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 30-50 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 (RTOG) 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 5-85 Gy, and a multivariate Cox proportional hazards (PH) model was used to determine which of these parameters were significantly associated with time to Grade ≥2 late rectal toxicity. Results Doses <60 Gy have no detectable impact on the fit of the LKB model, as expected based on the small estimate of the volume parameter (n=0.077). Furthermore, there is 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 PH 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 appear to be ≥75 Gy. It is hypothesized that cases of Grade ≥2 late rectal toxicity occurring among patients with V75 less than about 12% may be due to a “background” level of risk, likely due mainly to biological factors.

Preliminary analysis of risk factors for late rectal toxicity after helical tomotherapy for prostate cancer

“…In these data, no evidence was found of any influence of the intermediate doses on the risk of ≥ Grade 2 late rectal toxicities. The critical dose for this endpoint seemed to be ≥75 Gy [15]. The results of our present study suggests that patients with advanced age are at risk of rectal complication.…”

Comparative effectiveness study of patient‐reported outcomes after proton therapy or intensity‐modulated radiotherapy for prostate cancer

“…IMRT and PT both produce “high radiation dose” volumes that conform to the target; IMRT does so at the expense of exposing a larger volume of nontargeted tissue to “low and moderate radiation doses.” Thus, toxicities and functional outcomes related to high radiation dose exposure, such as rectal bleeding, are expected to be similar between IMRT and PT if target doses and daily doses are similar . Conversely, the rate of toxicities related to larger volumes of nontargeted tissue receiving low‐dose and moderate‐dose radiation exposure might be expected to be higher with IMRT than with PT.…”

Patient‐reported outcomes after 3‐dimensional conformal, intensity‐modulated, or proton beam radiotherapy for localized prostate cancer

“…Furthermore, data also suggest that rectal volumes receiving intermediate doses of radiotherapy are the best predictors of late toxicity 35‐37. Other researchers, however, have published data to suggest that the volume of rectum exposed to the highest doses of radiation (ie, ≥70 Gy) is the strongest predictor of late toxicity and that such toxicity in fact may be independent of the prescription dose 38‐40. Given this lack of consensus, further prospective studies are needed to address this issue.…”