Trimodality therapy in the modern era for management of bladder cancer

Treatment decision for muscle-invasive bladder cancer (MIBC) often poses a challenge for physicians and patients. Radical cystectomy (RC) with neoadjuvant chemotherapy remains to be the most widely used curative treatment for MIBC (1,2). However, RC is a major surgery and poses substantial risk of complications and perioperative mortality, especially in older patients with significant comorbidities (3). Bladder-preserving trimodality therapy (TMT) with maximally safe transurethral resection of bladder tumor (TURBT) followed by chemoradiotherapy (CRT), on the other hand, is an effective and less-invasive alternative to RC. Despite this, it is estimated that only ~10–20% of patients receive TMT for definitive treatment of MIBC (4-6). The low rates of TMT utilization are likely multifactorial, which includes the lack of prospective randomized trials to demonstrate equipoise between TMT and RC, misconceptions regarding TMT, and inexperience with this treatment modality. This commentary aims to narrate the establishment of TMT as an effective MIBC therapy and the aspiring role of TMT in the modern era.

The first prospective trial in the 1980s provided key insights into the combined efficacy of CRT for MIBC—improved locoregional control of radiotherapy (RT) with concurrent cisplatin (7). This paved way to several small RTOG trials that evaluated CRT with concurrent cisplatin backbone (8-13). Pooled analyses of the RTOG trials with a total of 468 patients demonstrated clinical complete response (cCR) rate of 69%; 5-year and 10-year overall survival (OS) rates were 57% and 36%, respectively, and 5-year and 10-year disease-specific survival (DSS) rates were 71% and 65%, respectively. Of note, non-muscle-invasive local recurrences post-CRT (31% at 5-year) were more common than muscle-invasive recurrences (13% at 5 years) (14). In addition, two large single-institutional experiences with TMT demonstrated comparable efficacy of bladder preservation therapy to prospective trials. One institutional series of 348 MIBC patients treated with TMT demonstrated 10-year OS and DSS rates of 35% and 59%, respectively, while another series of 415 patients showed 10-year DSS rates of 42% (15,16).

Still, the therapeutic benefit of concurrent chemotherapy with RT needed validation with large phase 3 randomized trial. To this goal, BC2001 trial randomized 360 MIBC patients to RT alone vs. CRT with concurrent mitomycin/5-FU. At 10-year follow-up, CRT improved locoregional control [hazard ratio (HR) =0.61; 95% confidence interval (CI): 0.43–0.86; P=0.004] and invasive locoregional control (HR =0.55; 95% CI: 0.36–0.84; P=0.006) compared to RT alone, which translated to non-statistically-significant improvement in DFS (HR =0.78; 95% CI: 0.60–1.02; P=0.069), metastasis-free survival (HR =0.78; 95% CI: 0.58–1.05; P=0.089), and OS (HR =0.88; 95% CI: 0.69–1.13; P=0.3). Patients who received CRT also had lower rates of needing salvage cystectomy at 5-year compared to RT alone (14% vs. 22%) (17,18). Regarding concurrent chemotherapy options, BC2001 also established the efficacy of mitomycin/5-FU as an appropriate regimen in TMT, especially one with less renal toxicity. Further expanding the radiosensitizer repertoire, RTOG 0712 demonstrated that concurrent gemcitabine is yet another acceptable regimen compared to cisplatin-based chemotherapy (19).

RT can be delivered in conventional fractionation (64–64.8 Gy in 1.8–2.0 Gy per fraction) or with hypofractionation (55 Gy in 2.75 Gy per fraction). BC2001 and BCON (another UK bladder trial that randomized patients to RT ± hypoxic sensitizers carbogen/nicotinamide) trials allowed for both fractionations in a non-randomized fashion (17,20). Interestingly, a recent meta-analysis of the two trials showed that patients who received hypofractionation with 55 Gy in 20 fractions was associated with lower risk of invasive locoregional recurrence compared to those that received 64 Gy in 32 fractions (HR =0.71; 95% CI: 0.52–0.96), while both fractionations demonstrated similar toxicity (21).

It is interesting to note that, in the United States, earlier trials and historical paradigm of bladder preservation was done in a split-course fashion, which entails induction CRT to ~40–45 Gy followed by cystoscopic evaluation, and only patients who have achieved cCR will then proceed to consolidative CRT with additional ~20–25 Gy (5). On the other hand, treatment paradigm in Europe favored continuous CRT course, which is followed by cystoscopic surveillance to monitor for local recurrence. Salvage cystectomy is indicated if cCR was not achieved in split-course protocol (early salvage) or at the time of local recurrence with either split-course or continuous regimens (delayed salvage). While unproven, the rationale for split-course is to allow earlier selection of patients with unfavorable disease characteristics (i.e., those who did not achieved complete TURBT prior to induction CRT or those with disease that are less responsive to CRT) for early salvage cystectomy in hopes that this may improve outcome. In contrast, continuous CRT allows for full delivery of treatment to maximize tumor eradication and chance for bladder preservation. Post-operative complication rates from early vs. delayed salvage cystectomy appear to be comparable, although with greater proportion of cardiovascular complications associated with early salvage and more tissue healing complications with delayed salvage (22). In more recent years, paradigm with TMT has largely shifted towards continuous CRT regimens.

Despite having both prospective and retrospective evidence demonstrating favorable efficacy and outcome of TMT, this modality remains to be under-utilized in the real-world setting. One major hurdle is the lack of prospective data comparing TMT to RC, which has long been a standard-of-care treatment for MIBC. The SPARE trial was the only prospective trial randomizing MIBC patients to TMT vs. RC, but trial terminated after only enrollment of 45 patients due to poor accrual, which underscores the inherent challenges of comparing two treatment modalities that do not hold equipoise from the patients’ perspective (most patients would strongly favor one modality over another) (23). Given that there will likely never be a successful randomized control trial comparing TMT to cystectomy for MIBC, we must rely on real-world data on outcomes of TMT vs. surgery to address the comparability of the two modalities. Zlotta et al. recently reported a large multi-institutional retrospective study of 722 patients (n=440 underwent cystectomy, n=282 received TMT) with cT2–T4N0 MIBC who would have been eligible for either treatment modalities (i.e., solitary tumors <7 cm, no bilateral hydronephrosis, or no extensive carcinoma in situ). Patient outcomes by treatment modality were analyzed with propensity score matching (PSM) and inverse probability treatment weighting (IPTW). The study reported no significant differences in 5-year metastasis-free survival between TMT vs. cystectomy with either PSM (74% vs. 74%) or IPTW (75% vs. 74%). There were also no differences in DFS or cancer-specific survival between TMT vs. cystectomy, but interestingly, OS favored TMT. Because the PSM and IPTW analyses accounted for the use of peritreatment chemotherapy (which is best standard of care for patients undergoing cystectomy, but not for TMT), the study also performed a sensitivity analysis of comparing cystectomy patients who received chemotherapy vs. patients who received TMT—again, no differences in survival outcomes were found (24). Similarly, non-metastatic MIBC patients identified from The Netherlands Cancer Registry who received RC (n=1,101) vs. TMT (n=331), with median follow-up of 39 months, demonstrated comparable outcomes between the two treatment cohorts with 2-year DFS of 61.5% vs. 55.3% and 2-year OS of 74% vs. 66% (25). For clinically node-positive MIBC, Swinton et al. analyzed 163 cN+ patients who received definitive treatment with either RT (n=87) or RC (n=76) and showed that there was also no difference in OS or progression-free survival (PFS) for the entire cohort (OS: HR =0.94, 95% CI: 0.63–1.41, P=0.76; PFS: HR =0.74, 95% CI: 0.5–1.08, P=0.12), as well as no difference in outcomes in the subset of RT/RC patients that received chemotherapy (26). These studies, while limited by their retrospective nature, represent the most robust evidence to-date to support bladder-sparing TMT as an appropriate treatment option for the majority of MIBC patients with localized or locoregional disease.

Acute side effects of CRT can include transient symptoms of fatigue, cystitis, enteritis and hematological toxicities from concurrent chemotherapy. In some patients, the acute bowel and urinary effects can linger, constituting chronic bowel (diarrhea or looser stool) and urinary (nocturia or increased frequency/urgency) habit changes. Other potential late side effects of CRT can include radiation proctitis, radiation cystitis, and rare instances of small bowel obstruction or contracted bladder requiring surgical intervention. The Erlengen experience reported that 1.6% patients had salvage cystectomy due to having contracted bladder and 1.5% patients with bowel obstruction requiring surgery (16); it is important to note that these patients were treated from 1982–2000 and that modern radiation techniques would likely be associated with even lower rates of these major complications. In more modern prospective trials, BC2001 and BCON reported ~10–20% of grade 3/4 late toxicity with RT or CRT (18,21). Comparing the late toxicity of CRT to RC, the SPARE trial reported more patients who underwent RC (52%) with grade 3/4 toxicity compared to those who received CRT (27%) when excluding erectile dysfunction (23).

Quality-of-life (QoL) after MIBC treatments is an important consideration for patients. In the SPARE trial (randomizing TMT vs. RC) that failed to accrue, many patients who declined randomization selected TMT as their treatment of choice, which underscores the priority for many patients to strive for organ preservation. Moreover, from the limited number of accrued patients, the SPARE trial also showed that there was a greater decline in body image and male sexual function after RC compared to TMT (23). In a recent meta-analysis that strived to examine the QoL after definitive treatment for MIBC, 50 studies were included, although most studies evaluated surgical QoL outcomes. However, the strength of the study lies in pooling the “common denominator” of patient-reported QoL surveys across 18 studies—the European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire-C30 (EORTC QLQ-C30). Although only one of the 18 studies in the pooled analysis evaluated QoL after TMT (without direct comparison with RC), this TMT study showed a higher mean reported values for Global Health Score and Physical Functioning compared to surgical studies, with non-overlapping CIs between TMT and surgical approaches (27). Nevertheless, in the absence of large prospective randomized trials, head-to-head comparison of QoL after TMT vs. RC would not be possible, and this debate shall continue. However, for many patients, the QoL implications and preference for bladder preservation is indisputable. Therefore, given the comparable survival outcomes between TMT and RC as discussed earlier, TMT should be offered to patients who desire bladder preservation in the appropriate clinical settings.

Management of MIBC with variant histologies (other than pure urothelial carcinoma) often poses a dilemma regarding the appropriateness of TMT. This is summarized in a recent review by Brocklehurst et al. (28). In brief, patients with urothelial carcinoma with divergent differentiation (such as squamous differentiation or sarcomatoid features) treated with TMT was found to have comparable outcomes to those with pure urothelial carcinoma in a single-center retrospective study of 303 patients (29). On the other hand, non-urothelial carcinoma histologies (such as squamous cell or adenocarcinoma) are rare and currently lacks robust data to support the use of TMT. The exception to this is small cell carcinoma of the bladder, which follows a similar treatment paradigm as small cell lung cancer, with standard therapy consisting of neoadjuvant platinum/etoposide chemotherapy followed by local therapy with TMT or RC (30).

In conclusion, TMT is an appropriate and effective treatment for MIBC and should be viewed as a comparable alternative to RC in patients who favor organ preservation. The lack of equipoise between TMT and RC would likely remain for some physicians, citing the absence of level I evidence from randomized clinical trials to support the adoption of TMT as an equal alternative to RC. However, the impracticality of randomizing patients between TMT vs. RC should not deter the ample of real-world evidence that demonstrates favorable therapeutic and QoL outcomes of TMT. It is time that we push TMT into the mainstream and broaden the therapy repertoire for MIBC.

Acknowledgments

Funding: None.

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