Physics Contribution
Gastrointestinal Dose-Histogram Effects in the Context of Dose-Volume–Constrained Prostate Radiation Therapy: Analysis of Data From the RADAR Prostate Radiation Therapy Trial

https://doi.org/10.1016/j.ijrobp.2014.11.015Get rights and content

Purpose

To use a high-quality multicenter trial dataset to determine dose-volume effects for gastrointestinal (GI) toxicity following radiation therapy for prostate carcinoma. Influential dose-volume histogram regions were to be determined as functions of dose, anatomical location, toxicity, and clinical endpoint.

Methods and Materials

Planning datasets for 754 participants in the TROG 03.04 RADAR trial were available, with Late Effects of Normal Tissues (LENT) Subjective, Objective, Management, and Analytic (SOMA) toxicity assessment to a median of 72 months. A rank sum method was used to define dose-volume cut-points as near-continuous functions of dose to 3 GI anatomical regions, together with a comprehensive assessment of significance. Univariate and multivariate ordinal regression was used to assess the importance of cut-points at each dose.

Results

Dose ranges providing significant cut-points tended to be consistent with those showing significant univariate regression odds-ratios (representing the probability of a unitary increase in toxicity grade per percent relative volume). Ranges of significant cut-points for rectal bleeding validated previously published results. Separation of the lower GI anatomy into complete anorectum, rectum, and anal canal showed the impact of mid-low doses to the anal canal on urgency and tenesmus, completeness of evacuation and stool frequency, and mid-high doses to the anorectum on bleeding and stool frequency. Derived multivariate models emphasized the importance of the high-dose region of the anorectum and rectum for rectal bleeding and mid- to low-dose regions for diarrhea and urgency and tenesmus, and low-to-mid doses to the anal canal for stool frequency, diarrhea, evacuation, and bleeding.

Conclusions

Results confirm anatomical dependence of specific GI toxicities. They provide an atlas summarizing dose-histogram effects and derived constraints as functions of anatomical region, dose, toxicity, and endpoint for informing future radiation therapy planning.

Introduction

Association of toxicity incidence with dose-histogram (typically dose-volume) parameters has become standard methodology for the presentation of normal tissue toxicity subsequent to radiation therapy clinical trials (1). By investigating dose-volume cut-points that best discriminate between responding and nonresponding patients, it is possible to develop objective constraints. Constraints can be used to guide optimization of future patient treatments using instruments that are widely available via commercial radiation therapy treatment planning systems.

Multiple studies of gastrointestinal (GI) toxicity associated with radiation therapy for prostate carcinoma have been undertaken that identify dosimetric parameters that correlate with overall or individual rectal toxicities to guide ongoing radiation therapy practice 2, 3. Some studies have attempted to anatomically localize dose parameters contributing to specific toxicities. Peeters et al (4) examined dosimetric parameters derived for 3 anatomical regions of the lower GI tract, based on general identification of the anorectum, being “from the ischial tuberosities until the level of the inferior border of the sacroiliac joints, or when the rectum was no longer adjacent to the sacrum” (4). This allowed generic identification of the anal canal as the caudal 3 cm of the anorectum and the rectum as the remaining cranial part of the anorectum. Peeters et al (4) were able to distinguish associations of incontinence to parameters derived for the anal canal from other toxicities associated with parameters for the overall anorectum. Similarly, Heemsbergen et al (5) associated bleeding with dose to the more superior parts of anorectum relative to those associated with incontinence. More recently, Stenmark et al (6) demonstrated dominant associations of dosimetric parameters to quality-of-life factors, including incontinence and urgency, for inferior rectal anatomy.

With maturation of outcome data from the Trans-Tasman Radiation Oncology Group (TROG) 03.04 RADAR trial 7, 8, we undertook an analysis of dose-volume histogram (DVH) effects derived in the context of dose-volume–constrained radiation therapy. DVH parameters were derived as near-continuous functions of dose, using statistically robust techniques with a focus on calculation of appropriate significance levels, corrected for multiple testing.

Section snippets

RADAR trial

The RADAR trial (Randomised Androgen Deprivation and Radiotherapy, TROG 03.04) (7) examined the influence of duration of androgen deprivation with or without bisphosphonates, adjuvant with radiation therapy, for treatment of prostate carcinoma. Aspects of the extensive activities aimed at quality assessment of trial data have been previously presented 9, 10, 11.

Accrual was from Australia and New Zealand between 2003 and 2008. All participants received center-nominated radiation therapy to the

Participant and treatment demographics

A total of 1071 patients were recruited from 23 centers. After we excluded patients who received an HDR boost and those for whom complete treatment planning data were not archived (11), 754 patient datasets were available for analysis. Summaries of patient demographics and treatment planning and treatment (including DVH distributions) are provided in the supplementary Appendix EII (available online at www.redjournal.com).

Toxicity outcomes

Follow-up data used for analysis were exported from November 13, 2012,

Discussion

This investigation focused on a large dataset for a multicenter clinical trial undertaken under strict quality control and monitoring criteria. Routine assessment of participants was undertaken using well-established instruments (23) over an extensive follow-up period. This allowed, where toxicity definitions are consistent, validation of previous observations of dose-volume response for the rectum after radiation therapy for prostate carcinoma.

Although derivation of rectal histogram

Conclusions

Several limitations of this study should be highlighted, particularly in relation to the scope for translating the results to other datasets or treatment techniques: (1) The analysis method used makes use of a rank sum rather than a dichotomization of toxicity grades, requiring the use of toxicity prevalence rather than time-to-event data; (2) Although we have been unable to separately find differences in toxicity rates based on patient setup orientation, the dominance of supine orientation in

Acknowledgments

We acknowledge funding from Cancer Australia and the Diagnostics and Technology Branch of the Australian Government Department of Health and Ageing (grant 501106), the National Health and Medical Research Council (grants 300705, 455521, 1006447), the Health Research Council (New Zealand), Abbott Laboratories and Novartis Pharmaceuticals. We gratefully acknowledge the support of participating RADAR centers, the Trans-Tasman Radiation Oncology Group, Ben Hooton, Elizabeth van der Wath and Rachel

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Conflict of interest: Trans Tasman Radiation Oncology Group trial 03.04 was supported by grants from Australian and New Zealand governments and nongovernmental and institutional sources. Pharmaceuticals and trial logistic support were provided by Abbott Laboratories and Novartis Pharmaceuticals. No financial benefits were paid to trial investigators or listed authors.

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