A Mail Audit Independent Peer Review System for Dosimetry Verification of a Small Animal Irradiator.

Dedicated precision orthovoltage small animal irradiators have become widely available in the past decade and are commonly used for radiation biology research. However, there is a lack of dosimetric standardization among these irradiators, which affects the reproducibility of radiation-based animal studies. The purpose of this study was to develop a mail-based, independent peer review system to verify dose delivery among institutions using X-RAD 225Cx irradiators (Precision X-Ray, North Branford, CT). A robust, user-friendly mouse phantom was constructed from high-impact polystyrene and designed with dimensions similar to those of a typical laboratory mouse. The phantom accommodates three thermoluminescent dosimeters (TLDs) to measure dose. The mouse peer review system was commissioned in a small animal irradiator using anterior-posterior and posterior-anterior beams of 225 kVp and then mailed to three institutions to test the feasibility of the audit service. The energy correction factor for TLDs in the mouse phantom was derived to validate the delivered dose using this particular animal irradiation system. This feasibility study indicated that three institutions were able to deliver a radiation dose to the mouse phantom within ±10% of the target dose. The developed mail audit independent peer review system for the verification of mouse dosimetry can be expanded to characterize other commercially available orthovoltage irradiators, thereby enhancing the reproducibility of studies employing these irradiators.

Toward a New Framework for Clinical Radiation Biology.

Radiation biology has entered the era of precision oncology, and this article reviews time-tested factors that determine the effects of fractionated radiation therapy in a wide variety of tumor types and normal tissues: the association of tumor control with radiation dose, the importance of fractionation and overall treatment time, and the role of tumor hypoxia. Therapeutic gain can only be achieved if the increased tumor toxicity produced by biological treatment modifications is balanced against injury to early-responding and late-responding normal tissues. Developments in precision oncology and immuno-oncology will allow an emphasis on treatment individualization and predictive biomarker development.

Modeling the effect of intratumoral heterogeneity of radiosensitivity on tumor response over the course of fractionated radiation therapy.

BACKGROUND: Standard radiobiology theory of radiation response assumes a uniform innate radiosensitivity of tumors. However, experimental data show that there is significant intratumoral heterogeneity of radiosensitivity. Therefore, a model with heterogeneity was developed and tested using existing experimental data to show the potential effects from the presence of an intratumoral distribution of radiosensitivity on radiation therapy response over a protracted radiation therapy treatment course. METHODS: The standard radiation response curve was modified to account for a distribution of radiosensitivity, and for variations in the repopulation rates of the tumor cell subpopulations. Experimental data from the literature were incorporated to determine the boundaries of the model. The proposed model was then used to show the changes in radiosensitivity of the tumor during treatment, and the effects of fraction size, α/ß ratio and variation of the repopulation rates of tumor cells. RESULTS: In the presence of an intratumoral distribution of radiosensitivity, there is rapid selection of radiation-resistant cells over a course of fractionated radiation therapy. Standard treatment fractionation regimes result in the near-complete replacement of the initial population of sensitive cells with a population of more resistant cells. Further, as treatment progresses, the tumor becomes more resistant to further radiation treatment, making each fractional dose less efficacious. A wider initial distribution induces increased radiation resistance. Hypofractionation is more efficient in a heterogeneous tumor, with increased cell kill for biologically equivalent doses, while inducing less resistance. The model also shows that a higher growth rate in resistant cells can account for the accelerated repopulation that is seen during the clinical treatment of patients. CONCLUSIONS: Modeling of tumor cell survival with radiosensitivity heterogeneity alters the predicted tumor response, and explains the induction of radiation resistance by radiation treatment, the development of accelerated repopulation, and the potential beneficial effects of hypofractionation. Tumor response to treatment may be better predicted by assaying for the distribution of radiosensitivity, or the extreme of the radiosensitivity, rather than measuring the initial, general radiation sensitivity of the untreated tumor.

Y90 Radioembolization Dosimetry: Concepts for the Interventional Radiologist.

Transarterial radioembolization (TARE) with beta particle emitting microspheres via Yttrium-90 decay has become a fundamental component of the contemporary Interventional Oncology practice. TARE continues to advance as a result of increased utilization, clinical study, technological improvements, and evolving applications. To maximize TARE safety and efficacy, a core understanding of dosimetry is essential. The intent of this overview is to provide the reader with a general survey of radiation physics and biology, device differentiation, patient selection, anatomic assessment, activity administration models, and procedural techniques involved with TARE dosimetry.

CLINICAL APPLICATIONS OF BIOMARKERS OF RADIATION EXPOSURE: LIMITATIONS AND POSSIBLE SOLUTIONS THROUGH COORDINATED RESEARCH.

Dosimetric biomarkers have been effectively and intensively used for a long time in the area of radiation protection. In contrast to that, no robust standards or widely accepted protocols for application of these end-points in radiotherapy, diagnostic and interventional radiology and nuclear medicine exist to date. The International Atomic Energy Agency (IAEA) organized the review of the available data on the possibilities of the use of dosimetric biomarkers in medical irradiation scenarios. The resultant Technical Report also contains a summary of identified problems, gaps in knowledge, limitations in methodology and recommendations for their overcoming. This work provided a conceptual background for the initiation of a new IAEA Coordinated Research Project E35010, MEDBIODOSE (2017-21), which is aimed specifically at the development and improvement of applications of biodosimetric markers in clinical practice.

PROPOSAL FOR A EUROPEAN METROLOGY NETWORK ON BIOLOGICAL IONISING RADIATION EFFECTS.

Progress in the field of ionising radiation (IR) metrology achieved in the BioQuaRT project raised the question to what extent radiobiological investigations would benefit from metrological support of the applied methodologies. A panel of experts from the medical field, fundamental research and radiation protection attended a workshop at Physikalisch-Technische Bundesanstalt to consult on metrology needs related to biological radiation effects. The panel identified a number of metrological needs including the further development of experimental and computational techniques for micro- and nanodosimetry, together with the determination of related fundamental material properties and the establishment of rigorous uncertainty budgets. In addition to this, a call to develop a metrology support for assisting quality assurance of radiobiology experiments was expressed. Conclusions from the workshop were presented at several international conferences for further discussion with the scientific community and stakeholder groups that led to an initiative within the metrology community to establish a European Metrology Network on biological effects of IR.

Standards and Methodologies for Characterizing Radiobiological Impact of High-Z Nanoparticles.

Research on the application of high-Z nanoparticles (NPs) in cancer treatment and diagnosis has recently been the subject of growing interest, with much promise being shown with regards to a potential transition into clinical practice. In spite of numerous publications related to the development and application of nanoparticles for use with ionizing radiation, the literature is lacking coherent and systematic experimental approaches to fully evaluate the radiobiological effectiveness of NPs, validate mechanistic models and allow direct comparison of the studies undertaken by various research groups. The lack of standards and established methodology is commonly recognised as a major obstacle for the transition of innovative research ideas into clinical practice. This review provides a comprehensive overview of radiobiological techniques and quantification methods used in in vitro studies on high-Z nanoparticles and aims to provide recommendations for future standardization for NP-mediated radiation research.

Prostate Dose-painting Radiotherapy and Radiobiological Guided Optimisation Enhances the Therapeutic Ratio.

AIMS: To describe the treatment of 11 patients with radiobiologically guided dose-painting radiotherapy and report on toxicity. MATERIALS AND METHODS: Boost volumes were identified with functional magnetic resonance imaging scans in 11 patients with high-risk prostate cancer. Patients were treated using a dose-painting approach; the boost dose was limited to 86 Gy in 37 fractions, while keeping the rectal normal tissue complication probability to 5-6%. Rotational intensity-modulated radiotherapy was used with daily image guidance and fiducial markers. RESULTS: The median dose to the prostate (outside the boost volume) and urethra was 75.4 Gy/37 fractions (range 75.1-75.8 Gy), whereas the median boost dose was 83.4 Gy (range 79.0-87.4 Gy). The tumour control probability (TCP) (Marsden model) increased from 71% for the standard plans to 83.6% [76.6-86.8%] for the dose-painting boost plans. The mean (Lyman-Kutcher-Burman) normal tissue complication probability for rectal bleeding was 5.2% (range 3.3-6.2%) and 5.2% for faecal incontinence (range 3.6-7.8%). All patients tolerated the treatment well, with a low acute toxicity profile. At a median follow-up of 36 months (range 24-50) there was no grade 3 late toxicity. Two patients had grade 2 late urinary toxicity (urethral stricture, urinary frequency and urgency), one patient had grade 1 and one grade 2 late rectal toxicity. The mean prostate-specific antigen at follow-up was 0.81 ng/ml after stopping hormone therapy; one patient relapsed biochemically at 32 months (2.70 ng/ml). CONCLUSIONS: The toxicity for this radiobiological guided dose-painting protocol was low, but we have only treated a small cohort with limited follow-up time. The advantages of this treatment approach should be established in a clinical trial.

Twenty years of radiobiology in clinical practice: the Italian contribution.

AIMS AND BACKGROUND: To present the Italian state-of-the-art contribution to radiobiology of external beam radiotherapy, brachytherapy, and radionuclide radiotherapy. METHODS AND STUDY DESIGN: A survey of the literature was carried out, using PubMed, by some independent researchers of the Italian group of radiobiology. Each paper was reviewed by researchers of centers not comprising its authors. The survey was limited to papers in English published over the last 20 years, written by Italian investigators or in Italian institutions, excluding review articles. RESULTS: A total of 135 papers have been published in journals with an impact factor, with an increase in the number of published papers over time, for external beam radiotherapy rather than radionuclide radiotherapy. The quantity and quality of the papers researched constitutes a proof of the enduring interest in clinical radiobiology among Italian investigators. CONCLUSIONS: The survey could be useful to individuate expert partners for an Italian network on clinical radiobiology, addressing future collaborative investigations.

Current status and recommendations for the future of research, teaching, and testing in the biological sciences of radiation oncology: report of the American Society for Radiation Oncology Cancer Biology/Radiation Biology Task Force, executive summary.

In early 2011, a dialogue was initiated within the Board of Directors (BOD) of the American Society for Radiation Oncology (ASTRO) regarding the future of the basic sciences of the specialty, primarily focused on the current state and potential future direction of basic research within radiation oncology. After consideration of the complexity of the issues involved and the precise nature of the undertaking, in August 2011, the BOD empanelled a Cancer Biology/Radiation Biology Task Force (TF). The TF was charged with developing an accurate snapshot of the current state of basic (preclinical) research in radiation oncology from the perspective of relevance to the modern clinical practice of radiation oncology as well as the education of our trainees and attending physicians in the biological sciences. The TF was further charged with making suggestions as to critical areas of biological basic research investigation that might be most likely to maintain and build further the scientific foundation and vitality of radiation oncology as an independent and vibrant medical specialty. It was not within the scope of service of the TF to consider the quality of ongoing research efforts within the broader radiation oncology space, to presume to consider their future potential, or to discourage in any way the investigators committed to areas of interest other than those targeted. The TF charge specifically precluded consideration of research issues related to technology, physics, or clinical investigations. This document represents an Executive Summary of the Task Force report.

Theoretical implications of incorporating relative biological effectiveness into radiobiological equivalence relationships.

OBJECTIVE: Earlier radiobiological equivalence relationships as derived for low-linear energy transfer (LET) radiations are revisited in the light of newer radiobiological models that incorporate an allowance for relative biological effectiveness (RBE). METHODS: Linear-quadratic (LQ) radiobiological equations for calculating biologically effective dose at both low- and high-LET radiations are used to derive new conditions of equivalence between a variety of radiation delivery techniques. The theoretical implications are discussed. RESULTS: The original (pre-LQ) concept of equivalence between fractionated and continuous radiotherapy schedules, in which the same physical dose is delivered in each schedule, inherently assumed that low-LET radiation would be used in both schedules. LQ-based equivalence relationships that allow for RBE and are derived assuming equal total physical dose between schedules are shown to be valid only in limited circumstances. Removing the constraint of equality of total physical dose allows the identification of more general (and more practical) relationships. CONCLUSION: If the respective schedules under consideration for equivalence both involve radiations of identical LET, then the original equivalence relationships remain valid. However, if the compared schedules involve radiations of differing LET, then new (and more restrictive) equivalence relationships are found to apply. ADVANCES IN KNOWLEDGE: Theoretically derived equivalence relationships based on the LQ model provide a framework for the design and intercomparison of a wide range of clinical techniques including those involving high- and/or low-LET radiations. They also provide a means of testing for the validity of variously assumed tissue repair kinetics.

The implementation of the Gynaecological Groupe Européen de Curiethérapie - European Society for Therapeutic Radiology and Oncology radiobiology considerations in the conversion of low dose rate to pulsed dose rate treatment schedules for gynaecological brachytherapy.

AIMS: This paper details the considerations and calculations made by this centre for the implementation of the biologically equivalent dose in 2 Gy fractions (EQD2) radiobiology calculations recommended by the Gynaecological Groupe Européen de Curiethérapie - European Society for Therapeutic Radiology and Oncology, in converting our cervix, body of uterus and vaginal vault low dose rate (LDR) treatment prescription schedules for caesium-137 to equivalent pulsed dose rate (PDR) protocols using iridium-192. MATERIALS AND METHODS: The assumptions made in order to calculate the EQD2 for both the LDR and the corresponding PDR schedules are detailed. The source geometries and prescription points are discussed for all standard treatment schedules. The prescription point for vaginal vault treatments has been altered to a 5 mm depth rather than the applicator surface, and the prescribed dose for all applicator sizes has been normalised at this depth. RESULTS: The calculated PDR schedules are presented, with corresponding target and organ at risk values given for LDR and PDR versions of standard treatment schedules. A standard 32.5 Gy point A cervix prescription used in Manchester with LDR has been converted to 2 × 19 Gy for PDR. CONCLUSIONS: PDR schedules have been calculated to correspond with our established LDR treatments in terms of EQD2 dose to the target. There is a theoretical improvement in the therapeutic ratio due to a reduction in the calculated EQD2 to organs at risk.

Sourcing and using stem cell lines for radiation research: Potential, challenges and good stem cell culture practice.

PURPOSE: Exposition of best practice in management and experimental use of human stem cell lines in radiobiological research. This paper outlines the key challenges to be addressed by radiobiologists wishing to use human pluripotent stem cell (hPSC) lines in their research including human embryonic stem cell (hESC) lines and human induced pluirpotency stem (hiPSC) lines. It emphasises the importance of guidance already established for cell culture in general and outlines some further considerations specific to the culture of human pluripotent stem cell lines which may impact on the interpretation of data from radiobiological studies using these cells. Fundamental standards include obtaining cells from bona fide suppliers with suitable quality controls, screening cell lines to ensure absence of mycoplasma and authentication of cell lines by DNA profiling. For hESC and hiPSC lines, it is particularly important to recognise the significance of phenotypic and genetic stability and this paper will address approaches to reduce their impact. Quality assured banking of these two types of stem cell lines will facilitate reliable supply of quality controlled cells that can provide standardisation between laboratories and in the same laboratory over time. CONCLUSIONS: hPSC lines could play an important role in future radiobiological research providing certain fundamental principles of good stem cell culture practice are adopted at the outset of such work.

Dosimetry and spectral analysis of a radiobiological experiment using laser-driven proton beams.

Laser-driven proton and ion acceleration is an area of increasing research interest given the recent development of short pulse-high intensity lasers. Several groups have reported experiments to understand whether a laser-driven beam can be applied for radiobiological purposes and in each of these, the method to obtain dose and spectral analysis was slightly different. The difficulty with these studies is that the very large instantaneous dose rate is a challenge for commonly used dosimetry techniques, so that other more sophisticated procedures need to be explored. This paper aims to explain a method for obtaining the energetic spectrum and the dose of a laser-driven proton beam irradiating a cell dish used for radiobiology studies. The procedure includes the use of a magnet to have charge and energy separation of the laser-driven beam, Gafchromic films to have information on dose and partially on energy, and a Monte Carlo code to expand the measured data in order to obtain specific details of the proton spectrum on the cells. Two specific correction factors have to be calculated: one to take into account the variation of the dose response of the films as a function of the proton energy and the other to obtain the dose to the cell layer starting from the dose measured on the films. This method, particularly suited to irradiation delivered in a single laser shot, can be applied in any other radiobiological experiment performed with laser-driven proton beams, with the only condition that the initial proton spectrum has to be at least roughly known. The method was tested in an experiment conducted at Queen's University of Belfast using the TARANIS laser, where the mean energy of the protons crossing the cells was between 0.9 and 5 MeV, the instantaneous dose rate was estimated to be close to 109 Gy s−1 and doses between 0.8 and 5 Gy were delivered to the cells in a single laser shot. The combination of the applied corrections modified the initial estimate of dose by up to 40%.

[Probabilities of organs at risk damage: history and mathematical models]. / Probabilités de lésion des organes à risque: historique et principaux modèles mathématiques d'estimation.

The a priori evaluation of normal tissue complication probability is an important issue for the radiation oncologist looking for the best therapeutic index. The advances in radiobiological and technological knowledge provide a better understanding of the determinants of radiation effects. The amount of information required to optimize the treatment modalities justifies the use of mathematical models linking the treatment characteristics (dose, volume, treatment time...) to the likelihood of complications. The radiation oncologist needs a minimal understanding of the mathematical models and their limits to justify his prescriptions.

Stereotactic body radiation therapy (SBRT) and respiratory gating in lung cancer: dosimetric and radiobiological considerations.

The purpose of this study was to assess the impact of respiratory gating on tumor and normal tissue dosimetry in patients treated with SBRT for early stage non-small cell lung cancer (NSCLC). Twenty patients with stage I NSCLC were studied. Treatment planning was performed using four-dimensional computed tomography (4D CT) with free breathing (Plan I), near-end inhalation (Plan II), and near-end exhalation (Plan III). The prescription dose was 60 Gy in three fractions. The tumor displacement was most pronounced for lower peripheral lesions (average 7.0 mm, range 4.1-14.3 mm) when compared to upper peripheral (average 2.4mm, range 1.0-5.1 mm) or central lesions (average 2.9 mm, range 1.0-4.1 mm). In this study, the pencil beam convolution (PBC) algorithm with modified Batho power law for tissue heterogeneity was used for dose calculation. There were no significant differences in tumor and normal tissue dosimetry among the three gated plans. Tumor location however, significantly influenced tumor doses because of the necessity of respecting normal tissue constraints of centrally located structures. For plans I, II and III, average doses to central lesions were lower as compared with peripheral lesions by 4.88 Gy, 8.24 Gy and 6.93 Gy for minimum PTV and 0.98, 1.65 and 0.87 Gy for mean PTV dose, respectively. As a result, the mean single fraction equivalent dose (SFED) values were also lower for central compared to peripheral lesions. In addition, central lesions resulted in higher mean doses for lung, esophagus, and ipsilateral bronchus by 1.24, 1.93 and 7.75 Gy, respectively. These results indicate that the tumor location is the most important determinant of dosimetric optimization of SBRT plans. Respiratory gating proved unhelpful in the planning of these patients with severe COPD.

Basic principles of radiobiology applied to radiosurgery and radiotherapy of benign skull base tumors.

Various types of ionizing radiation may be used therapeutically for benign skull base tumors. Treatment may involve single-dose radiosurgery, or may be fractionated into multiple doses. Designing and implementing a radiotherapy plan that maximizes the therapeutic ratio requires knowledge of the biophysical and radiobiological principles involved in these treatments. These basic radiobiological tenets are discussed in this chapter, with the focus on radiotherapy of benign skull base tumors. Animal and clinical data, however, acquired from the radiation of malignant tumors are necessarily included, as they comprise much of our knowledge of fractionation schedules, central nervous system (CNS) toxicity, and CNS volume effects.

Adverse event reporting and developments in radiation biology after normal tissue injury: International Atomic Energy Agency consultation.

PURPOSE: Recent research has enhanced our understanding of radiation injury at the molecular-cellular and tissue levels; significant strides have occurred in standardization of adverse event reporting in clinical trials. In response, the International Atomic Energy Agency, through its Division of Human Health and its section for Applied Radiation Biology and Radiotherapy, organized a consultation meeting in Atlanta (October 2, 2004) to discuss developments in radiobiology, normal tissue reactions, and adverse event reporting. METHODS AND MATERIALS: Representatives from cooperative groups of African Radiation Oncology Group, Curriculo Radioterapeutica Ibero Latino Americana, European Organization for Research and Treatment of Cancer, National Cancer Institute of Canada Clinical Trials Group, Radiation Therapy Oncology Group, and Trans-Tasman Radiation Oncology Group held the meeting discussion. RESULTS: Representatives of major radiotherapy groups/organizations and prominent leaders in radiotherapy discussed current understanding of normal tissue radiobiologic effects, the design and implementation of future clinical and translational projects for normal tissue injury, and the standardization of adverse-event reporting worldwide. CONCLUSIONS: The consensus was to adopt NCI comprehensive adverse event reporting terminology and grading system (CTCAE v3.0) as the new standard for all cooperative group trials. Future plans included the implementation of coordinated research projects focusing on normal tissue biomarkers and data collection methods.