USANZ and TROG Inter-group Phase 3 Trial (TROG 02.03) Concurrent Weekly Cisplatin Plus Radiation Therapy in Localized Muscle Invasive Bladder Cancer: Compliance< Toxicity< Quality of Life and Overall Results

Abstract

This phase III trial investigated combination of weekly cisplatin and radiation therapy compared with radiation therapy (RT) alone in the definitive treatment of localised muscle-invasive bladder cancer. The investigative arm was adopted from our previous phase II studies (TROG 97.01 and 99.06). Eligible adult patients with localized Stage T2-T4a, non-bulky (< 7 cm in maximum dimension) bladder cancer of predominant transitional cell carcinoma histology were randomized (1:1) to receive either definitive 3 D conformal RT to the bladder (64Gy/32fractions) alone or concurrently with weekly cisplatin (35mg/m2).The main exclusion criteria were: presence of extensive/ multifocal carcinoma in situ, significantly reduced bladder capacity and any contraindications to the use of pelvic RT or cisplatin chemotherapy. An initial maximal transurethral resection of the bladder tumour preceded randomisation.The primary outcome was local failure at 3 years. Secondary endpoints included complete response rate at 3 months, disease free and overall survival (DFS and OS), patterns of failure, acute and late toxicity and Quality of life (QOL). QOL was measured using the EORTC QLC-C30 and bladder cancer (QLQ-BLM30) modules. QOL aspect of definitive therapy has previously not been investigated in a Phase III study. To determine the sample size the 3 year local failure rate with RT was estimated to be 70% and that with chemoradiation therapy to be 45%. To demonstrate this difference between the 2 arms with 80% power and 95% confidence it was estimated that 138 patients would be required. Allowing for a loss of 5-10% of patients to analysis the accrual target was set at 150 patients over 4 years. Slow accrual lead the trial to be closed after only 68 patients were randomised. The majority of patients were > 70 years old and or had significant co-morbidities. Compliance with RT overall was excellent. About15% of patients in the chemoradiation arm required a significant reduction in cisplatin dose delivery mainly because of declining renal function. Acute and late toxicity was similar in the two arms, but chemoradiation had a greater impact on QOL. Recovery however did follow and the improved bladder QOL was maintained in surviving patients. Notwithstanding the small sample size, in terms of local failure rates and other tumour specific end points interesting trends have emerged in favour of the chemoradiation therapy. Whilst weekly cisplatin chemoradiation in this challenging group of patients has an acceptable acute toxicity profile, it has the potential to impact on Qol .The domains affected do recover with satisfactory bladder function being sustained. The regimen also holds promise in terms of potential to improve local control, DFS and OS.