Prostate external beam radiotherapy combined with high-dose-rate brachytherapy: dose-volume parameters from deformably-registered plans correlate with late gastrointestinal complications

Calyn R Moulton, Michael J House, Victoria Lye, Colin I Tang, Michele Krawiec, David J Joseph, James W Denham, Martin A Ebert, Calyn R Moulton, Michael J House, Victoria Lye, Colin I Tang, Michele Krawiec, David J Joseph, James W Denham, Martin A Ebert

Abstract

Background: Derivation of dose-volume correlated with toxicity for multi-modal treatments can be difficult due to the perceived need for voxel-by-voxel dose accumulation. With data available for a single-institution cohort with long follow-up, an investigation was undertaken into rectal dose-volume effects for gastrointestinal toxicities after deformably-registering each phase of a combined external beam radiotherapy (EBRT)/high-dose-rate (HDR) brachytherapy prostate treatment.

Methods: One hundred and eighteen patients received EBRT in 23 fractions of 2 Gy and HDR (TG43 algorithm) in 3 fractions of 6.5 Gy. Results for the Late Effects of Normal Tissues - Subjective, Objective, Management and Analytic toxicity assessments were available with a median follow-up of 72 months. The HDR CT was deformably-registered to the EBRT CT. Doses were corrected for dose fractionation. Rectum dose-volume histogram (DVH) parameters were calculated in two ways. (1) Distribution-adding: parameters were calculated after the EBRT dose distribution was 3D-summed with the registered HDR dose distribution. (2) Parameter-adding: the EBRT DVH parameters were added to HDR DVH parameters. Logistic regressions and Mann-Whitney U-tests were used to correlate parameters with late peak toxicity (dichotomised at grade 1 or 2).

Results: The 48-80, 40-63 and 49-55 Gy dose regions from distribution-adding were significantly correlated with rectal bleeding, urgency/tenesmus and stool frequency respectively. Additionally, urgency/tenesmus and anorectal pain were associated with the 25-26 Gy and 44-48 Gy dose regions from distribution-adding respectively. Parameter-adding also indicated the low-mid dose region was significantly correlated with stool frequency and proctitis.

Conclusions: This study confirms significant dose-histogram effects for gastrointestinal toxicities after including deformable registration to combine phases of EBRT/HDR prostate cancer treatment. The findings from distribution-adding were in most cases consistent with those from parameter-adding. The mid-high dose range and near maximum doses were important for rectal bleeding. The distribution-adding mid-high dose range was also important for stool frequency and urgency/tenesmus. We encourage additional studies in a variety of institutions using a variety of dose accumulation methods with appropriate inter-fraction motion management.

Trial registration: NCT NCT00193856 . Retrospectively registered 12 September 2005.

Keywords: Deformable registration; Distribution-adding; Gastrointestinal toxicity.

Figures

Fig. 1
Fig. 1
Late peak toxicity grades for various toxicity types over the follow-up period. The toxicity types (abbreviation) are rectal bleeding (bleeding), CTC proctitis (proctitis), stool frequency (frequency), diarrhoea, urgency/tenesmus (urgency), anorectal pain (pain) and completeness of evacuation (evacuation). The toxicity rates are reported as cumulative percentages of the 118 patients. The thresholds for subsequently grouping patients into toxicity/no toxicity groups are indicated by the red dashed lines
Fig. 2
Fig. 2
Registration evaluation using structure overlaps. Illustration of the structure overlap metric used to assess major misalignment of rectum volume (Top). Overlap of the EBRT rectum/registered HDR rectum was expressed as a percentage of the volume of the registered HDR rectum. Structure overlap results for the 118 patients after the rigid plus multi-pass DIR are provided (Bottom)
Fig. 3
Fig. 3
Odds ratios from univariate ordinal regression of distribution-adding VX and peak late toxicity. The toxicities are rectal bleeding (a), stool frequency (b), diarrhoea (c), anorectal pain (d) and urgency/tenesmus (e). The peak late toxicities for rectal bleeding and stool frequency were dichotomised at grade 2 whereas diarrhoea, anorectal pain and urgency/tenesmus were dichotomised at grade 1. A red dot is used to indicate the doses at which odds ratios are significantly different from a value of one (95 % confidence intervals do not include one). Abbreviations: VX, percentage of the rectal volume receiving at least X Gy after applying an α/β = 3 Gy; EQD2 Gy, equivalent dose in 2-Gy fractions using α/β = 3 Gy; 95 % CI, 95 % confidence interval
Fig. 4
Fig. 4
Median distribution-adding VX for the toxicity and no toxicity groups. The toxicity groups are based on peak late toxicity. The peak late toxicities for rectal bleeding (a) and stool frequency (b) were dichotomised at grade 2 whereas diarrhoea (c), anorectal pain (d) and urgency/tenesmus (e) were dichotomised at grade 1. The red curve and p-value axis indicate doses at which median VX values for the toxicity and no toxicity groups are significantly different (p-value < 0.05). Abbreviations: VX, percentage of the rectal volume receiving at least X Gy after applying an α/β = 3 Gy; EQD2 Gy, equivalent dose in 2-Gy fractions using α/β = 3 Gy
Fig. 5
Fig. 5
Median distribution-adding DX% for the toxicity and no toxicity groups. The peak late toxicities for rectal bleeding (a) and stool frequency (b) were dichotomised at grade 2 whereas diarrhoea (c) and urgency/tenesmus (d) were dichotomised at grade 1. The red curve and p-value axis indicate doses at which median DX% values for the toxicity and no toxicity groups are significantly different (p-value < 0.05). Abbreviations: DX%, minimum dose to the most irradiated X percentage of rectal volume after applying an α/β = 3 Gy; EQD2 Gy, equivalent dose in 2-Gy fractions using α/β = 3 Gy

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