Physics Contribution
Estimates of Alpha/Beta (α/β) Ratios for Individual Late Rectal Toxicity Endpoints: An Analysis of the CHHiP Trial

https://doi.org/10.1016/j.ijrobp.2020.12.041Get rights and content
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Purpose

Changes in fraction size of external beam radiation therapy exert nonlinear effects on subsequent toxicity. Commonly described by the linear-quadratic model, fraction size sensitivity of normal tissues is expressed by the α/β ratio. We sought to study individual α/β ratios for different late rectal effects after prostate external beam radiation therapy.

Methods and Materials

The CHHiP trial (ISRCTN97182923) randomized men with nonmetastatic prostate cancer 1:1:1 to 74 Gy/37 fractions (Fr), 60 Gy/20 Fr, or 57 Gy/19 Fr. Patients in the study had full dosimetric data and zero baseline toxicity. Toxicity scales were amalgamated to 6 bowel endpoints: bleeding, diarrhea, pain, proctitis, sphincter control, and stricture. Lyman-Kutcher-Burman models with or without equivalent dose in 2 Gy/Fr correction were log-likelihood fitted by endpoint, estimating α/β ratios. The α/β ratio estimate sensitivity was assessed using sequential inclusion of dose modifying factors (DMFs): age, diabetes, hypertension, inflammatory bowel or diverticular disease (IBD/diverticular), and hemorrhoids. 95% confidence intervals (CIs) were bootstrapped. Likelihood ratio testing of 632 estimator log-likelihoods compared the models.

Results

Late rectal α/β ratio estimates (without DMF) ranged from bleeding (G1 + α/β = 1.6 Gy; 95% CI, 0.9-2.5 Gy) to sphincter control (G1 + α/β = 3.1 Gy; 95% CI, 1.4-9.1 Gy). Bowel pain modelled poorly (α/β, 3.6 Gy; 95% CI, 0.0-840 Gy). Inclusion of IBD/diverticular disease as a DMF significantly improved fits for stool frequency G2+ (P = .00041) and proctitis G1+ (P = .00046). However, the α/β ratios were similar in these no-DMF versus DMF models for both stool frequency G2+ (α/β 2.7 Gy vs 2.5 Gy) and proctitis G1+ (α/β 2.7 Gy vs 2.6 Gy). Frequency-weighted averaging of endpoint α/β ratios produced: G1 + α/β ratio = 2.4 Gy; G2 + α/β ratio = 2.3 Gy.

Conclusions

We estimated α/β ratios for several common late adverse effects of rectal radiation therapy. When comparing dose-fractionation schedules, we suggest using late a rectal α/β ratio ≤ 3 Gy.

Cited by (0)

Emma Hall and Sarah Gulliford made equal contributions to this work.

Disclosures: D.B. reports grants from Cancer Research UK, during the conduct of the study. D.D. reports personal fees from The Institute of Cancer Research, during the conduct of the study, and a patent (EP1933709B1) issued. A.T. reports grants, personal fees, and other from Elekta, grants from Accuray, grants from Varian, other from Janssen, other from Astellas, other from Bayer, other from Ferring, other from Genesis health care, outside the submitted work.

E.H. reports grants from Cancer Research UK, during the conduct of the study; grants from Accuray, grants from Varian Medical Systems, grants and nonfinancial support from Astra Zeneca, grants and nonfinancial support from Janssen-Cilag, grants and nonfinancial support from Bayer, grants from Roche Products Ltd, grants and nonfinancial support from Merck Sharp & Dohm, grants from Prostate Cancer UK, and grants and nonfinancial support from Aventis Pharma Limited (Sanofi), outside the submitted work.

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