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 (NTCP) model using censored time-to-event data for grade ≥2 late rectal toxicity among patients treated on Radiation Therapy Oncology Group (RTOG) 94-06, a dose-escalation trial designed to determine the maximum tolerated dose for 3D conformal radiotherapy (3D-CRT) of prostate cancer. Methods and Materials The Lyman NTCP model was fitted to data from 1010 of the 1084 patients accrued on RTOG 94-06 using an approach that accounts for censored observations. Separate fits were obtained using dose-volume histograms (DVH) for whole rectum and dose-wall histograms (DWH) 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 DVH data, with 95% profile-likelihood confidence intervals, were TD50=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 DWH 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 versus 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 3D-CRT of prostate cancer.

Local Control and Toxicity in a Large Cohort of Central Lung Tumors Treated With Stereotactic Body Radiation Therapy

“…To account for the interaction between the inherent latency of complication onset and the variation in the follow up times of individual patients, we employed the method of Farewell. [9-11] Kaplan-Meier analysis was used to assess whether there was any significant difference in the risk of pulmonary toxicity between patients with tumors (GTV) within the NFZ and patients with tumors outside the NFZ but PTV approaching mediastinal structures.…”

Do Intermediate Radiation Doses Contribute to Late Rectal Toxicity? An Analysis of Data From Radiation Therapy Oncology Group Protocol 94-06

“…Of the 1084 patients enrolled on RTOG 94-06, data from 1010 patients were available for analyses of late rectal toxicity, as described previously (10). For the present analysis, one patient was excluded who stopped treatment after 15 fractions (without toxicity) and had a maximum dose to rectum of only 28.4 Gy.…”

“…The data from RTOG 94-06 are described in detail in our previous study (10). Briefly, the trial included 5 dose levels ranging from 68.4-79.2 Gy delivered in daily fractions of 1.8-2.0 Gy, with no specific normal tissue constraints.…”

“…Rectal toxicity was scored prospectively using RTOG criteria at prescribed intervals. The dose-volume histogram (DVH) was computed for rectum as a solid structure, as described previously (10). The RTOG Publications Committee and the Institutional Review Boards of The University of Texas MD Anderson Cancer Center, Washington University Medical Center, and the American College of Radiology approved these secondary analyses.…”

“…We previously reported a fit of the LKB model to the Grade ≥2 late rectal toxicity from RTOG 94-06 using a technique in which event times and patient follow-up were taken into account (10). In the LKB model (11,12), the effective dose to an organ at risk is $$D_{eff}={\left(\Sigma {\left(D_i\right)}^{1∕n}\cdot {\nu }_i\right)}^n$$ where n is the volume parameter, D i is the dose to subvolume v i , and the sum extends over all dose bins in the DVH.…”