CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer

Lung cancer is the leading cause of cancer mortality worldwide and most patients are unsuitable for ‘gold standard’ treatment, which is concurrent chemoradiotherapy. CONCORDE is a platform study seeking to establish the toxicity profiles of multiple novel radiosensitisers targeting DNA repair proteins in patients treated with sequential chemoradiotherapy. Time-to-event continual reassessment will facilitate efficient dose-finding. Abbreviations ATM: Ataxia telangiectasia mutated ATR: Ataxia telangiectasia and Rad3 related cfDNA: Cell-free DNA CRT: Chemoradiotherapy CT: Computed tomography CTCAE: Common terminology criteria for adverse events CTRad: Clinical and Translational Radiotherapy Research Working Group DDRi: DNA damage response inhibitor DLT: Dose limiting toxicity DNA: Deoxyribonucleic acid DNA-PK: DNA-dependent protein kinase ECOG: Eastern Cooperative Oncology Group EORTC: European Organisation for Research and Treatment of Cancer ICRU: International Commission on Radiation Units and Measurements IMPs: Investigational medicinal products LA: Locally advanced MRC: Medical Research Council NCRI: National Cancer Research Institute NSCLC: Non-small cell lung cancer PARP: Poly (ADP-ribose) polymerase PET: Positron emission tomography PFS: Progression free survival PROMs: Patient-reported outcome measures RECIST: Response evaluation criteria in solid tumours RP2D: Recommended phase II dose RT: Radiotherapy SACT: Systemic anti-cancer therapy SRC: Safety review committee TiTE-CRM: Time to event continual reassessment method TNM: Tumour node metastasi

Whole pelvic helical tomotherapy for locally advanced cervical cancer: technical implementation of IMRT with helical tomothearapy

<p>Abstract</p> <p>Background</p> <p>To review the experience and to evaluate the treatment plan of using helical tomotherapy (HT) for the treatment of cervical cancer.</p> <p>Methods</p> <p>Between November 1st, 2006 and May 31, 2009, 10 cervical cancer patients histologically confirmed were enrolled. All of the patients received definitive concurrent chemoradiation (CCRT) with whole pelvic HT (WPHT) followed by brachytherapy. During WPHT, all patients were treated with cisplatin, 40 mg/m²intravenously weekly. Toxicity of treatment was scored according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE v3.0).</p> <p>Results</p> <p>The mean survival was 25 months (range, 3 to 27 months). The actuarial overall survival, disease-free survival, locoregional control and distant metastasis-free rates at 2 years were 67%, 77%, 90% and 88%, respectively. The average of uniformity index and conformal index was 1.06 and 1.19, respectively. One grade 3 of acute toxicity for diarrhea, thrombocytopenia and three grade 3 leucopenia were noted during CCRT. Only one grade 3 of subacute toxicity for thrombocytopenia was noted. There were no grade 3 or 4 subacute toxicities of anemia, leucopenia, genitourinary or gastrointestinal effects. Compared with conventional whole pelvic radiation therapy (WPRT), WPHT decreases the mean dose to rectum, bladder and intestines successfully.</p> <p>Conclusion</p> <p>HT provides feasible clinical outcomes in locally advanced cervical cancer patients. Long-term follow-up and enroll more locally advanced cervical carcinoma patients by limiting bone marrow radiation dose with WPHT technique is warranted.</p

A closed parameterization of DNA-damage by charged particles as a function of energy - A geometrical approach

Purpose: To present a closed formalism calculating charged particle radiation damage induced in DNA. The formalism is valid for all types of charged particles and due to its closed nature is suited to provide fast conversion of dose to DNA-damage. Methods: The induction of double strand breaks in DNA--strings residing in irradiated cells is quantified using a single particle model. This leads to a proposal to use the cumulative Cauchy distribution to express the mix of high and low LET type damage probability generated by a single particle. A microscopic phenomenological Monte Carlo code is used to fit the parameters of the model as a function of kinetic energy related to the damage to a DNA molecule embedded in a cell. The model is applied for four particles: electrons, protons, alpha--particles, and carbon ions. A geometric interpretation of this observation using the impact ionization mean free path as a quantifier, allows extension of the model to very low energies. Results: The mathematical expression describes the model adequately using a chi--square test ($\chi^2/NDF < 1$). This applies to all particle types with an almost perfect fit for protons, while the other particles seem to result in some discrepancies at very low energies. The implementation calculating a strict version of the RBE based on complex damage alone is corroborated by experimental data from the measured RBE. The geometric interpretation generates a unique dimensionless parameter $k$ for each type of charged particle. In addition, it predicts a distribution of DNA damage which is different from the current models.Comment: 19 pages, 15 figures and 1 appendi

Monte Carlo calculation of beam quality correction factors in proton beams using detailed simulation of ionization chambers

This work calculates beam quality correction factors (k Q) in monoenergetic proton beams using detailed Monte Carlo simulation of ionization chambers. It uses the Monte Carlo code penh and the electronic stopping powers resulting from the adoption of two different sets of mean excitation energy values for water and graphite: (i) the currently ICRU 37 and ICRU 49 recommended and and (ii) the recently proposed and . Twelve different ionization chambers were studied. The k Q factors calculated using the two different sets of I-values were found to agree with each other within 1.6% or better. k Q factors calculated using current ICRU I-values were found to agree within 2.3% or better with the k Q factors tabulated in IAEA TRS-398, and within 1% or better with experimental values published in the literature. k Q factors calculated using the new I-values were also found to agree within 1.1% or better with the experimental values. This work concludes that perturbation correction factors in proton beams - currently assumed to be equal to unity - are in fact significantly different from unity for some of the ionization chambers studied.Postprint (author's final draft

Characterization and calibration of thermoluminescent dosimeters of LiF:Mg, Ti in the quantity Hp(0.07)

The extremity dosimeters are devices used to quantifying the radiation dose that the occupationally exposed individual receives in specific regions of the body during the work time. Dosimeter calibration is essential so that the dosimeter response is equivalent to the received dose. Tests such as batch homogeneity and lower detection limit are part of the dosimeter calibration process. The rod phantom simulates the region of interest regarding the interaction with radiation and the scattered dose. The extremity dosimeters used were the LiF:Mg,Ti thermoluminescent dosimeters

Dosimetric characterization of a synthetic single crystal diamond detector in a clinical 62 MeV ocular therapy proton beam

A synthetic single crystal diamond based Schottky photodiode was tested at INFN-LNS on the proton beam line (62 MeV) dedicated to the radiation treatment of ocular disease. The diamond detector response was studied in terms of pre-irradiation dose, linearity with dose and dose rate, and angular dependence. Depth dose curves were measured for the 62 MeV pristine proton beam and for three unmodulated range-shifted proton beams; furthermore, the spread-out Bragg peak was measured for a modulated therapeutic proton beam. Beam parameters, recommended by the ICRU report 78, were evaluated to analyze depth-dose curves from diamond detector. Measured dose distributions were compared with the corresponding dose distributions acquired with reference plane-parallel ionization chambers. Field size dependence of the output factor (dose per monitor unit) in a therapeutic modulated proton beam was measured with the diamond detector over the range of ocular proton therapy collimator diameters (5-30 mm). Output factors measured with the diamond detector were compared to the ones by a Markus ionization chamber, a Scanditronix Hi-p Si stereotactic diode and a radiochromic EBT2 film. Signal stability within 0.5% was demonstrated for the diamond detector with no need of any pre-irradiation dose. Dose and dose rate dependence of the diamond response was measured: deviations from linearity resulted to be within ±0.5% over the investigated ranges of 0.5-40.0 Gy and 0.3-30.0 Gy/min respectively. Output factors from diamond detector measured with the smallest collimator (5 mm in diameter) showed a maximum deviation of about 3% with respect to the high resolution radiochromic EBT2 film. Depth-dose curves measured by diamond for unmodulated and modulated beams were in good agreement with those from the reference plane-parallel Markus chamber, with relative differences lower than ±1% in peak-to-plateau ratios, well within experimental uncertainties. A 2.5% variation in diamond detector response was observed in angular dependence measurements carried-out by varying the proton beam incidence angle in the polar direction. The dosimetric characterization of the tested synthetic single crystal diamond detector clearly indicates its suitability for relative dosimetry in ocular therapy proton beams, with no need of any correction factors accounting for dose rate and linear energy transfer dependence

Beam Tests of Ionization Chambers for the NuMI Neutrino Beam

We have conducted tests at the Fermilab Booster of ionization chambers to be used as monitors of the NuMI neutrino beamline. The chambers were exposed to proton fluxes of up to 10$^{12}$ particles/cm$^2$/1.56$\mu$s. We studied space charge effects which can reduce signal collection from the chambers at large charged particle beam intensities.Comment: submitted to IEEE Trans Nucl. Sc

A Quality Control Study on Involved Node Radiation Therapy in the European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfomi H10 Trial on Stages I and II Hodgkin Lymphoma:Lessons Learned

Purpose: Involved node radiation therapy (INRT) was introduced in the European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfomi H10 trial, a large multicenter trial in early-stage Hodgkin Lymphoma. The present study aimed to evaluate the quality of INRT in this trial. Methods and Materials: A retrospective, descriptive study was initiated to evaluate INRT in a representative sample encompassing approximately 10% of all irradiated patients in the H10 trial. Sampling was stratified by academic group, year of treatment, size of the treatment center, and treatment arm, and it was done proportional to the size of the strata. The sample was completed for all patients with known recurrences to enable future research on relapse patterns. Radiation therapy principle, target volume delineation and coverage, and applied technique and dose were evaluated using the EORTC Radiation Therapy Quality Assurance platform. Each case was reviewed by 2 reviewers and, in case of disagreement also by an adjudicator for a consensus evaluation. Results: Data were retrieved for 66 of 1294 irradiated patients (5.1%). Data collection and analysis were hampered more than anticipated by changes in archiving of diagnostic imaging and treatment planning systems during the running period of the trial. A review could be performed on 61 patients. The INRT principle was applied in 86.6%. Overall, 88.5% of cases were treated according to protocol. Unacceptable variations were predominately due to geographic misses of the target volume delineations. The rate of unacceptable variations decreased during trial recruitment. Conclusions: The principle of INRT was applied in most of the reviewed patients. Almost 90% of the evaluated patients were treated according to the protocol. The present results should, however, be interpreted with caution because the number of patients evaluated was limited. Individual case reviews should be done in a prospective fashion in future trials. Radiation therapy Quality Assurance tailored to the clinical trial objectives is strongly recommended.</p