Novel imaging and image-guided therapy of prostate cancer

Whole-gland prostate surgery and radiotherapy, the established approaches to localised prostate cancer (PCa), usually cause substantial adverse effects. Targeted image-guided cancer therapy has gained acceptance through improved PCa detection, localization and characterization by magnetic resonance imaging (MRI) and prostate-specific membrane antigen positron emission tomography-computed tomography (PSMA PET-CT). Focal therapy offers a potentially better trade-off between disease control and preservation of genitourinary and bowel function. MRI-guided transurethral ultrasound ablation (TULSA), a recently introduced treatment modality, uses therapeutic ultrasound directed through the urethra to thermally ablate the prostate under real-time MRI control. The applicability of TULSA to focal therapy of primary PCa, palliative therapy of symptomatic locally advanced PCa, and treatment of locally radiorecurrent PCa was investigated in a prospective setting. TULSA was shown to be a safe and effective method for local PCa control. Thermal injury was restricted to the planned treatment volume. This method enabled whole-gland ablation and focal ablation anywhere in the prostate. Furthermore, TULSA achieved local symptom relief in palliative care and encouraging preliminary oncological control in salvage care. These promising phase 1 study results enabled progression to phase 2 studies of patients with localised PCa and salvage of patients with radiorecurrent PCa. The diagnostic accuracy of MRI and PSMA PET-CT was studied to determine the extent of primary PCa, to plan TULSA treatment and evaluate treatment response. PSMA PET-CT was found to be a more sensitive method for detecting metastatic disease and appeared to accurately reflect the extent of local disease before and after TULSA treatment. PSMA PET-CT appears to detect some falsepositive bone lesions. The advantages of using MRI and PSMA PET-CT in treatment planning and monitoring treatment response are under further investigation. These studies have shown 18F-PSMA-1007 PET-CT to be effective in PCadiagnosis and TULSA to be effective in PCa therapyModernit kuvantamismenetelmät ja kuvantamisohjatut hoidot eturauhassyövässä Vakiintuneet paikallisen eturauhassyövän (PCa) hoitomenetelmät, leikkaus ja sädehoito, kohdistuvat koko rauhaseen ja aiheuttavat merkittäviä haittavaikutuksia. Magneettikuvantamisella (MRI) ja eturauhassyövän entsyymikuvantamisella (PSMA PET-TT) PCa:n havaitseminen, paikallistaminen ja karakterisointi ovat tarkentuneet. Kohdennetut kuvantamisohjatut syöpähoidot ovat siksi saaneet hyväksynnän ja tarjoavat mahdollisesti optimaalisemman vaihtoehdon hoidon hyödyn ja sen virtsa- ja sukupuolielimiin kohdistuvien haittojen suhdetta ajatellen. MRI-ohjattu eturauhasen kuumennushoito (TULSA) on uusi menetelmä, jossa virtsaputken kautta kudosta tuhoavaa ultraääntä ohjataan eturauhaseen reaaliaikaisessa MRI-ohjauksessa ja -valvonnassa. TULSA:n käyttökelpoisuutta primaarin PCa:n kohdennetussa hoidossa, paikallisesti edenneen PCa:n palliatiivisessa hoidossa ja sädehoidon jälkeen paikallisesti uusiutuneen PCa:n hoidossa tutkittiin prospektiivisessa tutkimusasetelmassa. TULSA-menetelmän todettiin tuhoavan turvallisesti ja tehokkaasti eturauhaskudosta. Lämpövaurio rajautui suunnitellulle hoitoalueelle. Menetelmä mahdollisti kuumennushoidon käytön kaikkialla eturauhasessa, koko rauhasessa tai paikallisemmin. Lisäksi TULSA-hoito lievensi paikallisoireita palliatiivisilla potilailla ja oli tehokas sädehoidon jälkeen paikallisesti uusiutuneessa PCa:ssä. Lupaavien ensimmäisen vaiheen tutkimustulosten takia olemme siirtyneet toisen vaiheen tutkimuksiin näillä uusilla indikaatioilla. MRI:n ja PSMA PET-TT:n diagnostista tarkuutta tutkittiin primaarin PCa:n levinneisyyden selvittelyssä ja TULSA-hoidon suunnittelussa sekä hoitovasteen arvioinnissa. PSMA PET-TT:n havaittiin olevan herkempi menetelmä etäpesäkkeiden tunnistamisessa ja se näytti tarkasti taudin laajuuden ennen ja jälkeen TULSAhoidon. PSMA PET-TT tunnistaa myös vääriä positiivisia luustomuutoksia. MRI:n ja PSMA PET-TT:n kliinistä hyötyä TULSA-hoidon suunnittelussa ja hoitovasteen seurannassa tutkitaan edelleen. Tutkimuksemme ovat osoittaneet PSMA PET-TT:n hyödyllisyyden PCa:n diagnostiikassa ja TULSA:n turvallisuuden ja tehon PCa:n hoidossa

Ablaatiohoidot - sädehoidon jälkeen paikallisesti uusiutuneen eturauhassyövän hoitovaihtoehto

Uusien kuvantamismenetelmien myötä eturauhassyövän paikantaminen ja riskiluokitus ovat tarkentuneet. Magneettikuvauksella pystytään usein luotettavasti visualisoimaan ennusteen kannalta merkittävin syöpäkasvain. Modernit kuvantamisohjatut ablatiiviset eli kudosta tuhoavat hoitomenetelmät kohdistuvat hoidettavaan elimeen niin, että pyritään välttämään ympäröivien kudosten vaurioita. Koko rauhasen käsittäviin ablaatiohoitoihin vaikuttaa liittyvän suotuisampi haittavaikutusprofiili kuin leikkaukseen ja sädehoitoon. Primaarikasvaimeen kohdistuvassa hoidossa eli rauhasen osan hoitostrategiassa (fokaaliterapia) elämänlaadulliset haitat näyttävät edelleen vähentyvän ilman, että tehossa olisi merkittävästi eroa koko rauhasen hoitoihin verrattuna. Tieteellinen näyttö koko rauhasen ja rauhasen osan ablaatiohoitojen pitkäaikaistehosta paikallisen eturauhassyövän hoidossa on toistaiseksi niukkaa, ja ablaatio- ja standardihoitoja vertailevat tutkimukset puuttuvat. Sen sijaan sädehoidon jälkeen paikallisesti uusiutuneen eturauhassyövän ablatiiviset hoitomenetelmät tuovat uuden tehokkaan hoidon tähän vaativaan kliiniseen ongelmaan

Fiducial markers and their impact on ablation outcome for patients treated with MR-guided transurethral ablation (TULSA): a retrospective technical analysis

Objectives: Fiducial markers improve accuracy in external beam radiation therapy (EBRT) for treatment of prostate cancer (PCa). However, many patients recur after EBRT necessitating additional treatment, such as MR-guided transurethral ultrasound ablation (TULSA). Residual markers may compromise TULSA through ultrasound field distortions and generation of local susceptibility artifacts. The objective was to investigate how markers affect the ablation outcome during clinical TULSA treatments.Subjects and methods: A retrospective analysis was performed on nine patients with radiorecurrent PCa and residual markers who received TULSA. The MR susceptibility artifact was quantified as a function of marker type, size and orientation, in particular for thermometry. The spatial distribution of markers inside the prostate was recorded, and the resulting impact on the thermal dose was measured. The thermal dose measurements were directly compared to the residual enhancing prostatic tissue observed on the immediate and control post-TULSA contrast enhanced (CE) image.Results: Successful thermal dose accumulation to the target boundary occurred for 14/20 (70%) of markers, confirmed with CE imaging. Gold markers situated simultaneously close to the urethra (≤12 mm) and far from the target boundary (≥13 mm) reduced the ultrasound depth of heating. Nitinol markers produced large, hypointense artifacts that disrupted thermometry and compromised treatment. Artifacts from gold markers were less pronounced, but when located near the target boundary, also affected treatment.Conclusion: Marker composition, orientation and location inside the prostate can all potentially impact treatment outcome. Proper patient selection through detailed MRI screening is critical to ensure successful radiorecurrent PCa treatment outcomes with TULSA.</p

Deep learning prediction of non-perfused volume without contrast agents during prostate ablation therapy

The non-perfused volume (NPV) is an important indicator of treatment success immediately after prostate ablation. However, visualization of the NPV first requires an injection of MRI contrast agents into the bloodstream, which has many downsides. Purpose of this study was to develop a deep learning model capable of predicting the NPV immediately after prostate ablation therapy without the need for MRI contrast agents. A modified 2D deep learning UNet model was developed to predict the post-treatment NPV. MRI imaging data from 95 patients who had previously undergone prostate ablation therapy for treatment of localized prostate cancer were used to train, validate, and test the model. Model inputs were T1/T2-weighted and thermometry MRI images, which were always acquired without any MRI contrast agents and prior to the final NPV image on treatment-day. Model output was the predicted NPV. Model accuracy was assessed using the Dice-Similarity Coefficient (DSC) by comparing the predicted to ground truth NPV. A radiologist also performed a qualitative assessment of NPV. Mean (std) DSC score for predicted NPV was 85% ± 8.1% compared to ground truth. Model performance was significantly better for slices with larger prostate radii (> 24 mm) and for whole-gland rather than partial ablation slices. The predicted NPV was indistinguishable from ground truth for 31% of images. Feasibility of predicting NPV using a UNet model without MRI contrast agents was clearly established. If developed further, this could improve patient treatment outcomes and could obviate the need for contrast agents altogether.</p

Comparison of reprojected bone SPECT/CT and planar bone scintigraphy for the detection of bone metastases in breast and prostate cancer

Objective The aim of this study was to compare reprojected bone SPECT/CT (RBS) against planar bone scintigraphy (BS) in the detection of bone metastases in breast and prostate cancer patients. Methods Twenty-six breast and 105 prostate cancer patients with high risk for bone metastases underwent Tc-99m-HMDP BS and whole-body SPECT/CT, 1.5-T whole-body diffusion-weighted MRI and F-18-NaF or F-18-PSMA-1007 PET/CT within two prospective clinical trials (NCT01339780 and NCT03537391). Consensus reading of all imaging modalities and follow-up data were used to define the reference standard diagnosis. The SPECT/CT data were reprojected into anterior and posterior views to produce RBS images. Both BS and RBS images were independently double read by two pairs of experienced nuclear medicine physicians. The findings were validated against the reference standard diagnosis and compared between BS and RBS on the patient, region and lesion levels. Results All metastatic patients detected by BS were also detected by RBS. In addition, three metastatic patients were missed by BS but detected by RBS. The average patient-level sensitivity of two readers for metastases was 75% for BS and 87% for RBS, and the corresponding specificity was 79% for BS and 39% for RBS. The average region-level sensitivity of two readers was 64% for BS and 69% for RBS, and the corresponding specificity was 96% for BS and 87% for RBS. Conclusion Whole-body bone SPECT/CT can be reprojected into more familiar anterior and posterior planar images with excellent sensitivity for bone metastases, making additional acquisition of planar BS unnecessary.Peer reviewe

Salvage Magnetic Resonance Imaging–guided Transurethral Ultrasound Ablation for Localized Radiorecurrent Prostate Cancer: 12-Month Functional and Oncological Results

BackgroundUp to half of all men who undergo primary radiotherapy for localized prostate cancer (PCa) experience local recurrence.ObjectiveTo evaluate the safety and early functional and oncological outcomes of salvage magnetic resonance imaging–guided transurethral ultrasound ablation (sTULSA) for men with localized radiorecurrent PCa.Design, setting, and participantsThis prospective, single-center phase 1 study (NCT03350529) enrolled men with biopsy-proven localized PCa recurrence after radiotherapy. Multiparametric magnetic resonance imaging (mpMRI) and 18F prostate-specific membrane antigen-1007 (18F PSMA-1007) positron emission tomography (PET)-computed tomography (CT) were used to confirm organ-confined disease localization. Patients underwent either whole-gland or partial sTULSA, depending on their individual tumor characteristics.Outcome measurements and statistical analysisPatients were followed at 3-mo intervals. Adverse events (AEs, Clavien-Dindo scale), functional status questionnaires (Expanded Prostate Cancer Index [EPIC]-26, International Prostate Symptom Score, International Index of Erectile Function-5), uroflowmetry, and prostate-specific antigen (PSA) were assessed at every visit. Disease control was assessed at 1 yr using mpMRI and 18F-PSMA-1007 PET-CT, followed by prostate biopsies.Results and limitationsEleven patients (median age 69 yr, interquartile range [IQR] 68–74) underwent sTULSA (3 whole-gland, 8 partial sTULSA) and have completed 12-mo follow-up. Median PSA was 7.6 ng/ml (IQR 4.9–10) and the median time from initial PCa diagnosis to sTULSA was 11 yr (IQR 9.5–13). One grade 3 and three grade 2 AEs were reported, related to urinary retention and infection. Patients reported a modest degradation in functional status, most significantly a 20% decline in the EPIC-26 irritative/obstructive domain at 12 mo. A decline in maximum flow rate (24%) was also observed. At 1 yr, 10/11 patients were free of any PCa in the targeted ablation zone, with two out-of-field recurrences. Limitations include the nonrandomized design, limited sample size, and short-term oncological outcomes.ConclusionssTULSA appears to be safe and feasible for ablation of radiorecurrent PCa, offering encouraging preliminary oncological control.Patient summaryWe present safety and 1-yr functional and oncological outcomes of magnetic resonance imaging–guided transurethral ultrasound ablation (TULSA) as a salvage treatment for local prostate cancer recurrence after primary radiation. Salvage TULSA is safe and shows the ability to effectively ablate prostate cancer recurrence, with acceptable toxicity.</div

Palliative MRI-guided transurethral ultrasound ablation for symptomatic locally advanced prostate cancer

Purpose Locally advanced prostate cancer can cause bladder outlet obstruction, gross hematuria and frequent hospitalization. While these complications are commonly treated by palliative transurethral resection of the prostate, the improvement is often insufficient. The purpose of this study was to evaluate the safety and feasibility of MRI-guided transurethral ultrasound ablation as an alternative palliative treatment option (pTULSA) for men suffering from symptomatic locally advanced prostate cancer. Methods This prospective, phase one study included 10 men in need of palliative surgical intervention due to urinary retention and gross hematuria caused by locally advanced prostate cancer. Patients were followed for 1 year at 3-month intervals. Time without catheter, time without hematuria, reduction in hospitalization time, and adverse events were measured. Results Ten patients with locally advanced prostate cancer were enrolled, all having continuous catheterization due to urinary retention and nine had gross hematuria before treatment. At 1 week post-pTULSA five patients were catheter-free. At last follow-up catheter-free and gross hematuria-free rates were 70% and 100%, respectively. Average hospitalization time from local complications reduced from 7.3 to 1.4 days in the 6 months before and after pTULSA. No > Grade 2 treatment related adverse events were reported, with all five being urinary tract infections. Conclusions pTULSA appears safe and feasible for palliative ablation of locally advanced prostate cancer. The therapy seems to accomplish long-term hematuria control, can relieve bladder outlet obstruction in selected patients, and seems to reduce the burden of hospitalization due to local complications.</div

Histopathological evaluation of prostate specimens after thermal ablation may be confounded by the presence of thermally-fixed cells

Purpose: Prostate cancer can be eradicated with heat exposure. However, high and rapid temperature elevations may cause thermofixation giving the appearance of viable tissue. The purpose was to characterize the immunoprofile and evaluate the viability of prostate regions with suspected thermofixation. Methods and materials: A prospective, ethics-approved and registered study (NCT03350529) enrolled six patients with MRI-visible, biopsy-concordant prostate cancer to undergo lesion-targeted MRI-guided transurethral ultrasound ablation (TULSA) followed by radical prostatectomy at 3 weeks, to evaluate the accuracy and efficacy of TULSA with whole-mount histology as a reference standard. If ambiguity about complete necrosis within the ablated region remained after hematoxylin-eosin staining, viability was assessed by immunohistochemistry. Treatment day MRI-thermometry and 3-week contrast-enhanced MRI post-TULSA were examined to assess ablation success and correlation with histopathology. Results: One patient presented with an apparently viable subregion inside the ablated area, surrounded by necrosis on H&E staining, located where temperature was highest on MRI-thermometry and tissues completely devascularized on MRI. Immunoprofile of the apparently viable tissue revealed changes in staining patterns suggesting thermofixation; the most significant evidence was the negative cytokeratin 8 staining detected with Cam5.2 antibody. A comprehensive literature review supports these observations of thermofixation with similar findings in prostate and other tissues. Conclusion: Thermally-fixed cells can sustain morphology on H&E staining. Misinterpretation of treatment failure may occur, if this phenomenon is not recognized and immunohistochemistry performed. Based on the previous literature and the current study, Cam5.2 staining for cytokeratin 8 appears to be a practical and reliable tool for distinguishing thermally-fixed from viable cells.</p

Prospective comparison of F-18-PSMA-1007 PET/CT, whole-body MRI and CT in primary nodal staging of unfavourable intermediate- and high-risk prostate cancer

Purpose To prospectively compare F-18-prostate-specific membrane antigen (PSMA)-1007 positron emission tomography (PET)/CT, whole-body magnetic resonance imaging (WBMRI) including diffusion-weighted imaging (DWI) and standard computed tomography (CT), in primary nodal staging of prostate cancer (PCa). Methods Men with newly diagnosed unfavourable intermediate- or high-risk PCa prospectively underwent F-18-PSMA-1007 PET/CT, WBMRI with DWI and contrast-enhanced CT within a median of 8 days. Six readers (two for each modality) independently reported pelvic lymph nodes as malignant, equivocal or benign while blinded to the other imaging modalities. Sensitivity, specificity and accuracy were reported according to optimistic (equivocal lesions interpreted as benign) and pessimistic (equivocal lesions interpreted as malignant) analyses. The reference standard diagnosis was based on multidisciplinary consensus meetings where available histopathology, clinical and follow-up data were used. Results Seventy-nine patients completed all the imaging modalities, except for one case of interrupted WBMRI. Thirty-one (39%) patients had pelvic lymph node metastases, which were detected in 27/31 (87%), 14/31 (45%) and 8/31 (26%) patients by F-18-PSMA-1007 PET/CT, WBMRI with DWI and CT, respectively (optimistic analysis). In 8/31 (26%) patients, only F-18-PSMA-1007 PET/CT detected malignant lymph nodes, while the other two imaging modalities were reported as negative. At the patient level, sensitivity and specificity values for F-18-PSMA-1007 PET/CT, WBMRI with DWI and CT in optimistic analysis were 0.87 (95%CI 0.71-0.95) and 0.98 (95%CI 0.89-1.00), 0.37 (95%CI 0.22-0.55) and 0.98 (95%CI 0.89-1.00) and 0.26 (95%CI 0.14-0.43) and 1.00 (95%CI 0.93-1.00), respectively. Conclusion F-18-PSMA-1007 PET/CT showed significantly greater sensitivity in nodal staging of primary PCa than did WBMRI with DWI or CT, while maintaining high specificity.Peer reviewe