, P<0.01), with a trend toward improved 2-year DFS (68 versus 56%, P=0.07) and 2-year OS (71 versus 60%, P=0.11). About 53% of patients had urothelial cell carcinoma (UCC) and 41% had SCC, suggesting a population potentially more similar to those treated in the United States. In an unplanned subset analysis, patients with UCC demonstrated an LRFS benefit similar to those with SCC with 2-year LRFS of 100 versus 67% (P<0.01). Toxicity was improved compared with historical controls with the late grade at least 3 gastrointestinal toxicity rate of 7 versus 2% for the ACRT versus chemotherapy alone groups, respectively. How this regimen would be integrated into accepted treatment paradigms today is uncertain, given that cisplatin-based neoadjuvant chemotherapy (NAC) was not part of the trial design by Zaghloul et al. [34]

Advances in radiotherapy techniques can reduce late grade 3 or higher gastrointestinal toxicity beyond the 7% reported in the ACRT arm using 3-dimensional conformal radiotherapy (3DCRT). Intensitymodulated radiation therapy (IMRT) and image guidance allow radiation oncologists to deliver doses of at least 50Gy to clinical target volumes within the pelvis, while avoiding excessive doses to organs at risk [36■]. Inferring from the results of pelvic IMRT in the treatment of other tumors, rates of severe late gastrointestinal or genitourinary toxicities are exceedingly low. IMRT can spare bowel and the urinary diversion in the postoperative setting. Although once considered a contraindication to ART, there is a small series using modern imaging and techniques that show that orthotopic neobladders can tolerate postoperative radiation therapy [37]. In a study evaluating the effect on bowel and rectal dose of three different treatment modalities, Baumman et al. found a dosimetric advantage for IMRT and pencil beam-scanned proton radiotherapy over 3DRT to improve rectal and bowel dose [38].

The clinical importance of these results is being investigated in multiple clinical trials of postoperative radiotherapy using IMRT have recently opened or are in development around the world, including the GETUG-AFU 30 trial in France (NCT03333356) and the proposed National Cancer Research Institute trial in the United Kingdom as well as single institution trials at Tata Memorial Hospital in India (NCT02951325), the University of Ghent in Belgium, and the NCI in Cairo. Unfortunately, a NRG trial (NRG-GU001) was terminated because of slow accural. Pelvic IMRT has led to renewed interest in ART with a survey of US radiation oncologists finding that 46% of radiation oncologists had used ART and were more likely to perform adjuvant radiotherapy if IMRT was used [39]. Given this growing interest in ART, the National Comprehensive Cancer Network guidelines were revised in 2016 to include ART as an option for patients with at least pT3 disease. In addition, ART may have an OS benefit after radical cystectomy for patients with positive surgical margins [33].

FUTURE DIRECTIONS: IMMUNOTHERAPY

There is a growing interest in adding immunotherapy to TMT and ART. The treatment of choice for decades in patients with high-risk bladder cancer, intravesical immunotherapy with Bacille Calmette Guerin causes an inflammatory response that activates the innate and adaptive immunity, resulting in an immune response against bladder tumors mediated by cytotoxic T cells (CTLs). Checkpoint inhibitors work in a similar manner by targeting immune cascade to induce the production of CTLs. Recently, several clinical trials that have demonstrated activity of checkpoint inhibitors in metastatic bladder cancer, both in patients who have progressed after first-line platinum-based chemotherapy or cisplatin-intolerant patients [40-42].

One study found that expression of programmed death-ligand 1 (PD-L1) in bladder tumors was associated with lower rates of cCR and lower rates of local control with TMT [43]. Their in-vivo mouse model demonstrated that inhibition of PD-L1combinedwith irradiation resulted in increased CTL recruitment and subsequent tumor cytolysis compared with irradiation alone. The hypothesis for combining radiotherapy with immunotherapy is that this will improve control of the primary tumor secondary to radiosensitization as well as results in immune memory that may invoke a systemic effect. There are studies in progress that assess the utility of the immunotherapy in the perioperative setting or in conjunction with radiation therapy for the management of MIBC (NCT03244384, NCT02632409, and NCT02450331). A small ongoing Phase II study in New Zealand (NCT02662062) is studying the safety and best response achieved with use of pembrolizumab with concurrent radiation in patients planned for bladder preservation, whereas a similar study at New York University (NCT02621151) looking at pembrolizumab and gemcitabine with concurrent radiation therapy is enrolling as well. The Southwest Oncology Group/NRG 1806 is a phase III trial in development, which will study whether the addition of atezolizumab, an immune checkpoint inhibitor, will improve outcomes. Future efforts should continue to explore the synergistic effect of radiation therapy and immunotherapy both with ART and TMT.

CONCLUSION

There is a growing role for radiation therapy in the trimodality management of MIBC. ART may play an important role in preventing LRR and subsequent distant metastasis after NAC and radical cystectomy and is more feasible with modern radiation therapy techniques such as IMRT or proton therapy. TMT for patients unable or unwilling to undergo radical cystectomy appears to have comparable outcomes with expanded eligibility in the elderly and cisplatin-intolerant. We look forward to future clinical trials that will investigate the synergistic effects of radiation and immunotherapy both in the TMT and ART setting.

KEY POINTS.

• TMT is an excellent treatment option for properly selected patients wishing to preserve their native bladder with oncologic outcomes similar to radical cystectomy and better QALYs. This applies to patients with variant histology.

• Adjuvant sequential sandwich chemotherapy and radiation therapy improves LRFS over adjuvant chemotherapy alone.

• There will likely be an increased role of combining immunotherapy and radiotherapy in both TMT and adjuvant therapy.