Do intermediate radiation doses contribute to late rectal toxicity? An analysis of data from radiation therapy oncology group protocol 94-06

Abstract

Purpose: To investigate whether the volumes of rectum exposed to intermediate doses, from 30 to 50 Gy, contribute to the risk of Grade ≥ 2 late rectal toxicity among patients with prostate cancer receiving radiotherapy.

Methods and materials: Data from 1009 patients treated on Radiation Therapy Oncology Group protocol 94-06 were analyzed using three approaches. First, the contribution of intermediate doses to a previously published fit of the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model was determined. Next, the extent to which intermediate doses provide additional risk information, after taking the LKB model into account, was investigated. Third, the proportion of rectum receiving doses higher than a threshold, VDose, was computed for doses ranging from 5 to 85 Gy, and a multivariate Cox proportional hazards model was used to determine which of these parameters were significantly associated with time to Grade ≥ 2 late rectal toxicity.

Results: Doses <60 Gy had no detectable impact on the fit of the LKB model, as expected on the basis of the small estimate of the volume parameter (n = 0.077). Furthermore, there was no detectable difference in late rectal toxicity among cohorts with similar risk estimates from the LKB model but with different volumes of rectum exposed to intermediate doses. The multivariate Cox proportional hazards model selected V75 as the only value of VDose significantly associated with late rectal toxicity.

Conclusions: There is no evidence from these data that intermediate doses influence the risk of Grade ≥ 2 late rectal toxicity. Instead, the critical doses for this endpoint seem to be ≥ 75 Gy. It is hypothesized that cases of Grade ≥ 2 late rectal toxicity occurring among patients with V75 less than approximately 12% may be due to a "background" level of risk, likely due mainly to biological factors.

Copyright © 2012 Elsevier Inc. All rights reserved.

Figures

Figure 1

Box plots illustrating the wide variation in rectal V10-V80 among patients treated on RTOG 94-06.

Figure 2

Panel A) Hypothetical dose-volume histogram in which each dose bin from 0-80 Gy contains an equal subvolume of the organ at risk. Panel B) Relative reduction in Deff resulting from omission of doses between D and D+1 Gy from the DVH in panel A (equation 4), and plotted as a function of omitted dose D. As shown, the relative reduction in Deff depends on D and on the value of the volume parameter, n.

Figure 3

Solid curve: mean relative reduction in Deff, calculated for each patient using equation (4) with volume parameter n=0.077 and averaged over all patients. Dashed curves show ±1 standard deviation.

Figure 4

Panel A) Percentage of rectum receiving doses between 30 and 50 Gy (V30 minus V50) plotted against Deff computed using n=0.077. Panels B-D) Kaplan-Meier curves showing freedom from Grade ≥2 late rectal toxicity as a function of time after start of radiotherapy (RT) among patients with Deff ranging from 64-68 Gy, 66-68 Gy, or 68-70 Gy, divided into two subgroups at the median value of V30-V50 for each cohort.

Figure 5

Kaplan-Meier incidence of Grade ≥2 late rectal toxicity 8 years after start of radiotherapy in each of 10 patient subgroups, grouped by V75. The cohort with V75=0% includes 117 patients; other cohorts include 99-100 patients each. Points are plotted at the mean value of V75 per subgroup. Horizontal error bars show ± 1 standard deviation; vertical error bars show ± 1 standard error computed using the method of Greenwood (13).

Figure 6

Kaplan-Meier incidence of Grade ≥2 late rectal toxicity at 8 years after the start of radiotherapy in each of 10 subgroups of 100-101 patients each, grouped by Deff computed using n=0.077. Points are plotted at the mean value of Deff per subgroup. Error bars are as in Figure 5. Curves show fits of the LKB model with (solid) or without (dashed) a background level of toxicity included.