A randomized trial of single versus multiple fractions (Fx) for re-irradiation (RE-RT) of painful bone metastases (PBM): NCIC CTG SC.20.

9502 Background: The optimal RE-RT dose and fractionation schedule for PBM is uncertain. Methods: Patients (pts) with PBM after previous radiation (RT) to the same site were stratified by previous Fx schedule and pain response and randomized to 8 Gy in 1 Fx or 20 Gy in 5 Fx (8 Fx if previous RT was to spine/whole pelvis in multiple Fx). The primary endpoint was overall response rate (RR) at 2 months using the International Consensus schema (Chow 2002) which combines Brief Pain Inventory worst pain score and opioid analgesic use. We tested if 8Gy was non-inferior (NI), analyzed by intention to treat (ITT) and a per-protocol (PP) sensitivity analysis excluding those who were ineligible, inevaluable or received non-allocated therapy. Sample size was calculated using an expected RR of 70% with 20Gy and a NI margin of 10% (i.e. upper boundary of 1-sided 95% CI for the RR difference). Pts reported adverse events (AEs) by questionnaire on Day 14. Quality of life (QoL) was assessed using the EORTC QLQ C30. Results: Between 01/2004 and 06/2012, we enrolled 850 pts from 9 countries. Most common cancers were prostate (27%), breast (26%) and lung (22%). Before the 2 month assessment, 98 (11%) pts died. By ITT, the 2-month RR was available in 66% (557/850) and was 119/425 (28%) with 8Gy and 136/425 (32%) with 20Gy (P=0.2); the upper boundary of the 95% CI for RR difference = 9.2% and is less than the pre-specified NI margin. By PP analysis, 2-month RR was available in 521 and was 117/258 (45.3%) with 8Gy and 135/263 (51.3%) with 20Gy (P=0.17); the upper boundary of the 95% CI for RR difference = 13.2%, which exceeds 10% non-inferiority boundary. Day 14 AEs differing by treatment were: lack of appetite (P=0.01), vomiting (P= 0.001), diarrhea (P=0.02) and skin reddening (P=0.002); all were worse with 20Gy. There were 30 vs 20 pathological fractures and 7 vs 2 spinal cord compressions with 8Gy and 20Gy, respectively (P=NS). No difference in QoL existed between arms. Conclusions: In pts with PBM receiving RE-RT, the 2-month RR obtained with 8Gy is non-inferior to 20 Gy when assessed by ITT but findings were not robust to a PP sensitivity analysis. When choosing between options tested, trade-offs exist between pain response and acute toxicity. Clinical trial information: NCT00080912.