Navigating the straits: realizing the potential of proton FLASH through physics advances and further pre-clinical characterization.

Ultra-high dose-rate 'FLASH' radiotherapy may be a pivotal step forward for cancer treatment, widening the therapeutic window between radiation tumour killing and damage to neighbouring normal tissues. The extent of normal tissue sparing reported in pre-clinical FLASH studies typically corresponds to an increase in isotoxic dose-levels of 5-20%, though gains are larger at higher doses. Conditions currently thought necessary for FLASH normal tissue sparing are a dose-rate ≥40 Gy s, dose-per-fraction ≥5-10 Gy and irradiation duration ≤0.

ImmunoChemoradiation for Non-Small Cell Lung Cancer: A Meta-Analysis of Factors Influencing Survival Benefit in Combination Trials.

Purpose: Adding immune checkpoint blockade (ICB) to concurrent chemoradiotherapy (cCRT) has improved overall survival (OS) for inoperable locally advanced non-small cell lung cancer. Trials of cCRT-ICB are heterogeneous for factors such as tumor stage and histology, programmed cell death ligand-1 (PDL-1) status, and cCRT-ICB schedules. We therefore aimed to determine the ICB contribution to survival across studies and identify factors associated with survival gain.

Sorting lung tumor volumes from 4D-MRI data using an automatic tumor-based signal reduces stitching artifacts.

Purpose: To investigate whether a novel signal derived from tumor motion allows more precise sorting of 4D-magnetic resonance (4D-MR) image data than do signals based on normal anatomy, reducing levels of stitching artifacts within sorted lung tumor volumes.

Methods: (4D-MRI) scans were collected for 10 lung cancer patients using a 2D T2-weighted single-shot turbo spin echo sequence, obtaining 25 repeat frames per image slice. For each slice, a tumor-motion signal was generated using the first principal component of movement in the tumor neighborhood (TumorPC1).

Roadmap for precision preclinical x-ray radiation studies.

This Roadmap paper covers the field of precision preclinical x-ray radiation studies in animal models. It is mostly focused on models for cancer and normal tissue response to radiation, but also discusses other disease models. The recent technological evolution in imaging, irradiation, dosimetry and monitoring that have empowered these kinds of studies is discussed, and many developments in the near future are outlined.

Collection efficiencies of ionization chambers in pulsed radiation beams: an exact solution of an ion recombination model including free electron effects.

Boag(1996) formulated a key model of collection efficiency for ionization chambers in pulsed radiation beams, in which some free electrons form negatively charged ions with a density that initially varies exponentially across the chamber. This non-uniform density complicates ion recombination calculations, in comparison with Boag's 1950 work in which a collection efficiency formula,, was straightforwardly obtained assuming a uniform negative ion cloud. Boag(1996) therefore derived collection efficiency formulae',″ and'″ based on three approximate descriptions of the exponentially-varying negative ion cloud, each uniform within a region.

Dose-Response Analysis Describes Particularly Rapid Repopulation of Non-Small Cell Lung Cancer during Concurrent Chemoradiotherapy.

(1) Purpose: We analysed overall survival (OS) rates following radiotherapy (RT) and chemo-RT of locally-advanced non-small cell lung cancer (LA-NSCLC) to investigate whether tumour repopulation varies with treatment-type, and to further characterise the low / ratio found in a previous study. (2) Materials and methods: Our dataset comprised 2-year OS rates for 4866 NSCLC patients (90.5% stage IIIA/B) belonging to 51 cohorts treated with definitive RT, sequential chemo-RT (sCRT) or concurrent chemo-RT (cCRT) given in doses-per-fraction ≤3 Gy over 16-60 days.

A Biomathematical Model of Tumor Response to Radioimmunotherapy With αPDL1 and αCTLA4.

There is evidence of synergy between radiotherapy and immunotherapy. Radiotherapy can increase liberation of tumor antigens, causing activation of antitumor T-cells. This effect can be boosted with immunotherapy.

Quantitative Analysis of Radiation-Associated Parenchymal Lung Change.

We present a novel classification system of the parenchymal features of radiation-induced lung damage (RILD). We developed a deep learning network to automate the delineation of five classes of parenchymal textures. We quantify the volumetric change in classes after radiotherapy in order to allow detailed, quantitative descriptions of the evolution of lung parenchyma up to 24 months after RT, and correlate these with radiotherapy dose and respiratory outcomes.

Improving Outcomes in NSCLC: Optimum Dose Fractionation in Radical Radiotherapy Matters.

Introduction: We analyzed a comprehensive national radiotherapy data set to compare outcomes of the most frequently used moderate hypofractionation regimen (55 Gy in 20 fractions) and conventional fractionation regimen (60-66 Gy in 30-33 fractions).

Methods: A total of 169,863 cases of NSCLC registered in England from January 2012 to December 2016 obtained from the Public Health England were divided into cohort 1 (training set) diagnosed in 2012 to 2013 and cohort 2 (validation set) diagnosed in 2014 to 2016. Radiotherapy data were obtained from the National Radiotherapy Dataset and linked by National Health Service number to survival data from the Office of National Statistics and Hospital Episode Statistics, from which surgical data and Charlson comorbidity index were obtained.

The PTW microSilicon diode: Performance in small 6 and 15 MV photon fields and utility of density compensation.

Purpose: We have experimentally and computationally characterized the PTW microSilicon 60023-type diode's performance in 6 and 15 MV photon fields ≥5 × 5 mm projected to isocenter. We tested the detector on- and off-axis at 5 and 15 cm depths in water, and investigated whether its response could be improved by including within it a thin airgap.

Methods: Experimentally, detector readings were taken in fields generated by a Varian TrueBeam linac and compared with doses-to-water measured using Gafchromic film and ionization chambers.

Associations between cardiac irradiation and survival in patients with non-small cell lung cancer: Validation and new discoveries in an independent dataset.

Introduction: In 'IDEAL-6' patients (N = 78) treated for locally-advanced non-small-cell lung cancer using isotoxically dose-escalated radiotherapy, overall survival (OS) was associated more strongly with V, the left atrial (LA) wall volume receiving 64-73 Gy equivalent dose in 2 Gy fractions (EQD2), than with whole-heart irradiation measures. Here we test this in an independent cohort 'OX-RT' (N = 64) treated routinely.

Methods: Using Cox regression analysis we assessed how strongly OS was associated with V, with whole-heart volumes receiving 64-73 Gy EQD2 or doses above 10-to-70 Gy thresholds, and with principal components of whole-heart dose-distributions.

Report of AAPM Task Group 155: Megavoltage photon beam dosimetry in small fields and non-equilibrium conditions.

Small-field dosimetry used in advance treatment technologies poses challenges due to loss of lateral charged particle equilibrium (LCPE), occlusion of the primary photon source, and the limited choice of suitable radiation detectors. These challenges greatly influence dosimetric accuracy. Many high-profile radiation incidents have demonstrated a poor understanding of appropriate methodology for small-field dosimetry.

Cardiac-sparing radiotherapy for locally advanced non-small cell lung cancer.

Background: We have carried out a study to determine the scope for reducing heart doses in photon beam radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC).

Materials And Methods: Baseline VMAT plans were created for 20 LA-NSCLC patients following the IDEAL-CRT isotoxic protocol, and were re-optimized after adding an objective limiting heart mean dose (MD). Reductions in MD achievable without breaching limits on target coverage or normal tissue irradiation were determined.

Classification of tolerable/intolerable mucosal toxicity of head-and-neck radiotherapy schedules with a biomathematical model of cell dynamics.

Purpose: The purpose of this study is to present a biomathematical model based on the dynamics of cell populations to predict the tolerability/intolerability of mucosal toxicity in head-and-neck radiotherapy.

Methods And Materials: Our model is based on the dynamics of proliferative and functional cell populations in irradiated mucosa, and incorporates the three As: Accelerated proliferation, loss of Asymmetric proliferation, and Abortive divisions. The model consists of a set of delay differential equations, and tolerability is based on the depletion of functional cells during treatment.

Vascular assessment in small bowel obstruction: can CT predict requirement for surgical intervention?

Purpose: Small bowel obstruction (SBO) is a common cause of emergency presentations for abdominal pain and can be complicated by mesenteric ischemia. Computed tomography is currently central to diagnosis and management planning. Currently accepted signs identify secondary effects of the root physiological insult, which is vascular obstruction.

A mathematical model of dynamics of cell populations in squamous epithelium after irradiation.

Purpose: To develop multi-compartment mechanistic models of dynamics of stem and functional cell populations in epithelium after irradiation. We present two models, with three (3C) and four (4C) compartments respectively. We use delay differential equations, and include accelerated proliferation, loss of division asymmetry, progressive death of abortive stem cells, and turnover of functional cells.

Density compensated diodes for small field dosimetry: comprehensive testing and implications for design.

Purpose: In small megavoltage photon fields, the accuracies of an unmodified PTW 60017-type diode dosimeter and six diodes modified by adding airgaps of thickness 0.6-1.6 mm and diameter 3.

Long-Term Results from the IDEAL-CRT Phase 1/2 Trial of Isotoxically Dose-Escalated Radiation Therapy and Concurrent Chemotherapy for Stage II/III Non-small Cell Lung Cancer.

Purpose: The IDEAL-CRT phase 1/2 multicenter trial of isotoxically dose-escalated concurrent chemoradiation for stage II/III non-small cell lung cancer investigated two 30-fraction schedules of 5 and 6 weeks' duration. We report toxicity, tumor response, progression-free survival (PFS), and overall survival (OS) for both schedules, with long-term follow-up for the 6-week schedule.

Methods And Materials: Patients received isotoxically individualized tumor radiation doses of 63 to 71 Gy in 5 weeks or 63 to 73 Gy in 6 weeks, delivered concurrently with 2 cycles of cisplatin and vinorelbine.

Chemoradiotherapy of locally-advanced non-small cell lung cancer: Analysis of radiation dose-response, chemotherapy and survival-limiting toxicity effects indicates a low α/β ratio.

Purpose: To analyse changes in 2-year overall survival (OS) with radiotherapy (RT) dose, dose-per-fraction, treatment duration and chemotherapy use, in data compiled from prospective trials of RT and chemo-RT (CRT) for locally-advanced non-small cell lung cancer (LA-NSCLC).

Material And Methods: OS data was analysed for 6957 patients treated on 68 trial arms (21 RT-only, 27 sequential CRT, 20 concurrent CRT) delivering doses-per-fraction ≤4.0 Gy.

Buparlisib with thoracic radiotherapy and its effect on tumour hypoxia: A phase I study in patients with advanced non-small cell lung carcinoma.

Background: Pre-clinically, phosphoinositide 3-kinase (PI3K) inhibition radiosensitises tumours by increasing intrinsic radiosensitivity and by reducing tumour hypoxia. We assessed whether buparlisib, a class 1 PI3K inhibitor, can be safely combined with radiotherapy in patients with non-small cell lung carcinoma (NSCLC) and investigated its effect on tumour hypoxia.

Methods: This was a 3 + 3 dose escalation and dose expansion phase I trial in patients with advanced NSCLC.

Accelerated, Dose escalated, Sequential Chemoradiotherapy in Non-small-cell lung cancer (ADSCaN): a protocol for a randomised phase II study.

Introduction: Lung cancer is the most common cause of cancer mortality in the UK, and non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Most patients present with inoperable disease; therefore, radiotherapy plays a major role in treatment. However, the majority of patients are not suitable for the gold standard treatment (concurrent chemoradiotherapy) due to performance status and comorbidities.

Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer.

Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer.

Reply to comment on 'origins of the changing detector response in small megavoltage photon radiation fields'.

Andreo and Benmakhlouf (2017 Phys. Med. Biol.