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Purpose Emerging evidence suggests a detrimental prognostic association between radiation-induced lymphopenia (RIL) and pathologic response, progression-free survival, and overall survival (OS) in patients who undergo radiation therapy for cancer. The aim of this study was to systematically review and meta-analyze the prognostic impact of RIL on OS in patients with solid tumors. Methods and Materials PubMed/MEDLINE and Embase were systematically searched. The analysis included intervention and prognostic studies that reported on the prognostic relationship between RIL and survival in patients with solid tumors. An overall pooled adjusted hazard ratio (aHR) was calculated using a random-effects model. Subgroup analyses for different patient-, tumor-, treatment-, and study-related characteristics were performed using meta-regression. Results Pooling of 21 cohorts within 20 eligible studies demonstrated a statistically significant association between OS and grade ≥3 versus grade 0-2 RIL (n = 16; pooled aHR, 1.65; 95% confidence interval [CI], 1.43-1.90) and grade 4 RIL versus grade 0-3 (n = 5; aHR, 1.53; 95% CI, 1.24-1.90). Moderate heterogeneity among aHRs was observed, mostly attributable to overestimated aHRs in 7 studies likely subject to model-overfitting. Subgroup analysis showed significant prognostic impact of grade ≥3 RIL in 4 brain tumor (aHR, 1.63; 95% CI, 1.06-2.51), 4 lung cancer (aHR, 1.52; 95% CI, 1.01-2.29), and 3 pancreatic cancer (aHR, 1.92; 95% CI, 1.10-3.36) cohorts. Conclusions This meta-analysis demonstrates a significant detrimental prognostic association between grade ≥3 lymphopenia and OS in patients receiving radiation therapy for solid tumors. This finding appears consistent for tumors of the brain, thorax, and upper abdomen and provides an imperative to further elucidate the potential survival benefit of lymphopenia-mitigating strategies.

Purpose Irradical resection of non-small-cell lung cancer (NSCLC) is a detrimental prognostic factor. Recently, Rasing et al. presented an internationally validated risk score for pre-treatment prediction of irradical resection. We hypothesized that chemoradiation therapy (CRT) could serve as an alternative approach in patients with a high risk score and compared overall survival (OS) outcomes between surgery and CRT. Methods Patients from a population-based cohort with stage IIB–III NSCLC between 2015 and 2018 in The Netherlands were selected. Patients with a ‘Rasing score’ > 4 who underwent surgery were matched with patients who underwent CRT using 1:1 nearest-neighbor propensity score matching. The primary endpoint of OS was compared using a Kaplan–Meier analysis. Results In total, 2582 CRT and 638 surgery patients were eligible. After matching, 523 well-balanced pairs remained. Median OS in the CRT group was 27.5 months, compared with 45.6 months in the surgery group (HR 1.44, 95% CI 1.23–1.70, p p = 0.039). Conclusion In NSCLC patients at high predicted risk of irradical resection, CRT appears to yield inferior survival compared with surgery. Therefore, choosing CRT instead of surgery cannot solely be based on the Rasing score. Since patients receiving an R1–2 resection do have detrimental outcomes compared with primary CRT, the treatment decision should be based on additional information, such as imaging features, comorbidities, patient preference, and the surgeon’s confidence in achieving an R0 resection.

BACKGROUND The incidence of grade 4 lymphopenia in patients treated with chemoradiotherapy (CRT) according to Chemoradiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) regimen is unclear. The primary aim was to determine the incidence of grade 4 lymphopenia during CROSS for esophageal cancer. Secondary aims were to externally validate a prediction model for grade 4 lymphopenia and compare overall survival between patients with and without grade 4 lymphopenia. METHODS Patients who underwent CRT for esophageal cancer between 2014 and 2019 were eligible for inclusion. Patients with a planned radiation dose of 41.4 Gy (CROSS) or 50.4 Gy ("extended-CROSS") and concurrent carboplatin and paclitaxel were included. The primary outcome was the incidence of grade 4 lymphopenia during CRT defined according to Common Terminology Criteria for Adverse Events version 5.0 (i.e. lymphocyte count nadir

Objective. To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival. Methods. In a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated. Results. 52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute >_ grade 3 toxicities were regarding skin/ mucosa and pain (54% and 37%). Late >_grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years. Conclusions. Definitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

SamenvattingHet doel van deze studie was de oncologische en functionele uitkomsten van salvage cryochirurgie (sCC) te beoordelen bij lokaal recidief prostaatcarcinoom na radiotherapie (rrPCA). De studie werd uitgevoerd bij 169 patiënten. Er vond retrospectieve analyse plaats van recidiefvrije overleving (BRFS), algehele overleving, metastasevrije overleving, androgeendeprivatietherapie (ADT)-vrije overleving, functionele uitkomsten en complicaties. De mediane follow-up was 36 maanden (IQR = 18–66). BRFS na vijf en acht jaar was 52% (95%-BI = 43–62) en 45% (95%-BI = 35–57), respectievelijk. PSA bij initiële diagnose, de initiële behandeling, het interval tussen de primaire behandeling en SCS, leeftijd bij SCS en post-SCS PSA-nadir waren significante voorspellers van BRFS. De vijf-jaars ADT-vrije overleving was 70% (95%-BI = 62–79). Complicaties van graad III of hoger traden op bij 1,2% van de patiënten. Bij 19% en 92% van de patiënten trad new onset urine-incontinentie respectievelijk erectiele disfunctie op, bij 6,5% persisterende urinaire fistels en bij 12% desobstructie. SCS heeft aanvaardbare oncologische resultaten, maar kan gepaard gaan met ernstige complicaties (urine-incontinentie, stenose en fistels).

Highlights • Biochemical failure rates after focal salvage high-dose-rate brachytherapy are high. • Evidence on predictors for failure is limited to whole-gland salvage radiotherapy. • Two prediction models for biochemical failure were developed and internally validated. • Based on pre- and post-salvage characteristics we can identify high-risk patients. • These models can be used for patient counselling at baseline and during follow-up., Background and purpose Magnetic resonance-guided focal salvage high-dose-rate brachytherapy (FS-HDR-BT) for radiorecurrent prostate cancer (PCa) shows low toxicity rates. However, biochemical failure (BF) after treatment occurs frequently. We developed two prediction models for BF (Phoenix definition) with the aim of enhancing patient counselling before FS-HDR-BT and during follow-up. Materials and methods A prospective cohort of 150 radiorecurrent PCa patients treated with FS-HDR-BT between 2013 and 2020 was used for model development and internal validation. Multivariable Cox Proportional Hazards regression was applied. For model 1, only pre-salvage variables were included as candidate predictors. For model 2, additional (post-)salvage characteristics were tested. After calibration, nomograms and webtools were constructed. Finally, three risk groups were identified. Results Sixty-one patients (41%) experienced BF. At baseline (model 1), age, gross tumour volume, pre-salvage PSA, and pre-salvage PSA doubling time (PSADT) were predictive of BF. During follow-up (model 2), age, pre-salvage PSA and PSADT, seminal vesicle involvement, post-salvage time to PSA nadir, and percentage PSA reduction were predictive of BF. The adjusted C-statistics were 0.73 (95% CI: 0.66–0.81) and 0.84 (95% CI: 0.78–0.90), respectively, with acceptable calibration. Estimated 2-year biochemical disease-free survival for the low-, intermediate-, and high-risk groups were 84%, 70%, and 31% (model 1), and 100%, 71%, and 5% (model 2). Conclusion Two models are provided for prediction of BF in patients with radiorecurrent PCa treated with FS-HDR-BT. Based on pre- and post-salvage characteristics, we are able to identify patients with a high risk of BF. These findings can aid patient counselling for FS-HDR-BT.

Background Prostate cancer oligometastatic disease can be treated using stereotactic body radiotherapy (SBRT) in order to postpone start of systemic treatments such as androgen deprivation therapy (ADT). 68Ga-PSMA-PET/CT imaging allows for diagnosis of oligometastases at lower PSA values. We analysed a cohort of patients with prostate cancer lymph node oligometastases detected on PSMA-PET/CT. Materials and methods Ninety patients with metachronous oligometastatic prostate cancer received SBRT for 1-3 lymph node metastases diagnosed on 68Ga-PSMA-PET/CT. The primary end point was progression free survival (PFS), with disease progression defined as occurrence of either target lesion progression, new metastatic lesion or biochemical progression. Secondary outcomes were biochemical PFS (BPFS), ADT-free survival (ADT-FS), toxicity and quality of life (QoL). Baseline patient characteristics were tested for association with PFS and a preliminary risk score was created. Results Median follow-up was 21 months (interquartile range 10-31 months). Median PFS and BPFS were 16 and 21 months, respectively. Median ADT-FS was not reached (73% (95%-CI 62-86%) at 24 months). In multivariable analysis, younger age, higher PSA prior to SBRT and extrapelvic location were associated with shorter PFS. Grade 1 fatigue was the most predominant acute toxicity (34%). Highest grade toxicity was grade 2 for acute and late events. QoL analysis showed mild, transient increase in fatigue at 1-4 weeks after SBRT. Conclusion A median PFS of 16 months was attained after SBRT for patients with PSMA-PET positive oligometastatic lymph nodes from prostate cancer. Higher pre-SBRT PSA, younger age and extrapelvic location were found to be predictors of shorter PFS.

For localised prostate cancer, focal therapy offers an organ-sparing alternative to radical treatments (radiotherapy or prostatectomy). Currently, there is no randomised comparative effectiveness data evaluating cancer control of both strategies. Following the eligibility criteria PSA

Highlights • Prophylactic cranial irradiation (PCI) use declined in The Netherlands. • Independent predictors for prescription of PCI were identified. • An alarming increase of practice variation was observed. • Alternative MRI surveillance is not strictly adhered to., Introduction Controversy has arisen regarding the benefit of prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC), particularly since the 2017 Takahashi trial publication that supports MRI surveillance in extensive-stage (ES-)SCLC. The primary aim of this study was to assess trends and determinants in PCI use over the years 2010–2018. A secondary aim was to determine contemporary practice considerations among radiation oncologists (ROs). Methods A nationwide population-based cohort study was conducted using the Netherlands Cancer Registry data on all newly diagnosed SCLC patients (2010–2018). The change in PCI frequency over the years and determinants for PCI were analyzed using logistic regression models. Second, an online survey was performed among Dutch lung cancer ROs in 2020. Results Among 10,264 eligible patients, 4,894 (47%) received PCI. Compared to 2010–2014, PCI use significantly decreased in 2017–2018 in ES-SCLC (OR 0.68, 95%CI 0.60–0.77) and LS-SCLC (OR 0.56, 95%CI 0.47–0.67). Incidence year, age, performance status, and thoracic radiotherapy were independent determinants for PCI. Among 41 survey participants, PCI was recommended always/sometimes/never by 22%/71%/7% in ES-SCLC and 54%/44%/2% in LS-SCLC. For ES-SCLC and LS-SCLC, 63% and 25% of ROs, respectively, confirmed influence of the Takahashi trial on PCI recommendations. Denial of such influence was associated with insufficient institutional MRI capacity. Conclusions A significant declining trend of PCI use in both ES-SCLC and LS-SCLC was observed in The Netherlands since 2017. The Takahashi trial seems an explanation for this trend even in LS-SCLC, with differential influence of the trial depending on institutional MRI capacity. An alarming increase in practice variation regarding PCI was found which stresses the importance of ongoing trials.

Highlights • Adapt-to-Shape (ATS) workflows enable high-precision MR-guided radiotherapy. • Online, manual contour adaptation is a time-consuming step in the ATS workflow. • Trained radiation therapists adapt contours for prostate cancer treatment. • CTV contours by radiation therapists are well-suited for MR-Linac prostate cancer treatment., Background and purpose Magnetic resonance (MR)-guided linear accelerator (MR-Linac) systems have changed radiotherapy workflows. The addition of daily online contour adaptation allows for higher precision treatment, but also increases the workload of those involved. We train radiation therapists (RTTs) to perform daily online contour adaptation for MR-Linac treatment of prostate cancer (PCa) patients. The purpose of this study was to evaluate these prostate contours by performing an interfraction and interobserver analysis. Materials and methods Clinical target volume (CTV) contours generated online by RTTs from 30 low-intermediate risk PCa patients, treated with 5x7.25 Gy, were used. Two physicians (Observers) judged the RTTs contours and performed adaptations when necessary. Interfraction relative volume differences between the first and the subsequent fractions were calculated for the RTTs, Observer 1, and Observer 2. Additionally, interobserver dice’s similarity coefficient (DSC) for fraction 2–5 was calculated with the RTTs- and physician-adapted contours. Clinical acceptability of the RTTs contours was judged by a third observer. Results Mean (SD) online contour adaptation time was 12.6 (±3.8) minutes and overall median (interquartile range [IQR]) relative volume difference was 9.3% (4.4–13.0). Adaptations by the observers were mostly performed at the apex and base of the prostate. Median (IQR) interobserver DSC between RTTs and Observer 1, RTTs and Observer 2, and Observer 1 and 2 was 0.99 (0.98–1.00), 1.00 (0.98–1.00), and 1.00 (0.99–1.00), respectively. Contours were acceptable for clinical use in 113 (94.2%) fractions. Dose-volume histogram (DVH) analysis showed significant CTV underdosage for one of the seven identified outliers. Conclusion Daily online contour adaptation by RTTs is clinically feasible for MR-Linac treatment of PCa.

Highlights • Severe toxicity is as low as 3% (GU), 0% (GI) and 15% (ED). • Lower impact is predicted for patients with favorable function at baseline. • Lower dose to the urethra (D10%, Background and purpose Local re-treatment of radiorecurrent prostate cancer is potentially curative. However, the increased risk of severe toxicity may outweigh the opportunity of cancer control. This study aims to evaluate treatment-related toxicity from ultrafocal salvage high-dose-rate brachytherapy (HDR-BT) and to investigate potential risk factors. Materials and methods Toxicity data from 150 treated patients (July 2013–November 2019) was collected from a prospective registry. The treatment aim was to deliver a single dose of 19 Gy to the recurrent lesion as identified on multiparametric MRI and PET-CT. Treating physicians graded genitourinary (GU) and gastro-intestinal (GI) toxicity and erectile dysfunction (ED) using the Common Terminology Criteria for Adverse Events (CTCAE) 4.0, at baseline and during follow-up. Domains with substantial (≥10%) new-onset grade ≥ 2 toxicity were further evaluated using mixed effects logistic regression to find potential risk factors. Results Median follow-up time was 20 months (IQR 12–31). Over time, new-onset grade 2 and 3 toxicity was recorded in 41% and 3% (GU), 5% and 0% (GI) and 22% and 15% (ED). While GI toxicity remained stably low, grade ≥ 2 GU toxicity and ED were seen twice as frequent in the late phase (>3 months after treatment). Significant risk factors for grade ≥ 2 toxicity were baseline GU toxicity (grade ≥ 2), baseline ED (grade ≥ 2), IPSS (cut-off ≥ 14) and urethral dose (D10%, cut-off ≥ 17 Gy). Conclusion Ultrafocal salvage HDR-BT is a safe re-treatment option, especially in patients with a favorable symptom profile at baseline. Adherence to urethral dose constraints is important to avoid GU toxicity.

Focal therapy (FT) ablates areas of prostate cancer rather than treating the whole gland. We compared oncological outcomes of FT to radical prostatectomy (RP). Using prospective multicentre databases of 761 FT and 572 RP cases (November/2005-September/2018), patients with PSA

Objectives To evaluate the oncological and functional outcomes of salvage cryosurgery (SCS) for radiorecurrent prostate cancer (rrPCa). Patients and methods A total of 169 consecutive patients with biopsy confirmed rrPCa were retrospectively analysed. All patients underwent SCS in a single referral centre between 2006 and 2018. The primary outcome was biochemical recurrence-free survival (BRFS) according to the Phoenix definition (prostate-specific antigen [PSA] nadir +2 ng/mL). The secondary outcomes were overall survival, BRFS defined as a PSA level of >0.5 ng/mL, metastasis-free survival, androgen-deprivation therapy (ADT)-free survival, and functional outcomes. Complications were classified according to the Clavien-Dindo system. PSA was measured every 3-6 months postoperatively. Functional outcomes were scored as reported by patients at outpatient visits. Kaplan-Meier survival analysis and uni- and multivariable Cox regression were performed. Results The median (interquartile range) follow-up was 36 (18-66) months. The BRFS after 5 and 8 years was 52% (95% confidence interval [CI] 43-62%) and 45% (95% CI 35-57%), respectively. At multivariable analysis PSA level at initial diagnosis, initial treatment, interval between primary treatment and SCS, age at SCS, and post-SCS PSA nadir were significant factors for BRFS. The 5-year ADT-free survival was 70% (95% CI 62-79%). Clavien-Dindo Grade ≥III complications occurred in 1.2% (two/169) of patients. In all, 19% (29/156) of patients had new-onset urinary incontinence defined as >1 pad/24 h and 92% (57/62) of patients had new-onset erectile dysfunction. Persistent urinary fistula occurred in 6.5% (11/169) of patients. Conclusions The present study shows acceptable oncological outcomes of SCS considering the salvage character of the treatment. The occurrence of serious complications such as urinary incontinence and fistula should not be underestimated.

In men with recurrence of prostate cancer post radiation therapy, further treatment remains a challenge. The default salvage option of androgen-deprivation therapy (ADT) has adverse effects. Alternatively, selected men may be offered salvage therapy to the prostate. Herein, we present long-term oncological outcomes of two whole-gland ablation techniques, cryotherapy (sCT) and high-intensity-focused ultrasound (sHIFU). Men undergoing sCT (1995–2004) and sHIFU (2006–2018) at Western University were identified. Oncological endpoints included biochemical recurrence (BCR), ADT initiation, metastases, castration resistance (CRPC), and prostate cancer-specific mortality (PCSM). Survival analysis with competing risks of mortality was performed. Multivariable analysis was performed using Fine and Gray regression. A total of 187 men underwent sCT and 113 sHIFU. Mean (SD) age of the entire cohort was 69.9 (5.9 years), median pre-radiation PSA 9.6 ng/ml (IQR 6.1–15.2), and pre-salvage PSA 4.5 ng/ml (IQR 2.8–7.0). Median total follow-up was 116 months (IQR 67.5–173.8). A total of 170 (57.6%) developed BCR, 68 (23.4%) metastases, 143 (49.3%) were started on ADT, 58 (20.1%) developed CRPC, and 162 (56%) patients died of which 59 (36.4%) were of prostate cancer. On multivariable analysis, sHIFU (HR 1.65, 95% CI 1.15–2.36, p = 0.006) and pre-salvage PSA (HR 1.09, 95% CI 1.06–1.13, p

Purpose Most patients with local prostate cancer recurrence after radiation therapy undergo palliative androgen deprivation therapy because whole-gland salvage treatments have a high risk of severe toxicity. Focal treatment reduces this risk while offering a second opportunity for cure. We report updated outcomes of ultrafocal salvage high-dose-rate brachytherapy (HDR-BT). Methods and Materials Prospectively collected data from the first 50 treated patients were analyzed. Disease status was assessed by 3T multiparametric magnetic resonance imaging (MRI), 18F-Choline or 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography, and systematic or tumor-targeted biopsies. Ultrafocal salvage HDR-BT (1 × 19 Gy) was performed by implanting the clinical target volume (CTV: gross tumor volume + 5 mm margin) under fused transrectal ultrasound/MRI guidance. Follow-up included toxicity grading (using Common Terminology Criteria for Adverse Events 4.0), quality of life assessment, and prostate-specific antigen (PSA) testing. Results Median follow-up was 31 months. Median CTV D95% was 18.8 Gy. We observed 2% grade 3 genitourinary toxicity, no grade 3 gastrointestinal toxicity, and 22% newly developed grade 3 erectile dysfunction. Five of 13 patients (38%) with self-reported pretreatment potency (International Index of Erectile Function >17) remained potent. Clinically relevant quality of life deterioration was reported for only 6 of 31 items and was not statistically significant. Biochemical failure (nadir + 2) occurred in 26 patients. Among intraprostatic recurrences, 73% were in field. After 2.5 years, biochemical disease-free survival was 51% (95% confidence interval, 37%-69%), metastases-free survival was 75% (64%-89%), androgen deprivation therapy–free survival was 90% (82%-99%), and overall survival was 98% (94%-100%). Presalvage PSA, CTV size, and stage ≥T3 were significantly associated with biochemical failure. Higher-risk patients (stage ≥T3, PSA ≥10, or PSA double time ≤9 months) had 25% biochemical disease-free survival at 2.5 years versus 71% for lower-risk patients. Conclusions At this early stage, MRI-guided ultrafocal HDR-BT seems to be a safe salvage treatment option, with acceptable biochemical control in a well-selected group of patients and potential for effectively postponing androgen deprivation therapy.

Objectives To assess change in functional outcomes after a second focal high-intensity focused ultrasonography (HIFU) treatment compared with outcomes after one focal HIFU treatment. Patients and methods In this multicentre study (2005-2016), 821 men underwent focal HIFU for localized non-metastatic prostate cancer. The patient-reported outcome measures of International Prostate Symptom Score (IPSS), pad usage and erectile function (EF) score were prospectively collected for up to 3 years. To be included in the study, completion of at least one follow-up questionnaire was required. The primary outcome was comparison of change in functional outcomes between baseline and follow-up after one focal HIFU procedure vs after a second focal HIFU procedure, using IPSS, Expanded Prostate Cancer Index Composite (EPIC) and International Index of Erectile Function (IIEF) questionnaires. Results Of 821 men, 654 underwent one focal HIFU procedure and 167 underwent a second focal HIFU procedure. A total of 355 (54.3%) men undergoing one focal HIFU procedure and 65 (38.9%) with a second focal HIFU procedure returned follow-up questionnaires, respectively. The mean age and prostate-specific antigen level were 66.4 and 65.6 years, and 7.9 and 8.4 ng/mL, respectively. After one focal HIFU treatment, the mean change in IPSS was -0.03 (P = 0.02) and in IIEF (EF score) it was -0.4 (P = 0.02) at 1-2 years, with no subsequent decline. Absolute rates of erectile dysfunction increased from 9.9% to 20.8% (P = 0.08), leak-free continence decreased from 77.9% to 72.8% (P = 0.06) and pad-free continence from 98.6% to 94.8% (P = 0.07) at 1-2 years, respectively. IPSS prior to second focal HIFU treatment compared to baseline IPSS prior to first focal HIFU treatment was lower by -1.3 (P = 0.02), but mean IPSS change was +1.4 at 1-2 years (P = 0.03) and +1.2 at 2-3 years (P = 0.003) after the second focal HIFU treatment. The mean change in EF score after the second focal HIFU treatment was -0.2 at 1-2 years (P = 0.60) and -0.5 at 2-3 years (P = 0.10), with 17.8% and 6.2% of men with new erectile dysfunction. The rate of new pad use was 1.8% at 1-2 years and 2.6% at 2-3 years. Conclusion A second focal HIFU procedure causes minor detrimental effects on urinary function and EF. These data can be used to counsel patients with non-metastatic prostate cancer prior to considering HIFU therapy.

INTRODUCTION AND OBJECTIVE:Micro-ultrasound (micro-US) is a novel US-based imaging modality that allows real-time targeted prostate biopsies with mpMRI fusion. Its high resolution relying on a 29 M...

Background Focal cryotherapy can be used to treat patients with clinically significant nonmetastatic prostate cancer to reduce side effects. Objective Early-medium-term cancer control and functional outcomes. Design, setting, and participants A prospective registry-based case series of 122 consecutive patients undergoing focal cryotherapy between October 1, 2013, and November 30, 2016, in five UK centres. Median follow-up was 27.8mo [interquartile range (IQR) 19.5–36.7]. A total of 35 patients (28.7%) had National Comprehensive Cancer Network (NCCN) high risk and 87 (71.3%) had intermediate risk disease. Risk and zonal stratification included multiparametric magnetic resonance imaging (mpMRI) with targeted and systematic biopsies, or transperineal mapping biopsies. Intervention Focal cryoablation of MR-visible tumours. Outcome measurements and statistical analysis Follow-up involved prostate-specific antigen (PSA) monitoring, mpMRI, and for-cause biopsies. Primary outcome was failure-free survival (FFS), defined as transition to radical, whole-gland, or systemic therapy, or metastases/death. Secondary outcomes included adverse events and functional outcomes. Results and limitations A total of 80 (65.6%) had anterior ablation, 23 (19.7%) combined posterior and anterior ablation, and two (1.6%) posterior ablation alone (SeedNet or Visual-ICE, BTG plc). Median age was 68.7yr (IQR 64.9–73.8) and preoperative PSA 10.8ng/ml (IQR 7.8–15.6). Overall FFS at 3yr was 90.5% [95% confidence interval (CI) 84.2–97.3]. When stratified for the NCCN risk group, 3-yr outcomes were 84.7% (95% CI 71.4–100) in high risk and 93.3% (95% CI 86.8–100) in intermediate risk. At last follow-up, incontinence defined as any pad use was 0/69 (0%) and erectile dysfunction (defined as erections insufficient for penetration) was 5/31 (16.1%). Limitations include lack of long-term outcomes. Conclusions Focal cryotherapy primarily for anterior intermediate and high-risk prostate cancer results in good rates of cancer control and low rates of treatment-related side effects. Patient summary In this multicentre study of 122 patients undergoing focal cryotherapy for medium- to high-risk prostate cancer, at 3yr, no patient died from their cancer whilst failure-free survival, was approximately 90%. None of the patients needed pads for managing urine leakage, although 16% had erection problems.

Objective: To assess risk factors for nodal failure (NF) after definitive (chemo)radiotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) for patients treated in the EMBRACE I study. Materials and methods: Data for pelvic NF and para-aortic (PAO) NF (NFPAO) were analysed. After multiple imputation, univariable and multivariable Cox-regression was performed for clinical and treatment-related variables. For patients with affected pelvic nodes but no PAO nodes at diagnosis, additional analyses were performed for two subgroups: 1. ‘small pelvis’ nodes in internal and external iliac, obturator, parametrial, presacral and/or common iliac (CI) region and 2. any CI nodes (subgroup of 1). Results: 1338 patients with 152 NF and 104 NFPAO events were analysed with a median follow-up of 34.2 months (IQR 16.4–52.7). For the entire group, larger tumour width, nodal risk groups (in particular any CI nodes without PAO nodes), local failure, and lower Hb-nadir increased the risk of NF. Elective PAO-irradiation was independently associated with a decreased risk of NFPAO (HR 0.53, 95%-CI 0.28–1.00, p = 0.05). For subgroup 1, having ‘any CI nodes without PAO nodes’ and local failure significantly increased NF risk. Additionally, elective PAO-irradiation was associated with less risk of NFPAO (HR 0.38, 95%-CI 0.17–0.86, p = 0.02). For subgroup 2 only local failure was associated with higher risk of NF. Conclusion: In this patient cohort, nodal disease and tumour width at diagnosis, as well as local failure, are risk factors for NF after definitive treatment. Having either ‘any PAO nodes’ (with or without pelvic nodes) or ‘any CI nodes’ (without PAO nodes) are stronger risk factors than involvement of nodes in the small pelvis alone. Elective PAO-irradiation was associated with significantly less NFPAO, particularly in patients with nodal disease in the ‘small pelvis’ and/or CI region at time of diagnosis.

For patients with early stage or medically inoperable lung cancer, stereotactic body radiotherapy (SBRT) is a general accepted and effective treatment option. The role of SBRT in ultra-central tumors remains controversial. The aim of this single-center retrospective analysis was to evaluate the safety and efficacy of protracted SBRT with 60 Gy in 12 fractions (with a biological effective dose (BED10) of 90–150 Gy) for patients with ultra-central lung tumors. Patients with ultra-central lung tumors treated in our institution with 60 Gy in 12 fractions from January 2012 until April 2020 were included. Ultra-central tumors were defined as planning target volume (PTV) abutting or overlapping the main bronchi and/or trachea and/or esophagus. Data regarding patient-, tumor-, and treatment-related characteristics were evaluated. A total of 72 patients met the criteria for ultra-central tumor location. The PTV abutted the main bronchus, trachea or esophagus in 79%, 22% and 28% of cases, respectively. At a median follow-up of 19 months, 1- and 2-year local control rates were 98% and 85%, respectively. Overall survival rates at 1 and 2 years were 77% and 52%, respectively. Grade 3 or higher toxicity was observed in 21%, of which 10 patients (14% of total) died of bronchopulmonary hemorrhage. A significant difference between patients with or without grade ≥3 toxicity was found for the mean dose (Dmean) to the main bronchus (p = 0.003), where a Dmean BED3 of ≥91 Gy increased the risk of grade ≥3 toxicity significantly. A protracted SBRT regimen of 60 Gy in 12 fractions for ultra-central lung tumors leads to high local control rates with toxicity rates similar to previous series, but with substantial risk of fatal bronchopulmonary hemorrhage. Therefore, possible risk factors of bronchopulmonary hemorrhage such as dose to the main bronchus should be taken into account.

Highlight • Quantitative mpMRI parameters predict failure of salvage HIFU in radiorecurrent prostate cancer • Tumour microenvironment might produce heat-sinks which counter the effect of HIFU • Ve value measured in the DCE sequence of the mpMRI is an independent predictor of treatment failure, Objectives Focal salvage HIFU is a feasible therapeutic option in some men who have recurrence after primary radiotherapy for prostate cancer. We aimed to determine if multi-parametric quantitative parameters, in addition to clinical factors, might have a role in independently predicting focal salvage HIFU outcomes. Methods A retrospective registry analysis included 150 consecutive men who underwent focal salvage HIFU (Sonablate500) (2006-2015); 89 had mpMRI available. Metastatic disease was excluded by nodal assessment on pelvic MRI, a radioisotope bone-scan and/or choline or FDG PET/CT scan. All men had mpMRI and either transperineal template prostate mapping biopsy or targeted and systematic TRUS-biopsy. mpMRI included T2‐weighted, diffusion‐weighted and dynamic contrast‐enhancement. Pre-HIFU quantitative mpMRI data was obtained using Horos DICOM Viewer v3.3.5 for general MRI parameters and IB DCE v2.0 plug-in. Progression-free survival (PFS) was defined by biochemical failure and/or positive localized or distant imaging results and/or positive biopsy and/or systemic therapy and/or metastases/prostate cancer‐specific death. Potential predictors of PFS were analyzed by univariable and multivariable Cox-regression. Results Median age at focal salvage HIFU was 71 years (interquartile range [IQR] 65–74.5) and median PSA pre-focal salvage treatment was 5.8ng/ml (3.8-8). Median follow-up was 35 months (23-47) and median time to failure was 15 months (7.8–24.3). D-Amico low, intermediate and high-risk disease was present in 1% (1/89), 40% (36/89) and 43% (38/89) prior to focal salvage HIFU (16% missing data). 56% (50/89) failed by the composite outcome. A total of 22 factors were evaluated on univariable and 8 factors on multivariable analysis. The following quantitative parameters were included: Ktrans, Kep, Ve, Vp, IS, rTTP and TTP. On univariable analysis, PSA, prostate volume at time of radiotherapy failure and Ve (median) value were predictors for failure. Ve represents extracellular fraction of the whole tissue volume. On multivariable analysis, only Ve (median) value remained as an independent predictor. Conclusions One pharmacokinetic quantitative parameter based on DCE sequences seems to independently predict failure following focal salvage HIFU for radio-recurrent prostate cancer. This likely relates to the tumor microenvironment producing heat-sinks which counter the heating effect of HIFU. Further validation in larger datasets and evaluating mechanisms to reduce heat-sinks are required.

We compared clinically significant prostate cancer detection by visual estimation and image fusion targeted transperineal prostate biopsy.This multicenter study included patients with multiparametric magnetic resonance imaging lesions undergoing visual estimation or image fusion targeted transperineal biopsy (April 2017-March 2020). Propensity score matching was performed using demographics (age and ethnicity), clinical features (prostate specific antigen, prostate volume, prostate specific antigen density and digital rectal examination), multiparametric magnetic resonance imaging variables (number of lesions, PI-RADS® score, index lesion diameter, whether the lesion was diffuse and radiological T stage) and biopsy factors (number of cores, operator experience and anesthetic type). Matched groups were compared overall and by operator grade, PI-RADS score, lesion multiplicity, prostate volume and anesthetic type using targeted-only and targeted plus systematic histology. Multiple clinically significant prostate cancer thresholds were evaluated (primary: Gleason ≥3+4).A total of 1,071 patients with a median age of 67.3 years (IQR 61.3-72.4), median prostate specific antigen of 7.5 ng/ml (IQR 5.3-11.2) and 1,430 total lesions underwent targeted-only biopsies (visual estimation: 372 patients, 494 lesions; image fusion: 699 patients, 936 lesions). A total of 770 patients with a median age of 67.4 years (IQR 61-72.1), median prostate specific antigen of 7.1 ng/ml (IQR 5.2-10.6) and 919 total lesions underwent targeted plus systematic biopsies (visual estimation: 271 patients, 322 lesions; image fusion: 499 patients, 597 lesions). Matched comparisons demonstrated no overall difference in clinically significant prostate cancer detection between visual estimation and image fusion (primary: targeted-only 54% vs 57.4%, p=0.302; targeted plus systematic 51.2% vs 58.2%, p=0.123). Senior urologists had significantly higher detection rates using image fusion (primary: targeted-only 45.4% vs 63.7%, p=0.001; targeted plus systematic 39.4% vs 64.5%, p0.001).We found no overall difference in clinically significant prostate cancer detection, although image fusion may be superior in experienced hands.

Highlights • We analyzed patient-reported quality of life in 100 patients who underwent ultrafocal salvage HDR-brachytherapy. • Patient-reported bowel symptoms were neglible. • Urinary complaints increased and sexual functioning declined over time. • Lower impact is predicted for patients with favorable function at baseline and lower dose to the urethra., Purpose For patients with a localized prostate cancer recurrence after radiotherapy, focal salvage treatment offers a less toxic alternative to whole-gland treatments, with the potential of preserving health-related quality of life (HR-QoL). With a focus on the patient’s perspective of treatment, this study aims to describe HR-QoL after ultrafocal salvage high-dose-rate brachytherapy (HDR-BT), and to explore predictive factors affecting HR-QoL. Material and methods We included 100 patients treated with ultrafocal salvage HDR-BT. Prostate cancer-related HR-QoL was assessed by the EORTC QLQ-PR25 questionnaire. Domains were urinary symptoms, bowel symptoms and sexual activity/functioning. For each domain, a mixed effects model was made to estimate HR-QoL trends over time. For domains showing clinically relevant change (≥10 points difference), the mixed effects model was used to explore potential predictors (age, baseline HR-QoL score, T-stage, tumor location, CTV size, dose to organs at risk and history of ADT). Results Median follow-up was 20 months (IQR 13–30). Mean questionnaire response rate was 86% (range 72–100%). Median baseline scores were 12 (urinary), 0 (bowel) and 67/50 (sexual activity/functioning). Urinary symptoms and sexual functioning showed clinically relevant deterioration over time (maximum difference of 11 and 12 points, respectively). Worse baseline score and higher administered dose to the urethra (≥16 Gy) were predictive of increased urinary symptoms (p

Men in whom external beam radiotherapy fails are usually placed on delayed hormone therapy. Some of these men have localized recurrence that might be suitable for further local therapy. We describe patterns of recurrence and suitability for focal ablative therapy in those undergoing transperineal template prostate mapping biopsies.The study included 145 consecutive patients (December 2007 to May 2014) referred with suspicion of recurrence due to rising prostate specific antigen after external beam radiotherapy or brachytherapy who underwent transperineal template prostate mapping biopsies. Suitability for focal ablative therapy required the cancer to be unifocal or unilateral, or bilateral/multifocal with 1 dominant index lesion and secondary lesions with Gleason score 3+3=6 with no more than 3 mm cancer core involvement.Mean patient age was 70.7 (SD 5.8) years. Median prostate specific antigen at time of transperineal template prostate mapping biopsy was 4.5 ng/ml (IQR 2.5-7.7). Overall 75.9% (110) were suitable for a form of focal salvage treatment, 40.7% (59) were suitable for quadrant ablation, 14.5% (21) hemiablation, 14.5% (21) bilateral focal ablation and 6.2% (9) for index lesion ablation.Three-quarters of patients who have localized radiorecurrent prostate cancer may be suitable for focal ablative therapy to the prostate based on transperineal template prostate mapping biopsies.

INTRODUCTION AND OBJECTIVE:Targeted prostate biopsy can be done using visual-estimation (cognitive) targeting or using MRI-ultrasound fusion platforms. We compared cancer detection of these two app...

INTRODUCTION AND OBJECTIVE:Risk stratification groups were developed and validated using staging based on DRE. It may be inappropriate to apply MRI staging to these risk stratification systems beca...

INTRODUCTION AND OBJECTIVE:Renal colic is a common urological problem with a lifetime incidence of approximately 8-19% in males and 3-5% in females. The MIMIC Study was a 4171 patient cohort study ...

Background Patients who are surgically treated for stage I to III non-small cell lung cancer (NSCLC) have dismal prognosis after incomplete (R1-R2) resection. Our study aimed to develop a prediction model to estimate the chance of incomplete resection based on preoperative patient-, tumor-, and treatment-related factors. Methods From a Dutch national cancer database, NSCLC patients who had surgical treatment without neoadjuvant therapy were selected. Thirteen possible predictors were analyzed. Multivariable logistic regression was used to create a prediction model. External validation was applied in the American National Cancer Database, whereupon the model was adjusted. Discriminatory ability and calibration of the model was determined after internal and external validation. The prediction model was presented as nomogram. Results Of 7156 patients, 511 had an incomplete resection (7.1%). Independent predictors were histology, cT stage, cN stage, extent of surgery, and open vs thoracoscopic approach. After internal validation, the corrected C statistic of the resulting nomogram was 0.72. Application of the nomogram to an external data set of 85,235 patients with incomplete resection in 2485 patients (2.9%) resulted in a C statistic of 0.71. Calibration revealed good overall fit of the nomogram in both cohorts. Conclusions An internationally validated nomogram is presented providing the ability to predict the individual chance of incomplete resection in patients with stage I to III NSCLC planned for resection. In case of a high predicted risk of incomplete resection, alternative treatment strategies could be considered, whereas a low risk further supports the use of surgical procedures.

INTRODUCTION: In patients with esophageal cancer, occurrence of severe radiation-induced lymphopenia during chemoradiation therapy has been associated with worse progression-free and overall survival. The aim of this study was to develop and validate a pretreatment clinical nomogram for the prediction of grade 4 lymphopenia. METHODS AND MATERIALS: A development set of consecutive patients who underwent chemoradiation therapy for esophageal cancer and an independent validation set of patients from another institution were identified. Grade 4 lymphopenia was defined as an absolute lymphocyte count nadir during chemoradiation therapy of

Irradical (R1-2) resection for non-small cell lung cancer (NSCLC) is associated with a dismal prognosis. Adjuvant treatment attempts to improve survival outcomes, but evidence on the optimal strategy is limited. The purpose of this study was to compare overall survival (OS) between different adjuvant treatment strategies in these patients. Out of 8,528 patients with newly diagnosed NSCLC from 2015-2018, those with an R1-2 resection were identified from the Netherlands Cancer Registry. First, OS was compared between adjuvant treatment groups ‘no therapy’, ‘radiotherapy (RT) only’, ‘chemotherapy only’, and ‘chemo- and radiotherapy (CRT)’ using multinomial propensity score-weighted Cox regression analysis. Second, three 1:1 propensity score-matched sets were created for chemotherapy vs no chemotherapy, RT only vs no therapy, and CRT vs chemotherapy only. Kaplan-Meier and Cox regression analyses for OS were performed in each set. With a median follow-up of 23 months, 427 patients were selected. In the weighted regression analysis, compared to no adjuvant therapy, chemotherapy and CRT were associated with improved OS (HR 0.41, 95%CI: 0.22-0.76; and HR 0.55, 95%CI: 0.37-0.81, respectively), whereas RT was not (HR 1.04, 95%CI: 0.73-1.50). In the matched sets, OS was improved after chemotherapy (+/- RT) compared to no chemotherapy (HR 0.47, 95%CI: 0.32-0.69). No OS difference was observed between matched groups of RT only vs no adjuvant therapy (HR 1.13, 95%CI: 0.74-1.72), nor for CRT vs chemotherapy only (HR 1.37, 95%CI: 0.70-2.71). Adjuvant chemotherapy, but not radiotherapy, improves survival after an R1-2 resection in stage I-III NSCLC.

The potential to provide base-load electricity as well as industrial and domestic heat places geothermal energy in a unique position in the future energy mix. As estimated by the International Energy Agency, geothermal power can contribute to 3.5% to the worldwide power and 3.9% to heat production by 2050. This includes the development of Enhanced Geothermal Systems (EGS) in low-enthalpy systems. The EGS technology is still in an early stage of development and the intended upscaling of power plant capacities presupposes the assurance of efficiency, profitability and safety of geothermal facilities. Pushing EGS technologies towards market maturity requires a long-term strategic approach and massive investments in research and development. Comprehensive multidisciplinary research programs combining fundamental and applied concepts tackling technological, economic and ecological and safety challenges along the EGS process chain are needed. The Karlsruhe Institute of Technology has defined a broad research program on EGS technology development following the necessity of a transdisciplinary approach. Research activities cover the whole process chain including system integration and span from fundamental to applied research across scales. The research concept is embedded in the national research program of the Helmholtz Association and is structured in four clusters: reservoir characterization and engineering; thermal water circuit; materials and geo-processes; and power plant operation. The proximity to industry closely interlinked with fundamental research forms the basis of a target-orientated concept. It combines the disciplines geosciences, geophysics, material sciences, engineering, geochemistry and numerics. The present paper aims at giving an overview of geothermal research at KIT and emphases the need for concerted research efforts at the international level to accelerate technological breakthrough of EGS as essential part of a future sustainable energy system.

Purpose : Salvage treatments for localized radiorecurrent prostate cancer can be performed safely when a focal and image guided approach is used. Due to the low toxicity, the opportunity exists to investigate a second salvage treatment when a second locally recurrent prostate cancer occurs. Here, we describe a second salvage treatment procedure of 4 patients. Material and methods : Four patients with a pathologically proven second local recurrence were treated in an outpatient magnetic resonance imaging (MRI)-guided setting with a single fraction of 19 Gy focal high-dose-rate brachytherapy (HDR-BT). Delineation was performed using choline-PET-CT or a 68Ga-PSMA PET in combination with multiparametric 3 Tesla MRI in all four patients. Toxicity was measured using common toxicity criteria for adverse events (CTCAE) version 4.0. Results : With a median follow-up of 12 months (range, 6-15), there were 2 patients with biochemical recurrence as defined by the Phoenix-definition. There were no patients with grade 3 or more toxicity. In all second salvage HDR-BT treatments, the constraints for rectum, bladder, and urethra were met. Median treatment volume (GTV) was 4.8 cc (range, 1.9-6.6 cc). A median of 8 catheters (range, 6-9) were used, and the median dose to the treatment volume (GTV) was a D95: 19.3 Gy (SD 15.5-19.4 Gy). Conclusions : Second focal salvage MRI-guided HDR-BT for a select group of patients with a second locally recurrent prostate cancer is feasible. There was no grade 3 or more acute toxicity for these four patients.

INTRODUCTION AND OBJECTIVE:Although multi-parametric MRI (mpMRI) has high sensitivity and negative predictive value, the lower specificity can lead to a high prevalence of equivocal lesions which a...

Purpose To compare open surgical anastomotic revision with endourological techniques for the treatment of ureteroenteric strictures in patients with urinary diversions. Methods All records of patients treated for ureteroenteric strictures in our clinic between 1989 and 2016 were retrospectively reviewed. In 76 patients, 161 completed procedures were analyzed: 26 open revisions vs. 135 endourological treatments, including balloon dilation, Wallstent and/or laser vaporization. Results Median follow-up was 34 months. At 60 months, patency rates were 69% (95% CI 52–92%) after open vs. 27% (95% CI 19–39%) after endo-treatment (p = 0.003); median patency duration was 15.5 vs. 5 months, respectively (p = 0.014). Eventually, 15% of patients required open surgery after primary endo-treatment and 21% received endoscopic re-treatment after primary open surgery. Cox regression analysis revealed no confounding factors among the risk factors added to the model. Complication rates were higher after open surgery (27% Clavien 2, 12% Clavien 3–4 vs. 5% Clavien 1–2, 3% Clavien 3, p = 0.528). Median postoperative hospital stay was 14 days (open) vs. 2 days (endo), p

Objective To compare the clinical validity and utility of Likert assessment and the Prostate Imaging Reporting and Data System (PI-RADS) v2 in the detection of clinically significant and insignificant prostate cancer. Patients and methods A total of 489 pre-biopsy multiparametric magnetic resonance imaging (mpMRI) scans in consecutive patients were subject to prospective paired reporting using both Likert and PI-RADS v2 by expert uro-radiologists. Patients were offered biopsy for any Likert or PI-RADS score ≥4 or a score of 3 with PSA density ≥0.12 ng/mL/mL. Utility was evaluated in terms of proportion biopsied, and proportion of clinically significant and insignificant cancer detected (both overall and on a 'per score' basis). In those patients biopsied, the overall accuracy of each system was assessed by calculating total and partial area under the receiver-operating characteristic (ROC) curves. The primary threshold of significance was Gleason ≥3 + 4. Secondary thresholds of Gleason ≥4 + 3, Ahmed/UCL1 (Gleason ≥4 + 3 or maximum cancer core length [CCL] ≥6 or total CCL≥6) and Ahmed/UCL2 (Gleason ≥3 + 4 or maximum CCL ≥4 or total CCL ≥6) were also used. Results The median (interquartile range [IQR]) age was 66 (60-72) years and the median (IQR) prostate-specific antigen level was 7 (5-10) ng/mL. A similar proportion of men met the biopsy threshold and underwent biopsy in both groups (83.8% [Likert] vs 84.8% [PI-RADS v2]; P = 0.704). The Likert system predicted more clinically significant cancers than PI-RADS across all disease thresholds. Rates of insignificant cancers were comparable in each group. ROC analysis of biopsied patients showed that, although both scoring systems performed well as predictors of significant cancer, Likert scoring was superior to PI-RADS v2, exhibiting higher total and partial areas under the ROC curve. Conclusions Both scoring systems demonstrated good diagnostic performance, with similar rates of decision to biopsy. Overall, Likert was superior by all definitions of clinically significant prostate cancer. It has the advantages of being flexible, intuitive and allowing inclusion of clinical data. However, its use should only be considered once radiologists have developed sufficient experience in reporting prostate mpMRI.