Estimates of alpha/beta ratios for individual late urinary toxicity endpoints: analysis of a cohort trial

Abstract

Purpose or Objective Using data from an international prospective cohort study of prostate cancer (PCa) patients receiving radical radiotherapy (RT), this analysis aims to estimate α/β ratios for individual urinary toxicity (tox) endpoints: grade 2+ (G2+) urinary frequency, G2+ urinary incontinence and G1+ haematuria. Owing to a previously suggested consequential component of late bladder damage, we also considered the impact of including the total treatment time in NTCP models. Materials and Methods Non-metastitic PCa patients (pts) were enrolled in 8 countries (04-2014/03-2016). RT was prescribed according to local regimens, but centres used standardised data collection (including baseline symptoms). Tox was scored using CTCAE. Pts in the study had full 3D dosimetric information; we used solid bladder DVHs. Data were available for 1009 pts. We fitted the probability of late urinary tox within 24 months with the Logit-EUD sigmoid model, explicitly including the α/β ratios and also allowing a term for the impact of total treatment time. The general expression for the NTCP model is in fig 2a. Four parameters describe the model (EUD50, k, n, α/β). A fifth parameter γ was needed for RT time correction. We used the Maximum Likelihood method (Optimization Toolbox, Matlab) to obtain the best estimates of the model parameters. We compared models including the new estimates of α/β with models with α/β=3Gy (conventional value for late tox). Results The cohort included 678 conventionally fractionated pts and 331 hypofractionated pts (Fig 1a). Fig 1b shows the incidence of the tox endpoints within the different subcohorts and Fig 1c the distribution of toxicity events as a function of dose and dose/fraction. We found a consequential effect between acute and late tox for all endpoints. Conclusion We found a greater unexpected impact of hypofractionation on RT induced urinary tox. This could be explained by a bladder α/β<0.3Gy or, radiobiologically more plausible, by introducing a time factor likely to represent a previously hypothesised consequential component of late effect.