Bladder cancer is the ninth most common solid tumour worldwide, with increased incidence in developed countries.1Dependent on the local depth of invasion, non-metastatic tumours can be classified as non-invasive (Tis, Ta, and T1) or muscle invasive (T2—4). Presently, radical cystectomy is the standard therapy for muscle invasive tumours. However, urinary diversion and reconstruction can cause substantial morbidity and, subsequently, affect quality of life and health outcomes of these patients.2 Therefore, an alternative treatment option that can preserve the bladder and maintain the same oncological benefit is one of the main goals for oncologists treating this group of patients. Strategies that aim to preserve the bladder have been successfully developed as a standard treatment in non-invasive tumours, reserving radical cystectomy for patients with high-risk tumours. In the case of invasive tumours, a trimodality therapy including transurethral resection, chemotherapy, and radiotherapy is the most promising approach.

The Radiation Therapy Oncology Group (RTOG) 0233 trial, published in The Lancet Oncology,4 provides evidence about the feasibility of bladder preservation in patients with muscle invasive cancer. In this randomised phase 2 trial, treatment started with an aggressive transurethral resection followed by chemoradiotherapy. The two trial arms differed in terms of the chemotherapy regimen that was combined with twice-daily radiotherapy: cisplatin plus fluorouracil (47 patients) or cisplatin plus paclitaxel (46 patients). Chemoradiotherapy was also divided into induction and consolidation treatments. For patients in both treatment groups, after induction chemotherapy, assessment by transurethral resection defined their response and subsequent treatment plan. Patients either continued with the protocol in case of complete or near complete response (Ta and Tis) or underwent radical cystectomy in case of maintenance of a T1 or higher stage. Finally, adjuvant treatment was done with a triplet regimen of gemcitabine, cisplatin, and paclitaxel.

The RTOG 0233 trial4 was designed to assess completion and safety as primary endpoints. In the study, most patients were T2 (88 [95%] of 93 patients) and had a performance status of 0 (84 [90%] of 93 patients). Effectiveness between paclitaxel and fluorouracil regimens could not be compared because of the sample size and study design, but notably both arms achieved a 5-year bladder-intact survival of more than 65%. This finding suggests that, independent of the chemoradiotherapy regimen administered, treatment that preserves the bladder can successfully avoid cystectomy in most patients. These results need to be cautiously compared with historical data or other similar trials.

Completion rates for overall treatment were much the same between treatment groups. 31 (67%) of 39 patients in the paclitaxel group who completed the consolidation phase went on to complete the whole treatment regimen, as did 25 (53%) of 39 patients in the fluorouracil group. However, these rates were lower than the 90% rate that was expected by investigators). Most patients (39 [85%] of 46 patients in the paclitaxel group and 39 [83%] of 47 patients in the fluorouracil group) finished induction and consolidation with chemoradiotherapy, but a subset was unable to finish the adjuvant part, presumably related to toxicity. Induction and consolidation were relatively well tolerated, but adjuvant chemotherapy caused very high rates of grade 3—4 toxicities (34 [85%] of 40 assessable patients in the paclitaxel group and 31 [76%] of 41 assessable patients in the fluorouracil group). Triplet therapy with cisplatin, gemcitabine, and paclitaxel has been successfully tested in advanced bladder cancer,5 but very little clinical experience has been gathered on this triplet after chemotherapy and pelvic irradiation. In the RTOG study,4 adjuvant treatment seemed to improve efficacy, with a 5-year overall survival of 81% noted for those who completed the entire course versus 49% for those who did not receive adjuvant chemotherapy. Perhaps the administration of a less toxic regimen could maintain the benefit, while reducing side-effects.

RTOG 0233 incorporated paclitaxel with cisplatin as an active combination in bladder-preserving treatment, with much the same compliancy, safety, and efficacy as cisplatin plus fluorouracil. Results also suggested that adjuvant therapy with a triplet regimen might not be the best option in these patients because of the frequent occurrence of grade 3—4 toxicity. As a result of the high complexity of trimodality treatment, multidisciplinary assessment of patients, treatment, and follow-up is essential to obtain successful results.

A long time has passed since the first studies assessed organ preservation as a therapeutic approach in muscle invasive bladder cancer,6 but some questions remain. Enough data exist about the success of trimodality treatments, but we are not able to clearly identify which patients should be treated with a strategy that seeks to preserve the bladder and which patients need to undergo immediate radical cystectomy. Another query to be solved is whether bladder preservation is associated with better quality of life. Side-effects of chemotherapy or radiotherapy might overcome the theoretical benefits of preservation of the bladder and avoidance of morbidity of major surgery. Phase 2 or retrospective studies can contribute relevant clinical data about the best treatment approach and selection of patients, but a phase 3 trial comparing surgery with bladder preservation will define the non-inferiority in terms of efficacy, and will provide higher levels of evidence to answer these questions.

Source: Lancet