Publications by authors named "Max Peters"

56 Publications

Risk factors for nodal failure after radiochemotherapy and image guided brachytherapy in locally advanced cervical cancer: An EMBRACE analysis.

Radiother Oncol 2021 Sep 2;163:150-158. Epub 2021 Sep 2.

University Medical Center Utrecht, Department of Radiation Oncology, Utrecht, The Netherlands.

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 (NF) 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 NF 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 NF (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 NF (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 NF, particularly in patients with nodal disease in the 'small pelvis' and/or CI region at time of diagnosis.
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http://dx.doi.org/10.1016/j.radonc.2021.08.020DOI Listing
September 2021

Adjuvant Treatment Following Irradical Resection of Stage I-III Non-small Cell Lung Cancer: A Population-based Study.

Curr Probl Cancer 2021 Aug 14:100784. Epub 2021 Aug 14.

Department of Radiation Oncology, The Netherlands, University Medical Center Utrecht. Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Electronic address:

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.
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http://dx.doi.org/10.1016/j.currproblcancer.2021.100784DOI Listing
August 2021

Severe lymphopenia acquired during chemoradiotherapy for esophageal cancer: incidence and external validation of a prediction model.

Radiother Oncol 2021 Aug 25. Epub 2021 Aug 25.

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

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 <0.2 µL). The secondary outcome measures were the prediction model's external performance (i.e. discrimination and calibration). Overall survival for patients with versus without grade 4 lymphopenia was compared using Kaplan-Meier analysis.

Results: A total of 219 patients were included of whom 176 patients (80%) underwent CROSS and 43 patients (20%) extended-CROSS. The incidence of grade 4 lymphopenia was 11% in CROSS and 33% in extended-CROSS (p<0.001). External discrimination yielded a c-statistic of 0.80 (95% confidence interval: 0.70-0.89). External calibration of the model was poor in CROSS but fair in extended-CROSS. Adjusted calibration using intercept correction (adjusted for the lower a-priori risk for grade 4 lymphopenia in CROSS) showed fair agreement between the observed and predicted risk for grade 4 lymphopenia. Median overall survival in patients with versus without grade 4 lymphopenia was 12.7 versus 42.5 months (p=0.045).

Conclusion: The incidence of grade 4 lymphopenia is significantly higher in esophageal cancer patients receiving extended-CROSS compared to those receiving CROSS. The prediction model demonstrated good external performance in the setting of the CROSS-regimen and could be used to identify patients at high-risk for grade 4 lymphopenia who might be eligible for lymphopenia-mitigating strategies.
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http://dx.doi.org/10.1016/j.radonc.2021.08.009DOI Listing
August 2021

The Influence of Severe Radiation-Induced Lymphopenia on Overall Survival in Solid Tumors: A Systematic Review and Meta-Analysis.

Int J Radiat Oncol Biol Phys 2021 Jul 28. Epub 2021 Jul 28.

Departments of Radiation Oncology.

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.
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http://dx.doi.org/10.1016/j.ijrobp.2021.07.1695DOI Listing
July 2021

Progression-free survival in patients with Ga-PSMA-PET-directed SBRT for lymph node oligometastases.

Acta Oncol 2021 Oct 29;60(10):1342-1351. Epub 2021 Jul 29.

Department of Radiotherapy, University Medical Center Utrecht, Utrecht, The Netherlands.

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.
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http://dx.doi.org/10.1080/0284186X.2021.1955970DOI Listing
October 2021

Phase II study of definitive chemoradiation for locally advanced squamous cell cancer of the vulva: An efficacy study.

Gynecol Oncol 2021 Jul 20. Epub 2021 Jul 20.

University Medical Center Utrecht, Department of Radiation Oncology Utrecht, Netherlands.

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.
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http://dx.doi.org/10.1016/j.ygyno.2021.07.020DOI Listing
July 2021

Development and internal validation of multivariable prediction models for biochemical failure after MRI-guided focal salvage high-dose-rate brachytherapy for radiorecurrent prostate cancer.

Clin Transl Radiat Oncol 2021 Sep 29;30:7-14. Epub 2021 Jun 29.

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.

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.
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http://dx.doi.org/10.1016/j.ctro.2021.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261471PMC
September 2021

Ultra-central lung tumors: safety and efficacy of protracted stereotactic body radiotherapy.

Acta Oncol 2021 Aug 30;60(8):1061-1068. Epub 2021 Jun 30.

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: 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 (BED) of 90-150 Gy) for patients with ultra-central lung tumors.

Materials And Methods: 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.

Results: 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 () to the main bronchus ( = 0.003), where a BED of ≥91 Gy increased the risk of grade ≥3 toxicity significantly.

Discussion: 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.
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http://dx.doi.org/10.1080/0284186X.2021.1942545DOI Listing
August 2021

Can quantitative analysis of multi-parametric MRI independently predict failure of focal salvage HIFU therapy in men with radio-recurrent prostate cancer?

Urol Oncol 2021 May 25. Epub 2021 May 25.

Imperial Prostate, Division of Surgery, Department of Surgery and Cancer, Imperial College, London, UK.

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.
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http://dx.doi.org/10.1016/j.urolonc.2021.04.017DOI Listing
May 2021

In Reply to Murgic and Chung.

Int J Radiat Oncol Biol Phys 2021 06;110(2):618-619

Department of Radiotherapy, University Medical Center Utrecht, Utrecht, Netherlands.

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http://dx.doi.org/10.1016/j.ijrobp.2021.01.021DOI Listing
June 2021

Conventional radical versus focal treatment for localised prostate cancer: a propensity score weighted comparison of 6-year tumour control.

Prostate Cancer Prostatic Dis 2021 May 1. Epub 2021 May 1.

Imperial Prostate, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK.

Background: 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.

Methods: Following the eligibility criteria PSA < 20 ng/mL, Gleason score ≤ 7 and T-stage ≤ T2c, we included 830 radical (440 radiotherapy, 390 prostatectomy) and 530 focal therapy (cryotherapy, high-intensity focused ultrasound or high-dose-rate brachytherapy) patients treated between 2005 and 2018 from multicentre registries in the Netherlands and the UK. A propensity score weighted (PSW) analysis was performed to compare failure-free survival (FFS), with failure defined as salvage treatment, metastatic disease, systemic treatment (androgen deprivation therapy or chemotherapy), or progression to watchful waiting. The secondary outcome was overall survival (OS). Median (IQR) follow-up in each cohort was 55 (28-83) and 62 (42-83) months, respectively.

Results: At baseline, radical patients had higher PSA (10.3 versus 7.9) and higher-grade disease (31% ISUP 3 versus 11%) compared to focal patients. After PSW, all covariates were balanced (SMD < 0.1). 6-year weighted FFS was higher after radical therapy (80.3%, 95% CI 73.9-87.3) than after focal therapy (72.8%, 95% CI 66.8-79.8) although not statistically significant (p = 0.1). 6-year weighted OS was significantly lower after radical therapy (93.4%, 95% CI 90.1-95.2 versus 97.5%, 95% CI 94-99.9; p = 0.02). When compared in a three-way analysis, focal and LRP patients had a higher risk of treatment failure than EBRT patients (p < 0.001), but EBRT patients had a higher risk of mortality than focal patients (p = 0.008).

Conclusions: Within the limitations of a cohort-based analysis in which residual confounders are likely to exist, we found no clinically relevant difference in cancer control conferred by focal therapy compared to radical therapy at 6 years.
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http://dx.doi.org/10.1038/s41391-021-00369-6DOI Listing
May 2021

Prophylactic cranial irradiation in patients with small cell lung cancer in The Netherlands: A population-based study.

Clin Transl Radiat Oncol 2021 Mar 12;27:157-163. Epub 2021 Feb 12.

Department of Radiation Oncology, University Medical Center Utrecht, The Netherlands.

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.
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http://dx.doi.org/10.1016/j.ctro.2021.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903055PMC
March 2021

Evaluation of daily online contour adaptation by radiation therapists for prostate cancer treatment on an MRI-guided linear accelerator.

Clin Transl Radiat Oncol 2021 Mar 14;27:50-56. Epub 2021 Jan 14.

Department of Radiation Oncology, University Medical Center Utrecht, The Netherlands.

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.
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http://dx.doi.org/10.1016/j.ctro.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822780PMC
March 2021

Focal therapy compared to radical prostatectomy for non-metastatic prostate cancer: a propensity score-matched study.

Prostate Cancer Prostatic Dis 2021 06 28;24(2):567-574. Epub 2021 Jan 28.

Imperial Prostate, Division of Surgery, Department of Surgery and Cancer, Imperial College London, London, UK.

Introduction: Focal therapy (FT) ablates areas of prostate cancer rather than treating the whole gland. We compared oncological outcomes of FT to radical prostatectomy (RP).

Methods: Using prospective multicentre databases of 761 FT and 572 RP cases (November/2005-September/2018), patients with PSA < 20 ng/ml, Gleason 
Results: 335 radical prostatectomy and 501 focal therapy patients were eligible for matching. For focal therapy, 420 had HIFU and 81 cryotherapy. Cryotherapy was used predominantly for anterior cancer. After matching, 246 RP and 246 FT cases were identified. For radical prostatectomy, mean (SD) age was 63.4 (5.6) years, median (IQR) PSA 7.9 g/ml (6-10) and median (IQR) follow-up 64 (30-89) months. For focal therapy, these were 63.3 (6.9) years, 7.9 ng/ml (5.5-10.6) and 49 [34-67] months, respectively. At 3, 5 and 8 years, FFS (95%CI) was 86% (81-91%), 82% (77-88%) and 79% (73-86%) for radical prostatectomy compared to 91% (87-95%), 86% (81-92%) and 83% (76-90%) following focal therapy (p = 0.12).

Conclusions: In patients with non-metastatic low- intermediate prostate cancer, oncological outcomes over 8 years were similar between focal therapy and radical prostatectomy.
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http://dx.doi.org/10.1038/s41391-020-00315-yDOI Listing
June 2021

Determining the safety of ultrafocal salvage high-dose-rate brachytherapy for radiorecurrent prostate cancer: A toxicity assessment of 150 patients.

Clin Transl Radiat Oncol 2021 Mar 11;27:1-7. Epub 2020 Dec 11.

Department of Radiotherapy, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.

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.
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http://dx.doi.org/10.1016/j.ctro.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750686PMC
March 2021

A Comparison of Prostate Cancer Detection between Visual Estimation (Cognitive Registration) and Image Fusion (Software Registration) Targeted Transperineal Prostate Biopsy.

J Urol 2021 Apr 18;205(4):1075-1081. Epub 2020 Nov 18.

Imperial Prostate, Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.

Purpose: We compared clinically significant prostate cancer detection by visual estimation and image fusion targeted transperineal prostate biopsy.

Materials And Methods: 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).

Results: 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%, p <0.001).

Conclusions: We found no overall difference in clinically significant prostate cancer detection, although image fusion may be superior in experienced hands.
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http://dx.doi.org/10.1097/JU.0000000000001476DOI Listing
April 2021

Health-related quality of life after ultrafocal salvage high-dose-rate brachytherapy for radiorecurrent prostate cancer: reporting the patient's perspective.

Clin Transl Radiat Oncol 2020 Nov 17;25:81-87. Epub 2020 Oct 17.

Department of Radiotherapy, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.

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 < 0.01 and p = 0.03). Better baseline score was predictive of better sexual functioning (p < 0.01).

Conclusion: Ultrafocal salvage HDR-BT has negligible impact on bowel symptoms but does affect urinary symptoms and sexual functioning. Lower impact is predicted for patients with favorable urinary and sexual function at baseline. Urethral dose constraints should be closely monitored.
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http://dx.doi.org/10.1016/j.ctro.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586050PMC
November 2020

Functional and oncological outcomes of salvage cryosurgery for radiorecurrent prostate cancer.

BJU Int 2021 Jul 4;128(1):46-56. Epub 2020 Nov 4.

Department of Urology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.

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.
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http://dx.doi.org/10.1111/bju.15269DOI Listing
July 2021

Long-term outcomes of two ablation techniques for treatment of radio-recurrent prostate cancer.

Prostate Cancer Prostatic Dis 2021 03 19;24(1):186-192. Epub 2020 Aug 19.

Departments of Urology and Oncology, Western University, London, ON, Canada.

Background: 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).

Methods: 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.

Results: 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 < 0.0001) were associated with a higher risk of BCR. Similarly, sHIFU patients had a higher risk of CRPC (HR 2.31, 95% CI 1.23-4.35, p = 0.009). The cumulative incidence (for both treatments) of PCSM was 16.5% (95% CI 12.2-21.4%) at 10 years and 28.4% (95% CI 22.1-34.9%) at 20 years, with no difference between treatment modalities. Pre-salvage PSA was a common predictor for the measured oncological outcomes.

Conclusions: Although sHIFU had higher BCR and CRPC rates, there were no differences in PCSM when compared with sCT. The long-term oncological data on two ablation techniques highlighted that only 50% of patients started ADT after 10-year follow-up.
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http://dx.doi.org/10.1038/s41391-020-00265-5DOI Listing
March 2021

Predicting Incomplete Resection in Non-Small Cell Lung Cancer Preoperatively: A Validated Nomogram.

Ann Thorac Surg 2021 03 31;111(3):1052-1058. Epub 2020 Jul 31.

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.

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.
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http://dx.doi.org/10.1016/j.athoracsur.2020.05.165DOI Listing
March 2021

Patient-Reported Outcomes of Oligometastatic Patients After Conventional or Stereotactic Radiation Therapy to Bone Metastases: An Analysis of the PRESENT Cohort.

Int J Radiat Oncol Biol Phys 2020 05 30;107(1):39-47. Epub 2020 Jan 30.

Department of Radiation Oncology, University Medical Center Utrecht, Heidelberglaan Utrecht, The Netherlands.

Purpose: Stereotactic body radiation therapy (SBRT) has become a widely adopted treatment for patients with oligometastatic disease, despite limited evidence of superiority. We compared pain response and quality of life (QoL) in patients with oligometastatic disease treated with conventionally fractionated 3-dimensional radiation therapy (3DCRT) or SBRT to bone metastases.

Methods And Materials: We included patients with oligometastatic disease (≤5 lesions within ≤3 organs) treated within the prospective PRESENT cohort. Main outcomes were pain response, clinical local control, and QoL 2, 4, and 8 weeks and 3, 6, and 12 months after treatment. Pain response was assessed only in patients who reported pain at baseline and was defined according to international consensus criteria.

Results: Of 131 patients with oligometastatic disease, 66 patients were treated with 3DCRT and 65 patients with SBRT. A pain response was achieved in 81% (3DCRT) versus 84% (SBRT) with a median duration of 23 weeks (range, 1-58) and 24 weeks (range, 0-50), respectively. Reirradiation was needed in 33% versus 5% of the patients, respectively. None of the QoL subscales were significantly different between both groups.

Conclusions: In patients with oligometastatic disease, SBRT to bone metastases did not improve pain response or QoL compared with 3DCRT. Reirradiation was less often needed in the SBRT group.
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http://dx.doi.org/10.1016/j.ijrobp.2019.12.041DOI Listing
May 2020

MRI-Guided Ultrafocal Salvage High-Dose-Rate Brachytherapy for Localized Radiorecurrent Prostate Cancer: Updated Results of 50 Patients.

Int J Radiat Oncol Biol Phys 2020 05 30;107(1):126-135. Epub 2020 Jan 30.

Department of Radiotherapy, University Medical Center Utrecht, the Netherlands.

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.
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http://dx.doi.org/10.1016/j.ijrobp.2020.01.023DOI Listing
May 2020

Evaluation of functional outcomes after a second focal high-intensity focused ultrasonography (HIFU) procedure in men with primary localized, non-metastatic prostate cancer: results from the HIFU Evaluation and Assessment of Treatment (HEAT) registry.

BJU Int 2020 06 11;125(6):853-860. Epub 2020 Feb 11.

Imperial Urology, Imperial College Healthcare NHS Trust, Charing Cross Hospital, London, UK.

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.
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http://dx.doi.org/10.1111/bju.15004DOI Listing
June 2020

Likert vs PI-RADS v2: a comparison of two radiological scoring systems for detection of clinically significant prostate cancer.

BJU Int 2020 01 1;125(1):49-55. Epub 2019 Nov 1.

Imperial Prostate, Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK.

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.
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http://dx.doi.org/10.1111/bju.14916DOI Listing
January 2020

Assessment of Return to Baseline Urinary and Sexual Function Following Primary Focal Cryotherapy for Nonmetastatic Prostate Cancer.

Eur Urol Focus 2021 Mar 5;7(2):301-308. Epub 2019 Oct 5.

Department of Urology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK.

Background: The oncological outcomes in men with clinically significant prostate cancer following focal cryotherapy are promising, although functional outcomes are under-reported.

Objective: To determine the impact of focal cryotherapy on urinary and sexual function, specifically assessing return to baseline function.

Design, Setting, And Participants: Between October 2013 and November 2016, 58 of 122 men who underwent focal cryotherapy for predominantly anterior clinically significant localised prostate cancer within a prospective registry returned patient-reported outcome measure questionnaires, which included International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF-15) questionnaires.

Intervention: Standard cryotherapy procedure using either the SeedNet or the Visual-ICE cryotherapy system.

Outcome Measurements And Statistical Analysis: Primary outcome was return to baseline function of IPSS score and IIEF erectile function (EF) subdomain. Cumulative incidence and Cox-regression analyses were performed.

Results And Limitations: Probability of returning to baseline IPSS function was 78% at 12 mo and 87% at both 18 and 24 mo, with recovery seen up to 18 mo. For IIEF (EF domain), the probability of returning to baseline function was 85% at 12 mo and 89% at both 18 and 24 mo, with recovery seen up to 18 mo. Only the preoperative IIEF-EF score was associated with a poor outcome (hazard ratio 0.96, 95% confidence interval 0.93-0.999, p =  0.04). The main limitation was that only half of the patients returned their questionnaires.

Conclusions: In men undergoing primary focal cryotherapy, there is a high degree of preservation of urinary and erectile function with return to baseline function occurring from 3 mo and continuing up to 18 mo after focal cryotherapy.

Patient Summary: In men who underwent focal cryotherapy for prostate cancer, approximately nine in 10 returned to their baseline urinary and sexual function. Keeping in mind that level 1 evidence and long-term data are still needed, in men who wish to preserve urinary and sexual function, focal cryotherapy may be considered an alternative treatment option to radical therapy.
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http://dx.doi.org/10.1016/j.euf.2019.09.004DOI Listing
March 2021

Prediction of Severe Lymphopenia During Chemoradiation Therapy for Esophageal Cancer: Development and Validation of a Pretreatment Nomogram.

Pract Radiat Oncol 2020 Jan - Feb;10(1):e16-e26. Epub 2019 Jul 29.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

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 <0.2 × 10/μL. Multivariable logistic regression analysis was used to create a prediction model for grade 4 lymphopenia in the development set, which was internally validated using bootstrapping and externally validated by applying the model to the validation set. The model was presented as a nomogram yielding 4 risk groups.

Results: Among 860 included patients, 322 (37%) experienced grade 4 lymphopenia. Higher age, larger planning target volume in interaction with lower body mass index, photon- rather than proton-based therapy, and lower baseline absolute lymphocyte count were predictive in the final model (corrected c-statistic, 0.76). External validation in 144 patients, among whom 58 (40%) had grade 4 lymphopenia, yielded a c-statistic of 0.71. Four nomogram-based risk groups yielded predicted risk rates of 10%, 24%, 43%, and 70%, respectively.

Conclusions: A pretreatment clinical nomogram was developed and validated for the prediction of grade 4 radiation-induced lymphopenia during chemoradiation therapy for esophageal cancer. The nomogram can risk stratify individual patients suitable for lymphopenia-mitigating strategies or potential future therapeutic approaches to ultimately improve survival.
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http://dx.doi.org/10.1016/j.prro.2019.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564893PMC
June 2020

In Reply to David and Kamrava.

Int J Radiat Oncol Biol Phys 2019 08;104(5):1183-1184

Department of Radiation Therapy, University Medical Center Utrecht, The Netherlands.

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http://dx.doi.org/10.1016/j.ijrobp.2019.05.017DOI Listing
August 2019

Reply to Zhipeng Mai's Letter to the Editor re: Taimur T. Shah, Max Peters, David Eldred-Evans, et al. Early-Medium-Term Outcomes of Primary Focal Cryotherapy to Treat Nonmetastatic Clinically Significant Prostate Cancer from a Prospective Multicentre Registry. Eur Urol 2019;76:98-105.

Eur Urol 2019 09 29;76(3):e63-e64. Epub 2019 May 29.

Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; Department of Urology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK.

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http://dx.doi.org/10.1016/j.eururo.2019.05.023DOI Listing
September 2019

Factors associated with spontaneous stone passage in a contemporary cohort of patients presenting with acute ureteric colic: results from the Multi-centre cohort study evaluating the role of Inflammatory Markers In patients presenting with acute ureteric Colic (MIMIC) study.

BJU Int 2019 09 14;124(3):504-513. Epub 2019 May 14.

British Urology Researchers in Surgical Training (BURST), London, UK.

Objectives: To assess the relationship of white blood cell count (WBC) and other routinely collected inflammatory and clinical markers including stone size, stone position, and medical expulsive therapy use (MET), with spontaneous stone passage (SSP) in a large contemporary cohort of patients with acute ureteric colic, as there are conflicting data on the role of WBC and other inflammatory markers in SSP in patients with acute ureteric colic.

Patients And Methods: Multicentre retrospective cohort study coordinated by the British Urology Researchers in Surgical Training (BURST) Research Collaborative at 71 secondary care hospitals across four countries (UK, Republic of Ireland, Australia, and New Zealand). In all, 4170 patients presented with acute ureteric colic and a computed tomography confirmed single ureteric stone. Our primary outcome measure was SSP, as defined by the absence of need for intervention to assist stone passage (SP). Multivariable mixed effects logistic regression was used to explore the relationship between key patient factors and SSP.

Results: In all, 2518 patients were discharged with conservative management and had further follow-up with a SSP rate of 74% (n = 1874/2518). Sepsis after discharge with conservative management was reported in 0.6% (n = 16/2518). On multivariable analysis neither WBC, neutrophils count, nor C-reactive protein (CRP) predicted SSP, with an adjusted odds ratio (OR) of 0.97 (95% confidence interval [CI] 0.91-1.04, P = 0.38), 1.06 (95% CI 0.99-1.13, P = 0.1) and 1.00 (95% CI 0.99-1.00, P = 0.17), respectively. MET also did not predict SSP (adjusted OR 1.11, 95% CI 0.76-1.61). However, stone size and stone position were significant predictors. SSP for stones <5 mm was 89% (95% CI 87-90) compared to 49% (95% CI 44-53) for stones ≥5-7 mm, and 29% (95% CI 23-36) for stones >7 mm. For stones in the upper ureter the SSP rate was 52% (95% CI 48-56), middle ureter was 70% (95% CI 64-76), and lower ureter was 83% (95% CI 81-85).

Conclusion: In contrast to the previously published literature, we found that in patients with acute ureteric colic who are discharged with initial conservative management neither WBC, neutrophil count, nor CRP, helps determine the likelihood of SSP. We also found no overall benefit from the use of MET. Stone size and position are important predictors and our present findings represent the most comprehensive SP rates for each millimetre increase in stone size from a large contemporary cohort adjusting for key potential confounders. We anticipate that these data will aid clinicians managing patients with acute ureteric colic and help guide management decisions and the need for intervention.
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http://dx.doi.org/10.1111/bju.14777DOI Listing
September 2019

MRI-Guided Ultrafocal HDR Brachytherapy for Localized Prostate Cancer: Median 4-Year Results of a feasibility study.

Int J Radiat Oncol Biol Phys 2019 08 27;104(5):1045-1053. Epub 2019 Mar 27.

Department of Radiotherapy, University Medical Center Utrecht, Utrecht, Netherlands.

Purpose: For the treatment of localized prostate cancer, focal therapy has the potential to cure with fewer side effects than traditional whole-gland treatments. We report an update on toxicity, quality of life (QoL), and tumor control in our magnetic resonance imaging (MRI)-guided ultrafocal high-dose-rate brachytherapy cohort.

Methods And Materials: Disease status was evaluated by systematic biopsies and 3T multiparametric MRI. The brachytherapy implant procedure under fused transrectal ultrasound/MRI guidance was followed by a 1.5 T MRI for contour adjustments and catheter position verification. A single dose of 19 Gy was delivered to the tumor with a margin of 5 mm. Genitourinary (GU) toxicity, gastrointestinal (GI) toxicity, and erectile dysfunction (ED) were graded with the Common Terminology Criteria for Adverse Events version 4.0. QoL was measured with RAND-36, European Organisation for Research and Treatment of Cancer QLQ-C30 and PR25. International Prostate Symptom Scores and International Index of Erectile Function scores were obtained. Prostate-specific antigen level was monitored, with biochemical recurrence defined as nadir + 2 ng/mL (Phoenix).

Results: Thirty patients with National Comprehensive Cancer Network low- (13%) to intermediate-risk (87%) prostate cancer were treated between May 2013 and April 2016. Median follow-up was 4 years. Median age was 71 years (interquartile range, 68-73) and median initial prostate-specific antigen level was 7.3 ng/mL (5.2-8.1). Maximum Gleason score was 4 + 3 = 7 (in 2 patients). All tumors were radiologic (MRI) stage T2. No grade >2 GU or >1 GI toxicity occurred. International Prostate Symptom Scores only deteriorated temporarily. Mild pretreatment ED deteriorated to moderate/severe ED in 50% of patients. Long-term clinically relevant QoL deterioration was seen in sexual activity and tiredness, whereas emotional and cognitive functioning improved. At 4 years, biochemical disease-free survival was 70% (95% confidence interval, 52%-93%), metastases-free survival was 93% (85%-100%), and overall survival was 100%. Of intraprostatic recurrences, 7 of 9 were out of field.

Conclusions: Ultrafocal high-dose-rate brachytherapy conveys minimal GU or GI toxicity and has a marginal effect on QoL. An early decline in erectile function was seen. Tumor control outcomes are poor (biochemical disease-free survival of 70% [52%-93%] at 4 years), most likely as a result of poor patient selection.
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http://dx.doi.org/10.1016/j.ijrobp.2019.03.032DOI Listing
August 2019
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