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Introduction: Studies that assessed the efficacy of pre-operative immune checkpoint blockade (ICB) in locally advanced urothelial cancer of the bladder showed encouraging pathological complete response rates, suggesting that a bladder-sparing approach may be a viable option in a subset of patients. Chemoradiation is an alternative for radical cystectomy with similar oncological outcomes, but is still mainly used in selected patients with organconfined tumors or patients ineligible to undergo radical cystectomy. We propose to sequentially administer ICB and chemoradiation to patients with (locally advanced) muscle-invasive bladder cancer. Methods: The INDIBLADE trial is an investigator-initiated, single-arm, multicenter phase 2 trial. Fifty patients with cT2-4aN0-2M0 urothelial bladder cancer will be treated with ipilimumab 3 mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43 followed by chemoradiation. The primary endpoint is the bladder-intact event-free survival (BI-EFS). Events include: local or distant recurrence, salvage cystectomy, death and switch to platinum-based chemotherapy. We will also evaluate the potential of multiparametric magnetic resonance imaging of the bladder to identify non-responders, and we will assess the clearance of circulating tumor DNA as a biomarker for ICB treatment response. Discussion: This is the first trial in which the efficacy of induction combination ICB followed by chemoradiation is being evaluated to provide bladderpreservation in patients with (locally advanced) urothelial bladder cancer. [ABSTRACT FROM AUTHOR]

INTRODUCTION Despite the benefits from concurrent chemoradiotherapy (CCRT) regimens in patients with locally advanced non-small cell lung cancer (NSCLC), more efficacious treatment options are needed. Cetuximab, a monoclonal antibody that selectively binds to the epidermal growth factor receptor, has demonstrated activity in patients with metastatic NSCLC. This study assessed whether combining cetuximab with CCRT is feasible. METHODS Patients with inoperable locally advanced NSCLC received cetuximab (400 mg/m2 on day 1, 250 mg/m2 q1w in weeks 2-6) in addition to radiotherapy (66 Gy in 24 fractions weeks 2-6) and cisplatin (6 mg/m2 q1d during weeks 2-6) daily. Early response was monitored using FDG PET/CT-scans performed 4 weeks after treatment and response was evaluated by a CT scan 6 weeks after the last fraction of radiotherapy RESULTS Between March and July 2008, 12 consecutive patients were enrolled. Ten patients completed protocol treatment. Although generally well tolerated, two patients were unable to complete protocol treatment. Acneiform rash and dysphagia were the most common side effects (grade ⩽3 according to CTCAE v 3.0). No unexpected toxicities were observed. Early response monitoring revealed a metabolic response in 8 (out of 10) patients. The CT scan evaluation showed a partial response in 8 patients. Four (out of 12) patients showed progressive disease after 12 months of follow-up. CONCLUSIONS The addition of cetuximab to CCRT in patients with NSCLC was generally well tolerated and early clinical responses were observed with this new therapy combination. A randomized phase II study comparing CCRT with CCRT and cetuximab is ongoing. [ABSTRACT FROM AUTHOR]

INTRODUCTION Despite the benefits from concurrent chemoradiotherapy (CCRT) regimens in patients with locally advanced non-small cell lung cancer (NSCLC), more efficacious treatment options are needed. Cetuximab, a monoclonal antibody that selectively binds to the epidermal growth factor receptor, has demonstrated activity in patients with metastatic NSCLC. This study assessed whether combining cetuximab with CCRT is feasible. METHODS Patients with inoperable locally advanced NSCLC received cetuximab (400 mg/m2 on day 1, 250 mg/m2 q1w in weeks 2-6) in addition to radiotherapy (66 Gy in 24 fractions weeks 2-6) and cisplatin (6 mg/m2 q1d during weeks 2-6) daily. Early response was monitored using FDG PET/CT-scans performed 4 weeks after treatment and response was evaluated by a CT scan 6 weeks after the last fraction of radiotherapy. RESULTS Between March and July 2008, 12 consecutive patients were enrolled. Ten patients completed protocol treatment. Although generally well tolerated, two patients were unable to complete protocol treatment. Acneiform rash and dysphagia were the most common side effects (grade ≤3 according to CTCAE v 3.0). No unexpected toxicities were observed. Early response monitoring revealed a metabolic response in 8 (out of 10) patients. The CT scan evaluation showed a partial response in 8 patients. Four (out of 12) patients showed progressive disease after 12 months of follow-up. CONCLUSIONS The addition of cetuximab to CCRT in patients with NSCLC was generally well tolerated and early clinical responses were observed with this new therapy combination. A randomized phase II study comparing CCRT with CCRT and cetuximab is ongoing. [ABSTRACT FROM AUTHOR]

Purpose: Patients with advanced penile squamous cell carcinoma have a poor prognosis (21% 2-year overall survival [OS] from diagnosis). We assessed the activity of atezolizumab (anti-PD-L1) in patients with advanced penile cancer, with or without radiotherapy (RT)., Patients and Methods: A single-center, nonrandomized phase II study with two treatment arms was conducted in 32 patients with histologically confirmed advanced penile cancer. All patients received atezolizumab (1,200 mg) once every 3 weeks. Twenty patients, who were expected to benefit from RT for locoregional disease control, received additional irradiation. The primary end point was 1-year progression-free survival (PFS) for the complete cohort and was reached if the actual 1-year PFS was at least 35%. Secondary end points included OS, objective response rate (ORR), and tolerability. Exploratory biomarker analyses were conducted in pretreatment specimens., Results: Median follow-up was 29.1 months (IQR, 18.1-33.5). Grade 3-4 adverse events related to atezolizumab or RT were observed in 3/32 (9.4%) and 13/20 (65%) patients, respectively. One-year PFS was 12.5% (95% CI, 5.0 to 31.3), which did not meet the study's primary end point. Median OS was 11.3 months (95% CI, 5.5 to 18.7). In the objective response-evaluable population (n = 30; 93.8%), the ORR was 16.7% (95% CI, 6 to 35), including 2 (6.7%) complete responders and 3 (10%) partial responders. Improved PFS was observed in patients with high-risk human papillomavirus (hrHPV)-positive tumors ( P = .003) and those with high infiltration of intratumoral CD3 + CD8 + T cells ( P = .037)., Conclusion: Although the primary end point of 1-year PFS was not met, durable antitumor activity to atezolizumab was observed in a subset of patients. Biomarkers, such as hrHPV and intratumoral CD3 + CD8 + T-cell infiltration, may help to better select responders.

Purpose of Review: Studies on treatment options for patients with locally advanced vulvar cancer (LAVC) are scarce, and high-level evidence for a primary treatment choice is lacking. Furthermore, current treatment options are associated with extensive morbidity and high complication rates. More effective treatment options are urgently needed. This review describes current treatment possibilities, focusing on literature regarding neoadjuvant chemotherapy (NACT) followed by surgery., Recent Findings: Although data are heterogeneous and limited, NACT followed by surgery might be an effective and well tolerated treatment alternative associated with lower morbidity compared with current treatment options, such as excenterative surgery or definitive chemoradiation., Summary: Up until now, several studies describe an overall response rate of 40-86%. Surgery turned out to be possible in 40-90% of the LAVC patients who received NACT. Prospective studies on the efficacy and safety of NACT followed by surgery with a homogeneous chemotherapy regimen are urgently awaited. NACT should, at this point, still be considered investigational., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Concurrent chemoradiotherapy (CRT) as a definitive treatment option for patients with nonmetastatic muscle-invasive bladder carcinoma (MIBC) is increasingly being applied in clinical practice., Objective: To assess the oncological and toxicity outcomes in a contemporary cohort of nonmetastatic MIBC patients treated with concurrent CRT in daily practice., Design Setting and Participants: Patients with nonmetastatic MIBC (cT2-4aN0M0) who had received CRT with curative intent between January 2010 and April 2020 in three centers were retrospectively identified. The CRT consisted of 66 Gy (or biologically equivalent) plus either mitomycin C and fluorouracil/capecitabine or cisplatinum., Outcome Measurements and Statistical Analysis: The primary endpoint was the 2-yr locoregional disease-free survival (LDFS) estimate. Secondary endpoints were complete response, disease-specific survival (DSS), overall survival (OS), bladder intact event-free survival (BI-EFS), and severe adverse events (<90 d of starting CRT). Kaplan-Meier survival and Cox multivariable regression analyses were performed., Results and Limitations: We included data of 240 MIBC patients with a median age of 74 yr and a median follow-up of 27 mo (interquartile range 11-44). Complete response on first cystoscopy after CRT was seen in 209 cases (90%). The 2-yr LDFS was 76% (95% confidence interval [CI] 70-82%); the 5-yr OS and DSS were 50% (95% CI 42-59%) and 70% (95% CI 62-79%), respectively. On multivariable analysis, cT2 versus cT3-4 tumor stage was significantly associated with better DSS (hazard ratio 1.02, 95% CI 1-1.05, p = 0.024). The 2-yr BI-EFS was 75% (95% CI 69-82%). Forty-three (17%) patients experienced a severe adverse event (grade ≥3). Limitations include retrospective design and heterogeneous administration of CRT., Conclusions: Concurrent CRT is a safe and effective treatment modality for nonmetastatic MIBC., Patient Summary: Chemoradiotherapy for the treatment of muscle-invasive bladder carcinoma is increasingly being applied. In this study, we reviewed the outcomes of this bladder-sparing treatment using a series of patients treated in three hospitals in daily practice. We found that administration of chemoradiotherapy can be safe and effective., (© 2022 The Author(s).)

Purpose . We propose a neural network for fast prediction of realistic, time-parametrized deformations between pairs of input segmentations. The proposed method was used to generate a library of planning CTVs for cervical cancer radiotherapy. Methods. A 3D convolutional neural network (CNN) was introduced to predict a stationary velocity field given the distance maps of the cervix CTV in empty and full bladder anatomy. Diffeomorphic deformation trajectories between the two states were obtained by time integration. Intermediate deformation states were used to populate a library of cervix CTVs. The network was trained on cervix CTV deformations of 20 patients generated by finite element modeling (FEM). Validation was performed on FEM data of 9 healthy volunteers. Additionally, for these subjects, CTV deformations were observed in a series of repeat MR scans as the bladder filled from empty to full. Predicted and FEM libraries were compared, and benchmarked against the observed deformations. Finally, for an independent test set of 20 patients the predicted libraries were evaluated clinically, and compared to the current method. Results. The median Dice score over the validation subjects between the predicted and FEM libraries was >0.95 throughout the deformation, with a median 90 percentile surface distance of <3 mm. The ability to cover observed CTVs was similar for both the FEM-based and the proposed method, with residual offsets being about twice as large as the difference between the two methods. Clinical evaluation showed improved library properties over the method currently used in clinic. Conclusions. We proposed a CNN trained on FEM deformations, which predicts the deformation trajectory between two input states of the cervix CTV in one forward pass. We applied this to CTV library prediction for cervical cancer. The network is able to mimic FEM deformations well, while being much faster and simpler in use., (© 2021 Institute of Physics and Engineering in Medicine.)

Background and Purpose: Magnetic resonance (MR) guided radiotherapy utilizes MR images for (online) plan adaptation and image guidance. The aim of this study was to investigate the impact of variation in MR acquisition time and scan resolution on image quality, interobserver variation in contouring and interobserver variation in registration., Materials and Methods: Nine patients with prostate cancer were included. Four T2-weighted 3D turbo spin echo (T2w 3D TSE) sequences were acquired with different acquisition times and resolutions. Two radiologists assessed image quality, conspicuity of the capsule, peripheral zone and central gland architecture and motion artefacts on a 5 point scale. Images were delineated by two radiation oncologists and interobserver variation was assessed by the 95% Hausdorff distance. Seven observers registered the MR images on the planning CT. Registrations were compared on systematic offset and interobserver variation., Results: Acquisition times ranged between 1.3 and 6.3 min. Overall image quality and capsule definition were significantly worse for the MR sequence with an acquisition time of 1.3 min compared to the other sequences. Median 95% Hausdorff distance showed no significant differences in interobserver variation of contouring. Systematic offset and interobserver variation in registration were small (<1 mm) and of no clinical significance., Conclusions: Our results can be used to effectively shorten overall fraction time for online adaptive MR guided radiotherapy by optimising the imaging sequence used for registration. From the sequences studied, a sequence of 3.1 min with anisotropic voxels of 1.2 × 1.2 × 2.4 mm 3 provided the shortest acquisition time without compromising image quality., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: NKI-AvL is part of the Elekta MR-linac Consortium and we acknowledge financial and technical support from Elekta AB (Stockholm, Sweden) under a research agreement., (© 2021 Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

Objectives: To examine the anatomical distribution of prostate cancer (PCa) recurrence on gallium-68 prostate-specific membrane antigen ( 68 Ga-PSMA) positron-emission tomography (PET)/computed tomography (CT) in patients with biochemical recurrence (BCR) after undergoing radical prostatectomy (RP) with pathological lymph node metastasis (pN1) in their extended pelvic lymph node dissection (ePLND), and to compare the location of PCa recurrence with the location of the initial lymph node metastasis at ePLND., Materials and Methods: We retrospectively reviewed 100 patients with BCR (PSA 0.05-5.00 ng/mL) after RP with pN1 ePLND who underwent 68 Ga-PSMA PET/CT to guide salvage therapy. Clinical and pathological features and anatomical locations of PCa recurrence on 68 Ga-PSMA PET/CT were obtained, and management impact was recorded., Results: In all, 68 patients (68%) had a positive and 32 patients (32%) had a negative 68 Ga-PSMA PET/CT result. Of the 68 patients with a positive 68 Ga-PSMA PET/CT, 44 (65%) showed abnormal uptake only in the pelvic area, seven (10%) only outside the pelvic area, and 17 (25%) both within and outside the pelvic area. 68 Ga-PSMA PET/CT-positive pelvic lymph nodes were often (84%) detected on the same side as the lymph node metastasis diagnosed at ePLND. Based on the outcomes of the 68 Ga-PSMA PET/CT, change of management was noted in 68% of the patients., Conclusion: Recurrence of PCa on 68 Ga-PSMA PET/CT was limited to the pelvis in the majority of patients with BCR after RP with pN1 ePLND. Moreover, recurrence was often detected on the same side as the lymph node metastasis at ePLND. The results confirm the diagnostic value of 68 Ga-PSMA PET/CT in patients with BCR after RP with pN1 ePLND. Prospective studies are needed to support the long-term benefit of 68 Ga-PSMA PET/CT-dictated management changes., (© 2020 The Authors BJU International Published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: Oligometastatic prostate cancer (OMPC) is a heterogeneous disease state that is imperfectly understood, and its clinical implications are unclear., Objective: To determine the consensus of a Dutch multidisciplinary expert panel on biological aspects, treatment goals, and management of OMPC in daily clinical practice., Design, Setting, and Participants: The study comprised a modified Delphi method including an explorative survey with various statements and questions, followed by a consensus meeting to discuss and determine the agreement with revised statements and related items. The panel consisted of 34 Dutch representatives from urology, medical and radiation oncology, radiology, nuclear medicine, and basic research., Outcome Measurements and Statistical Analysis: Agreement was determined with statements (five-point scale). Consensus was defined as ≥75% panel agreement with a statement., Results and Limitations: Consensus existed for 56% of statements. The panel agreed that OMPC comprises a limited metastatic spread in the hormone-sensitive setting, in both the synchronous and the metachronous presentation. Limited metastatic spread was believed to involve three to five metastases and a maximum of two organs. Prostate-specific membrane antigen positron emission tomography/computed tomography scan was currently perceived as the most accurate diagnostic imaging modality. Although there was a consensus that targeted treatment of all metastases in OMPC will delay further dissemination of the disease, opinions on specific treatment regimens were divided. Panel outcomes were limited by the lack of scientific evidence on OMPC., Conclusions: A multidisciplinary panel reached a consensus that OMPC is a specific disease state requiring a tailored treatment approach. OMPC registries and clinical studies should focus on both the biology and the clinical parameters in relation to optimal treatment strategies in synchronous and metachronous OMPC., Patient Summary: A group of Dutch medical specialists agreed that prostate cancer patients having few metastases may benefit from a new therapeutic approach. Clinical studies need to determine which treatment is best for each specific situation., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Biochemical failure after external beam radiotherapy (RT) for node-positive prostate cancer (PC N+ ) frequently involves nodal recurrences, in most cases out of field. This raises the question if current RTOG-based elective nodal fields can still be considered optimal. Modern diagnostic tools like PSMA PET/CT and choline PET/CT can visualize nodal recurrences with unprecedented accuracy. We evaluated recurrence patterns on PET/CT after RT for PC N+ , with the aim to explore options for improved nodal target definition., Methods and Materials: Data of all patients treated with curative intent EBRT for PC N+ in NKI-AVL from 2008 to 2018 were retrospectively reviewed. EBRT comprised 70 Gy to the prostate or 66-70 Gy to the prostate bed, 60 Gy to involved nodes, and 52,5-56 Gy (46 Gy EQD2) to RTOG-based elective nodal fields, in 35 fractions. Locations of recurrences on PET/CT were noted, and nodal locations were correlated with the applied EBRT fields., Results: 42 patients received PSMA (28) or choline (14) PET/CT at biochemical recurrence. 35 patients (83%) had a positive scan. At their first positive scan 17 patients had nodal metastasis, in some cases together with a local recurrence or distant disease. In-field nodal recurrences were uncommon (n = 3). Out-field nodal recurrences occurred more frequently (n = 14), with the majority (n = 12) just above the elective nodal field. These nodes were the single area of detectable failure in 6 patients (14%)., Conclusions: Current RT with RTOG-based nodal fields for PC N+ provides good in-field tumour control, but frequent out-field nodal recurrences suggest missed microscopic locations. Expanding elective fields to include the aorta bifurcation may prolong recurrence-free survival. Future research must address whether the potential benefits of this strategy outbalance additional toxicity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

Background and Purpose: Radiation dose escalation using hypofractionation might improve overall survival (OS). We investigated OS in a phase II multicenter study in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with hypofractionated concurrent chemoradiotherapy., Materials and Methods: A 2-armed phase II, multi-center study (NTR2230) was performed with the aim to assess the effect of cetuximab to concurrent chemoradiotherapy in LA-NSCLC patients (stage II/IIIA/B). Arm A received high dose radiotherapy (24 × 2.75 Gy) and concurrent daily low-dose cisplatin (6 mg/m(2)). Arm B received an identical treatment regimen with additional weekly cetuximab. Kaplan-Meier survival curves and 1-, 2- and 5-year OS proportions were calculated., Results: Between February 2009 and May 2011, 102 patients were randomly allocated in two arms. Median OS was 31.5 months (range 12.8-52.3), not significantly different between arms A and B; 33.0 (range 17.0-57.0) and 30.0 (11.0-52.0) months. 1-, 2- and 5-year OS rates were 74.5%, 59.4% and 37.3%, respectively. In multivariate analyses, worse performance score, V35 of the esophagus and the existence of comorbidities were significantly (P-value<0.05) associated with a shorter OS., Discussion: In this phase II trial, the median OS for the entire group was remarkably high; 31.5 months. Furthermore, 5-year OS was still 37.3%. Hypofractionation might contribute to improved OS in LA-NSCLC patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Conebeam-CT (CBCT) guidance is often used for setup verification of lung cancer patients treated with radiotherapy. The purpose of this study was to quantify intra-thoracic anatomical changes (ITACs) during the radiotherapy treatment and to hand over a decision support system to guide the radiation therapy technologist and radiation oncologist in prioritizing these changes., Materials and Methods: 1793 CBCT-scans of 177 lung cancer patients treated in 2010 in our institute with radical radiotherapy were evaluated. Our decision support system: "the Traffic Light Protocol", was retrospectively applied to these CBCT-scans. The protocol has four levels: red (immediate action before treatment), orange (action before next fraction), yellow (no action required) and green (no change)., Results: In 128 patients (72%), 210 ITACs were observed with a maximum level of red, orange and yellow in 12%, 36% and 24% respectively. Types of observed ITACs were, tumor regression (35%), tumor baseline shift (27%), changes in atelectasis (19%), tumor progression (10%), pleural effusion (6%) and infiltrative changes (3%)., Conclusions: ITACs have been observed in 72% of all lung cancer patients during the course of radical radiotherapy. The clinical relevance of the proposed ITAC classification in lung radiotherapy needs to be validated in a prospective analysis., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: To increase knowledge about lung tumor tissue levels of erlotinib and its primary active metabolite, and about erlotinib plasma levels in intercalated dosing schedules, a sensitive and accurate method for determination of erlotinib and O-desmethyl erlotinib (OSI-420) in human plasma and lung tumor tissue has been developed., Results: A method with HPLC-MS/MS was validated over a linear range from 5 to 2500 ng/ml in plasma and from 5.0 to 500 ng/ml for lung tumor tissue homogenate (50-5000 ng/g for lung tumor). Calibration curves in plasma were used to quantify analytes in lung tumor tissue homogenate. Lung tumor tissue of 15 patients has been collected and analyzed with the presented method., Conclusion: This method has been successfully validated and applied to determine plasma and lung tumor tissue concentrations of erlotinib and O-desmethyl erlotinib in patients with non-small-cell lung cancer.