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Background and purpose: Dose escalation in external radiotherapy of prostate cancer shows promising results in terms of biochemical disease-free survival. Boost volume delineation guidelines are sparse which may cause high interobserver variability. The aim of this research was to characterize gross tumor volume (GTV) delineations based on multiparametric magnetic resonance imaging (mpMRI) and prostate specific membrane antigen-positron emission tomography (PSMA-PET) in relation to histopathology-validated Gleason grade 4 and 5 regions.

Material and methods: The study participants were examined with [68Ga]PSMA-PET/mpMRI prior to radical prostatectomy. Four radiation oncologists delineated GTVs in 15 study participants, on four different image types; T2-weighted (T2w), diffusion weighted imaging (DWI), dynamic contrast enhanced (DCE) and PSMA-PET scans separately. The simultaneous truth and performance level estimation (STAPLE) algorithm was used to generate combined GTVs. GTVs were subsequently compared to histopathology. We analysed how Dice similarity coefficient (DSC) and lesion coverage are affected by using single versus multiple image types as well as by adding a clinical target volume (CTV) margin.

Results: Median DSC (STAPLE) for different GTVs varied between 0.33 and 0.52. GTVPSMA-PET/mpMRI generated the highest median lesion coverage at 0.66. Combining different image types achieved similar lesion coverage as adding a CTV margin to contours from a single image type, while reducing non-malignant tissue inclusion within the target volume.

Conclusion: The combined use of mpMRI or PSMA-PET/mpMRI shows promise, achieving higher DSC and lesion coverage while minimizing non-malignant tissue inclusion, in comparison to the use of a single image type with an added CTV margin.

Background: Multiparametric magnetic resonance imaging (mpMRI) and positron emission tomography (PET) are widely used for the management of prostate cancer (PCa). However, how these modalities complement each other in PCa risk stratification is still largely unknown. We aim to provide insights into the potential of mpMRI and PET for PCa risk stratification.

Methods: We analyzed data from 55 consecutive patients with elevated prostate-specific antigen and biopsy-proven PCa enrolled in a prospective study between December 2016 and December 2019. [68Ga]PSMA-11 PET (PSMA-PET), [11C]Acetate PET (Acetate-PET) and mpMRI were co-registered with whole-mount histopathology. Lower- and higher-grade lesions were defined by International Society of Urological Pathology (ISUP) grade groups (IGG). We used PET and mpMRI data to differentiate between grades in two cases: IGG 3 vs. IGG 2 (case 1) and IGG ≥ 3 vs. IGG ≤ 2 (case 2). The performance was evaluated by receiver operating characteristic (ROC) analysis.

Results: We find that the maximum standardized uptake value (SUVmax) for PSMA-PET achieves the highest area under the ROC curve (AUC), with AUCs of 0.72 (case 1) and 0.79 (case 2). Combining the volume transfer constant, apparent diffusion coefficient and T2-weighted images (each normalized to non-malignant prostatic tissue) results in AUCs of 0.70 (case 1) and 0.70 (case 2). Adding PSMA-SUVmax increases the AUCs by 0.09 (p < 0.01) and 0.12 (p < 0.01), respectively.

Conclusions: By co-registering whole-mount histopathology and in-vivo imaging we show that mpMRI and PET can distinguish between lower- and higher-grade prostate cancer, using partially discriminative cut-off values.

The current risk assessment of prostate cancer (PC) relies on histopathological samples from biopsies and clinical variables such as prostate-specific antigen (PSA). However, this comes with uncertainties and in some cases it can be challenging to separate patients who would benefit from radical treatment and those who would not. The risk assessment tools for PC need to be improved and preferably developed into predictive markers. Medical imaging using positron emission tomography (PET) and magnetic resonance imaging (MRI) are potential diagnostic modalities for achieving such improvements. Both PET and MRI have several clinical applications in PC already and are increasingly being incorporated at different steps in the clinical management. For example, MRI is used to guide targeted biopsies, and also as a guide during planning of external beam radiotherapy treatments with focal boosting of the macroscopic visible tumour. However, more precise and individual treatment strategies demand verification of both the characterisation regarding aggressiveness and spatial distribution of the disease. 

To evaluate the performance of PET and MRI in detection of biochemical recurrent PC after radical prostatectomy, a systematic literature review was conducted (study I). The results of this systematic review indicated that there is a large variety of available imaging methods for PC being used for detecting local and/or locoregional recurrence. Many of the included studies were based on evaluation of patients with high PSA levels yielding high sensitivities and specificities. A pooled mean sensitivity was calculated to 84% for multiparametric MRI (mpMRI) and Choline-PET/CT. Methodological variations between and within studies were observed which limited the possibility of performing a meaningful meta-analysis. No publications evaluating radiotracers binding to prostate-specific membrane antigen (PSMA) were included in the review, although the early literature of using PSMA-PET showed much promise. 

To introduce a PSMA-binding radiotracer to the clinical management of PC at Umeå University Hospital a clinical trial was performed with the aim to investigate the clinical performance of the radiotracer [⁶⁸Ga]PSMA-11. In this clinical trial we aimed to both evaluate the diagnostic performance and the safety of the radiotracer. To evaluate the safety, regarding radiation-exposure, absorbed organ doses as well as the effective dose were calculated in a cohort of six low-risk PC patients (study II). The results showed that the effective dose for [⁶⁸Ga]PSMA-11 was 0.022 mSv/MBq, and that the kidneys and lacrimal glands were the organs receiving the highest organ doses. Based on these results, which were in line with other clinically used radiotracers, we could conclude that [⁶⁸Ga]PSMA-11 is, from a radiation dosimetry perspective, a safe radiotracer to inject into patients. 

The diagnostic performance, specifically regarding detection of intraprostatic tumours using [⁶⁸Ga]PSMA-11 (PSMA)-PET, mpMRI and [11C]Acetate (ACE)-PET was evaluated in a cohort of 55 intermediate and high-risk PC patients planned for radical prostatectomy with the whole mount histopathology as the reference test (study IV). The imaging modalities were radiologically reviewed and compared. Sensitivity regarding detection of intraprostatic lesions was calculated for each imaging modality. Regarding detection of lesions with a volume >0.5 cc and with a ISUP grade ≥2, PSMA-PET and mpMRI showed similar performance with sensitivities of 69% and 73%, respectively while ACE-PET had a sensitivity of 36%. 

In this clinical study, a registration procedure between histopathology and in vivo images was developed and performed in all patients. This procedure included both a 3D printed patient-specific prostate-mould, an ex vivo MRI of the specimen and image registrations (study III). The uncertainty of the precision of the registration between histopathology data and in vivo data was evaluated by comparing positions of landmarks visible in the corresponding images. The uncertainty of the method was estimated to a median in-plane error of 1.7 mm [interquartile range: 1.0, 2.5] for the entire registration procedure. 

To conclude, the tools for risk assessment of PC need to be improved and developed into predictive markers. When in vivo data is correlated with histopathology data, such as the data set collected within this thesis, it is possible to identify new predictive markers that can be used to improve the clinical management of PC. 

Background: 68Ga-labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC ([68Ga]PSMA-11) has been increasingly used to image prostate cancer using positron emission tomography (PET)/computed tomography (CT) both during diagnosis and treatment planning. It has been shown to be of clinical value for patients both in the primary and secondary stages of prostate cancer. The aim of this study was to determine the effective dose and organ doses from injection of [68Ga]PSMA-11 in a cohort of low-risk prostate cancer patients.

Methods: Six low-risk prostate cancer patients were injected with 133–178 MBq [68Ga]PSMA-11 and examined with four PET/CT acquisitions from injection to 255 min post-injection. Urine was collected up to 4 h post-injection, and venous blood samples were drawn at 45 min, 85 min, 175 min, and 245 min post-injection. Kidneys, liver, lungs, spleen, salivary and lacrimal glands, and total body where delineated, and cumulated activities and absorbed organ doses calculated. The software IDAC-Dose 2.1 was used to calculate absorbed organ doses according to the International Commission on Radiological Protection (ICRP) publication 107 using specific absorbed fractions published in ICRP 133 and effective dose according to ICRP Publication 103. We also estimated the absorbed dose to the eye lenses using Monte Carlo methods.

Results: [68Ga]PSMA-11 was rapidly cleared from the blood and accumulated preferentially in the kidneys and the liver. The substance has a biological half-life in blood of 6.5 min (91%) and 4.4 h (9%). The effective dose was calculated to 0.022 mSv/MBq. The kidneys received approximately 40 mGy after an injection with 160 MBq [68Ga]PSMA-11 while the lacrimal glands obtained an absorbed dose of 0.12 mGy per administered MBq. Regarding the eye lenses, the absorbed dose was low (0.0051 mGy/MBq).

Conclusion: The effective dose for [68Ga]PSMA-11 is 0.022 mSv/MBq, where the kidneys and lacrimal glands receiving the highest organ dose.

Background and purpose: The diagnostic accuracy of new imaging techniques requires validation, preferably by histopathological verification. The aim of this study was to develop and present a registration procedure between histopathology and in-vivo magnetic resonance imaging (MRI) of the prostate, to estimate its uncertainty and to evaluate the benefit of adding a contour-correcting registration.

Materials and methods: For twenty-five prostate cancer patients, planned for radical prostatectomy, a 3D-printed prostate mold based on in-vivo MRI was created and an ex-vivo MRI of the specimen, placed inside the mold, was performed. Each histopathology slice was registered to its corresponding ex-vivo MRI slice using a 2D-affine registration. The ex-vivo MRI was rigidly registered to the in-vivo MRI and the resulting transform was applied to the histopathology stack. A 2D deformable registration was used to correct for specimen distortion concerning the specimen's fit inside the mold. We estimated the spatial uncertainty by comparing positions of landmarks in the in-vivo MRI and the corresponding registered histopathology stack.

Results: Eighty-four landmarks were identified, located in the urethra (62%), prostatic cysts (33%), and the ejaculatory ducts (5%). The median number of landmarks was 3 per patient. We showed a median in-plane error of 1.8 mm before and 1.7 mm after the contour-correcting deformable registration. In patients with extraprostatic margins, the median in-plane error improved from 2.1 mm to 1.8 mm after the contour-correcting deformable registration.

Conclusions: Our registration procedure accurately registers histopathology to in-vivo MRI, with low uncertainty. The contour-correcting registration was beneficial in patients with extraprostatic surgical margins.

Objective: PET/CT and multiparametric MRI (mpMRI) are important diagnostic tools in clinically significant prostate cancer (csPC). The aim of this study was to compare csPC detection rates with [⁶⁸Ga]PSMA-11-PET (PSMA)-PET, [¹¹C] Acetate (ACE)-PET, and mpMRI with histopathology as reference, to identify the most suitable imaging modalities for subsequent hybrid imaging. An additional aim was to compare inter-reader variability to assess reproducibility.

Methods: During 2016–2019, all study participants were examined with PSMA-PET/mpMRI and ACE-PET/CT prior to radical prostatectomy. PSMA-PET, ACE-PET and mpMRI were evaluated separately by two observers, and were compared with histopathology-defined csPC. Statistical analyses included two-sided McNemar test and index of specific agreement.

Results: Fifty-five study participants were included, with 130 histopathological intraprostatic lesions >0.05 cc. Of these, 32% (42/130) were classified as csPC with ISUP grade ≥2 and volume >0.5 cc. PSMA-PET and mpMRI showed no difference in performance (P = 0.48), with mean csPC detection rate of 70% (29.5/42) and 74% (31/42), respectively, while with ACE-PET the mean csPC detection rate was 37% (15.5/42). Interobserver agreement was higher with PSMA-PET compared to mpMRI [79% (26/33) vs 67% (24/38)]. Including all detected lesions from each pair of observers, the detection rate increased to 90% (38/42) with mpMRI, and 79% (33/42) with PSMA-PET.

Conclusion: PSMA-PET and mpMRI showed high csPC detection rates and superior performance compared to ACE-PET. The interobserver agreement indicates higher reproducibility with PSMA-PET. The combined result of all observers in both PSMA-PET and mpMRI showed the highest detection rate, suggesting an added value of a hybrid imaging approach.

Context: Local and regional recurrence after radical prostatectomy (RP) can be treated using salvage radiotherapy (SRT). If the recurrence can be delineated on diagnostic imaging, this could allow for increasingly individualized SRT.

Objective: This systematic review aimed at evaluating the evidence regarding the usefulness of positron emission tomography (PET) and magnetic resonance imaging (MRI) in identifying local and regional recurrences, with the aim to further individualize the SRT treatment.

Evidence acquisition: A systematic PubMed/Medline search was conducted in December 2015. Studies included were imaging studies of post-RP patients focusing on local and/or regional recurrence where sensitivity and specificity of MRI or PET were the primary end points. Only studies using biopsy, other histological analysis, and/or treatment follow-up as reference standard were included. Quality Assessment of Diagnostic Accuracy Studies-2 was used to score the study quality. Twenty-five articles were deemed of sufficient quality and included in the review.

Evidence synthesis: [¹¹C]Acetate had the highest pooled sensitivity (92%), while [¹¹C]choline and [¹⁸F]choline had pooled sensitivities of 71% and 84%, respectively. The PET tracer with highest pooled specificity was [¹¹C]choline (86%). Regarding MRI, MR spectroscopy combined with dynamic contrast enhanced (DCE) MRI showed the highest pooled sensitivity (89%). High pooled sensitivities were also seen using multiparametric MRI (84%), diffusion-weighted MRI combined with T2-weigthed (T2w) imaging (82%), and DCE MRI combined with T2w imaging (82%). These also showed high pooled specificities (85%, 89%, and 92%, respectively).

Conclusions: Both MRI and PET have adequate sensitivity and specificity for the detection of prostate cancer recurrences post-RP. Multiparametric MRI, using diffusion-weighted and/or DCE imaging, and the choline-labeled tracers showed high pooled sensitivity and specificity, although their ranges were broad.

Patient summary: After reviewing imaging studies of recurrent prostate cancer after prostatectomy, we concluded that choline positron emission tomography and diffusion-weighted magnetic resonance imaging can be proposed as the current standard, with high sensitivity and specificity.

BACKGROUND: The delineation of intraprostatic lesions is vital for correct delivery of focal radiotherapy boost in patients with prostate cancer (PC). Errors in the delineation could translate into reduced tumour control and potentially increase the side effects. The purpose of this study is to compare PET-based delineation methods with histopathology.

MATERIALS AND METHODS: The study population consisted of 15 patients with confirmed high-risk PC intended for prostatectomy. [68Ga]-PSMA-PET/MR was performed prior to surgery. Prostate lesions identified in histopathology were transferred to the in vivo [68Ga]-PSMA-PET/MR coordinate system. Four radiation oncologists manually delineated intraprostatic lesions based on PET data. Various semi-automatic segmentation methods were employed, including absolute and relative thresholds, adaptive threshold, and multi-level Otsu threshold.

RESULTS: The gross tumour volumes (GTVs) delineated by the oncologists showed a moderate level of interobserver agreement with Dice similarity coefficient (DSC) of 0.68. In comparison with histopathology, manual delineations exhibited the highest median DSC and the lowest false discovery rate (FDR) among all approaches. Among semi-automatic approaches, GTVs generated using standardized uptake value (SUV) thresholds above 4 (SUV > 4) demonstrated the highest median DSC (0.41), with 0.51 median lesion coverage ratio, FDR of 0.66 and the 95th percentile of the Hausdorff distance (HD95%) of 8.22 mm.

INTERPRETATION: Manual delineations showed a moderate level of interobserver agreement. Compared to histopathology, manual delineations and SUV > 4 exhibited the highest DSC and the lowest HD95% values. The methods that resulted in a high lesion coverage were associated with a large overestimation of the size of the lesions.