Radiobiological Data Research Articles

Fruit Flies Provide New Insights in Low-Radiation Background Biology at the INFN Underground Gran Sasso National Laboratory (LNGS).

Deep underground laboratories (DULs) were originally created to host particle, astroparticle or nuclear physics experiments requiring a low-background environment with vastly reduced levels of cosmic-ray particle interference. More recently, the range of science projects requiring an underground experiment site has greatly expanded, thus leading to the recognition of DULs as truly multidisciplinary science sites that host important studies in several fields, including geology, geophysics, climate and environmental sciences, technology/instrumentation development and biology. So far, underground biology experiments are ongoing or planned in a few of the currently operating DULs. Among these DULs is the Gran Sasso National Laboratory (LNGS), where the majority of radiobiological data have been collected. Here we provide a summary of the current scenario of DULs around the world, as well as the specific features of the LNGS and a summary of the results we obtained so far, together with other findings collected in different underground laboratories. In particular, we focus on the recent results from our studies of Drosophila melanogaster, which provide the first evidence of the influence of the radiation environment on life span, fertility and response to genotoxic stress at the organism level. Given the increasing interest in this field and the establishment of new projects, it is possible that in the near future more DULs will serve as sites of radiobiology experiments, thus providing further relevant biological information at extremely low-dose-rate radiation. Underground experiments can be nicely complemented with above-ground studies at increasing dose rate. A systematic study performed in different exposure scenarios provides a potential opportunity to address important radiation protection questions, such as the dose/dose-rate relationship for cancer and non-cancer risk, the possible existence of dose/dose-rate threshold(s) for different biological systems and/or end points and the possible role of radiation quality in triggering the biological response.

Dosimetrical and radiobiological approach to manage the dosimetric shift in the transition of dose calculation algorithm in radiation oncology: how to improve high quality treatment and avoid unexpected outcomes?

BackgroundFor a given prescribed dose of radiotherapy, with the successive generations of dose calculation algorithms, more monitor units (MUs) are generally needed. This is due to the implementation of successive improvements in dose calculation: better heterogeneity correction and more accurate estimation of secondary electron transport contribution. More recently, there is the possibility to report the dose-to-medium, physically more accurate compared to the dose-to-water as the reference one. This last point is a recent concern and the main focus of this study.MethodsIn this paper, we propose steps for a general analysis procedure to estimate the dosimetric alterations, and the potential clinical changes, between a reference algorithm and a new one. This includes dosimetric parameters, gamma index, radiobiology indices based on equivalent uniform dose concept and statistics with bootstrap simulation. Finally, we provide a general recommendation on the clinical use of new algorithms regarding the dose prescription or dose limits to the organs at risks.ResultsThe dosimetrical and radiobiological data showed a significant effect, which might exceed 5–10%, of the calculation method on the dose the distribution and clinical outcomes for lung cancer patients. Wilcoxon signed rank paired comparisons indicated that the delivered dose in MUs was significantly increased (> 2%) using more advanced dose calculation methods as compared to the reference one.ConclusionThis paper illustrates and explains the use of dosimetrical, radiobiologcal and statistical tests for dosimetric comparisons in radiotherapy. The change of dose calculation algorithm may induce a dosimetric shift, which has to be evaluated by the physicists and the oncologists. This includes the impact on tumor control and on the risk of toxicity based on normal tissue dose constraints. In fact, the alteration in dose distribution makes it hard to keep exactly the same tumor control probability along with the same normal tissue complication probability.

Secondary Malignancies in the Era of High-Precision Radiation Therapy.

Although modern radiation therapy delivers a localized distribution of ionizing energy that can be used to cure primary cancers for many patients, the inevitable radiation exposure to non-targeted normal tissue leads to a risk of a radiation-related new cancer. Modern therapies often produce a complex spectrum of secondary particles, both charged and uncharged, that must be considered both in their physical radiation transport throughout the patient and their potential to induce biological damage, which depends on the microscopic energy deposition from the cascade of primary, secondary, and downstream particles. This work summarizes the experimental data for relative biological effectiveness for particles associated with modern radiotherapy in light of their capacity to induce secondary malignancies in patients. A distinction is highlighted between the radiobiological experimental data and the coarser metrics used frequently in radiation protection. For critical assessment of the risks of secondary malignancies for patients undergoing radiation therapy, a detailed description of primary and secondary radiation fields is needed, though not routinely considered for individual patient treatments. Furthermore, not only the particle type, but also the microscopic dose and track structure, must be considered, which points to a demand for detailed physics models and high-performance computing strategies to model the risks.

NANODOSIMETRY: TOWARDS A NEW CONCEPT OF RADIATION QUALITY.

The biological action of ionizing charged particles is initiated at the DNA level, and the effectiveness with which the initial physical effect changes into measurable biological damage is likely ruled by the stochastics of ionizations produced by the incident ions in subcellular nanometric volumes. Based on this hypothesis, experimental nanodosimetry aims at establishing a new concept of radiation quality that builds on measurable characteristics of the particle track structure at the nanometer scale. Three different nanodosimetric detection systems have been developed to date that allow measurements of the number of ionizations produced by the passage of a primary particle in a nanometer-size gas volume (in unit density scale). Within the Italian project MITRA (MIcrodosimetry and TRAck structure), funded by the Italian Istituto Nazionale di Fisica Nucleare (INFN) and the EMRP Joint Research Project 'BioQuaRT' (Biologically Weighted Quantities in Radiotherapy), experiments have been carried out, in which the frequency distribution of ionizations produced by proton and carbon ion beams of given energy was measured with the three nanodosimetric detectors. Descriptors of the track structure can be derived from these distributions. In particular, the first moment M1, representing the mean number of ionizations produced in the target volume, and the cumulative probability Fk of measuring a number ν ≥ k of ionizations. The correlation between measured nanodosimetric quantities and experimental radiobiological data available in the literature is here presented and discussed.

Irradiation hypofractionnée du cancer de prostate : quelles connaissances radiobiologiques en 2017 ?

For prostate cancer, hypofractionation has been based since 1999 on radiobiological data, which calculated a very low alpha/beta ratio (1.2 to 1.5Gy). This suggested that a better local control could be obtained, without any toxicity increase. Consequently, two types of hypofractionated schemes were proposed: “moderate” hypofractionation, with fractions of 2.5 to 4Gy, and “extreme” hypofractionation, utilizing stereotactic techniques, with fractions of 7 to 10Gy. For moderate hypofractionation, the linear-quadratic (LQ) model has been used to calculate the equivalent doses of the new protocols. The available trials have often shown a “non-inferiority”, but no advantage, while the equivalent doses calculated for the hypofractionated arms were sometimes very superior to the doses of the conventional arms. This finding could suggest either an alpha/beta ratio lower than previously calculated, or a negative impact of other radiobiological parameters, which had not been taken into account. For “extreme” hypofractionation, the use of the LQ model is discussed for high dose fractions. Moreover, a number of radiobiological questions are still pending. The reduced overall irradiation time could be either a positive point (better local control) or a negative one (reduced reoxygenation). The prolonged duration of the fractions could lead to a decrease of efficacy (because allowing for reparation of sublethal lesions). Finally, the impact of the large fractions on the microenvironment and/or immunity remains discussed. The reported series appear to show encouraging short to mid-term results, but the results of randomized trials are still awaited. Today, it seems reasonable to only propose those extreme hypofractionated schemes to well-selected patients, treating small volumes with high-level stereotactic techniques.

Track structure characterization and its link to radiobiology

Within the Italian project MITRA (MIcrodosimetry and TRAck structure), funded by the Italian Istituto Nazionale di Fisica Nucleare (INFN), and the EMRP Joint Research Project “BioQuaRT” (Biologically Weighted Quantities in Radiotherapy), experiments have been carried out at the Tandem–Alpi accelerator facility of Legnaro National Laboratories (LNL), in which the frequency distribution of the number of ionisations produced by proton and carbon ion beams of given energy was measured with the PTB Ion Counter and the LNL StarTrack Counter. Descriptors of the track structure can be derived from these distribution; in particular, the first moment M1, representing the mean number of ionisations produced in the target volume, and the cumulative probabilities Fk of measuring cluster sizes ν ≥ k.Experimental radiobiological data have been compared with nanodosimetric quantities derived from measured ionisation-cluster size distributions. It was found that the cumulative probabilities Fk as a function of M1 behave in the same way as the inactivation cross sections as a function of LET, first increasing with increasing values of M1 and then showing a saturation effect.A comparison of Fk and radiobiological quantities is presented and discussed.

The radiobiology of laser-driven particle beams: focus on sub-lethal responses of normal human cells

Accelerated proton beams have become increasingly common for treating cancer. The need for cost and size reduction of particle accelerating machines has led to the pioneering investigation of optical ion acceleration techniques based on laser-plasma interactions as a possible alternative. Laser-matter interaction can produce extremely pulsed particle bursts of ultra-high dose rates (⩾ 109 Gy/s), largely exceeding those currently used in conventional proton therapy. Since biological effects of ionizing radiation are strongly affected by the spatio-temporal distribution of DNA-damaging events, the unprecedented physical features of such beams may modify cellular and tissue radiosensitivity to unexplored extents. Hence, clinical applications of laser-generated particles need thorough assessment of their radiobiological effectiveness. To date, the majority of studies have either used rodent cell lines or have focussed on cancer cell killing being local tumour control the main objective of radiotherapy. Conversely, very little data exist on sub-lethal cellular effects, of relevance to normal tissue integrity and secondary cancers, such as premature cellular senescence. Here, we discuss ultra-high dose rate radiobiology and present preliminary data obtained in normal human cells following irradiation by laser-accelerated protons at the LULI PICO2000 facility at Laser Lab Europe, France.

S-phase-specific radiosensitization by gemcitabine for therapeutic carbon ion exposure in vitro.

Densely ionizing charged particle irradiation offers physical as well as biological advantages compared with photon irradiation. Radiobiological data for the combination of such particle irradiation (i.e. therapeutic carbon ions) with commonly used chemotherapeutics are still limited. Recent in vitro results indicate a general prevalence of additive cytotoxic effects in combined treatments, but an extension of established multimodal treatment regimens with photons to the inclusion of particle therapy needs to evaluate possible peculiarities of using high linear energy transfer (LET) radiation. The present study investigates the effect of combined radiochemotherapy using gemcitabine and high-LET irradiation with therapeutic carbon ions. In particular, the earlier observation of S-phase specific radiosensitization with photon irradiation should be evaluated with carbon ions. In the absence of the drug gemcitabine, carbon ion irradiation produced the typical survival behavior seen with X-rays—increased relative biological efficiency, and depletion of the survival curve's shoulder. By means of serum deprivation and subsequent replenishment, ∼70% S-phase content of the cell population was achieved, and such preparations showed radioresistance in both treatment arms—,photon and carbon ion irradiation. Combined modality treatment with gemcitabine caused significant reduction of clonogenic survival especially for the S-phase cells. WIDR cells exhibited S-phase–specific radioresistance with high-LET irradiation, although this was less pronounced than for X-ray exposure. The combined treatment with therapeutic carbon ions and gemcitabine caused the resistance phenomenon to disappear phenotypically.

The Increase in Animal Mortality Risk following Exposure to Sparsely Ionizing Radiation Is Not Linear Quadratic with Dose.

IntroductionThe US government regulates allowable radiation exposures relying, in large part, on the seventh report from the committee to estimate the Biological Effect of Ionizing Radiation (BEIR VII), which estimated that most contemporary exposures- protracted or low-dose, carry 1.5 fold less risk of carcinogenesis and mortality per Gy than acute exposures of atomic bomb survivors. This correction is known as the dose and dose rate effectiveness factor for the life span study of atomic bomb survivors (DDREFLSS). It was calculated by applying a linear-quadratic dose response model to data from Japanese atomic bomb survivors and a limited number of animal studies.Methods and ResultsWe argue that the linear-quadratic model does not provide appropriate support to estimate the risk of contemporary exposures. In this work, we re-estimated DDREFLSS using 15 animal studies that were not included in BEIR VII’s original analysis. Acute exposure data led to a DDREFLSS estimate from 0.9 to 3.0. By contrast, data that included both acute and protracted exposures led to a DDREFLSS estimate from 4.8 to infinity. These two estimates are significantly different, violating the assumptions of the linear-quadratic model, which predicts that DDREFLSS values calculated in either way should be the same.ConclusionsTherefore, we propose that future estimates of the risk of protracted exposures should be based on direct comparisons of data from acute and protracted exposures, rather than from extrapolations from a linear-quadratic model. The risk of low dose exposures may be extrapolated from these protracted estimates, though we encourage ongoing debate as to whether this is the most valid approach. We also encourage efforts to enlarge the datasets used to estimate the risk of protracted exposures by including both human and animal data, carcinogenesis outcomes, a wider range of exposures, and by making more radiobiology data publicly accessible. We believe that these steps will contribute to better estimates of the risks of contemporary radiation exposures.

Microdosimetric and Biological Effects of Photon Irradiation at Different Energies in Bone Marrow.

To ensure reliability and reproducibility of radiobiological data, it is necessary to standardize dosimetry practices across all research institutions. The photoelectric effect predominates over other interactions at low energy and in high atomic number materials such as bone, which can lead to increased dose deposition in soft tissue adjacent to mineral bone due to secondary radiation particles. This may produce radiation effects that deviate from higher energy photon irradiation that best model exposure from clinical radiotherapy or nuclear incidences. Past theoretical considerations have indicated that this process should affect radiation exposure of neighboring bone marrow (BM) and account for reported differences in relative biological effectiveness (RBE) for hematopoietic failure in rodents. The studies described herein definitively estimate spatial dose distribution and biological effectiveness within the BM compartment for (137)Cs gamma rays and 320 kVp X rays at two levels of filtration: 1 and 4 mm Cu half-value layer (HVL). In these studies, we performed: 1. Monte Carlo simulations on a 5 μm resolution model of mouse vertebrae and femur derived from micro-CT images; 2. In vitro biological experiments irradiating BM cells plated directly on the surface of a bone-equivalent material (BEM); and 3. An in vivo study on BM cell survival in irradiated live mice. Simulation results showed that the relative dose increased in proximity to bone at the lower radiation energies and produced averaged values of relative dose over the entire BM volume within imaged trabecular bone of 1.17, 1.08 and 1.01 for beam qualities of 1 mm Cu HVL, 4 mm Cu HVL and (137)Cs, respectively. In accordance with Monte Carlo simulations, in vitro irradiation of BM cells located on BEM and in vivo whole-body irradiation at a prescribed dose to soft tissue of 6 Gy produced relative cell killing of hematopoietic progenitors (CFU-C) that significantly increased for the 1 mm Cu HVL X rays compared to radiation exposures of higher photon energies. Thus, we propose that X rays of the highest possible kVp and filtration be used to investigate radiation effects on the hematopoietic system, as this will allow for better comparisons with high-energy photon exposures applied in radiotherapy or as anticipated in a nuclear event.

Biophysics of NASA radiation quality factors.

NASA has implemented new radiation quality factors (QFs) for projecting cancer risks from space radiation exposures to astronauts. The NASA QFs are based on particle track structure concepts with parameters derived from available radiobiology data, and NASA introduces distinct QFs for solid cancer and leukaemia risk estimates. The NASA model was reviewed by the US National Research Council and approved for use by NASA for risk assessment for International Space Station missions and trade studies of future exploration missions to Mars and other destinations. A key feature of the NASA QFs is to represent the uncertainty in the QF assessments and evaluate the importance of the QF uncertainty to overall uncertainties in cancer risk projections. In this article, the biophysical basis for the probability distribution functions representing QF uncertainties was reviewed, and approaches needed to reduce uncertainties were discussed.

Review of NASA approach to space radiation risk assessments for Mars exploration.

Long duration space missions present unique radiation protection challenges due to the complexity of the space radiation environment, which includes high charge and energy particles and other highly ionizing radiation such as neutrons. Based on a recommendation by the National Council on Radiation Protection and Measurements, a 3% lifetime risk of exposure-induced death for cancer has been used as a basis for risk limitation by the National Aeronautics and Space Administration (NASA) for low-Earth orbit missions. NASA has developed a risk-based approach to radiation exposure limits that accounts for individual factors (age, gender, and smoking history) and assesses the uncertainties in risk estimates. New radiation quality factors with associated probability distribution functions to represent the quality factor's uncertainty have been developed based on track structure models and recent radiobiology data for high charge and energy particles. The current radiation dose limits are reviewed for spaceflight and the various qualitative and quantitative uncertainties that impact the risk of exposure-induced death estimates using the NASA Space Cancer Risk (NSCR) model. NSCR estimates of the number of "safe days" in deep space to be within exposure limits and risk estimates for a Mars exploration mission are described.

SBRT and extreme hypofractionation: A new era in prostate cancer treatments?

AimRadiation therapy (RT) is a standard therapeutic option for prostate cancer (PC). In the last decades, several innovative technology applications have been introduced. 3-Dimensional conformal RT, volumetric/rotational intensity modulated RT associated or not with image-guided RT, are becoming largely diffused in the treatment of PC. BackgroundConsidering that PC could have a low α/β ratio, similar to late-reacting normal tissues, it could also be highly responsive to fraction size. Thus, the reduction of the number of fractions and the increase of the dose/fraction seem to be reasonable choices in the treatment of this cancer. This review reported the technology evolution, the radiobiological and the clinical data about the role of extreme hypofractionated RT in the treatment approach of PC patients. Materials and methodsMedline search and analysis of published studies containing key words: prostate cancer, radiotherapy, stereotactic radiotherapy. ResultsRecent technological developments, combined with an improved knowledge of the radiobiological models in favor of a high sensitivity of PC to larger fraction sizes are opening a new scenario in its treatment, reporting favorable efficacy and acceptable toxicity, despite short follow-up. ConclusionThus, thanks to technological improvement and the recent radiobiological data, “extreme hypofractionated RT” has been strongly introduced in the last years as a potential solid treatment option for PC.

Future development of biologically relevant dosimetry.

Proton and ion beams are radiotherapy modalities of increasing importance and interest. Because of the different biological dose response of these radiations as compared with high-energy photon beams, the current approach of treatment prescription is based on the product of the absorbed dose to water and a biological weighting factor, but this is found to be insufficient for providing a generic method to quantify the biological outcome of radiation. It is therefore suggested to define new dosimetric quantities that allow a transparent separation of the physical processes from the biological ones. Given the complexity of the initiation and occurrence of biological processes on various time and length scales, and given that neither microdosimetry nor nanodosimetry on their own can fully describe the biological effects as a function of the distribution of energy deposition or ionization, a multiscale approach is needed to lay the foundation for the aforementioned new physical quantities relating track structure to relative biological effectiveness in proton and ion beam therapy. This article reviews the state-of-the-art microdosimetry, nanodosimetry, track structure simulations, quantification of reactive species, reference radiobiological data, cross-section data and multiscale models of biological response in the context of realizing the new quantities. It also introduces the European metrology project, Biologically Weighted Quantities in Radiotherapy, which aims to investigate the feasibility of establishing a multiscale model as the basis of the new quantities. A tentative generic expression of how the weighting of physical quantities at different length scales could be carried out is presented.

In vitro evaluation of photon and raster-scanned carbon ion radiotherapy in combination with gemcitabine in pancreatic cancer cell lines

Background: Pancreatic cancer is the fourth leading cause of cancer deaths, being responsible for 6% of all cancer-related deaths. Conventional radiotherapy with or without additional chemotherapy has been applied in the past in the context of neoadjuvant or adjuvant therapy concepts with only modest results, however new radiation modalities, such as particle therapy with promising physical and biological characteristics, present an alternative treatment option for patients with pancreatic cancer. Up until now the raster scanning technique employed at our institution for the application of carbon ions has been unique, and no radiobiological data using pancreatic cancer cells has been available yet. The aim of this study was to evaluate cytotoxic effects that can be achieved by treating pancreatic cancer cell lines with combinations of X-rays and gemcitabine, or alternatively with carbon ion irradiation and gemcitabine, respectively. Materials and Methods: Human pancreatic cancer cell lines AsPC-1, BxPC-3 and Panc-1 were irradiated with photons and carbon ions at various doses and treated with gemcitabine. Photon irradiation was applied with a biological cabin X-ray irradiator, and carbon ion irradiation was applied with an extended Bragg peak (linear energy transfer (LET) 103 keV/μm) using the raster scanning technique at the Heidelberg Ion Therapy Center (HIT). Responsiveness of pancreatic cancer cells to the treatment was measured by clonogenic survival. Clonogenic survival curves were then compared to predicted curves that were calculated employing the local effect model (LEM). Results: Cell survival curves were calculated from the surviving fractions of each combination experiment and compared to a drug control that was only irradiated with X-rays or carbon ions, without application of gemcitabine. In terms of cytotoxicity, additive effects were achieved for the cell lines Panc-1 and BxPC-3, and a slight radiosensitizing effect was observed for AsPC-1. Relative biological effectiveness (RBE) of carbon ion irradiation ranged from 1.5–4.5 depending on survival level and dose. Sensitizer enhancement ratio (SER) values calculated at 10% cell survival ranged from 1.24–1.66, depending on cell line, gemcitabine dose and irradiation modality. Experimentally ascertained survival curves matched those predicted by LEM-calculation. Conclusion: Our experiments have shown a combined treatment of irradiation and chemotherapy with gemcitabine to be a good means of achieving additive cytotoxic effects on pancreatic cancer cell lines. The data generated in this study will serve as radiobiological basis for further preclinical and clinical studies.

Radiation Risks of Medical Imaging: Separating Fact from Fantasy

During the past few years, several articles have appeared in the scientific literature that predict thousands of cancers and cancer deaths per year in the U.S. population caused by medical imaging procedures that use ionizing radiation. These predictions are computed by multiplying small and highly speculative risk factors by large populations of patients to yield impressive numbers of "cancer victims." The risk factors are acquired from the Biological Effects of Ionizing Radiation (BEIR) VII report without attention to the caveats about their use presented in the BEIR VII report. The principal data source for the risk factors is the ongoing study of survivors of the Japanese atomic explosions, a population of individuals that is greatly different from patients undergoing imaging procedures. For the purpose of risk estimation, doses to patients are converted to effective doses, even though the International Commission on Radiological Protection warns against the use of effective dose for epidemiologic studies or for estimation of individual risks. To extrapolate cancer incidence to doses of a few millisieverts from data greater than 100 mSv, a linear no-threshold model is used, even though substantial radiobiological and human exposure data imply that it is not an appropriate model. The predictions of cancers and cancer deaths are sensationalized in electronic and print public media, resulting in anxiety and fear about medical imaging among patients and parents. Not infrequently, patients are anxious about a scheduled imaging procedure because of articles they have read in the public media. In some cases, medical imaging examinations may be delayed or deferred as a consequence, resulting in a much greater risk to patients than that associated with imaging examinations. © RSNA, 2012.

Radiation-based approaches for therapy and palliation of advanced prostate cancer

Randomized clinical trials of palliative radiation therapy and radiopharmaceuticals are emphasized, and new concepts in targeted alpha-emitter therapy are introduced. Radiation therapy has a proven palliative role in the treatment of patients with advanced prostate cancer. Findings from 223radium clinical trials emphasize the importance of alpha particles as a new therapeutic modality in patients with bone metastatic castrate-resistant prostate cancer. We introduce the concept of alpha-emitting particles from both a basic and clinical perspective in the realm of bone-targeted radiopharmaceuticals and discuss how these agents compare and contrast with conventional beta-emitting radioisotopes. The physics, radiobiology, and survival data with 223radium are unique compared with previously used radiopharmaceuticals. Targeted alpha-emitting therapies such as 223radium have the capacity to change the way we treat patients with bone-metastatic prostate cancer.

An approach to assessing stochastic radiogenic risk in medical imaging

This letter suggests a formalism, the medical effective dose (MED), that is suitable for assessing stochastic radiogenic risks in diagnostic medical procedures. The MED is derived from radiobiological and probabilistic first principals, including: (1) The independence of radiation-induced biological effects in neighboring voxels at low doses; (2) the linear no-threshold assumption for stochastic radiation injury (although other dose-response relationships could be incorporated, instead); (3) the best human radiation dose-response data currently available; and (4) the built-in possibility that the carcinogenic risk to an irradiated organ may depend on its volume. The MED involves a dose-risk summation over irradiated voxels at high spatial resolution; it reduces to the traditional effective dose when every organ is irradiated uniformly and when the dependence of risk on organ volumes is ignored. Standard relative-risk tissue weighting factors can be used with the MED approach until more refined data become available. The MED is intended for clinical and phantom dosimetry, and it provides an estimate of overall relative radiogenic stochastic risk for any given dose distribution. A result of the MED derivation is that the stochastic risk may increase with the volume of tissue (i.e., the number of cells) irradiated, a feature that can be activated when forthcoming radiobiological research warrants it. In this regard, the MED resembles neither the standard effective dose (E) nor the CT dose index (CTDI), but it is somewhat like the CT dose-length product (DLP). The MED is a novel, probabilistically and biologically based means of estimating stochastic-risk-weighted doses associated with medical imaging. Built in, ab initio, is the ability to link radiogenic risk to organ volume and other clinical factors. It is straightforward to implement when medical dose distributions are available, provided that one is content, for the time being, to accept the relative tissue weighting factors published by the International Commission of Radiological Protection (ICRP). It requires no new radiobiological data and avoids major problems encountered by the E, CTDI, and CT-E formalisms. It makes possible relative inter-patient dosimetry, and also realistic intercomparisons of stochastic risks from different protocols that yield images of comparable quality.

Zastosowanie techniki SIB-IMRT w leczeniu skojarzonym z jednoczesną chemioterapią u chorych na nowotwory głowy i szyi w III i IVa stopniu zaawansowania. Ocena wczesnych wyników i tolerancji leczenia

Concomitant radiochemotherapy become the treatment of choice for locally advanced SCHNC. This strategy of treatment has a limitation, which is an acute and late toxicity. The IMRT technique provides the possibility of better sparing of healthy tissue. Radiobiological and clinical data also suggest that accelerated fractionation and higher dose per fraction given in GTV may produce better locoregional control. Therefore it might be expected that concomitant chemotherapy and SIB-IMRT radiotherapy could increase locoregional control and reduce acute and late radiation reactions. The evaluation of early results and toxicity of this treatment modality is presented. The evaluation of the early results and toxicity of SIB-IMRT radiotherapy given concomitantly with cisplatin for locally advanced squamous cell head and neck cancer (SCHNC). SIB-IMRT technique was applied. The boost volume was limited to the GTV + 3mm margin (macroscopic tumor extension was defined on the basis of CT and/or MRI examinations). Dose per fraction given to this volume was 2.25 Gy up to 67.5 Gy of total dose. The PTV-CTV + 3mm - was defined as an area of increased risk of microscopic spread. Dose per fraction given to this volume was 2 Gy up to 60 Gy. The PTV1-ETV+ 3mm (electively irradiated volume) received dose per fraction -1.8 Gy up to 54-56 Gy. Overall treatment time was 6 weeks (5 fractions per week, 30 fractions). Concomitant chemotherapy consisted of cisplatin in daily dose100mg/m2 given two times during irradiation (1 and 22 day of treatment). The evaluation of early tolerance was performed once weekly during the treatment than during the follow up every 2 months. The early reactions were scored according to the EORTC/RTOG scale. Between June 2006 and December 2009 99 patients diagnosed with III and IV clinical stage of SCHNC were treated with this method. 65 patients were diagnosed with oropharyngeal cancer, 18 with laryngeal cancer and 16 with hypopharyngeal cancer. PEG was performed at 65 patients before treatment for better alimentation during radiochemotherapy. No severe life risking complications were observed a no concequentional late effects were observed. Extended mucositis grade III according RTOG/EORTC scale were observed only in boost region in 80% patients just after treatment was completed. In 2 patients ulceration were observed in tumour side which have healed up spontaneously within two months after treatment. 55% patients were suffering for III xerostomia and 41% for middle after the treatment. Majority of side effects were cured within 4 months after irradiation. The PEG was removing in 92% patients 2 months after treatment. The median follow-up time is 28 months (ranged from 14 m to 58 m). Actuarial 2-years overall survival and disease-free survival is respectively 90% and 82%, probability of locoregional recurrence at 2-years is 14% and 5-years estimated is 17,5%. At the present moment it might be concluded that accelerated radiotherapy with SIB-IMRT given concomitantly with cisplatin produce excellent local control in patients treated of III-IV stage SCHNC without increasing toxicity.

Future of radiation therapy for malignant melanoma in an era of newer, more effective biological agents

The incidence of melanoma is rising. The primary initial treatment for melanoma continues to be wide local excision of the primary tumor and affected lymph nodes. Exceptions to wide local excision include cases where surgical excision may be cosmetically disfiguring or associated with increased morbidity and mortality. The role of definitive or adjuvant radiotherapy has largely been relegated to palliative measures because melanoma has been viewed as a prototypical radiotherapy-resistant cancer. However, the emerging clinical and radiobiological data summarized here suggests that many types of effective radiation therapy, such as radiosurgery for melanoma brain metastases, plaque brachytherapy for uveal melanoma, intensity modulated radiotherapy for melanoma of the head and neck, and adjuvant radiotherapy for selected high-risk, node-positive patients can improve outcomes. Similarly, although certain chemotherapeutic agents and biologics have shown limited responses, long-term control for unresectable tumors or disseminated metastatic disease has been rather disappointing. Recently, several powerful new biologics and treatment combinations have yielded new hope for this patient group. The recent identification of several clinically linked melanoma gene mutations involved in mitogen-activated protein kinase (MAPK) pathway such as BRAF, NRAS, and cKIT has breathed new life into the drive to develop more effective therapies. Some of these new therapeutic approaches relate to DNA damage repair inhibitors, cellular immune system activation, and pharmacological cell cycle checkpoint manipulation. Others relate to the investigation of more effective targeting and dosing schedules for underutilized therapeutics, such as radiotherapy. This paper summarizes some of these new findings and attempts to give some context to the renaissance in melanoma therapeutics and the potential role for multimodality regimens, which include certain types of radiotherapy as aids to locoregional control in sensitive tissues.