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Objectives.To derive a collection efficiency formula,fGauss, for cylindrical ionization chambers in pulsed radiation beams from a volume recombination model of Boaget al(1996Phys. Med. Biol.41885-97) including free electrons. To validatefGaussand a parallel plate chamber formulafexpusing an ion transport code and calculate changes in collection efficiencies caused by electric field charge screening at 0.1-100 mGy doses-per-pulse. And to determine collection efficienciesCE∞predicted at infinite voltage in the absence of avalanche effects by fitting scaled formulae to efficiencies computed for 100-400 V chamber voltages and 10 and 100 mGy doses-per-pulse.Approach.Calculations were performed for an idealized parallel plate chamber with 2 mm electrode separationd, and for an idealized cylindrical chamber with 0.5 and 2.333 mm inner and electrode radiirinandrout.Main results.fGaussandfexppredict the same collection efficiencies for cylindrical and parallel plate chambers satisfyingd2=(rout2-rin2)ln(rout/rin)/2, an equivalence condition met by the chambers studied. Without charge screening, efficiencies computed using the code equalledfGaussandfexp. With screening, efficiencies changed by ⩽0.03%, ⩽1.1% and ⩽21.3% at 1, 10 and 100 mGy doses-per-pulse, and differed between the chambers by ⩽0.9% and ⩽19.6% at ⩽10 and 100 mGy dose-per-pulse. For fits offexpandfGauss,CE∞values were ⩽1.2% and ⩽17.6% from unity at 10 and 100 mGy per pulse respectively, closer than for other formulae tested.Significance.Allowing for screening,fGaussandfexpdescribed computed collection efficiencies to within 0.03%, 1.1% and 21.3% at doses-per-pulse ⩽1, 10 and 100 mGy. Equivalence of the two chambers broke down at 100 mGy per pulse. Departures ofCE∞values from unity suggest that collection efficiencies determined experimentally by fittingfGaussorfexpto readings made at multiple voltages will be accurate to within 1.2% and 17.6% at 10 and 100 mGy per pulse respectively.
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Radiometria , Radiometria/instrumentaçãoRESUMO
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-1, dose-per-fraction ≥5-10 Gy and irradiation duration ≤0.2-0.5 s. Cyclotron proton accelerators are the first clinical systems to be adapted to irradiate deep-seated tumours at FLASH dose-rates, but even using these machines it is challenging to meet the FLASH conditions. In this review we describe the challenges for delivering FLASH proton beam therapy, the compromises that ensue if these challenges are not addressed, and resulting dosimetric losses. Some of these losses are on the same scale as the gains from FLASH found pre-clinically. We therefore conclude that for FLASH to succeed clinically the challenges must be systematically overcome rather than accommodated, and we survey physical and pre-clinical routes for achieving this.
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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. METHODS AND MATERIALS: Data were collated from cCRT-ICB clinical studies published 2018 to 2022 that treated 2196 patients with non-small cell lung cancer (99% stage 3). Associations between 2-year OS and ICB, CRT, patient and tumor factors were investigated using metaregression. A published model of survival after radiation therapy (RT) or CRT was extended to include ICB effects. The model was fitted simultaneously to the cCRT-ICB data and data previously compiled for RT/CRT treatments alone. The net ICB contribution (OS gain) and its associations with factors were described by fitted values of ICB terms added to the model. Statistical significance was determined by likelihood-ratio testing. RESULTS: The gain in 2-year OS from ICB was 9.9% overall (95% CI, 7.6%, 12.2%; P = .018). Both OS gain and 2-year OS itself rose with increasing planned ICB duration (P = .008, .002, respectively) and with tumor PDL-1 ≥ 1% (P = .034, .023). Fitted OS gains were also greater for patients with stage 3B/C disease (P = .021). OS gain was not associated with tumor histology, patient performance status, radiation therapy dose, ICB drug type (anti-PDL-1 vs anti-programmed cell death-1), or whether ICB began concurrently with or after cCRT. CONCLUSIONS: Fitted gains in 2-year OS due to ICB were higher in cohorts with greater fractions of stage 3B/C patients and patients with tumor PDL-1 ≥ 1%. OS gain was also significantly higher in a single cohort with a planned ICB duration of 2 years rather than 1, but was not associated with whether ICB treatment began during versus after CRT.
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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). Signals were also generated from displacements of the diaphragm (DIA) and upper and lower chest wall (UCW/LCW) and from slice body area changes (BA). Pearson r coefficients of correlations between observed tumor movement and respiratory signals were determined. TumorPC1, DIA, and UCW signals were used to compile image stacks showing each patient's tumor volume in a respiratory phase. Unsorted image stacks were also built for comparison. For each image stack, the presence of stitching artifacts was assessed by measuring the roughness of the compiled tumor surface according to a roughness metric (Rg). Statistical differences in weighted means of Rg between any two signals were determined using an exact permutation test. RESULTS: The TumorPC1 signal was most strongly correlated with superior-inferior tumor motion, and had significantly higher Pearson r values (median 0.86) than those determined for correlations of UCW, LCW, and BA with superior-inferior tumor motion (p < 0.05). Weighted means of ratios of Rg values in TumorPC1 image stacks to those in unsorted, UCW, and DIA stacks were 0.67, 0.69, and 0.71, all significantly favoring TumorPC1 (p = 0.02-0.05). For other pairs of signals, weighted mean ratios did not differ significantly from one. CONCLUSION: Tumor volumes were smoother in 3D image stacks compiled using the first principal component of tumor motion than in stacks compiled with signals based on normal anatomy.
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Artefatos , Neoplasias Pulmonares , Humanos , Carga Tumoral , Neoplasias Pulmonares/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Pulmão , RespiraçãoRESUMO
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. Finally, clinical translation and reverse translation are discussed.
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Radiometria , Animais , Raios X , Radiometria/métodos , Radiografia , Modelos Animais , Imagens de FantasmasRESUMO
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. Radioimmunotherapy has potential to increase tumor control rates. Biomathematical models of response to radioimmunotherapy may help on understanding of the mechanisms affecting response, and assist clinicians on the design of optimal treatment strategies. In this work we present a biomathematical model of tumor response to radioimmunotherapy. The model uses the linear-quadratic response of tumor cells to radiation (or variation of it), and builds on previous developments to include the radiation-induced immune effect. We have focused this study on the combined effect of radiotherapy and αPDL1/ αCTLA4 therapies. The model can fit preclinical data of volume dynamics and control obtained with different dose fractionations and αPDL1/ αCTLA4. A biomathematical study of optimal combination strategies suggests that a good understanding of the involved biological delays, the biokinetics of the immunotherapy drug, and the interplay between them, may be of paramount importance to design optimal radioimmunotherapy schedules. Biomathematical models like the one we present can help to interpret experimental data on the synergy between radiotherapy and immunotherapy, and to assist in the design of more effective treatments.
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Neoplasias , Radioimunoterapia , Humanos , Neoplasias/radioterapia , ImunoterapiaRESUMO
Objective.Boaget al(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,f, was straightforwardly obtained assuming a uniform negative ion cloud. Boaget al(1996) therefore derived collection efficiency formulaef',fâ³ andf'â³ based on three approximate descriptions of the exponentially-varying negative ion cloud, each uniform within a region. Collection efficiencies calculated by Boaget al(1996) using these formulae differed by a maximum of 5.1% relative (at 144 mGy dose-per-pulse with 212 V applied over a 1 mm electrode separation) and all three formulae are often used together. Here an exact solution of the exponentially-varying model is obtained.Approach.The exact solution was derived from a differential equation relating the number of negative ions collected from within some distance of the anode to numbers of ions initially located within that region. Using the resulting formula,fexp, collection efficiencies were calculated for a range of ionization chamber properties and doses-per-pulse, and compared withf,f',fâ³ andfâ³' values and results from an ion transport code.Main results.fexpvalues agreed to 5 decimal places with ion transport code results. The maximum relative difference betweenfexpandfâ³', which was often closest tofexp, was 0.78% for the chamber properties and doses-per-pulse studied by Boaget al(1996), rising to 6.1% at 1 Gy dose-per-pulse and 2 mm electrode separation.Significance.Use offexpshould reduce ambiguities in collection efficiencies calculated using the approximate formulae, although like themfexpdoes not account for electric field distortion, which becomes substantial at doses-per-pulse ≥100 mGy.
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Eletricidade , Elétrons , Íons , Radiometria/métodosRESUMO
(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 α/ß 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. Progressively more detailed dose-response models were fitted, beginning with a probit model, adding chemotherapy effects and survival-limiting toxicity, and allowing tumour repopulation and α/ß to vary with treatment-type and stage. Models were fitted using the maximum-likelihood technique, then assessed via the Akaike information criterion and cross-validation. (3) Results: The most detailed model performed best, with repopulation offsetting 1.47 Gy/day (95% confidence interval, CI: 0.36, 2.57 Gy/day) for cCRT but only 0.30 Gy/day (95% CI: 0.18, 0.47 Gy/day) for RT/sCRT. The overall fitted tumour α/ß ratio was 3.0 Gy (95% CI: 1.6, 5.6 Gy). (4) Conclusion: The fitted repopulation rates indicate that cCRT schedule durations should be shortened to the minimum in which prescribed doses can be tolerated. The low α/ß ratio suggests hypofractionation should be efficacious.
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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. Diagnostic CTs were available pre-RT, and at 3, 6, 12 and 24 months post-RT, for 46 subjects enrolled in a clinical trial of chemoradiotherapy for non-small cell lung cancer. All 230 CT scans were segmented using our network. The five parenchymal classes showed distinct temporal patterns. Moderate correlation was seen between change in tissue class volume and clinical and dosimetric parameters, e.g., the Pearson correlation coefficient was ≤0.49 between V30 and change in Class 2, and was 0.39 between change in Class 1 and decline in FVC. The effect of the local dose on tissue class revealed a strong dose-dependent relationship. Respiratory function measured by spirometry and MRC dyspnoea scores after radiotherapy correlated with the measured radiological RILD. We demonstrate the potential of using our approach to analyse and understand the morphological and functional evolution of RILD in greater detail than previously possible.
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PURPOSE: We have experimentally and computationally characterized the PTW microSilicon 60023-type diode's performance in 6 and 15 MV photon fields ≥5 × 5 mm2 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. An unmodified 60023-type diode was tested along with detectors modified to include 0.6, 0.8, and 1.0 mm thick airgaps. Computationally, doses absorbed by water and detectors' sensitive volumes were calculated using the EGSnrc/BEAMnrc Monte Carlo radiation transport code. Detector response was characterized using k Q c l i n , 4 cm f c l i n , 4 cm , a factor that corrects for differences in the ratio of dose-to-water to detector reading between small fields and the reference condition, in this study 5 cm deep on-axis in a 4 × 4 cm2 field. RESULTS: The greatest errors in measurements of small field doses made using uncorrected readings from the unmodified 60023-type detector were over-responses of 2.6% ± 0.5% and 5.3% ± 2.0% determined computationally and experimentally, relative to the reading-per-dose in the reference field. Corresponding largest errors for the earlier 60017-type detector were 11.9% ± 0.6% and 11.7% ± 1.4% over-responses. Adding even the thinnest, 0.6 mm, airgap to the 60023-type detector over-corrected it, leading to under-responses of up to 4.8% ± 0.6% and 5.0% ± 1.8% determined computationally and experimentally. Further, Monte Carlo calculations indicate that a detector with a 0.3 mm airgap would read correctly to within 1.3% on-axis. The ratio of doses at 15 and 5 cm depths in water in a 6 MV 4 × 4 cm2 field was measured more accurately using the unmodified 60023-type detector than using the 60017-type detector, and was within 0.3% of the ratio measured using an ion chamber. The 60023-type diode's sensitivity also varied negligibly as dose-rate was reduced from 13 to 4 Gy min-1 by decreasing the linac pulse repetition frequency, whereas the sensitivity of the 60017-type detector fell by 1.5%. CONCLUSIONS: The 60023-type detector performed well in small fields across a wide range of beam energies, field sizes, depths, and off-axis positions. Its response can potentially be further improved by adding a thin, 0.3 mm, airgap.
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Fótons , Radiometria , Método de Monte Carlo , Aceleradores de Partículas , ÁguaRESUMO
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 VLAwall-64-73-EQD2, 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 VLAwall-64-73-EQD2, 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. Additionally, we tested associations between OS and volumes of cardiac substructures receiving dose-ranges described by whole-heart principal components significantly associated with OS. RESULTS: In univariable analyses of OX-RT, OS was associated more strongly with VLAwall-64-73-EQD2 than with whole-heart irradiation measures, but more strongly still with VAortV-29-38-EQD2, the volume of the aortic valve region receiving 29-38 Gy EQD2. The best multivariable OS model included LA wall and aortic valve region mean doses, and the aortic valve volume receiving ≥38 Gy EQD2, VAortV-38-EQD2. In a subsidiary analysis of IDEAL-6, the best multivariable model included VLAwall-64-73-EQD2, VAortV-29-38-EQD2, VAortV-38-EQD2 and mean aortic valve dose. CONCLUSION: We propose reducing heart mean doses to the lowest levels possible while meeting protocol dose-limits for lung, oesophagus, proximal bronchial tree, cord and brachial plexus. This in turn achieves large reductions in VAortV-29-38-EQD2 and VLAwall-64-73-EQD2, and we plan to closely monitor patients with values of these measures still >0% (their median value in OX-RT) following reduction.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Átrios do Coração , Humanos , Neoplasias Pulmonares/radioterapia , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por ComputadorRESUMO
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. These incidents are a cause for concern because the use of small fields in various specialized radiation treatment techniques continues to grow rapidly. Reference and relative dosimetry in small and composite fields are the subject of the International Atomic Energy Agency (IAEA) dosimetry code of practice that has been published as TRS-483 and an AAPM summary publication (IAEA TRS 483; Dosimetry of small static fields used in external beam radiotherapy: An IAEA/AAPM International Code of Practice for reference and relative dose determination, Technical Report Series No. 483; Palmans et al., Med Phys 45(11):e1123, 2018). The charge of AAPM task group 155 (TG-155) is to summarize current knowledge on small-field dosimetry and to provide recommendations of best practices for relative dose determination in small megavoltage photon beams. An overview of the issue of LCPE and the changes in photon beam perturbations with decreasing field size is provided. Recommendations are included on appropriate detector systems and measurement methodologies. Existing published data on dosimetric parameters in small photon fields (e.g., percentage depth dose, tissue phantom ratio/tissue maximum ratio, off-axis ratios, and field output factors) together with the necessary perturbation corrections for various detectors are reviewed. A discussion on errors and an uncertainty analysis in measurements is provided. The design of beam models in treatment planning systems to simulate small fields necessitates special attention on the influence of the primary beam source and collimating devices in the computation of energy fluence and dose. The general requirements for fluence and dose calculation engines suitable for modeling dose in small fields are reviewed. Implementations in commercial treatment planning systems vary widely, and the aims of this report are to provide insight for the medical physicist and guidance to developers of beams models for radiotherapy treatment planning systems.
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Fótons , Radiometria , Agências Internacionais , Imagens de FantasmasRESUMO
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 (MDHeart). Reductions in MDHeart achievable without breaching limits on target coverage or normal tissue irradiation were determined. The process was repeated for objectives limiting the heart volume receiving ≥ 50 Gy (VHeart-50-Gy) and left atrial wall volume receiving ≥ 63 Gy (VLAwall-63-Gy). RESULTS: Following re-optimization, mean MDHeart, VHeart-50-Gy and VLAwall-63-Gy values fell by 4.8 Gy and 2.2% and 2.4% absolute respectively. On the basis of associations observed between survival and cardiac irradiation in an independent dataset, the purposefully-achieved reduction in MDHeart is expected to lead to the largest improvement in overall survival. It also led to useful knock-on reductions in many measures of cardiac irradiation including VHeart-50-Gy and VLAwall-63-Gy, providing some insurance against survival being more strongly related to these measures than to MDHeart. The predicted hazard ratio (HR) for death corresponding to the purposefully-achieved mean reduction in MDHeart was 0.806, according to which a randomized trial would require 1140 patients to test improved survival with 0.05 significance and 80% power. In patients whose baseline MDHeart values exceeded the median value in a published series, the average MDHeart reduction was particularly large, 8.8 Gy. The corresponding predicted HR is potentially testable in trials recruiting 359 patients enriched for greater MDHeart values. CONCLUSIONS: Cardiac irradiation in RT of LA-NSCLC can be reduced substantially. Of the measures studied, reduction of MDHeart led to the greatest predicted increase in survival, and to useful knock-on reductions in other cardiac irradiation measures reported to be associated with survival. Potential improvements in survival can be trialled more efficiently in a population enriched for patients with greater baseline MDHeart levels, for whom larger reductions in heart doses can be achieved.
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Carcinoma Pulmonar de Células não Pequenas/radioterapia , Coração/efeitos da radiação , Neoplasias Pulmonares/radioterapia , Tratamentos com Preservação do Órgão , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Vasos Coronários/efeitos da radiação , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Órgãos em Risco/efeitos da radiação , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada , Taxa de SobrevidaRESUMO
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. We calculate the sensitivity (sen) and specificity (spe) of the model in a dataset of 108 radiotherapy schedules, and compare the results with those obtained with three phenomenological classification models, two based on a biologically effective dose (BED) function describing the tolerability boundary (Fowler and Fenwick) and one based on an equivalent dose in 2 Gy fractions (EQD2 ) boundary (Strigari). We also perform a machine learning-like cross-validation of all the models, splitting the database in two, one for training and one for validation. RESULTS: When fitting our model to the whole dataset, we obtain predictive values (sen + spe) up to 1.824. The predictive value of our model is very similar to that of the phenomenological models of Fowler (1.785), Fenwick (1.806), and Strigari (1.774). When performing a k = 2 cross-validation, the specificity and sensitivity in the validation dataset decrease for all models, from Ë1.82 to Ë1.55-1.63. For Fowler, the worsening is higher, down to 1.49. CONCLUSIONS: Our model has proved useful to predict the tolerability/intolerability of a dataset of 108 schedules. As the model is more mechanistic than other available models, it could prove helpful when designing unconventional dose fractionations, schedules not covered by datasets to which phenomenological models of toxicity have been fitted.
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Neoplasias de Cabeça e Pescoço , Lesões por Radiação , Fracionamento da Dose de Radiação , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Mucosa , Pescoço , Dosagem RadioterapêuticaRESUMO
PURPOSE: To develop multi-compartment mechanistic models of dynamics of stem and functional cell populations in epithelium after irradiation. Methods and materials: 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. The models are used to fit experimental data on the variations of the number of cells in mice mucosa after irradiation with 13 Gy and 20 Gy. Akaike information criteria (AIC) was used to evaluate the performance of each model. RESULTS: Both 3C and 4C models provide good fits to experimental data for 13 Gy. Fits for 20 Gy are slightly poorer and may be affected by larger uncertainties and fluctuations of experimental data. Best fits are obtained by imposing constraints on the fitting parameters, so to have values that are within experimental ranges. There is some degeneration in the fits, as different sets of parameters provide similarly good fits. CONCLUSIONS: The models provide good fits to experimental data. Mechanistic approaches like this can facilitate the development of mucositis response models to nonstandard schedules/treatment combinations not covered by datasets to which phenomenological models have been fitted. Studying the dynamics of cell populations in multifraction treatments, and finding links with induced toxicity, is the next step of this work.
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Células Epiteliais/citologia , Células Epiteliais/efeitos da radiação , Modelos Biológicos , Diferenciação Celular/efeitos da radiação , Relação Dose-Resposta à RadiaçãoRESUMO
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 3.6 mm have been comprehensively characterized experimentally and computationally. The optimally thick airgap for density compensation was determined, and detectors were micro-CT imaged to investigate differences between experimentally measured radiation responses and those predicted computationally. METHODS: Detectors were tested on- and off-axis, at 5 and 15 cm depths in 6 and 15 MV fields ≥ 0.5 × 0.5 cm2. Computational studies were carried out using the EGSnrc/BEAMnrc Monte Carlo radiation transport code. Experimentally, radiation was delivered using a Varian TrueBeam linac and doses absorbed by water were measured using Gafchromic EBT3 film and ionization chambers, and compared with diode readings. Detector response was characterized via the [Formula: see text] formalism, choosing a 4 × 4 cm2 reference field. RESULTS: For the unmodified 60017 diode, the maximum error in small field doses obtained from diode readings uncorrected by [Formula: see text] factors was determined as 11.9% computationally at +0.25 mm off-axis and 5 cm depth in a 15 MV 0.5 × 0.5 cm2 field, and 11.7% experimentally at -0.30 mm off-axis and 5 cm depth in the same field. A detector modified to include a 1.6 mm thick airgap performed best, with maximum computationally and experimentally determined errors of 2.2% and 4.1%. The 1.6 mm airgap deepened the modified dosimeter's effective point of measurement by 0.5 mm. For some detectors significant differences existed between responses in small fields determined computationally and experimentally, micro-CT imaging indicating that these differences were due to within-tolerance variations in the thickness of an epoxy resin layer. CONCLUSIONS: The dosimetric performance of a 60017 diode detector was comprehensively improved throughout 6 and 15 MV small photon fields via density compensation. For this approach to work well with good detector-to-detector reproducibility, tolerances on dense component dimensions should be reduced to limit associated variations of response in small fields, or these components should be modified to have more water-like densities.
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Radiometria/instrumentação , Desenho de Equipamento , Método de Monte Carlo , Aceleradores de Partículas , Fótons , Doses de Radiação , Reprodutibilidade dos Testes , Água , Microtomografia por Raio-XRESUMO
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. Eligibility criteria were the same for both schedules. RESULTS: One-hundred twenty patients (6% stage IIB, 68% IIIA, 26% IIIB, 1% IV) were recruited from 9 UK centers, 118 starting treatment. Median prescribed doses were 64.5 and 67.6 Gy for the 36 and 82 patients treated using the 5- and 6-week schedules. Grade ≥3 pneumonitis and early esophagitis rates were 3.4% and 5.9% overall and similar for each schedule individually. Late grade 2 esophageal toxicity occurred in 11.1% and 17.1% of 5- and 6-week patients. Grade ≥4 adverse events occurred in 17 (20.7%) 6-week patients but no 5-week patients. Four adverse events were grade 5, with 2 considered radiation therapy related. After median follow-up of 51.8 and 26.4 months for the 6- and 5-week schedules, median OS was 41.2 and 22.1 months, respectively, and median PFS was 21.1 and 8.0 months. In exploratory analyses, OS was significantly associated with schedule (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.32-0.98; P = .04) and fractional clinical/internal target volume receiving ≥95% of the prescribed dose (HR, 0.88; 95% CI, 0.77-1.00; P = .05). PFS was also significantly associated with schedule (HR, 0.53; 95% CI, 0.33-0.86; P = .01). CONCLUSIONS: Toxicity in IDEAL-CRT was acceptable. Survival was promising for 6-week patients and significantly longer than for 5-week patients. Survival might be further lengthened by following the 6-week schedule with an immune agent, motivating further study of such combined optimized treatments.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia/efeitos adversos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Fracionamento da Dose de Radiação , Relação Dose-Resposta à Radiação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: To analyse changes in 2-year overall survival (OS2yr) 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: OS2yr data was analysed for 6957 patients treated on 68 trial arms (21 RT-only, 27 sequential CRT, 20 concurrent CRT) delivering doses-per-fraction ≤4.0â¯Gy. An initial model considering dose, dose-per-fraction and RT duration was fitted using maximum-likelihood techniques. Model extensions describing chemotherapy effects and survival-limiting toxicity at high doses were assessed using likelihood-ratio testing, the Akaike Information Criterion (AIC) and cross-validation. RESULTS: A model including chemotherapy effects and survival-limiting toxicity described the data significantly better than simpler models (pâ¯<â¯10-14), and had better AIC and cross-validation scores. The fitted α/ß ratio for LA-NSCLC was 4.0â¯Gy (95%CI: 2.8-6.0â¯Gy), repopulation negated 0.38 (95%CI: 0.31-0.47) Gy EQD2/day beyond day 12 of RT, and concurrent CRT increased the effective tumour EQD2 by 23% (95%CI: 16-31%). For schedules delivered in 2â¯Gy fractions over 40â¯days, maximum modelled OS2yr for RT was 52% and 38% for stages IIIA and IIIB NSCLC respectively, rising to 59% and 42% for CRT. These survival rates required 80 and 87â¯Gy (RT or sequential CRT) and 67 and 73â¯Gy (concurrent CRT). Modelled OS2yr rates fell at higher doses. CONCLUSIONS: Fitted dose-response curves indicate that gains of ~10% in OS2yr can be made by escalating RT and sequential CRT beyond 64â¯Gy, with smaller gains for concurrent CRT. Schedule acceleration achieved via hypofractionation potentially offers an additional 5-10% improvement in OS2yr. Further 10-20% OS2yr gains might be made, according to the model fit, if critical normal structures in which survival-limiting toxicities arise can be identified and selectively spared.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimiorradioterapia/efeitos adversos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Estudos Prospectivos , Doses de RadiaçãoRESUMO
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. Buparlisib dose levels were 50 mg, 80 mg and 100 mg once daily orally for 2 weeks, with palliative thoracic radiotherapy (20 Gy in 5 fractions) delivered during week 2. Tumour hypoxic volume (HV) was measured using 18F-fluoromisonidazole positron-emission tomography-computed tomography at baseline and following 1 week of buparlisib. RESULTS: Twenty-one patients were recruited with 9 patients evaluable for maximum tolerated dose (MTD) analysis. No dose-limiting toxicity was reported; therefore, 100 mg was declared the MTD, and 10 patients received this dose in the expansion phase. Ninety-four percent of treatment-related adverse events were ≤grade 2 with fatigue (67%), nausea (24%) and decreased appetite (19%) most common per patient. One serious adverse event (grade 3 hypoalbuminaemia) was possibly related to buparlisib. No unexpected radiotherapy toxicity was reported. Ten (67%) of 15 patients evaluable for imaging analysis were responders with 20% median reduction in HV at the MTD. CONCLUSION: This is the first clinical trial to combine a PI3K inhibitor with radiotherapy in NSCLC and investigate the effects of PI3K inhibition on tumour hypoxia. This combination was well tolerated and PI3K inhibition reduced hypoxia, warranting investigation into whether this novel class of radiosensitisers can improve radiotherapy outcomes.
Assuntos
Adenocarcinoma de Pulmão/terapia , Aminopiridinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/terapia , Neoplasias Pulmonares/terapia , Morfolinas/uso terapêutico , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Radiossensibilizantes/uso terapêutico , Hipóxia Tumoral , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/metabolismo , Idoso , Anorexia/induzido quimicamente , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/metabolismo , Quimiorradioterapia , Fadiga/induzido quimicamente , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Misonidazol/análogos & derivados , Náusea/induzido quimicamente , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , RadioterapiaRESUMO
Andreo and Benmakhlouf (2017 Phys. Med. Biol. 62 1518-32) have disputed a finding of Scott et al (2012 Phys. Med. Biol. 57 4461-76) that the variation with field-size of the response of small ion chambers and solid-state dosimeters in small megavoltage photon radiation fields can largely be attributed to density. Further evidence for this finding was provided by Fenwick et al (2018 Phys. Med. Biol. 63 125003), but Andreo and Benmakhlouf (2018 Phys. Med. Biol. 63 125003) have now challenged the methodology used in that study. Specifically, Andreo and Benmakhlouf suggest that mass stopping-powers of fictitious materials used in Monte Carlo radiation transport calculations should be adjusted with material density according to the polarization effect, as if the materials were real and created by compressing other real materials. In this reply, we observe that fictitious materials are not real, and therefore their densities, mass stopping-powers and microscopic radiation interaction cross-sections can be freely and independently chosen to provide the clearest answers to the questions being studied. And we note that the key role played by density in small field detector response was further confirmed by our group back in 2013, using fictitious materials in which mass stopping-powers were adjusted with density, as preferred by Andreo and Benmakhlouf, as well as being held fixed, with very similar results being obtained in both circumstances (Underwood et al 2013a Med. Phys. 40 082102).