Urethral and bladder dose-effect relations for late genitourinary toxicity following external beam radiotherapy for prostate cancer in the FLAME trial.

PURPOSE OR OBJECTIVES: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical disease-free survival increased, without significantly increasing toxicity. The aim of the present study was to investigate the association between radiation dose to the bladder and urethra and genitourinary (GU) toxicity grade ≥2 in the entire cohort. MATERIAL AND METHODS: The dose-effect relations of the urethra and bladder dose, separately, and GU toxicity grade ≥2 (CTCAE 3.0) up to five years after treatment were assessed. A mixed model analysis for repeated measurements was used, adjusting for age, diabetes mellitus, T-stage, baseline GU toxicity grade ≥1 and institute. Additionally, the association between the dose and separate GU toxicity subdomains were investigated. RESULTS: Dose-effect relations were observed for the dose (Gy) to the bladder D2 cm3 and urethra D0.1 cm3, with adjusted odds ratios of 1.14 (95% CI 1.12-1.16, p < 0.0001) and 1.12 (95% CI 1.11-1.14, p < 0.0001), respectively. Additionally, associations between the dose to the urethra and bladder and the subdomains urinary frequency, urinary retention and urinary incontinence were observed. CONCLUSION: Further increasing the dose to the bladder and urethra will result in a significant increase in GU toxicity following EBRT. Focal boost treatment plans should incorporate a urethral dose-constraint. Further treatment optimization to increase the focal boost dose without increasing the dose to the urethra and other organs at risk should be a focus for future research, as we have shown that a focal boost is beneficial in the treatment of prostate cancer.

Anorectal dose-effect relations for late gastrointestinal toxicity following external beam radiotherapy for prostate cancer in the FLAME trial.

BACKGROUND AND PURPOSE: The phase III FLAME trial (NCT01168479) showed an increase in five-year biochemical disease-free survival, with no significant increase in toxicity when adding a focal boost to external beam radiotherapy (EBRT) for localized prostate cancer [Kerkmeijer et al. JCO 2021]. The aim of this study was to investigate the association between delivered radiation dose to the anorectum and gastrointestinal (GI) toxicity (grade ≥2). MATERIAL AND METHODS: All patients in the FLAME trial were analyzed, irrespective of treatment arm. The dose-effect relation of the anorectal dose parameters (D2cm3 and D50%) and GI toxicity grade ≥2 in four years of follow-up was assessed using a mixed model analysis for repeated measurements, adjusted for age, cardiovascular disease, diabetes mellitus, T-stage, baseline toxicity grade ≥1, hormonal therapy and institute. RESULTS: A dose-effect relation for D2cm3 and D50% was observed with adjusted odds ratios of 1.17 (95% CI 1.13-1.21, p < 0.0001) and 1.20 (95% CI 1.14-1.25, p < 0.0001) for GI toxicity, respectively. CONCLUSION: Although there was no difference in toxicity between study arms, a higher radiation dose to the anorectum was associated with a statistically significant increase in GI toxicity following EBRT for prostate cancer. This dose-effect relation was present for both large and small anorectal volumes. Therefore, further increase in dose to the anorectum should be weighed against the benefit of focal dose escalation for prostate cancer.

Knowledge-Based Assessment of Focal Dose Escalation Treatment Plans in Prostate Cancer.

PURPOSE: In a randomized focal dose escalation radiation therapy trial for prostate cancer (FLAME), up to 95 Gy was prescribed to the tumor in the dose-escalated arm, with 77 Gy to the entire prostate in both arms. As dose constraints to organs at risk had priority over dose escalation and suboptimal planning could occur, we investigated how well the dose to the tumor was boosted. We developed an anatomy-based prediction model to identify plans with suboptimal tumor dose and performed replanning to validate our model. METHODS AND MATERIALS: We derived dose-volume parameters from planned dose distributions of 539 FLAME trial patients in 4 institutions and compared them between both arms. In the dose-escalated arm, we determined overlap volume histograms and derived features representing patient anatomy. We predicted tumor D98% with a linear regression on anatomic features and performed replanning on 21 plans. RESULTS: In the dose-escalated arm, the median tumor D50% and D98% were 93.0 and 84.7 Gy, and 99% of the tumors had a dose escalation greater than 82.4 Gy (107% of 77 Gy). In both arms organs at risk constraints were met. Five out of 73 anatomic features were found to be predictive for tumor D98%. Median predicted tumor D98% was 4.4 Gy higher than planned D98%. Upon replanning, median tumor D98% increased by 3.0 Gy. A strong correlation between predicted increase in D98% and realized increase upon replanning was found (ρ = 0.86). CONCLUSIONS: Focal dose escalation in prostate cancer was feasible with a dose escalation to 99% of the tumors. Replanning resulted in an increased tumor dose that correlated well with the prediction model. The model was able to identify tumors on which a higher boost dose could be planned. The model has potential as a quality assessment tool in focal dose escalated treatment plans.

Quantitative imaging for radiotherapy purposes.

Quantitative imaging biomarkers show great potential for use in radiotherapy. Quantitative images based on microscopic tissue properties and tissue function can be used to improve contouring of the radiotherapy targets. Furthermore, quantitative imaging biomarkers might be used to predict treatment response for several treatment regimens and hence be used as a tool for treatment stratification, either to determine which treatment modality is most promising or to determine patient-specific radiation dose. Finally, patient-specific radiation doses can be further tailored to a tissue/voxel specific radiation dose when quantitative imaging is used for dose painting. In this review, published standards, guidelines and recommendations on quantitative imaging assessment using CT, PET and MRI are discussed. Furthermore, critical issues regarding the use of quantitative imaging for radiation oncology purposes and resultant pending research topics are identified.

Quantitative MRI Changes During Weekly Ultra-Hypofractionated Prostate Cancer Radiotherapy With Integrated Boost.

Purpose: Quantitative MRI reflects tissue characteristics. As possible changes during radiotherapy may lead to treatment adaptation based on response, we here assessed if such changes during treatment can be detected. Methods and Materials: In the hypoFLAME trial patients received ultra-hypofractionated prostate radiotherapy with an integrated boost to the tumor in 5 weekly fractions. We analyzed T2 and ADC maps of 47 patients that were acquired in MRI exams prior to and during radiotherapy, and performed rigid registrations based on the prostate contour on anatomical T2-weighted images. We analyzed median T2 and ADC values in three regions of interest (ROIs): the central gland (CG), peripheral zone (PZ), and tumor. We analyzed T2 and ADC changes during treatment and compared patients with and without hormonal therapy. We tested changes during treatment for statistical significance with Wilcoxon signed rank tests. Using confidence intervals as recommended from test-retest measurements, we identified persistent T2 and ADC changes during treatment. Results: In the CG, median T2 and ADC values significantly decreased 12 and 8%, respectively, in patients that received hormonal therapy, while in the PZ these values decreased 17 and 18%. In the tumor no statistically significant change was observed. In patients that did not receive hormonal therapy, median ADC values in the tumor increased with 20%, while in the CG and PZ no changes were observed. Persistent T2 changes in the tumor were found in 2 out of 24 patients, while none of the 47 patients had persistent ADC changes. Conclusions: Weekly quantitative MRI could identify statistically significant ADC changes in the tumor in patients without hormonal therapy. On a patient level few persistent T2 changes in the tumor were observed. Long-term follow-up is required to relate the persistent T2 and ADC changes to outcome and evaluate the applicability of quantitative MRI for response based treatment adaptation.

Contouring of prostate tumors on multiparametric MRI: Evaluation of clinical delineations in a multicenter radiotherapy trial.

PURPOSE: To date no guidelines are available for contouring prostate cancer inside the gland, as visible on multiparametric (mp-) MRI. We assessed inter-institutional differences in interpretation of mp-MRI in the multicenter phase III FLAME trial. METHODS: We analyzed clinical delineations on mp-MRI and clinical characteristics from 260 patients across three institutes. We performed a logistic regression analysis to examine each institute's weighting of T2w, ADC and Ktrans intensity maps in the delineation of the cancer. As reviewing of all delineations by an expert panel is not feasible, we made a selection based on discrepancies between a published tumor probability (TP) model and each institute's clinical delineations using Areas Under the ROC Curve (AUC) analysis. RESULTS: Regression coefficients for the three institutes were -0.07, -0.27 and -0.11 for T2w, -1.96, -0.53 and -0.65 for ADC and 0.15, 0.20 and 0.62 for Ktrans, with significant differences between institutes for ADC and Ktrans. AUC analysis showed median AUC values of 0.92, 0.80 and 0.79. Five patients with lowest AUC values were reviewed by a uroradiologist. CONCLUSION: Regression coefficients revealed considerably different interpretations of mp-MRI in tumor contouring between institutes and demonstrated the need for contouring guidelines. Based on AUC values outlying delineations could efficiently be identified for review.

Repeatability of dose painting by numbers treatment planning in prostate cancer radiotherapy based on multiparametric magnetic resonance imaging.

Dose painting by numbers (DPBN) refers to a voxel-wise prescription of radiation dose modelled from functional image characteristics, in contrast to dose painting by contours which requires delineations to define the target for dose escalation. The direct relation between functional imaging characteristics and DPBN implies that random variations in images may propagate into the dose distribution. The stability of MR-only prostate cancer treatment planning based on DPBN with respect to these variations is as yet unknown. We conducted a test-retest study to investigate the stability of DPBN for prostate cancer in a semi-automated MR-only treatment planning workflow. Twelve patients received a multiparametric MRI on two separate days prior to prostatectomy. The tumor probability (TP) within the prostate was derived from image features with a logistic regression model. Dose mapping functions were applied to acquire a DPBN prescription map that served to generate an intensity modulated radiation therapy (IMRT) treatment plan. Dose calculations were done on a pseudo-CT derived from the MRI. The TP and DPBN map and the IMRT dose distribution were compared between both MRI sessions, using the intraclass correlation coefficient (ICC) to quantify repeatability of the planning pipeline. The quality of each treatment plan was measured with a quality factor (QF). Median ICC values for the TP and DPBN map and the IMRT dose distribution were 0.82, 0.82 and 0.88, respectively, for linear dose mapping and 0.82, 0.84 and 0.94 for square root dose mapping. A median QF of 3.4% was found among all treatment plans. We demonstrated the stability of DPBN radiotherapy treatment planning in prostate cancer, with excellent overall repeatability and acceptable treatment plan quality. Using validated tumor probability modelling and simple dose mapping techniques it was shown that despite day-to-day variations in imaging data still consistent treatment plans were obtained.