PURPOSE This study investigates whether focal boosting of the macroscopic visible tumor with external beam radiotherapy increases biochemical disease-free survival (bDFS) in patients with localized prostate cancer. PATIENTS AND METHODS In the phase III, multicenter, randomized controlled Focal Lesion Ablative Microboost in Prostate Cancer trial, 571 patients with intermediate- and high-risk prostate cancer were enrolled between 2009 and 2015. Patients assigned to standard treatment received 77 Gy (fractions of 2.2 Gy) to the entire prostate. The focal boost arm received an additional simultaneous integrated focal boost up to 95 Gy (fractions up to 2.7 Gy) to the intraprostatic lesion visible on multiparametric magnetic resonance imaging. Organ at risk constraints were prioritized over the focal boost dose. The primary end point was 5-year bDFS. Secondary end points were disease-free survival (DFS), distant metastases-free survival, prostate cancer-specific survival, overall survival, toxicity, and health-related quality of life. RESULTS Median follow-up was 72 months. Biochemical DFS was significantly higher in the focal boost compared with the standard arm (hazard ratio 0.45, 95% CI, 0.28 to 0.71, P < .001). At 5-year follow-up bDFS was 92% and 85%, respectively. We did not observe differences in prostate cancer-specific survival ( P = .49) and overall survival ( P = .50). The cumulative incidence of late genitourinary and GI toxicity grade ≥ 2 was 23% and 12% in the standard arm versus 28% and 13% in the focal boost arm, respectively. Both for late toxicity as health-related quality of life, differences were small and not statistically significant. CONCLUSION The addition of a focal boost to the intraprostatic lesion improved bDFS for patients with localized intermediate- and high-risk prostate cancer without impacting toxicity and quality of life. The Focal Lesion Ablative Microboost in Prostate Cancer study shows that a high focal boost strategy to improve tumor control while respecting organ at risk dose constraints is effective and safe.

Background and purpose: Local recurrences after radiotherapy for prostate cancer (PCa) often originate at the location of the macroscopic tumour(s). Since PCa cells are known to be sensitive to high fraction doses, hypofractionated whole gland stereotactic body radiotherapy (SBRT) in conjunction with a simultaneous ablative microboost to the macroscopic tumour(s) within the prostate could be a way to reduce the risk of local failure. We investigated the safety of this treatment strategy. Materials and methods:Patients with intermediate or high risk PCa were enrolled in a prospective phase II trial, called hypo-FLAME. All patients were treated with extreme hypofractionated doses of 35 Gy in 5 weekly fractions to the whole prostate gland with an integrated boost up to 50 Gy to the multiparametric (mp) MRI-defined tumour(s). Treatment related toxicity was measured using the CTCAE v4.0. The primary endpoint of the trial was treatment related acute toxicity.Results: Between April 2016 and December 2018, 100 men were treated in 4 academic centres. All patients were followed up for a minimum of 6 months. The median mean dose delivered to the visible tumour nodule(s) on mpMRI was 44.7 Gy in this trial. No grade ≥3 acute genitourinary (GU) or gastrointestinal (GI) toxicity was observed. Furthermore, 90 days after start of treatment, the cumulative acute grade 2 GU and GI toxicity rates were 34.0% and 5.0%, respectively. Conclusion:Simultaneous focal boosting to the macroscopic tumour(s) in addition to whole gland prostate SBRT is associated with acceptable acute GU and GI toxicity.

Background Migraine is much more common in females than in males, and occurrence is associated with changes in female sex hormones. Calcitonin gene-related peptide (CGRP) plays a key role in migraine, and variations in female sex hormones may affect CGRP sensitivity and/or production. Objectives Investigate repeatability, gender differences, influence of the menstrual cycle and of migraine on CGRP-dependent changes in dermal blood flow (DBF). Methods CGRP-dependent increases in DBF were assessed using laser Doppler perfusion imaging after topical application of 300 or 1000 µg capsaicin on the forearm of healthy subjects and migraine patients. Results In healthy males, DBF response did not vary over time and was comparable with DBF in male migraineurs. In healthy females, capsaicin-induced DBF responses to both doses of capsaicin were higher during menstruation compared to the late-secretory phase (p < 0.05); this menstrual cycle dependence was absent in female migraine patients. Compared to healthy subjects, female migraineurs displayed a higher DBF response both during menstruation and during the late-secretory phase (p < 0.05). Conclusions An increased capsaicin-induced, CGRP-mediated DBF response was observed during menstruation in healthy women, but in female migraine patients this increased response was not affected by the menstrual cycle.

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This study proposes optimal tracer-specific threshold-based window levels for PSMA PET-based intraprostatic gross tumour volume (GTV) contouring to reduce interobserver delineation variability.Methods: Nine 68 Ga-PSMA-11 and nine 18 F-PSMA-1007 PET scans including GTV delineations of four expert teams (GTVmanual) and a majority-voted GTV (GTVmajority) were assessed with respect to a registered histopathological GTV (GTVhisto) as gold standard reference. The standard uptake values (SUVs) per voxel were converted to a percentage (SUV%) relative to the SUVmax. The statistically optimised SUV% threshold (SOST) was defined as those that maximizes accuracy for threshold-based contouring. A leave-one-out cross-validation receiver operating characteristic (ROC) curve analysis was performed to determine the SOST for each tracer. The SOST analysis was performed twice, first using the GTVhisto contour as training structure (GTVSOST-H) and second using the GTVmajority contour as training structure (GTVSOST-MA) to correct for any limited misregistration. The accuracy of both GTVSOST-H and GTVSOST-MA was calculated relative to GTVhisto in the 'leave-one-out' patient of each fold and compared with the accuracy of GTVmanual.Results: ROC curve analysis for 68 Ga-PSMA-11 PET revealed a median threshold of 25 SUV% (range, 22-27 SUV%) and 41 SUV% (40-43 SUV%) for GTVSOST-H and GTVSOST-MA, respectively. For 18 F-PSMA-1007 PET a median threshold of 42 SUV% (39-45 SUV%) for GTVSOST-H and 44 SUV% (42-45 SUV%) for GTVSOST-MA was found. A significant pairwise difference was observed when comparing the accuracy of the GTVSOST-H contours with the median accuracy of the GTVmanual contours (median, -2.5%; IQR, -26.5 -0.2%; p = 0.020), whereas no significant pairwise difference was found for the GTVSOST-MA contours (median, -0.3%; IQR, -4.4 -0.6%; p = 0.199).Conclusions: Threshold-based contouring using GTVmajority-trained SOSTs achieves an accuracy comparable to manual contours in delineating GTVhisto. The median SOSTs of 41 SUV% for 68 Ga-PSMA-11 PET and 44 SUV% for 18 F-PSMA-1007 PET form a base for tracer-specific window levelling.

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To expand the current prediction tools for lymph node invasion (LNI) in prostate cancer (PCa) patients with today's state-of-the-art available tumor information, including multiparametric MRI (mpMRI)-based tumor (T) staging and detailed biopsy information. Materials and methods: PCa patients with registered ISUP-based biopsy information and mpMRI information, who underwent a radical prostatectomy with extended pelvic LN dissection, were selected. A LNI prediction tool was developed in 420 patients and externally validated in 187 patients. A concordance index was estimated to quantify the discriminative performance of the model. Results: In the development cohort, a median of 21 LN was removed per patient. Seventy one patients (16.9%) were diagnosed with LNI. Statistically significant predictors of LNI were the iPSA value, mpMRI-based T-stage, maximum tumor-length-in-one-core (mm) and ISUP grade group corresponding to the maximum tumor-involvement-in-one-core. The predictive accuracy of this LNI prediction tool was 79.7% after 5-fold internal cross validation and 72.5% at external validation. Conclusion: We report a contemporary, externally validated prediction tool for the presence of LNI in PCa patients. This prediction tool answers to the paradigm shift from systematic biopsies towards targeted biopsies by incorporating additional core-specific biopsy information instead of the percentage of positive cores. This new tool will also overcome stage migration, which is a potential risk when mpMRI information is used in digital rectal exam based nomograms.