Proton versus photon therapy for high-risk prostate cancer with dose escalation of dominant intraprostatic lesions: a preliminary planning study.

Background and purpose: This study aimed to investigate the feasibility of safe-dose escalation to dominant intraprostatic lesions (DILs) and assess the clinical impact using dose-volume (DV) and biological metrics in photon and proton therapy. Biological parameters defined as late grade ≥ 2 gastrointestinal (GI) and genitourinary (GU) derived from planned (D P) and accumulated dose (D A) were utilized. Materials and methods: In total, 10 patients with high-risk prostate cancer with multiparametric MRI-defined DILs were investigated. Each patient had two plans with a focal boost to the DILs using intensity-modulated proton therapy (IMPT) and volumetric-modulated arc therapy (VMAT). Plans were optimized to obtain DIL coverage while respecting the mandatory organ-at-risk constraints. For the planning evaluation, DV metrics, tumor control probability (TCP) for the DILs and whole prostate excluding the DILs (prostate-DILs), and normal tissue complication probability (NTCP) for the rectum and bladder were calculated. Wilcoxon signed-rank test was used for analyzing TCP and NTCP data. Results: IMPT achieved a higher Dmean for the DILs compared to VMAT (IMPT: 68.1 GyRBE vs. VMAT: 66.6 Gy, p < 0.05). Intermediate-high rectal and bladder doses were lower for IMPT (p < 0.05), while the high-dose region (V60 Gy) remained comparable. IMPT-TCP for prostate-DIL were higher compared to VMAT (IMPT: 86%; α/ß = 3, 94.3%; α/ß = 1.5 vs. VMAT: 84.7%; α/ß = 3, 93.9%; α/ß = 1.5, p < 0.05). Likewise, IMPT obtained a moderately higher DIL TCP (IMPT: 97%; α/ß = 3, 99.3%; α/ß = 1.5 vs. VMAT: 95.9%; α/ß = 3, 98.9%; α/ß = 1.5, p < 0.05). Rectal D A-NTCP displayed the highest GI toxicity risk at 5.6%, and IMPT has a lower GI toxicity risk compared to VMAT-predicted Quantec-NTCP (p < 0.05). Bladder D P-NTCP projected a higher GU toxicity than D A-NTCP, with VMAT having the highest risk (p < 0.05). Conclusion: Dose escalation using IMPT is able to achieve a high TCP for the DILs, with the lowest rectal and bladder DV doses at the intermediate-high-dose range. The reduction in physical dose was translated into a lower NTCP (p < 0.05) for the bladder, although rectal toxicity remained equivalent.

Predicting dice similarity coefficient of deformably registered contours using Siamese neural network.

Objective. Automatic deformable image registration (DIR) is a critical step in adaptive radiotherapy. Manually delineated organs-at-risk (OARs) contours on planning CT (pCT) scans are deformably registered onto daily cone-beam CT (CBCT) scans for delivered dose accumulation. However, evaluation of registered contours requires human assessment, which is time-consuming and subjects to high inter-observer variability. This work proposes a deep learning model that allows accurate prediction of Dice similarity coefficients (DSC) of registered contours in prostate radiotherapy.Approach. Our dataset comprises 20 prostate cancer patients with 37-39 daily CBCT scans each. The pCT scans and planning contours were deformably registered to each corresponding CBCT scan to generate virtual CT (vCT) scans and registered contours. The DSC score, which is a common contour-based validation metric for registration quality, between the registered and manual contours were computed. A Siamese neural network was trained on the vCT-CBCT image pairs to predict DSC. To assess the performance of the model, the root mean squared error (RMSE) between the actual and predicted DSC were computed.Main results. The model showed promising results for predicting DSC, giving RMSE of 0.070, 0.079 and 0.118 for rectum, prostate, and bladder respectively on the holdout test set. Clinically, a low RMSE implies that the predicted DSC can be reliably used to determine if further DIR assessment from physicians is required. Considering the event where a registered contour is classified as poor if its DSC is below 0.6 and good otherwise, the model achieves an accuracy of 92% for the rectum. A sensitivity of 0.97 suggests that the model can correctly identify 97% of poorly registered contours, allowing manual assessment of DIR to be triggered.Significance. We propose a neural network capable of accurately predicting DSC of deformably registered OAR contours, which can be used to evaluate eligibility for plan adaptation.

18F-FMISO PET-guided dose escalation with multifield optimization intensity-modulated proton therapy in nasopharyngeal carcinoma.

PURPOSE: The purpose of this study was to evaluate the radiotherapy planning feasibility of dose escalation with intensity-modulated proton therapy (IMPT) to hypoxic tumor regions identified on 18F-Fluoromisonidazole (FMISO) positron emission tomography and computed tomography (PET-CT) in NPC. MATERIALS AND METHODS: Nine patients with stages T3-4N0-3M0 NPC underwent 18F-FMISO PET-CT before and during week 3 of radiotherapy. The hypoxic volume (GTVhypo) is automatically generated by applying a subthresholding algorithm within the gross tumor volume (GTV) with a tumor to muscle standardized uptake value (SUV) ratio of 1.3 on the 18F-FMISO PET-CT scan. Two proton plans were generated for each patient, a standard plan to 70 Gy and dose escalation plan with upfront boost followed by standard 70GyE plan. The stereotactic boost was planned with single-field uniform dose optimization using two fields to deliver 10 GyE in two fractions to GTVhypo. The standard plan was generated with IMPT with robust optimization to deliver 70GyE, 60GyE in 33 fractions using simultaneous integrated boost technique. A plan sum was generated for assessment. RESULTS: Eight of nine patients showed tumor hypoxia on the baseline 18F-FMISO PET-CT scan. The mean hypoxic tumor volume was 3.9 cm3 (range .9-11.9cm3 ). The average SUVmax of the hypoxic volume was 2.2 (range 1.44-2.98). All the dose-volume parameters met the planning objectives for target coverage. Dose escalation was not feasible in three of eight patients as the D0.03cc of temporal lobe was greater than 75GyE. CONCLUSIONS: The utility of boost to the hypoxic volume before standard course of radiotherapy with IMPT is dosimetrically feasible in selected patients. Clinical trials are warranted to determine the clinical outcomes of this approach.

Predictors for late genitourinary toxicity in men receiving radiotherapy for high-risk prostate cancer using planned and accumulated dose.

Background and purpose: Significant deviations between bladder dose planned (DP) and dose accumulated (DA) have been reported in patients receiving radiotherapy for prostate cancer. This study aimed to construct multivariate analysis (MVA) models to predict the risk of late genitourinary (GU) toxicity with clinical and DP or DA as dose-volume (DV) variables. Materials and methods: Bladder DA obtained from 150 patients were compared with DP. MVA models were built from significant clinical and DV variables (p < 0.05) at univariate analysis. Previously developed dose-based-region-of-interest (DB-ROI) metrics using expanded ring structures from the prostate were included. Goodness-of-fit test and calibration plots were generated to determine model performance. Internal validation was accomplished using Bootstrapping. Results: Intermediate-high DA (V30-65 Gy and DB-ROI-20-50 mm) for bladder increased compared to DP. However, at the very high dose region, DA (D0.003 cc, V75 Gy, and DB-ROI-5-10 mm) were significantly lower. In MVA, single variable models were generated with odds ratio (OR) < 1. DB-ROI-50 mm was predictive of Grade ≥ 1 GU toxicity for DA and DP (DA and DP; OR: 0.96, p: 0.04) and achieved an area under the receiver operating curve (AUC) of > 0.6. Prostate volume (OR: 0.87, p: 0.01) was significant in predicting Grade 2 GU toxicity with a high AUC of 0.81. Conclusions: Higher DA (V30-65 Gy) received by the bladder were not translated to higher late GU toxicity. DB-ROIs demonstrated higher predictive power than standard DV metrics in associating Grade ≥ 1 toxicity. Smaller prostate volumes have a minor protective effect on late Grade 2 GU toxicity.

Dose-volume analysis of planned versus accumulated dose as a predictor for late gastrointestinal toxicity in men receiving radiotherapy for high-risk prostate cancer.

Background and purpose: Significant dose deviations have been reported between planned (DP) and accumulated (DA) dose in prostate radiotherapy. This study aimed to develop multivariate analysis (MVA) models associating Grade 1 and 2 gastrointestinal (GI) toxicity with clinical and DP or DA dosimetric variables separately. Materials and methods: Dose volume (DV) metrics were compared between DA and DP for 150 high-risk prostate cancer patients. MV models were generated from significant clinical and dosimetric variables (p < 0.05) at univariate level. Dose-based-region of interest (DB-ROI) metrics were included. Model performance was measured, and additional subgroup analysis were performed. Results: Rectal DA demonstrated a higher intermediate-high dose (V30-65 Gy and DB-ROI at 15-50 mm) compared to DP. Conversely, at the very high dose region, rectal DA (V75 Gy and DB-ROI at 5-10 mm) were significantly lower. In MVA, rectal DB-ROI at 10 mm was predictive for Grade ≥ 1 GI toxicity for DA and DP. Age, rectal DA for D0.03 cc, and rectal DP for DB-ROI 10 mm were predictors for Grade 2 GI toxicity. Subgroup analysis revealed that patients ≥ 72 years old and a rectal DA of ≥ 78.2 Gy were highly predictive of Grade 2 GI toxicity. Conclusions: The dosimetric impact of a higher dose rectal dose in DA due to volumetric changes was minimal and was not predictive of detrimental clinical toxicity apart from rectal D0.03 cc ≥ 78.2 Gy for Grade 2 GI toxicity. The use of the DB-ROI method can provide equivalent predictive power as the DV method in toxicity prediction.

Predictive modelling for late rectal and urinary toxicities after prostate radiotherapy using planned and delivered dose.

Background and purpose: Normal tissue complication probability (NTCP) parameters derived from traditional 3D plans may not be ideal in defining toxicity outcomes for modern radiotherapy techniques. This study aimed to derive parameters of the Lyman-Kutcher-Burman (LKB) NTCP model using prospectively scored clinical data for late gastrointestinal (GI) and genitourinary (GU) toxicities for high-risk prostate cancer patients treated using volumetric-modulated-arc-therapy (VMAT). Dose-volume-histograms (DVH) extracted from planned (DP) and accumulated dose (DA) were used. Material and methods: DP and DA obtained from the DVH of 150 prostate cancer patients with pelvic-lymph-nodes irradiation treated using VMAT were used to generate LKB-NTCP parameters using maximum likelihood estimations. Defined GI and GU toxicities were recorded up to 3-years post RT follow-up. Model performance was measured using Hosmer-Lemeshow goodness of fit test and the mean area under the receiver operating characteristics curve (AUC). Bootstrapping method was used for internal validation. Results: For mild-severe (Grade ≥1) GI toxicity, the model generated similar parameters based on DA and DP DVH data (DA-D50:71.6 Gy vs DP-D50:73.4; DA-m:0.17 vs DP-m:0.19 and DA/P-n 0.04). The 95% CI for DA-D50 was narrower and achieved an AUC of >0.6. For moderate-severe (Grade ≥2) GI toxicity, DA-D50 parameter was higher and had a narrower 95% CI (DA-D50:77.9 Gy, 95% CI:76.4-79.6 Gy vs DP-D50:74.6, 95% CI:69.1-85.4 Gy) with good model performance (AUC>0.7). For Grade ≥1 late GU toxicity, D50 and n parameters for DA and DP were similar (DA-D50: 58.8 Gy vs DP-D50: 59.5 Gy; DA-n: 0.21 vs DP-n: 0.19) with a low AUC of<0.6. For Grade ≥2 late GU toxicity, similar NTCP parameters were attained from DA and DP DVH data (DA-D50:81.7 Gy vs DP-D50:81.9 Gy; DA-n:0.12 vs DP-n:0.14) with an acceptable AUCs of >0.6. Conclusions: The achieved NTCP parameters using modern RT techniques and accounting for organ motion differs from QUANTEC reported parameters. DA-D50 of 77.9 Gy for GI and DA/DP-D50 of 81.7-81.9 Gy for GU demonstrated good predictability in determining the risk of Grade ≥2 toxicities especially for GI derived D50 and are recommended to incorporate as part of the DV planning constraints to guide dose escalation strategies while minimising the risk of toxicity.

Application of an automated dose accumulation workflow in high-risk prostate cancer - validation and dose-volume analysis between planned and delivered dose.

Inter-fraction organ variations cause deviations between planned and delivered doses in patients receiving radiotherapy for prostate cancer. This study compared planned (DP) vs accumulated doses (DA) obtained from daily cone-beam computed tomography (CBCT) scans in high-risk- prostate cancer with pelvic lymph nodes irradiation. An intensity-based deformable image registration algorithm used to estimate contours for DA was validated using geometrical agreement between radiation oncologist's and deformable image registration algorithm propagated contours. Spearman rank correlations (rs) between geometric measures and changes in organ volumes were evaluated for 20 cases. Dose-volume (DV) differences between DA and DP were compared (Wilcoxon rank test, p < 0.05). A novel region-of-interest (ROI) method was developed and mean doses were analyzed. Geometrical measures for the prostate and organ-at-risk contours were within clinically acceptable criteria. Inter-group mean (± SD) CBCT volumes for the rectum were larger compared to planning CT (pCT) (51.1 ± 11.3 cm3vs 46.6 ± 16.1 cm3), and were moderately correlated with variations in pCT volumes, rs = 0.663, p < 0.01. Mean rectum DV for DA was higher at V30-40 Gy and lower at V70-75 Gy, p < 0.05. Mean bladder CBCT volumes were smaller compared to pCT (198.8 ± 55 cm3vs 211.5 ± 89.1 cm3), and was moderately correlated with pCT volumes, rs = 0.789, p < 0.01. Bladder DA was higher at V30-65 Gy and lower at V70-75 Gy (p < 0.05). For the ROI method, rectum and bladder DA were lower at 5 to 10 mm (p < 0.01) as compared to DP, whilst bladder DA was higher than DP at 20 to 50 mm (p < 0.01). Generated DA demonstrated significant differences in organ-at-risk doses as compared to DP. A well-constructed workflow incorporating a ROI DV-extraction method has been validated in terms of efficiency and accuracy designed for seamless integration in the clinic to guide future plan adaptation.

Development of an automated radiotherapy dose accumulation workflow for locally advanced high-risk prostate cancer - A technical report.

An automated dose accumulation and contour propagation workflow using daily cone beam computed tomography (CBCTs) images for prostate cases that require pelvic lymph nodes irradiation (PLNs) was developed. This workflow was constructed using MIM® software with the intention to provide accurate dose transformations for plans with two different isocentres, whereby two sequential treatment phases were prescribed. The pre-processing steps for data extractions from treatment plans, CBCTs, determination of couch shift information and management of missing CBCTs are described. To ensure that the imported translational couch shifts were in the correct orientation and readable in MIM, phantom commissioning was performed. For dose transformation, rigid registration with corrected setup shifts and scaled fractional dose was performed for pCT to daily CBCTs, which were then deformed onto CBCT1 . Fractional dose summation resulted in the final accumulated dose for the patient allowing differences in dosimetry between the planned and accumulated dose to be analysed. Contour propagations of the prostate, bladder and rectum were performed within the same workflow. Transformed contours were then deformed onto daily CBCTs to generate trending reports for analysis, including Dice Similarity Coefficient (DSC) and Mean Distance to Agreement (MDA). Results obtained from phantom commissioning (DSC = 0.96, MDA = 0.89 mm) and geometrical analysis of the propagated contours for twenty patients; prostate (DSC: 0.9 ± 0.0, MDA: 1.0 ± 0.3 mm), rectum (DSC: 0.8 ± 0.1, mm, MDA: 1.7 ± 0.6 mm) and bladder (DSC: 0.8 ± 0.1, MDA: 2.8 ± 1.0 mm) were within clinically accepted tolerances for both DSC (>0.8) and MDA (< 0.3 mm). The developed workflow is being performed on a larger patient cohort for predictive model building, with the goal of correlating observed toxicity with the actual accumulated dose received by the patient.

Randomised prospective phase II trial in multiple brain metastases comparing outcomes between hippocampal avoidance whole brain radiotherapy with or without simultaneous integrated boost: HA-SIB-WBRT study protocol.

BACKGROUND: Recent evidence supports hippocampal avoidance with whole brain radiotherapy (HA-WBRT) as the recommended treatment option in patients with good prognosis and multiple brain metastases as this results in better neurocognitive preservation compared to whole brain radiotherapy. However, there is often poor tumour control with this technique due to the low doses given. Stereotactic Radiosurgery (SRS), a form of focused radiotherapy which is given to patients who have a limited number of brain metastases, delivers a higher radiation dose to the metastases resulting in better target lesion control. With improvements in radiation technology, advanced dose-painting techniques now allow a simultaneous integrated boost (SIB) dose to lesions whilst minimising doses to the hippocampus to potentially improve brain tumour control and preserve cognitive outcomes. This technique is abbreviated to HA-SIB-WBRT or HA-WBRT+SIB. METHODS: We hypothesise that the SIB in HA-SIB-WBRT (experimental arm) will result in better tumour control compared to HA-WBRT (control arm). This may also lead to better intracranial disease control as well as functional and survival outcomes. We aim to conduct a prospective randomised phase II trial in patients who have good performance status, multiple brain metastases (4-25 lesions) and a reasonable life expectancy (> 6 months). These patients will be stratified according to the number of brain metastases and randomised between the 2 arms. We aim for a recruitment of 100 patients from a single centre over a period of 2 years. Our primary endpoint is target lesion control. These patients will be followed up over the following year and data on imaging, toxicity, quality of life, activities of daily living and cognitive measurements will be collected at set time points. The results will then be compared across the 2 arms and analysed. DISCUSSION: Patients with brain metastases are living longer. Maintaining functional independence and intracranial disease control is thus increasingly important. Improving radiotherapy treatment techniques could provide better control and survival outcomes whilst maintaining quality of life, cognition and functional capacity. This trial will assess the benefits and possible toxicities of giving a SIB to HA-WBRT. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04452084 . Date of registration 30th June 2020.

Can Medical Students Lead Effective Quality Improvement Initiatives? A Systematic Review.

Quality improvement project (QUIP) concepts are becoming embedded into medical school curricula, with many students now expected to conduct a QUIP as part of their progression. This study aimed to assess whether student-led QUIPs can be effective and sustainable. A systematic literature search was conducted using 5 databases: MEDLINE, Embase, Ovid, CINAHL, and PsycINFO. The authors searched for articles published between January 28, 1978, and January 28, 2018. In all, 3965 articles were identified through database searching, and an additional 9 articles through hand searches. After screening and full-text analysis, 12 articles were included. Greater than 50% of QUIPs described a statistically significant improvement in the primary outcome. However, effective student-led QUIPs were not necessarily sustainable, with a mean final audit at 4.4 months. Medical students have the potential to produce effective QUIPs. There now needs to be a structured approach to give medical students the freedom to test and validate more unique interventions.

Intensity-modulated radiotherapy for whole pelvis irradiation in prostate cancer: A dosimetric and plan robustness study between photons and protons.

PURPOSE: To evaluate the dosimetric impact and plan robustness of using Pencil Beam Scanning (PBS) in patients that requires prophylactic pelvic lymph nodes (PLNs) irradiation for prostate cancer. MATERIAL AND METHODS: Five intermediate to high-risk prostate patients previously treated using volumetric modulated arc therapy (VMAT), were selected for this study. Comparative proton radiotherapy plans were generated, where a three-field intensity modulated proton therapy (IMPT) plan was for the phase 1 planning target volume (PTV1) with PLNs. A technique with two posterior oblique fields using single field uniform dose (SFUD) was used for phase 2 (PTV2) volume, that comprises of the prostate and proximal seminal vesicles (Pro + proxSVs). Plan evaluation was performed on PTV coverage and dose to the organs at risk (OARs) using VMAT plans as a baseline (BL). Robust analysis on clinical target volume (CTV) coverage for the PBS plans was simulated with a 3 and 5 mm setup errors and a 3.5% range uncertainty. RESULTS: For target coverage, PTV1 and PTV2 showed negligible differences with a comparable homogeneity index (HI) values for both modalities. Proton plans produced a statistically significant lower mean dose to the bladder (32.5 Gy(RBE) vs. 46.5 Gy) and rectum (33.6 Gy(RBE) vs. 42.7 Gy). Dose to the bladder and rectum was equivalent at the high dose region. For the bowel cavity, the mean dose for proton plans were 45% lower compared to VMAT plans. Similarly, proton plans were able to achieve an overall reduction in integral dose for both treatment phase. CTV coverage remained high with all the simulated setup and range errors. CONCLUSIONS: Proposed beam geometries for PTV1 and PTV2 proton plans presented good treatment accuracy with similar target coverage as the VMAT plans. Better sparing of OARs was achieved at the low-medium dose region for the proton plans.