No randomised trials comparing radical cystectomy versus bladder preservation have been undertaken. 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
The key evidence supporting this protocol is by James et alr in a phase III trial of 360 patients with cT2-T4aN0MO, randomising patients to receive radiotherapy versus chemo-radiotherapy. Radiotherapy was 64 Gy in 34 fractions or or 55 Gy in 20 fractions. Chemotherapy involved Fluorouracil infusion / Mitomycin C. One-third of patients in each arm receiving discretionary neo-adjuvant chemotherapy. At a median follow-up of 70 months, the 2-year recurrence free rate was 67% in the chemo-radiotherapy arm versus 54% in the radiotherapy alone arm (HR 0.68, 95%CI 0.48 - 0.96; p=0.03). Five-year OS rates were 48% and 35% respectively (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 chemo-therapy arm. The findings suggest this chemo-radiotherapy schedule is an alternative option to cisplatin/fluorouracil.
Fig 2 - Kaplan-Meier Analysis of Survival over 72 months of follow-up
(A) locoregional recurrence free survival (B) invasive locoregional recurrence free survival (C) overall survival P values were calculated by log-rank test stratified according to the randomisation group.
© N Engl J Med James 2012r
Gogna et al 2006r reported the combined analysis of two successive Phase II trials of chemo-radiotherapy (TROG 97.01 and TROG 99.06) utilising weekly cisplatin. In TROG 99.06, 43 patients received 64 Gy in 34 fractions with weekly cisplatin 35 mg/m2. Completion of the TROG 99 was 80%. The complete response (CR) rate at 6 months post RT was 70%. The local control (LC) 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 2014r published a combined analysis of six successive RTOG trials of multimodality therapy totalling 468 patients - five Phase II and one Phase III trial. In principle these studies offered induction chemo-radiotherapy followed by re-staging cystoscopy and then proceeded to immediate cystectomy if a CR was not achieved or onto completion of chemo-radiotherapy if CT was achieved (total dose approximately 64 Gy). However there was diversity of radiotherapy and chemotherapy schedules utilised. The CR rate to induction chemoradiotherapy was 69%. At a median follow-up of 4.3 years, 5-year OS was 57%, disease specific survival was 71%, local failure rate was 43%, 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
© Journal of Clinical Oncol, Mak 2014r
(A) Overall survival in all patients. (E) Disease specific survival n patients with a complete response after combined-modality therapy compared with patients who were non-responders
© Journal of Clinical Oncol, Mak 2014r
Pelvic nodal irradiation
Conformal radiotherapy 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 in the context 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 alone chemo-radiotherapy trials, pelvic nodal relapse rates of 5.5% have been reported.rr A randomised single institution trial comparing chemoRT to the bladder alone versus whole pelvis plus bladder boost, showed no significant difference in rates of bladder preservation, locoregional recurrence, disease free survival (DFS) and overall survival (OS) with a rate of nodal recurrence of 15% in both arms.r Elective nodal irradiation has been evaluated in successive RTOG bladder trials, however this remains an area of ongoing evaluation.r