Validation Strategies Supporting Clinical Integration of Prostate Segmentation Algorithms for Magnetic Resonance Imaging

Segmentation of the prostate in medical images is useful for prostate cancer diagnosis and therapy guidance. However, manual segmentation of the prostate is laborious and time-consuming, with inter-observer variability. The focus of this thesis was on accuracy, reproducibility and procedure time measurement for prostate segmentation on T2-weighted endorectal magnetic resonance imaging, and assessment of the potential of a computer-assisted segmentation technique to be translated to clinical practice for prostate cancer management. We collected an image data set from prostate cancer patients with manually-delineated prostate borders by one observer on all the images and by two other observers on a subset of images. We used a complementary set of error metrics to measure the different types of observed segmentation errors. We compared expert manual segmentation as well as semi-automatic and automatic segmentation approaches before and after manual editing by expert physicians. We recorded the time needed for user interaction to initialize the semi-automatic algorithm, algorithm execution, and manual editing as necessary. Comparing to manual segmentation, the measured errors for the algorithms compared favourably with observed differences between manual segmentations. The measured average editing times for the computer-assisted segmentation were lower than fully manual segmentation time, and the algorithms reduced the inter-observer variability as compared to manual segmentation. The accuracy of the computer-assisted approaches was near to or within the range of observed variability in manual segmentation. The recorded procedure time for prostate segmentation was reduced using computer-assisted segmentation followed by manual editing, compared to the time required for fully manual segmentation

MRI scans significantly change target coverage decisions in radical radiotherapy for prostate cancer

INTRODUCTION: Conventional clinical staging for prostate cancer has many limitations. This study evaluates the impact of adding MRI scans to conventional clinical staging for guiding decisions about radiotherapy target coverage. METHODS: This was a retrospective review of 115 patients who were treated between February 2002 and September 2005 with radical radiotherapy for prostate cancer. All patients had MRI scans approximately 2 weeks before the initiation of radiotherapy. The T stage was assessed by both conventional clinical methods (cT-staging) as well as by MRI (mT-staging). The radiotherapy target volumes were determined first based on cT-staging and then taking the additional mT staging into account. The number of times extracapsular extension or seminal vesicle invasion was incorporated into target volumes was quantified based on both cT-staging and the additional mT-staging. RESULTS: Extracapsular extension was incorporated into target volumes significantly more often with the addition of mT-staging (46 patients (40%) ) compared with cT-staging alone (37 patients (32%) ) (P = 0.002). Seminal vesicle invasion was incorporated into target volumes significantly more often with the addition of mT-staging (21 patients (18%) ) compared with cT-staging alone (three patients (3%) ) (P < 0.001). A total of 23 patients (20%) had changes to their target coverage based on the mT-staging. CONCLUSIONS: MRI scans can significantly change decisions about target coverage in radical radiotherapy for prostate cancer.Joe H. Chang, Daryl Lim Joon, Brandon T. Nguyen, Chee-Yan Hiew, Stephen Esler, David Angus, Michael Chao, Morikatsu Wada, George Quong, and Vincent Kho

Toward optimization of target planning for magnetic resonance image-targeted, 3D transrectal ultrasound-guided fusion prostate biopsy

The current clinical standard for diagnosis of prostate cancer (PCa) is 2D transrectal ultrasound (TRUS)-guided biopsy. However, this procedure has a false negative rate of 21-47% and therefore many patients return for repeat biopsies. A potential solution for improving upon this problem is “fusion” biopsy, where magnetic resonance imaging (MRI) is used for PCa detection and localization prior to biopsy. In this procedure, tumours are delineated on pre-procedural MRI and registered to the 3D TRUS needle guidance modality. However, fusion biopsy continues to yield false negative results and there remains a gap in knowledge regarding biopsy needle target selection. Within-tumour needle targets are currently chosen ad hoc by the operating clinician without accounting for guidance system and registration errors. The objective of this thesis was to investigate how the choice of target selection strategy and number of biopsy attempts made per lesion may affect PCa diagnosis in the presence of needle delivery error. A fusion prostate biopsy simulation software platform was developed, which allowed for the investigation of how needle delivery error affects PCa diagnosis and cancer burden estimation. Initial work was conducted using 3D lesions contoured on MRI by collaborating radiologists. The results indicated that more than one core must be taken from the majority of lesions to achieve a sampling probability 95% for a biopsy system with needle delivery error ≥ 3.5 mm. Furthermore, it was observed that the optimal targeting scheme depends on the relative levels of systematic and random needle delivery errors inherent to the specific fusion biopsy system. Lastly, PCa tumours contoured on digital histology images by genitourinary pathologists were used to conduct biopsy simulations. The results demonstrated that needle delivery error has a substantial impact on the biopsy core involvement observed, and that targeting of high-grade lesions may result in higher core involvement variability compared with lesions of all grades. This work represents a first step toward improving the manner in which lesions are targeted using fusion biopsy. Successful integration of these findings into current fusion biopsy system operation could lead to earlier PCa diagnosis with the need for fewer repeat biopsy procedures

Index lesion contouring on prostate MRI for targeted MRI/US fusion biopsy - Evaluation of mismatch between radiologists and urologists

PURPOSE: Mistargeting of focal lesions due to inaccurate segmentations can lead to false-negative findings on MRI-guided targeted biopsies. The purpose of this retrospective study was to examine inter-reader agreement of prostate index lesion segmentations from actual biopsy data between urologists and radiologists. METHOD: Consecutive patients undergoing transperineal MRI-targeted prostate biopsy for PI-RADS 3-5 lesions between January 2020 and December 2021 were included. Agreement between segmentations on T2w-images between urologists and radiologists was assessed with Dice similarity coefficient (DSC) and 95 % Hausdorff distance (95 % HD). Differences in similarity scores were compared using Wilcoxon test. Differences depending on lesion features (size, zonal location, PI-RADS scores, lesion distinctness) were tested with Mann-Whitney U test. Correlation with prostate signal-intensity homogeneity score (PSHS) and lesion size was tested with Spearman's rank correlation. RESULTS: Ninety-three patients (mean age 64.9 ± 7.1y, median serum PSA 6.5 [4.33-10.00]) were included. Mean similarity scores were statistically significantly lower between urologists and radiologists compared to radiologists only (DSC 0.41 ± 0.24 vs. 0.59 ± 0.23, p < 0.01; 95 %HD 6.38 ± 5.45 mm vs. 4.47 ± 4.12 mm, p < 0.01). There was a moderate and strong positive correlation between DSC scores and lesion size for segmentations from urologists and radiologists (ρ = 0.331, p = 0.002) and radiologists only (ρ = 0.501, p < 0.001). Similarity scores were worse in lesions ≤ 10 mm while other lesion features did not significantly influence similarity scores. CONCLUSION: There is significant mismatch of prostate index lesion segmentations between urologists and radiologists. Segmentation agreement positively correlates with lesion size. PI-RADS scores, zonal location, lesion distinctness, and PSHS show no significant impact on segmentation agreement. These findings could underpin benefits of perilesional biopsies

Prostate Tumor Volume Measurement on Digital Histopathology and Magnetic Resonance Imaging

An accurate assessment of prostate tumour burden supports appropriate treatment selection, ranging from active surveillance through focal therapy, to radical whole-prostate therapies. For selected patients, knowledge of the three-dimensional locations and sizes of prostate tumours on pre-procedural imaging supports planning of effective focal therapies that preferentially target tumours, while sparing surrounding healthy tissue. In the post-prostatectomy context, pathologic measurement of tumour burden in the surgical specimen may be an independent prognostic factor determining the need for potentially life-saving adjuvant therapy. An accurate and repeatable method for tumour volume assessment based on histology sections taken from the surgical specimen would be supportive both to the clinical workflow in the post-prostatectomy setting and to imaging validation studies correlating tumour burden measurements on pre-prostatectomy imaging with reference standard histologic tumour volume measurements. Digital histopathology imaging is enabling a transition to a more objective quantification of some surgical pathology assessments, such as tumour volume, that are currently visually estimated by pathologists and subject to inter-observer variability. Histologic tumour volume measurement is challenged by the traditional 3–5 mm sparse spacing of images acquired from sections of radical prostatectomy specimens. Tumour volume estimates may benefit from a well-motivated approach to inter-slide tumour boundary interpolation that crosses these large gaps in a smooth fashion. This thesis describes a new level set-based shape interpolation method that reconstructs smooth 3D shapes based on arbitrary 2D tumour contours on digital histology slides. We measured the accuracy of this approach and used it as a reference standard against which to compare previous approaches in the literature that are simpler to implement in a clinical workflow, with the aim of determining a method for histologic tumour volume estimation that is both accurate and amenable to widespread implementation. We also measured the effect of decreasing inter-slide spacing on the repeatability of histologic tumour volume estimation. Furthermore, we used this histologic reference standard for tumour volume to measure the accuracy, inter-observer variability, and inter-sequence variability of prostate tumour volume estimation based on radiologists’ contouring of multi-parametric magnetic resonance imaging (MPMRI). Our key findings were that (1) simple approaches to histologic tumour volume estimation that are based on 2- or 3-dimensional linear tumour measurements are more accurate than those based on 1-dimensional measurements; (2) although tumour shapes produced by smooth through-slide interpolation are qualitatively substantially different from those obtained from a planimetric approach normally used as a reference standard for histologic tumour volume, the volumes obtained were similar; (3) decreasing inter-slide spacing increases repeatability of histologic tumour volume estimates, and this repeatability decreases rapidly for inter-slide spacing values greater than 5 mm; (4) on MPMRI, observers consistently overestimated tumour volume as compared to the histologic reference standard; and (5) inter-sequence variability in MPMRI-based tumour volume estimation exceeded inter-observer variability

External validation of a convolutional neural network for the automatic segmentation of intraprostatic tumor lesions on 68Ga-PSMA PET images

Introduction: State of the art artificial intelligence (AI) models have the potential to become a "one-stop shop " to improve diagnosis and prognosis in several oncological settings. The external validation of AI models on independent cohorts is essential to evaluate their generalization ability, hence their potential utility in clinical practice. In this study we tested on a large, separate cohort a recently proposed state-of-the-art convolutional neural network for the automatic segmentation of intraprostatic cancer lesions on PSMA PET images.Methods: Eighty-five biopsy proven prostate cancer patients who underwent Ga-68 PSMA PET for staging purposes were enrolled in this study. Images were acquired with either fully hybrid PET/MRI (N = 46) or PET/CT (N = 39); all participants showed at least one intraprostatic pathological finding on PET images that was independently segmented by two Nuclear Medicine physicians. The trained model was available at and data processing has been done in agreement with the reference work.Results: When compared to the manual contouring, the AI model yielded a median dice score = 0.74, therefore showing a moderately good performance. Results were robust to the modality used to acquire images (PET/CT or PET/MRI) and to the ground truth labels (no significant difference between the model's performance when compared to reader 1 or reader 2 manual contouring).Discussion: In conclusion, this AI model could be used to automatically segment intraprostatic cancer lesions for research purposes, as instance to define the volume of interest for radiomics or deep learning analysis. However, more robust performance is needed for the generation of AI-based decision support technologies to be proposed in clinical practice

3D fusion of histology to multi-parametric MRI for prostate cancer imaging evaluation and lesion-targeted treatment planning

Multi-parametric magnetic resonance imaging (mpMRI) of localized prostate cancer has the potential to support detection, staging and localization of tumors, as well as selection, delivery and monitoring of treatments. Delineating prostate cancer tumors on imaging could potentially further support the clinical workflow by enabling precise monitoring of tumor burden in active-surveillance patients, optimized targeting of image-guided biopsies, and targeted delivery of treatments to decrease morbidity and improve outcomes. Evaluating the performance of mpMRI for prostate cancer imaging and delineation ideally includes comparison to an accurately registered reference standard, such as prostatectomy histology, for the locations of tumor boundaries on mpMRI. There are key gaps in knowledge regarding how to accurately register histological reference standards to imaging, and consequently further gaps in knowledge regarding the suitability of mpMRI for tasks, such as tumor delineation, that require such reference standards for evaluation. To obtain an understanding of the magnitude of the mpMRI-histology registration problem, we quantified the position, orientation and deformation of whole-mount histology sections relative to the formalin-fixed tissue slices from which they were cut. We found that (1) modeling isotropic scaling accounted for the majority of the deformation with a further small but statistically significant improvement from modeling affine transformation, and (2) due to the depth (mean±standard deviation (SD) 1.1±0.4 mm) and orientation (mean±SD 1.5±0.9°) of the sectioning, the assumption that histology sections are cut from the front faces of tissue slices, common in previous approaches, introduced a mean error of 0.7 mm. To determine the potential consequences of seemingly small registration errors such as described above, we investigated the impact of registration accuracy on the statistical power of imaging validation studies using a co-registered spatial reference standard (e.g. histology images) by deriving novel statistical power formulae that incorporate registration error. We illustrated, through a case study modeled on a prostate cancer imaging trial at our centre, that submillimeter differences in registration error can have a substantial impact on the required sample sizes (and therefore also the study cost) for studies aiming to detect mpMRI signal differences due to 0.5 – 2.0 cm3 prostate tumors. With the aim of achieving highly accurate mpMRI-histology registrations without disrupting the clinical pathology workflow, we developed a three-stage method for accurately registering 2D whole-mount histology images to pre-prostatectomy mpMRI that allowed flexible placement of cuts during slicing for pathology and avoided the assumption that histology sections are cut from the front faces of tissue slices. The method comprised a 3D reconstruction of histology images, followed by 3D–3D ex vivo–in vivo and in vivo–in vivo image transformations. The 3D reconstruction method minimized fiducial registration error between cross-sections of non-disruptive histology- and ex-vivo-MRI-visible strand-shaped fiducials to reconstruct histology images into the coordinate system of an ex vivo MR image. We quantified the mean±standard deviation target registration error of the reconstruction to be 0.7±0.4 mm, based on the post-reconstruction misalignment of intrinsic landmark pairs. We also compared our fiducial-based reconstruction to an alternative reconstruction based on mutual-information-based registration, an established method for multi-modality registration. We found that the mean target registration error for the fiducial-based method (0.7 mm) was lower than that for the mutual-information-based method (1.2 mm), and that the mutual-information-based method was less robust to initialization error due to multiple sources of error, including the optimizer and the mutual information similarity metric. The second stage of the histology–mpMRI registration used interactively defined 3D–3D deformable thin-plate-spline transformations to align ex vivo to in vivo MR images to compensate for deformation due to endorectal MR coil positioning, surgical resection and formalin fixation. The third stage used interactively defined 3D–3D rigid or thin-plate-spline transformations to co-register in vivo mpMRI images to compensate for patient motion and image distortion. The combined mean registration error of the histology–mpMRI registration was quantified to be 2 mm using manually identified intrinsic landmark pairs. Our data set, comprising mpMRI, target volumes contoured by four observers and co-registered contoured and graded histology images, was used to quantify the positive predictive values and variability of observer scoring of lesions following the Prostate Imaging Reporting and Data System (PI-RADS) guidelines, the variability of target volume contouring, and appropriate expansion margins from target volumes to achieve coverage of histologically defined cancer. The analysis of lesion scoring showed that a PI-RADS overall cancer likelihood of 5, denoting “highly likely cancer”, had a positive predictive value of 85% for Gleason 7 cancer (and 93% for lesions with volumes \u3e0.5 cm3 measured on mpMRI) and that PI-RADS scores were positively correlated with histological grade (ρ=0.6). However, the analysis also showed interobserver differences in PI-RADS score of 0.6 to 1.2 (on a 5-point scale) and an agreement kappa value of only 0.30. The analysis of target volume contouring showed that target volume contours with suitable margins can achieve near-complete histological coverage for detected lesions, despite the presence of high interobserver spatial variability in target volumes. Prostate cancer imaging and delineation have the potential to support multiple stages in the management of localized prostate cancer. Targeted biopsy procedures with optimized targeting based on tumor delineation may help distinguish patients who need treatment from those who need active surveillance. Ongoing monitoring of tumor burden based on delineation in patients undergoing active surveillance may help identify those who need to progress to therapy early while the cancer is still curable. Preferentially targeting therapies at delineated target volumes may lower the morbidity associated with aggressive cancer treatment and improve outcomes in low-intermediate-risk patients. Measurements of the accuracy and variability of lesion scoring and target volume contouring on mpMRI will clarify its value in supporting these roles

Comparison of [(11)C]choline positron emission tomography with T2- and diffusion-weighted magnetic resonance imaging for delineating malignant intraprostatic lesions

Purpose: To compare the accuracy of ¹¹C-choline (CHOL) positron emission tomography (PET) with the combination of T2-weighted (T2W) and diffusion-weighted (DW) magnetic resonance imaging (MRI) for delineating malignant intraprostatic lesions (IPLs) for guiding focal therapies and to investigate factors predicting the accuracy of CHOL-PET. Methods and Materials: This study included 21 patients who underwent CHOL-PET and T2W-/DW-MRI prior to radical prostatectomy. Two observers manually delineated IPL contours for each scan, and automatic IPL contours were generated on CHOL-PET based on varying proportions of the maximum standardized uptake value (SUV). IPLs identified on prostatectomy specimens defined the reference standard contours. The imaging-based contours were compared with the reference standard contours using Dice similarity coefficient (DSC), sensitivity and specificity. Factors that could potentially predict the DSC of the best contouring method were analyzed using linear models. Results: The best automatic contouring method, SUV60, had similar correlations (DSC 0.59) with the manual PET contours (DSC 0.52, P=0.127) and significantly better correlations than the manual MRI contours (DSC 0.37, P<0.001). The sensitivity and specificity values were 72% and 71% for SUV60; 53% and 86% for PET manual contouring; and 28% and 92% for MRI manual contouring. The tumor volume and transition zone pattern could independently predict the accuracy of CHOL-PET. Conclusions: CHOL-PET is superior to the combination of T2W- and DW-MRI for delineating IPLs. The accuracy of CHOL-PET is insufficient for gland-sparing focal therapies, 3 however may be accurate enough for focal boost therapies. The transition zone pattern is a new classification that may predict for how well CHOL-PET delineates IPLs.Joe H. Chang, Daryl Lim Joon, Ian D. Davis, Sze Ting Lee, Chee-Yan Hiew, Stephen Esler, Sylvia J. Gong, Morikatsu Wada, David Clouston, Richard O'Sullivan, Yin P. Goh, Damien Bolton, Andrew M. Scott, Vincent Kho

Treatment planning and dosimetric verification of cyberknife prostate SBRT (stereotactic body radiation therapy) on an MR-based 3D prostate model imaging insert in a pelvis phantom

Purpose of this study was to validate a novel CyberKnife stereotactic body radiotherapy (SBRT) treatment planning on an MRI-based 3D prostate model insert in an anthropomorphic pelvis phantom using Gafchromic EBT3 films to perform dosimetric measurements. The methodology of this study is based on a pelvis phantom and a physical printed 3D model of the prostate with dominant intra-prostatic-lesion and surrounding organs at risk segmented from a patient MR images. Cyberknife prostate treatment planning was performed to have at least 95% the planning target volumes (PTV: prostate expanded with margins of 5 mm in all directions except 3 mm posteriorly) covered by 3625 cGy (725x5) and a simultaneous dose escalation to 4750 cGy on the dominant intra-prostatic-lesion. Plan dosimetry verification was performed using Gafchromic EBT3 films on a Stereotactic Dose Verification Phantom. First, film calibration was done on Gafchromic EBT3 films exposed to various doses of 0-2500 cGy based on a LINAC (Trilogy) and CyberKnife monthly quality assurance (QA) for machine output calibration. Second, absolute dose measurements were taken by using films within the dose range 0-2250 cGy. Third, Gafchromic EBT3 films were placed in coronal and sagittal planes on the standard “blue phantom” or Stereotactic Dose Verification Phantom (SDVP) on which one fraction of the treatment plan is delivered for verification measurements. Then, on the prostate-pelvis phantom, a dosimetry inserts were used with films through the DIL region. After the calibration, the accuracy of absolute dose measurements with EBT3 was verified to be ≤ 1% in the dose range of interest (500-1500 cGy). On the SDVP phantom, comparison of films vs. plan for the coronal plane yielded ≥ 99.7% passing rates while for sagittal plane yielded ≥ 95.3% passing rates under the gamma criteria of ≤ 2% in dose and ≤ 2mm in distance to agreement (DTA). This study demonstrated that it is feasible to plan and deliver a SBRT treatment to prostate with a simultaneous dose escalation to the dominant intra-prostatic lesion