From once-weekly to semi-weekly whole prostate gland stereotactic radiotherapy with focal boosting: Primary endpoint analysis of the multicenter phase II hypo-FLAME 2.0 trial.

BACKGROUND AND PURPOSE: The hypo-FLAME trial showed that once-weekly (QW) focal boosted prostate stereotactic body radiotherapy (SBRT) is associated with acceptable acute genitourinary (GU) and gastrointestinal (GI) toxicity. Currently, we investigated the safety of reducing the overall treatment time (OTT) of focal boosted prostate SBRT from 29 to 15 days. MATERIAL AND METHODS: Patients with intermediate- and high-risk prostate cancer were treated with SBRT delivering 35 Gy in 5 fractions to the whole prostate gland with an iso-toxic boost up to 50 Gy to the intraprostatic lesion(s) in a semi-weekly (BIW) schedule. The primary endpoint was radiation-induced acute toxicity (CTCAE v5.0). Changes in quality of life (QoL) were examined in terms of proportions achieving a minimal clinically important change (MCIC). Finally, acute toxicity and QoL scores of the BIW schedule were compared with the results of the prior QW hypo-FLAME schedule (n = 100). RESULTS: Between August 2020 and February 2022, 124 patients were enrolled and treated BIW. No grade ≥3 GU or GI toxicity was observed. The 90-days cumulative incidence of grade 2 GU and GI toxicity rates were 47.5% and 7.4%, respectively. Patients treated QW scored significant less grade 2 GU toxicity (34.0%, p = 0.01). No significant differences in acute GI toxicity were observed. Furthermore, patients treated QW had a superior acute bowel and urinary QoL. CONCLUSION: Semi-weekly prostate SBRT with iso-toxic focal boosting is associated with acceptable acute GU and GI toxicity. Based on the comparison between the QW and BIW schedule, patients should be counselled regarding the short-term advantages of a more protracted schedule. Registration number ClinicalTrials.gov: NCT04045717.

Genomic Classifiers in Personalized Prostate Cancer Radiation Therapy Approaches: A Systematic Review and Future Perspectives Based on International Consensus.

Current risk-stratification systems for prostate cancer (PCa) do not sufficiently reflect the disease heterogeneity. Genomic classifiers (GC) enable improved risk stratification after surgery, but less data exist for patients treated with definitive radiation therapy (RT) or RT in oligo-/metastatic disease stages. To guide future perspectives of GCs for RT, we conducted (1) a systematic review on the evidence of GCs for patients treated with RT and (2) a survey of experts using the Delphi method, addressing the role of GCs in personalized treatments to identify relevant fields of future clinical and translational research. We performed a systematic review and screened ongoing clinical trials on ClinicalTrials.gov. Based on these results, a multidisciplinary international team of experts received an adapted Delphi method survey. Thirty-one and 30 experts answered round 1 and round 2, respectively. Questions with ≥75% agreement were considered relevant and included in the qualitative synthesis. Evidence for GCs as predictive biomarkers is mainly available to the postoperative RT setting. Validation of GCs as prognostic markers in the definitive RT setting is emerging. Experts used GCs in patients with PCa with extensive metastases (30%), in postoperative settings (27%), and in newly diagnosed PCa (23%). Forty-seven percent of experts do not currently use GCs in clinical practice. Expert consensus demonstrates that GCs are promising tools to improve risk-stratification in primary and oligo-/metastatic patients in addition to existing classifications. Experts were convinced that GCs might guide treatment decisions in terms of RT-field definition and intensification/deintensification in various disease stages. This work confirms the value of GCs and the promising evidence of GC utility in the setting of RT. Additional studies of GCs as prognostic biomarkers are anticipated and form the basis for future studies addressing predictive capabilities of GCs to optimize RT and systemic therapy. The expert consensus points out future directions for GC research in the management of PCa.

Urethral and bladder dose-effect relations for late genitourinary toxicity following external beam radiotherapy for prostate cancer in the FLAME trial.

PURPOSE OR OBJECTIVES: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical disease-free survival increased, without significantly increasing toxicity. The aim of the present study was to investigate the association between radiation dose to the bladder and urethra and genitourinary (GU) toxicity grade ≥2 in the entire cohort. MATERIAL AND METHODS: The dose-effect relations of the urethra and bladder dose, separately, and GU toxicity grade ≥2 (CTCAE 3.0) up to five years after treatment were assessed. A mixed model analysis for repeated measurements was used, adjusting for age, diabetes mellitus, T-stage, baseline GU toxicity grade ≥1 and institute. Additionally, the association between the dose and separate GU toxicity subdomains were investigated. RESULTS: Dose-effect relations were observed for the dose (Gy) to the bladder D2 cm3 and urethra D0.1 cm3, with adjusted odds ratios of 1.14 (95% CI 1.12-1.16, p < 0.0001) and 1.12 (95% CI 1.11-1.14, p < 0.0001), respectively. Additionally, associations between the dose to the urethra and bladder and the subdomains urinary frequency, urinary retention and urinary incontinence were observed. CONCLUSION: Further increasing the dose to the bladder and urethra will result in a significant increase in GU toxicity following EBRT. Focal boost treatment plans should incorporate a urethral dose-constraint. Further treatment optimization to increase the focal boost dose without increasing the dose to the urethra and other organs at risk should be a focus for future research, as we have shown that a focal boost is beneficial in the treatment of prostate cancer.

Patterns of Failure Following External Beam Radiotherapy With or Without an Additional Focal Boost in the Randomized Controlled FLAME Trial for Localized Prostate Cancer.

BACKGROUND: Focal dose escalation in external beam radiotherapy (EBRT) showed an increase in 5-yr biochemical disease-free survival in the Focal Lesion Ablative Microboost in Prostate Cancer (FLAME) trial. OBJECTIVE: To analyze the effect of a focal boost to intraprostatic lesions on local failure-free survival (LFS) and regional + distant metastasis-free survival (rdMFS). DESIGN, SETTING, AND PARTICIPANTS: Patients with intermediate- or high-risk localized prostate cancer were included in FLAME, a phase 3, multicenter, randomized controlled trial. INTERVENTION: Standard treatment of 77 Gy to the entire prostate in 35 fractions was compared to an additional boost to the macroscopic tumor of up to 95 Gy during EBRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: LFS and rdMFS, measured via any type of imaging, were compared between the treatment arms using Kaplan-Meier and Cox regression analyses. Dose-response curves were created for local failure (LF) and regional + distant metastatic failure (rdMF) using logistic regression. RESULTS AND LIMITATIONS: A total of 571 patients were included in the FLAME trial. Over median follow-up of 72 mo (interquartile range 58-86), focal boosting decreased LF (hazard ratio [HR] 0.33, 95% confidence interval [CI] 0.14-0.78) and rdMF (HR 0.58, 95% CI 0.35-0.93). Dose-response curves showed that a greater dose to the tumor resulted in lower LF and rdMF rates. CONCLUSIONS: A clear dose-response relation for LF and rdMF was observed, suggesting that adequate focal dose escalation to intraprostatic lesions prevents undertreatment of the primary tumor, resulting in an improvement rdMF. PATIENT SUMMARY: Radiotherapy is a treatment option for high-risk prostate cancer. The FLAME trial has shown that a high dose specifically targeted at the tumor within the prostate will result in better disease outcome, with less likelihood of regional and distant disease spread. The FLAME trial is registered on ClinicalTrials.gov as NCT01168479.

Anorectal dose-effect relations for late gastrointestinal toxicity following external beam radiotherapy for prostate cancer in the FLAME trial.

BACKGROUND AND PURPOSE: The phase III FLAME trial (NCT01168479) showed an increase in five-year biochemical disease-free survival, with no significant increase in toxicity when adding a focal boost to external beam radiotherapy (EBRT) for localized prostate cancer [Kerkmeijer et al. JCO 2021]. The aim of this study was to investigate the association between delivered radiation dose to the anorectum and gastrointestinal (GI) toxicity (grade ≥2). MATERIAL AND METHODS: All patients in the FLAME trial were analyzed, irrespective of treatment arm. The dose-effect relation of the anorectal dose parameters (D2cm3 and D50%) and GI toxicity grade ≥2 in four years of follow-up was assessed using a mixed model analysis for repeated measurements, adjusted for age, cardiovascular disease, diabetes mellitus, T-stage, baseline toxicity grade ≥1, hormonal therapy and institute. RESULTS: A dose-effect relation for D2cm3 and D50% was observed with adjusted odds ratios of 1.17 (95% CI 1.13-1.21, p < 0.0001) and 1.20 (95% CI 1.14-1.25, p < 0.0001) for GI toxicity, respectively. CONCLUSION: Although there was no difference in toxicity between study arms, a higher radiation dose to the anorectum was associated with a statistically significant increase in GI toxicity following EBRT for prostate cancer. This dose-effect relation was present for both large and small anorectal volumes. Therefore, further increase in dose to the anorectum should be weighed against the benefit of focal dose escalation for prostate cancer.

Automated treatment planning of prostate stereotactic body radiotherapy with focal boosting on a fast-rotating O-ring linac: Plan quality comparison with C-arm linacs.

PURPOSE: The integration of auto-segmentation and automated treatment planning methods on a fast-rotating O-ring linac may improve the time efficiency of online adaptive radiotherapy workflows. This study investigates whether automated treatment planning of prostate SBRT with focal boosting on the O-ring linac could generate plans that are of similar quality as those obtained through manual planning on clinical C-arm linacs. METHODS: For 20 men with prostate cancer, reference treatment plans were generated on a TrueBeam STx C-arm linac with HD120 MLC and a TrueBeam C-arm linac with Millennium 120 MLC using 6 MV flattened dual arc VMAT. Manual planning on the Halcyon fast-rotating O-ring linac was performed using 6 MV FFF dual arc VMAT (HA2-DL10) and triple arc VMAT (HA3-DL10) to investigate the performance of the dual-layer MLC system. Automated planning was performed for triple arc VMAT on the Halcyon linac (ET3-DL10) using the automated planning algorithms of Ethos Treatment Planning. The prescribed dose was 35 Gy to the prostate and 30 Gy to the seminal vesicles in five fractions. The iso-toxic focal boost to the intraprostatic tumor nodule(s) was aimed to receive up to 50 Gy. Plan deliverability was verified using portal image dosimetry measurements. RESULTS: Compared to the C-arm linacs, ET3-DL10 shows increased seminal vesicles PTV coverage (D99% ) and reduced high-dose spillage to the bladder (V37Gy ) and urethra (D0.035cc ) but this came at the cost of increased high-dose spillage to the rectum (V38Gy ) and a higher intermediate dose spillage (D2cm). No statistically significant differences were found when benchmarking HA2-DL10 and HA3-DL10 with the C-arm linacs. All plans passed the patient-specific QA tolerance limit. CONCLUSIONS: Automated planning of prostate SBRT with focal boosting on the fast-rotating O-ring linac is feasible and achieves similar plan quality as those obtained on clinical C-arm linacs using manual planning.

68Ga-PSMA-11 PET, 18F-PSMA-1007 PET, and MRI for Gross Tumor Volume Delineation in Primary Prostate Cancer: Intermodality and Intertracer Variability.

PURPOSE: To assess the intermodality and intertracer variability of gallium-68 (68Ga)- or fluorine-18 (18F)-labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) and biparametric magnetic resonance imaging (bpMRI)-based gross tumor volume (GTV) delineation for focal boosting in primary prostate cancer. METHODS: Nineteen prospectively enrolled patients with prostate cancer underwent a PSMA PET/MRI scan, divided into a 1:1 ratio between 68Ga-PSMA-11 and 18F-PSMA-1007, before radical prostatectomy (IWT140193). Four delineation teams performed manual contouring of the GTV based on bpMRI and PSMA PET imaging, separately. Index lesion coverage (overlap%) and interobserver variability were assessed. Furthermore, the distribution of the voxelwise normalized standardized uptake values (SUV%) was determined for the majority-voted (>50%) GTV (GTVmajority) and whole prostate gland to investigate intertracer variability. The median patientwise SUV% contrast ratio (SUV%-CR, calculated as median GTVmajority SUV% / median prostate gland without GTVmajority SUV%) was calculated according to the tracer used. RESULTS: A significant difference in overlap% favoring PSMA PET compared with bpMRI was found in the 18F subgroup (median, 63.0% vs 53.1%; P = .004) but was not present in the 68Ga subgroup (32.5% vs 50.6%; P = .100). Regarding interobserver variability, measured Sørensen-Dice coefficients (0.58 vs 0.72) and calculated mean distances to agreement (2.44 mm vs 1.22 mm) were statistically significantly lower and higher, respectively, for the 18F cohort compared with the 68Ga cohort. For the bpMRI-based delineations, the median Sørensen-Dice coefficient and mean distance to agreement were 0.63 and 1.76 mm, respectively. Median patientwise SUV%-CRs of 1.8 (interquartile range [IQR], 1.6-2.7) for 18F-PSMA and 3.3 (IQR, 2.7-5.9) for 68Ga-PSMA PET images were found. CONCLUSIONS: Both MRI and PSMA PET provided consistent intraprostatic GTV lesion detection. However, the PSMA tracer seems to have a major influence on the contour characteristics, owing to an apparent difference in SUV% distribution in the prostate gland.

A fatal wound complication following sequential anti-angiogenesis, immune checkpoint inhibition and ultra-hypofractionated radiotherapy.

PURPOSE: Multimodality treatments combining radiotherapy, immune therapy and/or targeted therapy are under heavy investigation. Promising data from clinical trials are emerging, nevertheless unexpected interactions and adverse events should not be overlooked. CASE PRESENTATION: Here we present a case study of a patient with metastatic colon adenocarcinoma treated sequentially with a chemotherapy/targeted therapy combination, immune checkpoint inhibitors and ultra-hypofractionated radiotherapy. After radiation treatment, the patient developed extensive posterior abdominal wall wounds coinciding with regression of the irradiated metastatic tumour mass and marked elevation of the inflammation parameters. CONCLUSION: This case represents an unusual fatal wound complication after palliative ultra-hypofractionated radiotherapy. Further research into synergistic effects of sequential radiotherapy and anti-angiogenesis therapy may provide an advantage in anticipating severe sequelae.

Focal Boost to the Intraprostatic Tumor in External Beam Radiotherapy for Patients With Localized Prostate Cancer: Results From the FLAME Randomized Phase III Trial.

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.

Optimal 68Ga-PSMA and 18F-PSMA PET window levelling for gross tumour volume delineation in primary prostate cancer.

PURPOSE: 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 68Ga-PSMA-11 and nine 18F-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 the 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 maximises 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 68Ga-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 18F-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 with manual contours in delineating GTVhisto. The median SOSTs of 41 SUV% for 68Ga-PSMA-11 PET and 44 SUV% for 18F-PSMA-1007 PET form a base for tracer-specific window levelling. TRIAL REGISTRATION: Clinicaltrials.gov ; NCT03327675; 31-10-2017.

Variation in adjuvant and early salvage radiotherapy after robot-assisted radical prostatectomy for prostate cancer: a population-based cohort study.

Purpose: The primary aim of the study was to assess the association between having a radiotherapy (RT) department on-site at the surgical centre and the performed postoperative treatment strategy for prostate cancer (PCa) patients. According to the current international guidelines, adjuvant radiotherapy (ART) or a regular prostate-specific antigen (PSA)-based follow-up with (early) salvage radiotherapy ((e)SRT) if needed is recommended in case of adverse pathological characteristics.Material and methods: Prospective data on consecutive robot-assisted radical prostatectomy (RARP) patients in Belgium from 2009 to 2016 were identified in the Belgian Robotic-Assisted-Laparoscopic-Prostatectomy (Be-RALP) database. Multivariable regression was used to evaluate patient- and facility-related factors associated with postoperative radiation treatment.Results: 2072 patients undergoing a RARP, suffering at least one of the following adverse pathological features, i.e., extracapsular extension (ECE), seminal vesicle invasion (SVI) or positive section margins (PSM), and with registered follow-up until 24 months were enrolled. After RARP, ART was applied to 9.1% and (e)SRT to 12.6% of the patients. Multivariable analysis demonstrated that patients were more likely to receive ART or (e)SRT if they were operated in a hospital with a RT department on-site (odds ratio, ART: 1.49 [1.07-2.07]; (e)SRT: 1.55 [1.16-2.06]). Furthermore, the presence of higher tumour category (T-category) and/or PSM on final pathology was associated with a higher chance of getting ART and (e)SRT (p < .01).Conclusion: Variations in ART and (e)SRT are not only driven by patient-related characteristics. In our nationwide cohort, the availability of a RT department on-site at the surgical centre was found to be an independent predictor for ART and (e)SRT, with a 1.5 times higher odds of receiving postoperative RT during the first 24 months after surgery.

Knowledge-Based Assessment of Focal Dose Escalation Treatment Plans in Prostate Cancer.

PURPOSE: In a randomized focal dose escalation radiation therapy trial for prostate cancer (FLAME), up to 95 Gy was prescribed to the tumor in the dose-escalated arm, with 77 Gy to the entire prostate in both arms. As dose constraints to organs at risk had priority over dose escalation and suboptimal planning could occur, we investigated how well the dose to the tumor was boosted. We developed an anatomy-based prediction model to identify plans with suboptimal tumor dose and performed replanning to validate our model. METHODS AND MATERIALS: We derived dose-volume parameters from planned dose distributions of 539 FLAME trial patients in 4 institutions and compared them between both arms. In the dose-escalated arm, we determined overlap volume histograms and derived features representing patient anatomy. We predicted tumor D98% with a linear regression on anatomic features and performed replanning on 21 plans. RESULTS: In the dose-escalated arm, the median tumor D50% and D98% were 93.0 and 84.7 Gy, and 99% of the tumors had a dose escalation greater than 82.4 Gy (107% of 77 Gy). In both arms organs at risk constraints were met. Five out of 73 anatomic features were found to be predictive for tumor D98%. Median predicted tumor D98% was 4.4 Gy higher than planned D98%. Upon replanning, median tumor D98% increased by 3.0 Gy. A strong correlation between predicted increase in D98% and realized increase upon replanning was found (ρ = 0.86). CONCLUSIONS: Focal dose escalation in prostate cancer was feasible with a dose escalation to 99% of the tumors. Replanning resulted in an increased tumor dose that correlated well with the prediction model. The model was able to identify tumors on which a higher boost dose could be planned. The model has potential as a quality assessment tool in focal dose escalated treatment plans.

Primary endpoint analysis of the multicentre phase II hypo-FLAME trial for intermediate and high risk prostate cancer.

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.

Development and External Validation of a Multiparametric Magnetic Resonance Imaging and International Society of Urological Pathology Based Add-On Prediction Tool to Identify Prostate Cancer Candidates for Pelvic Lymph Node Dissection.

PURPOSE: We sought to expand current prediction tools for lymph node invasion in patients with prostate cancer using current state-of-the-art available tumor information, including multiparametric magnetic resonance imaging based tumor stage and detailed biopsy information. MATERIALS AND METHODS: We selected patients with prostate cancer for study who had available registered information on ISUP (International Society of Urological Pathology) based biopsy grading and multiparametric magnetic resonance imaging, and who had undergone radical prostatectomy with extended pelvic lymph node dissection. We developed a lymph node invasion prediction tool in 420 patients and externally validated it in 187. A concordance index was estimated to quantify the discriminative performance of the model. RESULTS: In the development cohort a median of 21 lymph nodes were removed per patient and 71 patients (16.9%) were diagnosed with lymph node invasion. Statistically significant predictors of lymph node invasion were the initial prostate specific antigen value, multiparametric magnetic resonance imaging based T stage, maximum tumor length in 1 core in mm and ISUP grade group corresponding to the maximum tumor involvement in 1 core. The predictive accuracy of this lymph node invasion prediction tool was 79.7% after fivefold internal cross validation and 72.5% after external validation. CONCLUSIONS: We report a contemporary, externally validated prediction tool for lymph node invasion in patients with prostate cancer. This prediction tool is a response to the paradigm shift from systematic to targeted biopsies by incorporating additional core specific biopsy information instead of the percent of positive cores. This new tool will also overcome stage migration, which is a potential risk when multiparametric magnetic resonance imaging information is used in digital rectal examination based nomograms.

Stereotactic body radiation therapy with optional focal lesion ablative microboost in prostate cancer: Topical review and multicenter consensus.

Stereotactic body radiotherapy (SBRT) for prostate cancer (PCa) is gaining interest by the recent publication of the first phase III trials on prostate SBRT and the promising results of many other phase II trials. Before long term results became available, the major concern for implementing SBRT in PCa in daily clinical practice was the potential risk of late genitourinary (GU) and gastrointestinal (GI) toxicity. A number of recently published trials, including late outcome and toxicity data, contributed to the growing evidence for implementation of SBRT for PCa in daily clinical practice. However, there exists substantial variability in delivering SBRT for PCa. The aim of this topical review is to present a number of prospective trials and retrospective analyses of SBRT in the treatment of PCa. We focus on the treatment strategies and techniques used in these trials. In addition, recent literature on a simultaneous integrated boost to the tumor lesion, which could create an additional value in the SBRT treatment of PCa, was described. Furthermore, we discuss the multicenter consensus of the FLAME consortium on SBRT for PCa with a focal boost to the macroscopic intraprostatic tumor nodule(s).

Impact of Magnetic Resonance Imaging on Prostate Cancer Staging and European Association of Urology Risk Classification.

OBJECTIVE: To investigate the impact of magnetic resonance imaging (MRI) information on clinical staging, risk stratification, and treatment recommendations for prostate cancer (PCa) according to the European Association of Urology (EAU) guidelines. METHODS: We performed a single-center analysis of 180 men with PCa, undergoing clinical staging by digital rectal examination (DRE) as well as MRI before their robot-assisted radical prostatectomy. Patients were stratified according to the EAU guidelines into 4 well-defined risk categories, based on their clinical T-stage assessed by either DRE or MRI. Descriptive statistics of categorical variables are shown as frequencies and proportions. Differences between both scenarios (DRE- vs MRI-staged) were analyzed using a paired-samples sign test. RESULTS: Use of MRI information instead of DRE information leads to significant upstaging of clinical T-stage (33%) and EAU risk grouping (31%). When comparing these results with the pathologic T-stage, MRI showed a higher sensitivity than DRE to detect nonorgan-confined PCa (59% vs 41%; P <.01). In contrast, the specificity of MRI was lower than DRE (69% vs 95%; P <.01). Incorporation of MRI-based instead of DRE-based staging in the treatment decision process would alter the surgical treatment strategy in 49/180 patients (27%). CONCLUSION: The incorporation of MRI information substantially affects the treatment choice in PCa patients as compared to using the current available EAU guidelines based on DRE information. More specifically, treatment intensification would be recommended in 1 out of 4 patients.

Benefits of Elective Para-Aortic Radiotherapy for pN1 Prostate Cancer Using Arc Therapy (Intensity-Modulated or Volumetric Modulated Arc Therapy): Protocol for a Nonrandomized Phase II Trial.

BACKGROUND: In patients with prostate cancer (PCa) with histopathologically proven pelvic lymph node (LN) metastasis (pN1) after extended pelvic lymph node dissection (ePLND), multimodality treatment consisting of treatment of the primary tumor and whole pelvic radiotherapy (WPRT) combined with androgen deprivation therapy (ADT) offers promising results, leading to better cause-specific survival rates compared with ADT alone. However, in case more than one pelvic LN is invaded by the tumor, approximately 40% of the patients relapse biochemically and clinically. Clinical relapse is present in the para-aortic LNs (M1a disease) in up to 77% of the relapsing cases. OBJECTIVE: We hypothesize that, based on the evidence that positive LNs represent the door to hematogenous dissemination, elective para-aortic irradiation will reduce the development of both retroperitoneal nodal (M1a) and distant metastasis (M1b or M1c disease), postpone the need for palliative ADT, and prolong the time to castration-refractory disease. METHODS: To test this hypothesis, we will conduct a prospective, nonrandomized phase II trial to study the efficacy of additional elective para-aortic radiotherapy (PART) in pN1 patients compared with those who were historically treated with adjuvant WPRT alone. We aim to include 137 patients with PCa and presence of pN1 disease after ePLND. With this number of patients, an improvement of 15% in the 5-year clinical relapse-free survival can be detected with a power of 80%. RESULTS: Recruitment of patients for this trial started in 2017 and will be completed approximately by March 2020. CONCLUSIONS: This is the first phase II trial to investigate the benefits of an elective PART in patients with PCa. The results of this trial will potentially serve as a sound base for a later randomized phase III trial. All participants are given a PART information sheet and required to give written informed consent. Results are expected to be published in a peer-reviewed journal. TRIAL REGISTRATION: ClinicalTrials.gov NCT03079323; https://clinicaltrials.gov/ct2/show/NCT03079323 (Archived by WebCite at http://www.webcitation.org/73ELimv1d). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/11256.

Characterization of a novel liquid fiducial marker for multimodal image guidance in stereotactic body radiotherapy of prostate cancer.

PURPOSE: Liquid fiducial markers have shown to be a promising alternative to solid gold markers in terms of imaging artifact reduction, patient comfort, and compatibility with different imaging modalities. This study aims to investigate the performance of the novel BioXmark® liquid marker for state-of-the-art multimodal imaging used in prostate cancer (PCa) radiotherapy, encompassing kV CT/CBCT, multiparametric MRI, and kV x-ray imaging. In addition, automatic detection of the liquid markers in x-ray imaging for prostate motion monitoring during treatment was investigated. METHODS: A total of eight BioXmark® liquid markers with varying volumes (range 5-300 µL) were casted on a square grid into a gelatin phantom insert. A cylindrical gold marker (QLRAD, length = 7 mm, Ø = 1 mm) was inserted for reference. Liquid marker visibility and streaking artifacts in CT/CBCT imaging were evaluated by placing the gelatin phantom into a CIRS anthropomorphic phantom. Relevant MRI characteristics such as the T2 and T1 relaxation times, the ADC value, and the relative proton density (ρH) were quantified by placing the gelatin phantom insert next to a T1MES mapping phantom and a water-filled syringe for reference. Ex vivo multiparametric MRI images were acquired by placing the gelatin phantom next to a resected prostate specimen. Anterior-posterior x-ray projection images were obtained by placing the gelatin phantom insert on top of an anthropomorphic pelvic phantom with internal pelvic bony structures and were acquired for five positions relative to the bony anatomy and 24 clinically relevant x-ray exposure settings. To quantify individual automatic marker detection, single markers were artificially isolated in the x-ray images using postprocessing. RESULTS: Markers of all sizes were clearly visible on CT and CBCT images with only the largest marker volumes (100-300 µL) displaying artifacts similar in size to the gold fiducial marker. Artifact size increased with increasing liquid marker volume. Liquid markers displayed good contrast in ex vivo T1-weighted and ρH-weighted images. The markers were not visible in the ex vivo T2-weighted image. The liquid markers induced a chemical shift artifact in the obtained ADC-map. Automated detection in x-ray imaging was feasible with high detection success (four of five positions) for marker volumes in the range of 25-200 µL. None of the liquid markers were detected successfully when superimposed on a bony edge, independent of their size. CONCLUSIONS: This study is the first to show the compatibility of BioXmark® liquid markers with multimodal image-guided radiotherapy for PCa. Compared to a solid gold marker, they had favorable results in both visibility and induced imaging artifacts. Liquid marker visibility in MRI imaging of the prostate does not solely depend on the low ρH value (not visible on T2-weighted image) but is also influenced by its relaxation times. Automated marker detection in x-ray images was feasible but better adapted marker detection algorithms are necessary for marker localization in the presence of bony edges. Hence, the liquid marker provides a minimally invasive (fine needles) and highly applicable alternative to current solid gold markers for multimodal image-guided prostate radiotherapy treatments.

The influence of migraine and female hormones on capsaicin-induced dermal blood flow.

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.