The key evidence supporting this protocol is from a phase III trial by James et al. (n = 360).r Patients with muscle-invasive bladder cancer, cT2-T4a, N0, M0, were randomised to receive chemoradiation or radiation therapy alone. Chemotherapy involved fluorouracil infusion and mitomycin, with one-third of patients in each arm receiving discretionary neoadjuvant chemotherapy. Radiation therapy was 64 Gy in 32 fractions or or 55 Gy in 20 fractions. At a median follow-up of 70 months, the 2-year recurrence-free rate was 67% in the chemoradiation arm versus 54% in the radiation therapy alone arm (HR = 0.68, 95% CI:0.48-0.96, p = 0.03). Five-year overall survival rates were 48% with chemoradiation arm versus 35% with radiation alone (HR = 0.82, 95% CI:0.63-1.09, p = 0.16). A trend towards reduced cystectomy rates of 11.4% versus 16.8% (p = 0.07) at 2 years was observed in the chemotherapy arm. The findings suggest this chemoradiation schedule is an alternative option to cisplatin.
Fig 1. Kaplan-Meier analysis of survival over 72 months of follow-up
(A) locoregional disease-free survival; (B) invasive locoregional disease-free survival; (C) overall survival p-values were calculated by log-rank test stratified according to the randomisation group.
© N Engl J Med 2012r
No randomised trials comparing radical cystectomy versus trimodality bladder preservation have been completed. Several non-randomised prospective and retrospective studies of combined modality treatment have confirmed survival outcomes comparable to cystectomy alone.rrr Most studies of combined modality treatment report 5-year survival rates of 50-60%.rrr
Gogna et al. 2006 reported the combined analysis of two successive phase II trials of chemoradiation utilising weekly cisplatin (TROG 97.01 and TROG 99.06).r In TROG 99.06, 43 patients received 64 Gy in 32 fractions with weekly cisplatin 35 mg/m2. Completion of the TROG 99.06 was 80%. The complete response rate at 6 months post-radiation therapy completion was 70%. The local control rate (free of both superficial and invasive recurrence) at 5 years was 45%. At 5 years, 61% had retained a functional bladder. Within 12 months, 13% of patients had salvage surgery, of which 8% was for progressive/persistent or recurrent disease.
Mak et al. 2014 published a combined analysis of six successive multimodality RTOG trials 468 patients in total; one phase III trial and five phase II trials.r In principle, these studies offered induction chemoradiation followed by re-staging cystoscopy, and then proceeded to immediate cystectomy if a complete response was not achieved, or onto completion of chemoradiation if a complete response was achieved (total dose of approximately 64 Gy). However, a diverse range of radiation therapy and chemotherapy schedules were used. The complete response rate to induction chemoradiation was 69%. At a median follow-up of 4.3 years, 5-year overall survival was 57%, disease-specific survival was 71%, local failure rate was 43%, and intact bladder rate was 80%. The 10-year outcomes are presented in table 2. Of the 100 patients who underwent cystectomy, 62% were for incomplete response to induction, and 36% for salvage after delayed recurrence (5-year survival for this group was 45%).
Table 2. Pooled Long-Term Outcomes
© J Clin Oncol 2014r
Fig 2. Kaplan-Meier analysis of overall and disease-specific survival
(A) Overall survival in all patients; (E) Disease-specific survival in patients with a complete response after combined-modality therapy compared with patients who were non-responders.
© J of Clin Oncol 2014r
Pelvic nodal irradiation
Conformal radiation therapy techniques are allowing re-evaluation of tolerance, toxicity and efficacy of pelvic nodal irradiation. This is in the context of treating elective pelvic nodes or node positive disease at diagnosis, and of newer chemotherapy regimens. Pathological nodal involvement is reported in approximately 25% of patients who undergo cystectomy and lymph node dissection.r In studies of bladder only chemoradiation trials, pelvic nodal relapse rates of 5.5% have been reported.rr A randomised single institution trial which compared chemoradiation to the bladder alone versus whole pelvis plus bladder boost, showed no significant difference in rates of bladder preservation, locoregional recurrence, disease-free survival, or overall survival, and a rate of nodal recurrence of 15% in both arms.r For clinically node negative patients, elective nodal irradiation increases toxicity and there is no evidence that elective nodal irradiation improves outcomes.r
Intrafraction bladder filling
A study by Mangar et al. identified that in the 20 minute period it takes to set-up and deliver a radiation fraction, the bladder filling was 0.16ml/min in a linear fashion for the first 150 ml, indicating that a CTV to PTV expansion of 1.5 cm would account for approximately 95% of bladder expansion and location.r
Bladder IMRT / VMAT
For IMRT/VMAT techniques, toxicity and outcome data (series data) utilising various fractionation schedules, simultaneous integrated boosts, and with or without nodal volumes has been published.rrr While data remains limited, this is a field of continued interest.
Adaptive Radiation Therapy
The principle of bladder adaptive radiation therapy (ART) is to account for daily variation in bladder volume. Immediately following pre-treatment imaging and assessment, a 'plan of the day' is selected from a library of plans and used for treatment. Review of ART practices by Kibrom et al. indicates a number of techniques being trialled including online/off-line imaging, 'plan of the day', or daily re-planned/optimised techniques.r While ART has merit, it is yet to be determined how to apply ART in a sustainable and safe process, that is applicable to all radiation oncology centres and taking into account varying resources, staffing and skill sets. These challenges have been evaluated in the TROG 10.01 BOLART feasibility study, which demonstrated both the applicability and challenges in the execution of a bladder ART program.r