Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone.

Background: Abiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536).

Patients And Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as a ≥ 50% decrease confirmed ≥3 weeks later with this combination (phase II).

Respiratory motion compensation for simultaneous PET/MR based on highly undersampled MR data.

Purpose: Positron emission tomography (PET) of the thorax region is impaired by respiratory patient motion. To account for motion, the authors propose a new method for PET/magnetic resonance (MR) respiratory motion compensation (MoCo), which uses highly undersampled MR data with acquisition times as short as 1 min/bed.

Methods: The proposed PET/MR MoCo method (4D jMoCo PET) uses radial MR data to estimate the respiratory patient motion employing MR joint motion estimation and image reconstruction with temporal median filtering.

Tumor Delineation and Quantitative Assessment of Glucose Metabolic Rate within Histologic Subtypes of Non-Small Cell Lung Cancer by Using Dynamic F Fluorodeoxyglucose PET.

Purpose To assess whether dynamic fluorine 18 (F) fluorodeoxyglucose (FDG) positron emission tomography (PET) has added value over static F-FDG PET for tumor delineation in non-small cell lung cancer (NSCLC) radiation therapy planning by using pathology volumes as the reference standard and to compare pharmacokinetic rate constants of F-FDG metabolism, including regional variation, between NSCLC histologic subtypes. Materials and Methods The study was approved by the institutional review board. Patients gave written informed consent.

Real-time 4D dose reconstruction for tracked dynamic MLC deliveries for lung SBRT.

Purpose: This study provides a proof of concept for real-time 4D dose reconstruction for lung stereotactic body radiation therapy (SBRT) with multileaf collimator (MLC) tracking and assesses the impact of tumor tracking on the size of target margins.

Methods: The authors have implemented real-time 4D dose reconstruction by connecting their tracking and delivery software to an Agility MLC at an Elekta Synergy linac and to their in-house treatment planning software (TPS). Actual MLC apertures and (simulated) target positions are reported to the TPS every 40 ms.

Combine and conquer: challenges for targeted therapy combinations in early phase trials.

Our increasing understanding of cancer biology has led to the development of molecularly targeted anticancer drugs. The full potential of these agents has not, however, been realised, owing to the presence of de novo (intrinsic) resistance, often resulting from compensatory signalling pathways, or the development of acquired resistance in cancer cells via clonal evolution under the selective pressures of treatment. Combinations of targeted treatments can circumvent some mechanisms of resistance to yield a clinical benefit.

Functional Data Analysis Applied to Modeling of Severe Acute Mucositis and Dysphagia Resulting From Head and Neck Radiation Therapy.

Purpose: Current normal tissue complication probability modeling using logistic regression suffers from bias and high uncertainty in the presence of highly correlated radiation therapy (RT) dose data. This hinders robust estimates of dose-response associations and, hence, optimal normal tissue-sparing strategies from being elucidated. Using functional data analysis (FDA) to reduce the dimensionality of the dose data could overcome this limitation.

A kernel-based dose calculation algorithm for kV photon beams with explicit handling of energy and material dependencies.

Objective: Mimicking state-of-the-art patient radiotherapy with high-precision irradiators for small animals is expected to advance the understanding of dose-effect relationships and radiobiology in general. We work on the implementation of intensity-modulated radiotherapy-like irradiation schemes for small animals. As a first step, we present a fast analytical dose calculation algorithm for keV photon beams.

Non-coplanar trajectories to improve organ at risk sparing in volumetric modulated arc therapy for primary brain tumors.

Background And Purpose: To evaluate non-coplanar volumetric modulated arc radiotherapy (VMAT) trajectories for organ at risk (OAR) sparing in primary brain tumor radiotherapy.

Materials And Methods: Fifteen patients were planned using coplanar VMAT and compared against non-coplanar VMAT plans for three trajectory optimization techniques. A geometric heuristic technique (GH) combined beam scoring and Dijkstra's algorithm to minimize the importance-weighted sum of OAR volumes irradiated.

Worst case optimization for interfractional motion mitigation in carbon ion therapy of pancreatic cancer.

Introduction: The efficacy of radiation therapy treatments for pancreatic cancer is compromised by abdominal motion which limits the spatial accuracy for dose delivery - especially for particles. In this work we investigate the potential of worst case optimization for interfractional offline motion mitigation in carbon ion treatments of pancreatic cancer.

Methods: We implement a worst case optimization algorithm that explicitly models the relative biological effectiveness of carbon ions during inverse planning.

The Added Value of Circulating Tumor Cell Enumeration to Standard Markers in Assessing Prognosis in a Metastatic Castration-Resistant Prostate Cancer Population.

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease for which better prognostic models for survival are needed. We examined the added value of circulating tumor cell (CTC) enumeration relative to common prognostic laboratory measures from patients with CRPC. Utility of CTC enumeration as a baseline and postbaseline prognostic biomarker was examined using data from two prospective randomized registration-directed trials (COU-AA-301 and ELM-PC4) within statistical models used to estimate risk for survival.

Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients.

Purpose: To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients.

Experimental Design: Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8(+) T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines.

Advanced soft-tissue sarcoma and treatment options: critical appraisal of trabectedin.

Soft-tissue sarcomas (STS) are a heterogeneous group of rare solid tumors of mesenchymal origin. This paper reviews the current status of systemic treatment in advanced and metastatic soft tissue sarcomas, with an emphasis on trabectedin. Trabectedin is a unique type of chemotherapeutic agent with multiple potential mechanisms of action.

Impact of chemotherapy on the outcome of osteosarcoma of the head and neck in adults.

Background: There is an ongoing debate about the value of (neo-)adjuvant chemotherapy in high- and intermediate-grade osteosarcoma of the head and neck.

Methods: All records of patients older than 16 years diagnosed with osteosarcoma of the head and neck in the Netherlands between 1993 and 2013 were reviewed.

Results: We identified a total of 77 patients with an osteosarcoma of the head and neck; the 5-year overall survival (OS) was 55%.

First evaluation of the feasibility of MLC tracking using ultrasound motion estimation.

Purpose: To quantify the performance of the Clarity ultrasound (US) imaging system (Elekta AB, Stockholm, Sweden) for real-time dynamic multileaf collimator (MLC) tracking.

Methods: The Clarity calibration and quality assurance phantom was mounted on a motion platform moving with a periodic sine wave trajectory. The detected position of a 30 mm hypoechogenic sphere within the phantom was continuously reported via Clarity's real-time streaming interface to an in-house tracking and delivery software and subsequently used to adapt the MLC aperture.

Quality of treatment plans and accuracy of in vivo portal dosimetry in hybrid intensity-modulated radiation therapy and volumetric modulated arc therapy for prostate cancer.

Background And Purpose: Delivering selected parts of volumetric modulated arc therapy (VMAT) plans using step-and-shoot intensity modulated radiotherapy (IMRT) beams has the potential to increase plan quality by allowing specific aperture positioning. This study investigates the quality of treatment plans and the accuracy of in vivo portal dosimetry in such a hybrid approach for the case of prostate radiotherapy.

Material And Methods: Conformal and limited-modulation VMAT plans were produced, together with five hybrid IMRT/VMAT plans, in which 0%, 25%, 50%, 75% or 100% of the segments were sequenced for IMRT, while the remainder were sequenced for VMAT.

Towards an evidence-based model of fear of cancer recurrence for breast cancer survivors.

Purpose: In order to understand the multidimensional mechanism of fear of cancer recurrence (FCR) and to identify potential targets for interventions, it is important to empirically test the theoretical model of FCR. This study aims at assessing the validity of Lee-Jones et al.'s FCR model.

Regional Lung Ventilation Analysis Using Temporally Resolved Magnetic Resonance Imaging.

Objective: We propose a computer-aided method for regional ventilation analysis and observation of lung diseases in temporally resolved magnetic resonance imaging (4D MRI).

Methods: A shape model-based segmentation and registration workflow was used to create an atlas-derived reference system in which regional tissue motion can be quantified and multimodal image data can be compared regionally. Model-based temporal registration of the lung surfaces in 4D MRI data was compared with the registration of 4D computed tomography (CT) images.

Targeting Androgen Receptor Aberrations in Castration-Resistant Prostate Cancer.

Androgen receptor (AR) splice variants (SV) have been implicated in the development of metastatic castration-resistant prostate cancer and resistance to AR targeting therapies, including abiraterone and enzalutamide. Agents targeting AR-SV are urgently needed to test this hypothesis and further improve the outcome of patients suffering from this lethal disease. Clin Cancer Res; 22(17); 4280-2.

Required transition from research to clinical application: Report on the 4D treatment planning workshops 2014 and 2015.

Since 2009, a 4D treatment planning workshop has taken place annually, gathering researchers working on the treatment of moving targets, mainly with scanned ion beams. Topics discussed during the workshops range from problems of time resolved imaging, the challenges of motion modelling, the implementation of 4D capabilities for treatment planning, up to different aspects related to 4D dosimetry and treatment verification. This report gives an overview on topics discussed at the 4D workshops in 2014 and 2015.

Normal tissue complication probability (NTCP) modelling using spatial dose metrics and machine learning methods for severe acute oral mucositis resulting from head and neck radiotherapy.

Background And Purpose: Severe acute mucositis commonly results from head and neck (chemo)radiotherapy. A predictive model of mucositis could guide clinical decision-making and inform treatment planning. We aimed to generate such a model using spatial dose metrics and machine learning.

Fatigue in Advanced Cancer Patients: Congruence Between Patients and Their Informal Caregivers About Patients' Fatigue Severity During Cancer Treatment With Palliative Intent and Predictors of Agreement.

Context: Informal caregivers (ICs) are increasingly involved in the monitoring of symptoms during advanced cancer patients' treatment with palliative intent. A common but subjective symptom during this extended treatment phase is fatigue.

Objectives: This exploratory longitudinal study aimed to determine agreement between patients and ICs about patients' fatigue severity.