Late rectal toxicity on RTOG 94-06: analysis using a mixture Lyman model

Abstract

Purpose: To estimate the parameters of the Lyman normal-tissue complication probability model using censored time-to-event data for Grade ≥2 late rectal toxicity among patients treated on Radiation Therapy Oncology Group 94-06, a dose-escalation trial designed to determine the maximum tolerated dose for three-dimensional conformal radiotherapy of prostate cancer.

Methods and materials: The Lyman normal-tissue complication probability model was fitted to data from 1,010 of the 1,084 patients accrued on Radiation Therapy Oncology Group 94-06 using an approach that accounts for censored observations. Separate fits were obtained using dose-volume histograms for whole rectum and dose-wall histograms for rectal wall.

Results: With a median follow-up of 7.2 years, the crude incidence of Grade ≥2 late rectal toxicity was 15% (n = 148). The parameters of the Lyman model fitted to dose-volume histograms data, with 95% profile-likelihood confidence intervals, were TD(50) = 79.1 Gy (75.3 Gy, 84.3 Gy), m = 0.146 (0.107, 0.225), and n = 0.077 (0.041, 0.156). The fit based on dose-wall histogram data was not significantly different. Patients with cardiovascular disease had a significantly higher incidence of late rectal toxicity (p = 0.015), corresponding to a dose-modifying factor of 5.3%. No significant association with late rectal toxicity was found for diabetes, hypertension, rectal volume, rectal length, neoadjuvant hormone therapy, or prescribed dose per fraction (1.8 Gy vs. 2 Gy).

Conclusions: These results, based on a large cohort of patients from a multi-institutional trial, are expected to be widely representative of the ability of the Lyman model to describe the long-term risk of Grade ≥2 late rectal toxicity after three-dimensional conformal radiotherapy of prostate cancer.

Conflict of interest statement

Conflicts of interest: None

Copyright © 2010 Elsevier Inc. All rights reserved.

Figures

Figure 1

Panel A) Freedom from grade ≥2 late rectal toxicity in patient subgroups defined by NTCP (equations 1–3), computed using the parameter estimates in Table 2. Panel B) Incidence of grade ≥2 late rectal toxicity at 8 years in each of 10 subgroups of 101 patients each, grouped by Deff (equation 3), computed using n=0.077. Points are plotted at the mean value of Deff per subgroup. Horizontal error bars show ±1 standard deviation; vertical error bars show ±1 standard error.

Figure 2

Distribution of times to grade ≥2 late rectal toxicity among patients experiencing the endpoint (N=148). The dashed curve shows the fitted latent-time model (equation 4; parameter values in Table 2).

Figure 3

Panel A) NTCP computed for each patient in RTOG 94-06 using the parameter estimates of Peeters et al. (3) for late rectal bleeding (TD50=81 Gy, m=0.14, n=0.13), plotted against NTCP computed using the current parameter estimates (Table 2). Panel B) NTCP computed using the parameters of Rancati et al. (1) for grade ≥2 rectal bleeding among patients without prostatectomy (TD50=75.7 Gy, m=0.14, n=0.24), plotted against current NTCP. Panel C) NTCP computed using the parameters of Söhn et al. (4) for grade ≥2 late rectal toxicity scored using CTCAE version 3.0 criteria (22) (TD50=78.4 Gy, m=0.108, n=0.08), plotted against current NTCP. Panel D) NTCP computed using the “best overall” LKB parameter estimates from the QUANTEC meta-analysis (18) (TD50=76.9 Gy, m=0.13, n=0.09), plotted against current NTCP.

Figure 4

Incidence of grade ≥2 late rectal toxicity at 5 years by prescription dose level in RTOG 94-06. Points are plotted at the mean value of NTCP per dose level. Horizontal error bars show ±1 standard deviation; vertical error bars show ±1 standard error.