Methods
This retrospective analysis included 722 patients with clinical stage T2–T4N0M0 muscle-invasive urothelial carcinoma of the bladder (440 underwent radical cystectomy, 282 received trimodality therapy) who would have been eligible for both approaches, treated at three university centres in the USA and Canada between Jan 1, 2005, and Dec 31, 2017. All patients had solitary tumours less than 7 cm, no or unilateral hydronephrosis, and no extensive or multifocal carcinoma in situ. The 440 cases of radical cystectomy represent 29% of all radical cystectomies performed during the study period at the contributing institutions. The primary endpoint was metastasis-free survival. Secondary endpoints included overall survival, cancer-specific survival, and disease-free survival. Differences in survival outcomes by treatment were analysed using propensity scores incorporated in propensity score matching (PSM) using logistic regression and 3:1 matching with replacement and inverse probability treatment weighting (IPTW).
Findings
In the PSM analysis, the 3:1 matched cohort comprised 1119 patients (837 radical cystectomy, 282 trimodality therapy). After matching, age (71·4 years [IQR 66·0–77·1] for radical cystectomy vs 71·6 years [64·0–78·9] for trimodality therapy), sex (213 [25%] vs 68 [24%] female; 624 [75%] vs 214 [76%] male), cT2 stage (755 [90%] vs 255 [90%]), presence of hydronephrosis (97 [12%] vs 27 [10%]), and receipt of neoadjuvant or adjuvant chemotherapy (492 [59%] vs 159 [56%]) were similar between groups. Median follow-up was 4·38 years (IQR 1·6–6·7) versus 4·88 years (2·8–7·7), respectively. 5-year metastasis-free survival was 74% (95% CI 70–78) for radical cystectomy and 75% (70–80) for trimodality therapy with IPTW and 74% (70–77) and 74% (68–79) with PSM. There was no difference in metastasis-free survival either with IPTW (subdistribution hazard ratio [SHR] 0·89 [95% CI 0·67–1·20]; p=0·40) or PSM (SHR 0·93 [0·71–1·24]; p=0·64). 5-year cancer-specific survival for radical cystectomy versus trimodality therapy was 81% (95% CI 77–85) versus 84% (79–89) with IPTW and 83% (80–86) versus 85% (80–89) with PSM. 5-year disease-free survival was 73% (95% CI 69–77) versus 74% (69–79) with IPTW and 76% (72–80) versus 76% (71–81) with PSM. There were no differences in cancer-specific survival (IPTW: SHR 0·72 [95% CI 0·50–1·04]; p=0·071; PSM: SHR 0·73 [0·52–1·02]; p=0·057) and disease-free survival (IPTW: SHR 0·87 [0·65–1·16]; p=0·35; PSM: SHR 0·88 [0·67–1·16]; p=0·37) between radical cystectomy and trimodality therapy. Overall survival favoured trimodality therapy (IPTW: 66% [95% CI 61–71] vs 73% [68–78]; hazard ratio [HR] 0·70 [95% CI 0·53–0·92]; p=0·010; PSM: 72% [69–75] vs 77% [72–81]; HR 0·75 [0·58–0·97]; p=0·0078). Outcomes for radical cystectomy and trimodality therapy were not statistically different among centres for cancer-specific survival and metastasis-free survival (p=0·22–0·90). Salvage cystectomy was done in 38 (13%) trimodality therapy patients. Pathological stage in the 440 radical cystectomy patients was pT2 in 124 (28%), pT3–4 in 194 (44%), and 114 (26%) node positive. The median number of nodes removed was 39, the soft tissue positive margin rate was 1% (n=5), and the perioperative mortality rate was 2·5% (n=11).
Interpretation
This multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option.
Funding
Sinai Health Foundation, Princess Margaret Cancer Foundation, Massachusetts General Hospital.
Novel evidence on the role of trimodality therapy for MIBC
Commentary by Dr. Laura Mertens
In this study by Zlotta et al., the researchers address the crucial question of determining the optimal treatment for patients with muscle-invasive bladder cancer (MIBC). Due to the unavailability of randomised trials, their report aims to provide the ‘best evidence’ solidifying the role of trimodality therapy for MIBC. The authors conclude that trimodality therapy is an oncologically equivalent alternative to radical cystectomy and should be offered to all eligible candidates with MIBC, within the setting of multidisciplinary shared decision making, rather than being limited to patients who cannot undergo surgery.
This conclusion is based on a retrospective study involving 722 patients with localised urothelial MIBC (cT2-4N0M0) patients treated between 2005 and 2017 in three hospitals in Canada and the United States. Among these patients, 440 underwent radical cystectomy in Toronto and Los Angeles, while 282 received trimodality therapy in Toronto and Boston. The authors state that the patients ‘would have been eligible for’ both trimodality therapy and radical cystectomy. To be eligible for trimodality therapy, patients needed to meet specific criteria, including having cT2–T4N0M0 MIBC with a tumour size less than 7cm, solitary tumours, no or only unilateral hydronephrosis, adequate bladder function, and the absence of extensive or multifocal carcinoma in situ. Exclusion criteria encompassed primary non-urothelial cancers, contraindications to radiation (eg, previous pelvic radiation, history of inflammatory bowel disease), and concomitant upper tract urothelial cancer. The decision to pursue trimodality therapy or radical cystectomy was based on the patient’s choice following multidisciplinary discussions about treatment options.
The primary endpoint of this analysis was metastasis-free survival. Propensity score matching was employed to adjust for confounding factors. After matching, the variables: age, sex, cT-stage, hydronephrosis, and receipt of neoadjuvant or adjuvant chemotherapy, were accounted for. Notably, a relatively high proportion of patients had cT2 disease (90%), and 56-59% received perioperative chemotherapy. Using two different statistical methods for propensity score matching, the study demonstrated no significant difference in metastasis-free survival between trimodality therapy and radical cystectomy. Moreover, there were no differences in cancer-specific survival, or disease-free survival between trimodality therapy and radical cystectomy within the matched cohorts. Salvage cystectomy was done in 13% of the trimodality therapy patients.
Strengths of this study lie in the relatively large, multi-institutional cohort obtained from high-volume centres specialised in bladder cancer treatment. However, the study also has limitations, including its retrospective design, which may lead to potential imbalances between the cohorts despite propensity score matching – as this is not always an ideal approach for establishing causal inference, as it does not account for unobserved confounders. This may explain why overall survival favoured trimodality therapy. Additionally, the study utilised several relatively subjective ‘inclusion criteria’, as evidenced by the discordance between clinical and pathological stages.
Nevertheless, the study by Zlotta et al. sheds additional light on the debate regarding the optimal treatment for patients with organ-confined MIBC. The study demonstrates that trimodality is/has remained a valuable treatment for patients with MIBC if performed optimally. Because of this, the interest in trimodality treatment is likely to increase.