Plan robustness evaluation strategies in whole-pelvic proton therapy for high-risk prostate cancer patients within a randomised clinical trial.

BACKGROUND: Inter-fractional anatomical changes challenge robust delivery of whole-pelvic proton therapy for high-risk prostate cancer. Pre-treatment robust evaluation (PRE) takes uncertainties in isocenter shifts and distal beam edge in treatment plans into account. Using weekly control computed tomography scans (cCTs), the aim of this study was to evaluate the PRE strategy by comparing to an off-line during-treatment robust evaluation (DRE) while also assessing plan robustness with respect to protocol planning constraints. MATERIAL AND METHODS: Treatment plans and cCTs from ten patients included in the pilot phase of the PROstate PROTON Trial 1 were analysed. Treatment planning followed protocol guidelines with 78 Gy to the primary clinical target volume (CTVp) and 56 Gy to the elective target (CTVe) in 39 fractions. Recalculations of the treatment plans were performed for a total of 64 cCTs and dose/volume measures corresponding to clinical constraints were evaluated for this DRE against the simulated scenario interval from the PRE. RESULTS: Of the 64 cCTs, 59 showed DRE CTVp measures within the robustness range from the PRE; this was also the case for 39 of the cCTs for the CTVe measures. However, DRE CTVe coverage was still within constraints for 57 of the 64 cCTs. DRE dose/volume measures for CTVp fulfilled target coverage constraints in 59 of 64 cCTs. All DRE measures for the rectum, bladder, and bowel were inside the PRE range in 63, 39, and 31 cCTs, respectively. CONCLUSION: The PRE strategy predicted the DRE scenarios for CTVp and rectum. CTVe, bladder, and bowel showed more complex anatomical variations than simulated by the PRE isocenter shift. Both original and recalculated nominal treatment plans showed robust treatment delivery in terms of target coverage.

Patient-reported lower limb edema after primary radiotherapy for prostate cancer.

BACKGROUND: Secondary lymphedema is a known side effect to radiotherapy (RT), but limited information regarding prevalence and risk factors for lower limb edema (LLE) after curative radiotherapy in patients with prostate cancer (PCa) is available. This study provides a descriptive analysis of patient-reported LLE with analysis of risk factors in a cohort of patients with PCa treated with curative RT. MATERIAL AND METHODS: A total of 302 patients with PCa with prospective registration of patient-reported LLE (EORTC QLQ-PR25 (Question 46)) were included. Analysis of LLE was done with the calculation of prevalence rates and Kaplan-Meier statistics. Risk factors for LLE were analyzed multivariate with Cox regression analysis. RESULTS: At a median follow-up of 15 (3-51) months, the overall crude incidence of patients reporting 'quite a bit' or 'a lot' of LLE was 49 (16.2%) and 21 (7.0%), respectively. The baseline prevalence rate of 'quite a bit' and 'a lot' of LLE was 5.0% and 0.8%, respectively. During follow-up the prevalence rate for 'quite a bit' or 'a lot' of LLE increased significantly and remained constant from 6 months where 11.5% (±1.7%) reported 'quite a bit' and 2.9% (±0.5%) reported 'very much' LLE (p < 0.001), respectively.Significant risk factors (p < 0.10) for LLE in univariate analysis included lymph node irradiation (HR:2.325), baseline Body Mass Index (BMI) (HR:1.100), Charlson Comorbidity Index (HR:1.227), Androgen Deprivation Therapy (HR:2,979), and Performance Status (HR:0.594). Only high BMI (HR:1.091) remained significant in multivariate analysis with a three-fold increase in LLE in patients with BMI ≥ 30 compared to normal weight patients. CONCLUSION: Severe patient-reported LLE after curative RT for PCa is rare. Significantly more patients with a high BMI report 'quite a bit' or 'very much' LLE compared to patients with a normal BMI. Obese PCa patients could be offered a rehabilitation program for early detection and management of LLE.

Proton therapy planning and image-guidance strategies within a randomized controlled trial for high-risk prostate cancer.

The Danish Prostate Cancer Group is launching the randomized trial, PROstate PROTON Trial 1 (NCT05350475), that compares photons and protons to the prostate and pelvic lymph nodes in treatment of high-risk prostate cancer. The aim of the work described in this paper was, in preparation of this trial, to establish a strategy for conventionally fractionated proton therapy of prostate and elective pelvic lymph nodes that is feasible and robust. Proton treatments are image-guided based on gold fiducial markers and on-board imaging systems in line with current practice. Our established proton beam configuration consists of four coplanar fields; two posterior oblique fields and two lateral oblique fields, chosen to minimize range uncertainties associated with penetrating a varying amount of material from both treatment couch and patient body. Proton plans are robustly optimized to ensure target coverage while keeping normal tissue doses as low as is reasonably achievable throughout the course of treatment. Specific focus is on dose to the bowel as a reduction in gastrointestinal toxicity is the primary endpoint of the trial. Strategies have been established using previously treated patients and will be further investigated and evaluated through the ongoing pilot phase of the trial.

Towards range-guidance in proton therapy to detect organ motion-induced dose degradations.

Introduction.Internal organ motion and deformations may cause dose degradations in proton therapy (PT) that are challenging to resolve using conventional image-guidance strategies. This study aimed to investigate the potential ofrange guidanceusing water-equivalent path length (WEPL) calculations to detect dose degradations occurring in PT.Materials and methods. Proton ranges were estimated using WEPL calculations. Field-specific isodose surfaces in the planning CT (pCT), from robustly optimised five-field proton plans (opposing lateral and three posterior/posterior oblique beams) for locally advanced prostate cancer patients, were used as starting points. WEPLs to each point on the field-specific isodoses in the pCT were calculated. The corresponding range for each point was found in the repeat CTs (rCTs). The spatial agreement between the resulting surfaces in the rCTs (hereafter referred to as iso-WEPLs) and the isodoses re-calculated in rCTs was evaluated for different dose levels and Hausdorff thresholds (2-5 mm). Finally, the sensitivity and specificity of detecting target dose degradation (V95% < 95%) using spatial agreement measures between the iso-WEPLs and isodoses in the pCT was evaluated.Results. The spatial agreement between the iso-WEPLs and isodoses in the rCTs depended on the Hausdorff threshold. The agreement was 65%-88% for a 2 mm threshold, 83%-96% for 3 mm, 90%-99% for 4 mm, and 94%-99% for 5 mm, across all fields and isodose levels. Minor differences were observed between the different isodose levels investigated. Target dose degradations were detected with 82%-100% sensitivity and 75%-80% specificity using a 2 mm Hausdorff threshold for the lateral fields.Conclusion. Iso-WEPLs were comparable to isodoses re-calculated in the rCTs. The proposed strategy could detect target dose degradations occurring in the rCTs and could be an alternative to a fully-fledged dose re-calculation to detect anatomical variations severely influencing the proton range.

3D dose reconstruction based on in vivo dosimetry for determining the dosimetric impact of geometric variations in high-dose-rate prostate brachytherapy.

INTRODUCTION: In vivo dosimetry (IVD) can be used for source tracking (ST), i.e., estimating source positions, during brachytherapy. The aim of this study was to exploit IVD-based ST to perform 3D dose reconstruction for high-dose-rate prostate brachytherapy and to evaluate the robustness of the treatments against observed geometric variations. MATERIALS AND METHODS: Twenty-three fractions of high-dose-rate prostate brachytherapy were analysed. The treatment planning was based on MRI. Time-resolved IVD was performed using a fibre-coupled scintillator. ST was retrospectively performed using the IVD measurements. The ST identified 2D positional shifts of each treatment catheter and thereby inferred updated source positions. For each fraction, the dose was recalculated based on the source-tracked catheter positions and compared with the original plan dose using differences in dose volume histogram indices. RESULTS: Of 352 treatment catheters, 344 had shifts of less than 5 mm. Shifts between 5 and 10 mm were observed for 3 catheters, and shifts greater than 10 mm for 2 catheters. The ST failed for 3 catheters. The maximum relative difference in clinical target volume (prostate + 3 mm isotropic margin) D90% was 5%. In one fraction, the bladder D2cm3 dose increased by 18% (1.4 Gy) due to a single source position being inside the bladder rather than nearby as planned. The max increase in urethra dose was 1.5 Gy (15%). CONCLUSION: IVD-based 3D dose reconstruction for high-dose-rate prostate brachytherapy is feasible. The dosimetric impact of the observed catheter shifts was limited. Dose reconstruction can therefore aid in determining the dosimetric impact of geometric variations and errors in brachytherapy.

A phase I/II study of acute and late physician assessed and patient-reported morbidity following whole pelvic radiation in high-risk prostate cancer patients.

BACKGROUND: The aim of this study was to assess acute and late morbidity measured by the physician and patient-reported outcomes (PROs) in high-risk prostate cancer (PC) patients receiving whole pelvic intensity-modulated radiotherapy (IMRT) in the setting of a national clinical trial. MATERIAL AND METHODS: A total of 88 patients with adenocarcinoma of the prostate and high-risk parameters were enrolled from 2011 to 2013. All patients received 78 Gy in 39 fractions of IMRT delivering simultaneous 78 Gy to the prostate and 56 Gy to the seminal vesicles and lymph nodes. Physician-reported morbidity was assessed by CTCAE v.4.0. PROs were registered for gastro-intestinal (GI) by the RT-ARD score, genito-urinary (GU) by DAN-PSS, sexual and hormonal by EPIC-26, and quality of life (QoL) by EORTC QLQ-C30. RESULTS: Median follow-up (FU) time was 4.6 years. No persistent late CTCAE grade 3+ morbidity was observed. Prevalence of CTCAE grade 2+ GI morbidities varied from 0 to 6% at baseline throughout FU time, except for diarrhea, which was reported in 19% of the patients post-RT. PROs revealed increased GI morbidity (≥1 monthly episode) for "rectal urgency", "use of pads", "incomplete evacuation", "mucus in stool" and "bowel function impact on QoL" all remained significantly different (p < .05) at 60 months compared to baseline. CTCAE grade 2+ GU and sexual morbidity were unchanged. GU PROs on obstructive and irritative GU items (≥daily episode) increased during RT and normalized at 24 months. No clinically significant differences were found in sexual, hormonal, and QoL scores compared to baseline. CONCLUSIONS: Whole pelvic RT resulted in a mild to the moderate burden of late GI morbidities demonstrated by a relatively high prevalence of PROs. Whereas, physician-assessed morbidity revealed a low prevalence of late GI morbidity scores. This emphasizes the importance of using both PROs and physician-reported scoring scales when reporting late morbidity in clinical trials.

Anatomically robust proton therapy using multiple planning computed tomography scans for locally advanced prostate cancer.

BACKGROUND: Proton therapy (PT) is sensitive towards anatomical changes that may occur during a treatment course. The aim of this study was to investigate if anatomically robust PT (ARPT) plans incorporating patient-specific target motion improved target coverage while still sparing normal tissues, when applied on locally advanced prostate cancer patients where pelvic irradiation is indicated. MATERIAL AND METHODS: A planning computed tomography (CT) scan used for dose calculation and two additional CTs (acquired on different days) were used to make patient-specific targets for the ARPT plans on the eight included patients. The plans were compared to a conventional robust PT plan and a volumetric modulated arc therapy (VMAT) photon plan, which were derived from the planning CT (pCT). Worst-case robust optimisation was used for all proton plans with a setup uncertainty of 5 mm and a range uncertainty of 3.5%. Target coverage (V95% and D95%) and normal tissue doses (V5-75 Gy) were evaluated on 6-8 rCTs per patient. RESULTS: The ARPT plans improved the prostate target coverage for the most challenging patient compared to conventional robust PT plans (20% point increase for V95% and 31 Gy increase for D95%). Across the whole cohort the estimated mean value for V95% was 97% for the ARPT plans and 95% for the conventional robust PT plans. The ARPT plans had a slight, statistically insignificant increase in normal tissue doses compared to the conventional robust proton plans. Compared to VMAT, the ARPT plans significantly reduced the normal tissue doses in the low-to-intermediate dose range. CONCLUSIONS: While both proton plans reduced the low-to-intermediate normal tissue doses compared to VMAT, ARPT plans improved the target coverage for the most challenging patient without significantly increasing the normal tissue doses compared to conventional robust PT plans.

Accuracy of an in vivo dosimetry-based source tracking method for afterloading brachytherapy - A phantom study.

PURPOSE: To report on the accuracy of an in vivo dosimetry (IVD)-based source tracking (ST) method for high dose rate (HDR) prostate brachytherapy (BT). METHODS: The ST was performed on a needle-by-needle basis. A least square fit of the expected to the measured dose rate was performed using the active dwell positions in the given needle. Two fitting parameters were used to determine the position of each needle relative to the IVD detector: radial (away or toward the detector) and longitudinal (along the axis of the treatment needle). The accuracy of the ST was assessed in a phantom where the geometries of five HDR prostate BT treatments previously treated at our clinic were reproduced. For each of the five treatment geometries, one irradiation was performed with the detector placed in the middle of the implant. Furthermore, four additional irradiations were performed for one of the geometries where the detector was retracted caudally in four steps of 10-15 mm and up to 12 mm inferior of the most inferior active dwell position, which represented the prostate apex. The time resolved dose measurements were retrieved at a rate of 20 Hz using a detector based on an Al2 O3 :C radioluminescence crystal, which was placed inside a standard BT needle. Individual calibrations of the detector were performed prior to each of the nine irradiations. RESULTS: Source tracking could be applied in all needles across all nine irradiations. For irradiations with the detector located in the middle region of the implant (a total of 89 needles), the mean ± standard deviation (SD, k = 1) accuracy was -0.01 mm ± 0.38 mm and 0.30 mm ± 0.38 mm in the radial and longitudinal directions, respectively. Caudal retraction of the detector did not lead to reduced accuracy as long as the detector was located superior to the most inferior active dwell positions in all needles. However, reduced accuracy was observed for detector positions inferior to the most inferior active dwell positions which corresponded to detector positions in and inferior to the prostate apex region. Detector positions in the prostate apex and 12 mm inferior to the prostate resulted in mean ± SD (k = 1) ST accuracy of 0.7 mm ± 1 mm and 2.8 mm ± 1.6 mm, respectively, in radial direction, and -1.7 mm ± 1 mm and -2.1 mm ± 1.1 mm, respectively, in longitudinal direction. The largest deviations for the configurations with those detector positions were 2.6 and 5.4 mm, respectively, in the radial direction and -3.5 and -3.8 mm, respectively, in the longitudinal direction. CONCLUSION: This phantom study demonstrates that ST based on IVD during prostate BT is adequately accurate for clinical use. The ST yields submillimeter accuracy on needle positions as long as the IVD detector is positioned superior to at least one active dwell position in all needles. Locations of the detector inferior to the prostate apex result in decreased ST accuracy while detector locations in the apex region and above are advantageous for clinical applications.

Histopathological Features of MRI-Invisible Regions of Prostate Cancer Lesions.

BACKGROUND: Previous studies have reported tumor volume underestimation with multiparametric (mp)MRI in prostate cancer diagnosis. PURPOSE: To investigate why some parts of lesions are not visible on mpMRI by comparing their histopathology features to those of visible regions. STUDY TYPE: Retrospective. POPULATION: Thirty-four patients with biopsy-proven prostate cancer scheduled for prostatectomy (median 68.7 years). FIELD STRENGTH/SEQUENCE: T2 -weighted, diffusion-weighted imaging, T2 mapping, and dynamic contrast-enhanced MRI on two 3T systems and one 1.5T system. ASSESSMENT: Two readers delineated suspicious lesions on mpMRI. A pathologist delineated the lesions on histopathology. A patient-customized mold enabled the registration of histopathology and MRI. On histopathology we identified mpMRI visible and invisible lesions. Subsequently, within the visible lesions we identified regions that were visible and regions that were invisible on mpMRI. For each lesion and region the following characteristics were determined: size, location, International Society of Urological Pathology (ISUP) grade, and Gleason subpatterns (density [dense/intermediate], tumor morphology [homogeneous/heterogeneous], cribriform growth [yes/no]). STATISTICAL TESTS: With generalized linear mixed-effect modeling we investigated which features explain why a lesion or a region was invisible on MRI. We compared imaging values (T2 , ADC, and Ktrans ) for these features with one-way analysis of variance (ANOVA). RESULTS: Small, anterior, and ISUP grade 1-2 lesions (n = 34) were missed more frequent than large, posterior, ISUP grade ≥ 3 lesions (n = 35). Invisible regions on mpMRI had lower tumor density, heterogeneous tumor morphology, and were located in the transition zone. Both T2 and ADC values were higher in "intermediate" compared with "dense" regions (P = 0.002 and < 0.001) and in regions with heterogeneous compared with homogeneous morphology (P < 0.001 and 0.03). Ktrans was not significantly different (P = 0.24 and 0.99). DATA CONCLUSION: Regions of prostate cancer lesions that are invisible on mpMRI have different histopathology features than visible regions. This may have implications for monitoring during active surveillance and focal treatment strategies. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:1235-1246.

Needle migration and dosimetric impact in high-dose-rate brachytherapy for prostate cancer evaluated by repeated MRI.

PURPOSE: To quantify needle migration and dosimetric impact in high-dose-rate brachytherapy for prostate cancer and propose a threshold for needle migration. METHODS AND MATERIALS: Twenty-four high-risk prostate cancer patients treated with an HDR boost of 2 × 8.5 Gy were included. Patients received an MRI for planning (MRI1), before (MRI2), and after treatment (MRI3). Time from needle insertion to MRI3 was ∼3 hours. Needle migration was evaluated from coregistered images: MRI1-MRI2 and MRI1-MRI3. Dose volume histogram parameters from the treatment plan based on MRI1 were related to parameters based on needle positions in MRI2 or MRI3. Regression was used to model the average needle migration per implant and change in D90 clinical target volume, CTVprostate+3mm. The model fit was used for estimating the dosimetric impact in equivalent dose in 2 Gy fractions for dose levels of 6, 8.5, 10, 15, and 19 Gy. RESULTS: Needle migration was on average 2.2 ± 1.8 mm SD from MRI1-MRI2 and 5.0 ± 3.0 mm SD from MRI1-MRI3. D90 CTVprostate+3mm was robust toward average needle migration ≤3 mm, whereas for migration >3 mm D90 decreased by 4.5% per mm. A 3 mm of needle migration resulted in a decrease of 0.9, 1.7, 2.3, 4.8, and 7.6 equivalent dose in 2 Gy fractions for dose levels of 6, 8.5, 10, 15, and 19 Gy, respectively. CONCLUSIONS: Substantial needle migration in high-dose-rate brachytherapy occurs frequently in 1-3 hours following needle insertion. A 3-mm threshold of needle migration is proposed, but 2 mm may be considered for dose levels ≥15 Gy.

Time-resolved in vivo dosimetry for source tracking in brachytherapy.

PURPOSE: The purpose of this article is to demonstrate that brachytherapy source tracking can be realized with in vivo dosimetry. This concept could enable real-time treatment monitoring. METHODS: In vivo dosimetry was incorporated in the clinical routine during high-dose-rate prostate brachytherapy at Aarhus University Hospital. The dosimetry was performed with a radioluminescent crystal positioned in a dedicated brachytherapy needle in the prostate. The dose rate was recorded every 50-100 ms during treatment and analyzed retrospectively. The measured total delivered dose and dose rates for each dwell position with dwell times >0.7 s were compared with expected values. Furthermore, the distance between the source and dosimeter, which was derived from the measured dose rates, was compared with expected values. The measured dose rate pattern in each needle was used to determine the most likely position of the needle relative to the dosimeter. RESULTS: In total, 305 needles and 3239 dwell positions were analyzed based on 20 treatments. The measured total doses differed from the expected values by -4.7 ± 8.4% (1SD) with range (-17% to 12%). It was possible to determine needle shifts for 304 out of 305 needles. The mean radial needle shift between imaging and treatment was 0.2 ± 1.1 mm (1SD), and the mean longitudinal shift was 0.3 ± 2.0 mm (1SD). CONCLUSION: Time-resolved in vivo dosimetry can be used to provide geometric information about the treatment progression of afterloading brachytherapy. This information may provide a clear indication of errors and uncertainties during a treatment and, therefore, enables real-time treatment monitoring.

A biological modelling based comparison of radiotherapy plan robustness using photons vs protons for focal prostate boosting.

BACKGROUND AND PURPOSE: Focal tumour boosting is currently explored in radiotherapy of prostate cancer to increase tumour control. In this study we applied dose response models for both tumour control and normal tissue complications to explore the benefit of proton therapy (PT) combined with focal tumour boosting, also when accounting for inter-fractional motion. MATERIALS AND METHODS: CT scans of seven patients fused with MRI-based index volumes were used. Two volumetric modulated arc therapy (VMAT) plans were created for each patient; one with conventional dose (77 Gy) to the entire prostate, and one with an additional integrated boost (total dose of 95 Gy) to the index lesion. Two corresponding intensity modulated PT (IMPT) plans were created using two lateral opposing spot scanning beams. All plans were evaluated using an MRI-based tumour control probability (TCP) model and normal tissue complication probability (NTCP) models for the rectum and bladder. Plan robustness was evaluated using dose re-calculations on repeat cone-beam CTs. RESULTS: Across all plans, median TCP increased from 86% (range: 59-98%) without boost to 97% (range: 96-99%) with boost. IMPT plans had lower rectum NTCPs (e.g. 3% vs. 4% for boost plans) but higher bladder NTCPs (20% vs. 18% for boost plans), yet only the bladder NTCPs remained different in the cone beam CT-based re-calculations. CONCLUSIONS: Focal tumour boosting can be delivered with either VMAT or protons, and increases the predicted TCP. The small benefit of IMPT when assessing the planned dose distributions was lost when accounting for inter-fractional motion.

Validation of genetic predictors of late radiation-induced morbidity in prostate cancer patients.

INTRODUCTION: Normal tissue morbidity sets the dose limit for radiotherapy (RT) in cancer treatment and has importance for quality of life for cancer survivors. A previous study of prostate cancer patients treated with RT generated clinical data for radiation-induced morbidity measured by anorectal physiological methods and validated questionnaires. Other studies have identified genetic predictors associated with late radiation-induced morbidity outcome. We have expanded biobank material aiming to validate single nucleotide polymorphisms (SNPs) and a gene expression classifier with endpoints on patient-reported outcomes and biomechanical properties of the anorectum from our cohort matching originally published endpoints. MATERIALS AND METHODS: The present cohort of prostate cancer patients was treated with RT curative intent in 1999-2007. Nine SNPs associated with late radiation-induced morbidity were tested in 96 patients (rs2788612, rs1800629, rs264663, rs2682585, rs2268363, rs1801516, rs13035033, rs7120482 and rs17779457). A validated gene expression profile predictive of resistance to radiation-induced skin fibrosis was tested in 42 patients. An RT-induced anorectal dysfunction score (RT-ARD) served as a fibrosis-surrogate and a measure of overall radiation-induced morbidity. RESULTS: The lowest p-value found in the genotype analyses was for SNP rs2682585 minor allele (A) in the FSHR gene and the RT-ARD score with odds ratios (OR) = 1.76; 95% CI (0.98-3.17) p = .06, which was out of concordance with original data showing a protective effect of the minor allele. The gene expression profile in patients classified as fibrosis-resistant was associated with high RT-ARD scores OR 4.18; 95% CI (1.1-16.6), p = .04 conflicting with the hypothesis that fibrosis-resistant patients would experience lower RT-ARD scores. CONCLUSIONS: We aimed to validate nine SNPs and a gene expression classifier in a cohort of prostate cancer patients with unique scoring of radiation-induced morbidity. One significant association was found, pointing to the opposite direction of originally published data. We conclude that the material was not able to validate previously published genetic predictors of radiation-induced morbidity.

Evaluating the influence of organ motion during photon vs. proton therapy for locally advanced prostate cancer using biological models.

BACKGROUND: Proton therapy (PT) may have a normal tissue sparing potential when co-irradiating pelvic lymph nodes in patients with locally advanced prostate cancer, but may also be more sensitive towards organ motion in the pelvis. Building upon a previous study identifying motion-robust proton beam angles for pelvic irradiation, we aimed to evaluate the influence of organ motion for PT using biological models, and to compare this with contemporary photon-based RT. MATERIAL AND METHODS: Eight locally advanced prostate cancer patients with a planning CT (pCT) and 8-9 repeated CT scans (rCTs) were included. Two PT plans were created, one using two lateral opposed beams at gantry angles of 90°/270° and the other using two lateral oblique beams at 35°/325°; these were compared with volumetric modulated arc therapy (VMAT) plans. All plans were optimised on the pCT and subsequently re-calculated on each rCT (following rigid alignment on the prostate). Dose distributions in organs at risk (OARs) were evaluated using mean dose, generalized equivalent uniform doses (gEUDs) and normal tissue complication probabilities (NTCPs), while mean dose and the volume receiving 98% of the dose (V98%) were used for the targets. RESULTS: PT significantly reduced the mean dose to the OARs and a correlation was seen in the pCTs between the prostate PTV overlapping the relevant OAR and OAR NTCPs, as was also the case for the VMAT plans. The best prostate target coverage across the rCTs for the IMPT plans were seen with two lateral opposed beams, although a poor coverage of the lymph node target was apparent based on V98% compared to the VMAT plans. CONCLUSIONS: PT reduced the mean dose to normal tissues in the irradiation of pelvic lymph nodes and a strong association between the volume overlap and NTCPs in the pCTs were found.

Beam angle evaluation to improve inter-fraction motion robustness in pelvic lymph node irradiation with proton therapy.

BACKGROUND: Proton therapy dose distributions are sensitive to range variations, e.g. arising from inter-fraction organ motion. The aim of this study was to evaluate the inter-fraction motion robustness of proton beams from different beam angles in irradiation of pelvic lymph nodes (LNs). MATERIAL AND METHODS: Planning CT (pCT) and multiple repeat CT (rCT) scans of 18 prostate cancer patients were used. Considering left and right LNs separately, the average water equivalent path length (WEPL) over all ray paths in the beams eye view of the LNs were calculated for all gantry/couch angle combinations across all rCTs versus the corresponding pCT. Single beam proton plans were optimized on the pCT for all gantry angles (0° couch) and were re-calculated on all rCTs for each respective patient. WEPL and dose parameters were extracted and a statistical clustering analysis performed to identify patient sub-populations in terms of patterns in which angles were robust. RESULTS: The WEPL analysis showed a general pattern of least variation for 0° couch beam angles where three minima were found across gantry angles for the left LNs and two for the right LNs. The clustering analysis identified three patient sub-groups for the left LNs and two groups for the right LNs. The dose calculations showed similar results as the WEPL variation, e.g. for the left LNs angles around 25°-35°, 100°-110°, and 160°-170° were consistently preferable for both target and organs at risk. CONCLUSIONS: Sub-populations of patients with similar patterns of WEPL variations across beam angles were identified. The most robust angles found for WEPL variations were also confirmed by the dose/volume analysis.

Dosimetric impact of contouring and needle reconstruction uncertainties in US-, CT- and MRI-based high-dose-rate prostate brachytherapy treatment planning.

BACKGROUND AND PURPOSE: The purpose was to evaluate the dosimetric impact of target contouring and needle reconstruction uncertainties in an US-, CT- and MRI-based HDR prostate BT treatment planning. MATERIAL AND METHODS: US, CT, and MR images were acquired post-needle insertion in 22 HDR-BT procedures for 11 consecutive patients. Dose plans were simulated for an US-, CT- and MRI-based HDR-BT treatment planning procedure. Planning uncertainties in US- and CT-based plans were evaluated using MRI-based planning as reference. Target (CTVProstate) was re-contoured on MRI. Dose results were expressed in total equivalent dose given in 2Gy fractionation dose for EBRT (46Gy) plus 2 HDR-BT fractions. RESULTS: Uncertainties in US- and CT-based planning caused the planned CTVProstate-D90% to decrease with a mean of 2.9±5.0Gy (p=0.03) and 2.9±2.9Gy (p=0.001), respectively. The intra-observer contouring variation on MRI resulted in a mean variation of 1.6±1.5Gy in CTVProstate-D90%. Reconstruction uncertainties on US resulted in a dose variation of±3Gy to the urethra, whereas data for CT were not available for this. CONCLUSIONS: Uncertainties related to contouring and reconstruction in US- and CT-based HDR-BT treatment plans resulted in a systematic overestimation of the prescribed target dose. Inter-modality uncertainties (US and CT versus MR) were larger than MR intra-observer uncertainties.

Learning curve of MRI-based planning for high-dose-rate brachytherapy for prostate cancer.

PURPOSE: To evaluate introduction of MRI-based high-dose-rate brachytherapy (HDRBT), including procedure times, dose-volume parameters, and perioperative morbidity. METHODS AND MATERIALS: Study included 42 high-risk prostate cancer patients enrolled in a clinical protocol, offering external beam radiotherapy + two HDRBT 8.5 Gy boosts. Time was recorded for initiation of anesthesia (A), fixation of needle implant (B), end of MR imaging (C), plan approval (D), and end of HDRBT delivery (E). We defined time A-E as total procedure time, A-B as operating room time, B-C as MRI procedure time, C-D as treatment planning time, and D to E as treatment delivery time. Dose-volume parameters were retrieved from the dose planning system. Results from the first 21 patients were compared with the last 21 patients. RESULTS: Total procedure time, operating room time, MRI procedure time, and treatment planning time decreased significantly from average 7.6 to 5.3 hours (p < 0.01), 3.6 to 2.4 hours (p < 0.01), 1.6 to 0.8 hours (p < 0.01), and 2.0 to 1.3 hours (p < 0.01), respectively. HDRBT delivery time remained unchanged at 0.5 hours. Clinical target volume prostate+3mmD90 fulfilled planning aim in 92% of procedures and increased significantly from average 8.3 to 9.0 Gy (p < 0.01). Urethral D0.1 cm(3) and rectal D2 cm(3) fulfilled planning aim in 78% and 95% of procedures, respectively, and did not change significantly. Hematuria occurred in (95%), hematoma (80%), moderate to strong pain (35%), and urinary retention (5%) of procedures. CONCLUSIONS: After introduction of MRI-based HDRBT, procedure times were significantly reduced. D90 Clinical target volumeprostate+3mm fulfilled constraints in most patients and improved over time, but not at expense of an increased urethral or rectal dose.

Urinary bladder dose-response relationships for patient-reported genitourinary morbidity domains following prostate cancer radiotherapy.

BACKGROUND AND PURPOSE: Radiotherapy (RT) induced genitourinary (GU) morbidity is typically assessed by physicians as single symptoms or aggregated scores including symptoms from various domains. Here we apply a method to group patient-reported GU symptoms after RT for localized prostate cancer based on their interplay, and study how these relate to urinary bladder dose. MATERIALS AND METHODS: Data were taken from two Scandinavian studies (N=207/276) including men treated with external-beam RT (EBRT) to 78/70Gy (2Gy/fraction; median time-to-follow-up: 3.6-6.4y). Within and across cohorts, bladder dose-volume parameters were tested as predictors for GU symptom domains identified from two study-specific questionnaires (35 questions on frequency, incontinence, obstruction, pain, urgency, and sensory symptoms) using univariate and multivariate logistic regression analysis (MVA) with 10-fold cross-validation. Performance was evaluated using Area Under the Receiver Operating Characteristic Curve (Az). RESULTS: For the identified Incontinence (2-5 symptoms), Obstruction (3-5 symptoms), and Urgency (2-7 symptoms) domains, MVA demonstrated that bladder doses close to the prescription doses were the strongest predictors for Obstruction (Az: 0.53-0.57) and Urgency (Az: 0.60). For Obstruction, performance increased for the across cohort analysis (Az: 0.61-0.64). CONCLUSIONS: Our identified patient-reported GU symptom domains suggest that high urinary bladder doses, and increased focus on both obstruction and urgency is likely to further add to the understanding of GU tract RT responses.

Hyperpolarized magnetic resonance spectroscopy for assessing tumor hypoxia.

INTRODUCTION: Hypoxic tumor cells are radioresistant, therefore, identification of hypoxia is crucial. Hyperpolarized magnetic resonance spectroscopy (HPMRS) allows real time measurements of the conversion of pyruvate to lactate, the final step of anaerobic energy production, and may thus allow non-invasive identification of hypoxia or treatment-induced changes in oxygenation. The aim of the study was to investigate the usefulness of HPMRS as a means to assess tumor hypoxia and its dynamics during intervention. MATERIAL AND METHODS: C3H mammary carcinomas grown in CDF1 mice were used. To manipulate with tumor oxygenation, non-anaesthetized mice were gassed with air, 10% or 100% oxygen prior to administration of hyperpolarized [1-¹³C]pyruvate and HPMRS analysis. A direct assessment of tumor oxygen partial pressure (pO2) distributions were made using the Eppendorf oxygen electrode in a separate, but similarly treated, group of mice. RESULTS: Even though breathing 100% oxygen improved tumor oxygenation as evidenced by pO2 measurements, the mean (with 1 S.E.) [1-¹³C]lactate/[1-¹³C]pyruvate ratio was unaffected by this intervention, being 34 (30-37) in mice breathing air and 37 (33-42) in mice breathing 100% oxygen. In contrast, and in accordance with pO2 measurements, a significant increase in the [1-¹³C]lactate/[1-¹³C]pyruvate ratio was seen in 10% oxygen-breathing mice with a ratio of 46 (42-50). CONCLUSIONS: Although, no metabolic change was observed during 100% O2 breathing using HPMRS, the significant increase in the [1-¹³C]lactate/[1-¹³C]pyruvate ratio during 10% oxygen breathing suggests, that HPMRS can detect hypoxia-driven changes in the metabolic fate of pyruvate. To what extent and for what purposes HPMRS may best supplement or complement established techniques like hypoxia PET needs to be unraveled in future research.

Relationships between dose to the gastro-intestinal tract and patient-reported symptom domains after radiotherapy for localized prostate cancer.

BACKGROUND: Gastrointestinal (GI) morbidity after radiotherapy (RT) for prostate cancer is typically addressed by studying specific single symptoms. The aim of this study was to explore the interplay between domains of patient- reported outcomes (PROs) on GI morbidity, and to what extent these are explained by RT dose to the GI tract. MATERIAL AND METHODS: The study included men from two Scandinavian studies (N = 211/277) who had undergone primary external beam radiotherapy (EBRT) for localized prostate cancer to 70-78 Gy (2 Gy/fraction). Factor analysis was applied to previously identified PRO-based symptom domains from two study-specific questionnaires. Number of questions: 43; median time to follow-up: 3.6-6.4 years) and dose-response outcome variables were defined from these domains. Dose/volume parameters of the anal sphincter (AS) or the rectum were tested as predictors for each outcome variable using logistic regression with 10-fold cross-validation. Performance was assessed using area under the receiver operating characteristic curve (Az) and model frequency. RESULTS: Outcome variables from Defecation urgency (number of symptoms: 2-3), Fecal leakage (4-6), Mucous (4), and Pain (3-6) were defined. In both cohorts, intermediate rectal doses predicted Defecation urgency (mean Az: 0.53-0.54; Frequency: 70-75%), and near minimum and low AS doses predicted Fecal leakage (mean Az: 0.63-0.67; Frequency: 83-99%). In one cohort, high AS doses predicted Mucous (mean Az: 0.54; Frequency: 96%), whereas in the other, low AS doses and intermediate rectal doses predicted Pain (mean Az: 0.69; Frequency: 28-82%). CONCLUSION: We have demonstrated that Defecation urgency, Fecal leakage, Mucous, and Pain following primary EBRT for localized prostate cancer primarily are predicted by intermediate rectal doses, low AS doses, high AS doses, or a combination of low AS and intermediate rectal doses, respectively. This suggests that there is a domain-specific dose-response for the GI tract. To reduce risk of GI morbidity, dose distributions of both the AS region and the rectum should, therefore, be considered when prescribing prostate cancer RT.