Diminishing Returns From Ultrahypofractionated Radiation Therapy for Prostate Cancer

Abstract

Purpose: More than a decade of randomized controlled trials in prostate cancer has established a positive radiation dose response at moderate doses and a consistently low α/β ratio in the linear quadratic model for moderate hypofractionation. The recently published large randomized trial of ultrahypofractionated prostate cancer radiation therapy adds substantially to our current knowledge of dose response and fractionation sensitivity.

Methods and materials: Randomized trials of dose escalation and hypofractionation of radiation therapy were meta-analyzed to yield the overall best estimate of the α/β ratio. Additionally, a putative saturation of dose effect previously reported at approximately 80 Gy EQD2 was investigated by mapping the relative effectiveness assessed at 5 years onto a single reference dose-response curve.

Results: Meta-analysis of 14 randomized trials including 13,384 patients yielded a best estimate of α/β = 1.6 Gy (95% confidence interval, 1.3-2.0 Gy) but with highly significant heterogeneity (I2 = 70%, P = .0005). Further analysis indicated an association between increasing dose per fraction in the experimental arm and increasing α/β ratio (slope, 0.6 Gy increase in α/β per Gy increase in fraction size; P = .017). This deviation from the linear quadratic model could, however, also be explained by biochemical control maxing out at doses above approximately 80 Gy.

Conclusions: Biochemical control data from randomized controlled trials of dose-per-fraction escalation in prostate cancer radiation therapy are inconsistent with the presence of a constant fractionation sensitivity in the linear-quadratic model and/or a monotonic dose response for biochemical control beyond 80 Gy equivalent dose. These observations have a potential effect on the optimal doses in future trials and the interpretation of ongoing trials of ultrahypofractionation.

Conflict of interest statement

Conflict of Interest: IRV reports institutional research grants from Varian Medical Systems and ViewRay

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1

Forest plot of estimated α/β value of the included studies with 95% confidence interval. Studies are ordered according to inverse variance (IV) of the estimate. Nine studies of altered fractionation are included. The two experimental arms by Dearnaley et al from 2016 are included as individual studies and denoted by experimental arm dose rather than date of publication.

Figure 2

Estimated α/β value and 95% confidence interval as function of experimental arm fraction size. Linear regression model with 95% confidence (dashed) and prediction (dotted) bounds are shown for the best fitting model with slope=0.57 Gy/Gy (SEE=0.19, p=0.017). The linear regression is weighted by the inverse variance of the individual α/β estimates from 9 included studies. The two experimental arms by Dearnaley et al from 2016 are included as individual studies and denoted by experimental arm dose rather than date of publication.

Figure 3

A: Illustration of the study-specific dose offset, δDose, required for the control arm outcome to fall on a reference sigmoid dose-response curve with the steepness defined by meta-analysis of the normofractionated randomized dose-escalation studies. B: Experimental arm EQD2 and control probabilities after applying δDose, Note signs of systematic deviation from sigmoid shape at high doses. Error bars show 95% CI of the bPFS estimate as detailed in Methods and Materials. Nine studies of altered fractionation and five studies of dose escalation are included. The two experimental arms by Dearnaley et al from 2016 are included as individual studies and denoted by experimental arm dose rather than date of publication.

Figure 3

A: Illustration of the study-specific dose offset, δDose, required for the control arm outcome to fall on a reference sigmoid dose-response curve with the steepness defined by meta-analysis of the normofractionated randomized dose-escalation studies. B: Experimental arm EQD2 and control probabilities after applying δDose, Note signs of systematic deviation from sigmoid shape at high doses. Error bars show 95% CI of the bPFS estimate as detailed in Methods and Materials. Nine studies of altered fractionation and five studies of dose escalation are included. The two experimental arms by Dearnaley et al from 2016 are included as individual studies and denoted by experimental arm dose rather than date of publication.