Topic Editors

Dr. Gérard Baldacchino
CEA Paris-Saclay, CNRS and Université Paris-Saclay, Gif-sur-Yvette, France
Prof. Dr. Eric Deutsch
Radiation Oncology Department, Gustave Roussy Cancer Campus, 94805 Villejuif, France
Dr. Marie Dutreix
1. Institut Curie, PSL Research University, CNRS, INSERM, UMR 3347, 91405 Orsay, France
2. Université Paris-Saclay, CNRS, UMR 3347, 91405 Orsay, France
Institut des Sciences Moléculaires d’Orsay (UMR 8214) CNRS, Université Paris-Saclay, Université Paris Sud, 91405 Orsay, France
Dr. Erika Porcel
Institut des Sciences Moléculaires d’Orsay, Université Paris Saclay, CNRS UMR 8214, 91405 Orsay, France
Dr. Charlotte Robert
Molecular Predictors and New Targets in Oncology, Paris-Saclay University, Gustave Roussy, Villejuif, France
LCE, François Jacob Institute, CEA, Université Paris-Saclay, 92260 Fontenay-aux-Roses, France
Dr. João Santos Sousa
Laboratoire de Physique des Gaz et des Plasmas, CNRS, Université Paris-Saclay, Orsay, France
Dr. Aurélien de la Lande
Institut de Chimie Physique, CNRS, Université Paris Saclay, Paris, France

Innovative Radiation Therapies

Abstract submission deadline
closed (31 December 2023)
Manuscript submission deadline
30 June 2024
Viewed by
13004

Topic Information

Dear Colleagues,

With 9.6 million deaths in 2018, cancer is the second leading cause of death in the world (World Cancer Report, 2020). Each year, about 50% of all the people who have developed cancer are given radiation therapy at some point or another of their treatment. This non-invasive tool has become essential to treat tumors. Unfortunately, the conventional techniques currently used in clinic induce major side effects due to damage in healthy tissues. In addition, some tumors respond poorly to conventional treatments, in particular because of their radioresistance. Therefore, there is an urgent need for disruptions in technologies and protocols in the clinic to develop a precision medicine approach and personalized patient care.

This Topic is an initiative of the ambitious iNanoTheRad project of Université Paris-Saclay, which promotes innovative strategies based on irradiation by new sources (high-dose rates, high LET, spatially structured beams, plasmas) and the addition of tumor targeted nano-agents and drugs to improve the effects of radiotherapy. Strategies for treatment personalization based on artificial intelligence are also considered. This Topic is interdisciplinary and open to international experts and researchers in medical physics, radiation chemistry and physics, in numerical simulations and artificial intelligence, the development of radiation sources, radiobiology, nanoscience, nanomedicine, plasma medicine, radiotherapy, and oncology. It is intended to give visibility to important results and ideas concerning the formulation of the next generation of secured and personalized radiotherapy treatments from the lab bench to clinical applications.

Dr. Gérard Baldacchino
Prof. Dr. Eric Deutsch
Dr. Marie Dutreix
Prof. Dr. Sandrine Lacombe
Dr. Erika Porcel
Dr. Charlotte Robert
Dr. Emmanuelle Bourneuf
Dr. João Santos Sousa
Dr. Aurélien de la Lande
Topic Editors

Keywords

  • cancer
  • radiotherapy innovation
  • new radiation sources
  • new radiotherapy strategies
  • radiosensitizing nanoparticles
  • advanced strategies for radiotherapy
  • external radiotherapy in clinic
  • AI and imaging for radiation therapies
  • new sources and associated dosimetry for radiotherapy
  • new radiation therapies modalities
  • nanoparticle-enhanced radiotherapies in diagnosis and treatment
  • first principles simulations

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Cancers
cancers
5.2 7.4 2009 17.9 Days CHF 2900 Submit
Cells
cells
6.0 9.0 2012 16.6 Days CHF 2700 Submit
Journal of Clinical Medicine
jcm
3.9 5.4 2012 17.9 Days CHF 2600 Submit
Radiation
radiation
- - 2021 24.5 Days CHF 1000 Submit
Pharmaceutics
pharmaceutics
5.4 6.9 2009 14.2 Days CHF 2900 Submit
Applied Sciences
applsci
2.7 4.5 2011 16.9 Days CHF 2400 Submit
Nanomaterials
nanomaterials
5.3 7.4 2011 13.6 Days CHF 2900 Submit
Current Oncology
curroncol
2.6 2.6 1994 18 Days CHF 2200 Submit

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Published Papers (9 papers)

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9 pages, 802 KiB  
Article
Breast Volume Is a Predictor of Higher Heart Dose in Whole-Breast Supine Free-Breathing Volumetric-Modulated Arc Therapy Planning
Curr. Oncol. 2023, 30(12), 10530-10538; https://doi.org/10.3390/curroncol30120768 - 18 Dec 2023
Viewed by 799
Abstract
In breast cancer volumetric-modulated arc therapy (VMAT) planning, the rotation of the gantry around the target implies a greater dose spreading to the whole heart, compared to tangential-field standard treatment. A consecutive cohort of 121 breast cancer patients treated with the VMAT technique [...] Read more.
In breast cancer volumetric-modulated arc therapy (VMAT) planning, the rotation of the gantry around the target implies a greater dose spreading to the whole heart, compared to tangential-field standard treatment. A consecutive cohort of 121 breast cancer patients treated with the VMAT technique was investigated. The correlation of breast volume, heart volume and lung volume with mean heart dose (mHD) and mean and maximum LAD dose (mLAD dose, MLAD dose) was tested, and a subsequent a linear regression analysis was carried out. VMAT treatment plans from 56 left breast cancer and 65 right breast cancer patients were analyzed. For right-sided patients, breast volume was significantly correlated with mHD, mLAD and MLAD dose, while for left-sided patients, breast volume was significantly correlated with mHD and mLAD, while heart volume and lung volume were correlated with mHD, mLAD and MLAD dose. Breast volume was the only predictor of increased heart and LAD dose (p ≤ 0.001) for right-sided patients. In left-sided patients, heart and lung were also predictors of increased mHD (p = 0.005, p ≤ 0.001) and mean LAD dose (p = 0.009, p ≤ 0.001). In this study, we observed an increase in heart and LAD doses in larger-breasted patients treated with VMAT planning. In right-sided patients, breast volume was shown to be the only predictor of increased heart dose and LAD dose. Full article
(This article belongs to the Topic Innovative Radiation Therapies)
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13 pages, 26869 KiB  
Article
Automated Image Analysis of Transmission Electron Micrographs: Nanoscale Evaluation of Radiation-Induced DNA Damage in the Context of Chromatin
Cells 2023, 12(20), 2427; https://doi.org/10.3390/cells12202427 - 10 Oct 2023
Viewed by 801
Abstract
Background: Heavy ion irradiation (IR) with high-linear energy transfer (LET) is characterized by a unique depth dose distribution and increased biological effectiveness. Following high-LET IR, localized energy deposition along the particle trajectories induces clustered DNA lesions, leading to low electron density domains (LEDDs). [...] Read more.
Background: Heavy ion irradiation (IR) with high-linear energy transfer (LET) is characterized by a unique depth dose distribution and increased biological effectiveness. Following high-LET IR, localized energy deposition along the particle trajectories induces clustered DNA lesions, leading to low electron density domains (LEDDs). To investigate the spatiotemporal dynamics of DNA repair and chromatin remodeling, we established the automated image analysis of transmission electron micrographs. Methods: Human fibroblasts were irradiated with high-LET carbon ions or low-LET photons. At 0.1 h, 0.5 h, 5 h, and 24 h post-IR, nanoparticle-labeled repair factors (53BP1, pKu70, pKu80, DNA-PKcs) were visualized using transmission electron microscopy in interphase nuclei to monitor the formation and repair of DNA damage in the chromatin ultrastructure. Using AI-based software tools, advanced image analysis techniques were established to assess the DNA damage pattern following low-LET versus high-LET IR. Results: Low-LET IR induced single DNA lesions throughout the nucleus, and most DNA double-strand breaks (DSBs) were efficiently rejoined with no visible chromatin decondensation. High-LET IR induced clustered DNA damage concentrated along the particle trajectories, resulting in circumscribed LEDDs. Automated image analysis was used to determine the exact number of differently sized nanoparticles, their distance from one another, and their precise location within the micrographs (based on size, shape, and density). Chromatin densities were determined from grayscale features, and nanoparticles were automatically assigned to euchromatin or heterochromatin. High-LET IR-induced LEDDs were delineated using automated segmentation, and the spatial distribution of nanoparticles in relation to segmented LEDDs was determined. Conclusions: The results of our image analysis suggest that high-LET IR induces chromatin relaxation along particle trajectories, enabling the critical repair of successive DNA damage. Following exposure to different radiation qualities, automated image analysis of nanoparticle-labeled DNA repair proteins in the chromatin ultrastructure enables precise characterization of specific DNA damage patterns. Full article
(This article belongs to the Topic Innovative Radiation Therapies)
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18 pages, 2387 KiB  
Article
Early and Transient Formation of Highly Acidic pH Spikes in Water Radiolysis under the Combined Effect of High Dose Rate and High Linear Energy Transfer
Radiation 2023, 3(3), 165-182; https://doi.org/10.3390/radiation3030014 - 11 Sep 2023
Viewed by 1025
Abstract
(1) Background: Water radiolysis leads to the formation of hydronium ions H3O+ in less than 50 fs, resulting in the formation of transient acidic pH spikes in the irradiated water. The purpose of this study is to examine the time [...] Read more.
(1) Background: Water radiolysis leads to the formation of hydronium ions H3O+ in less than 50 fs, resulting in the formation of transient acidic pH spikes in the irradiated water. The purpose of this study is to examine the time evolution of these spikes of acidity under irradiation conditions combining both high absorbed dose rate and high-LET radiation. (2) Methods: The early space–time history of the distributions of the various reactive species was obtained using our Monte Carlo multitrack chemistry simulation code IONLYS-IRT. To simulate different LETs, we used incident protons of varying energies as radiation sources. The “instantaneous pulse” (or Dirac) model was used to investigate the effect of dose rate. (3) Results: One major finding is that the combination of high dose rates and high LETs is clearly additive, with a very significant impact on the pH of the solution. For example, at 1 ns and for a dose rate of ~107 Gy/s, the pH drops from ~4.7 to 2.7 as the LET increases from ~0.3 to 60 keV/μm. (4) Conclusions: Confirming previous work, this purely radiation chemical study raises the question of the possible importance and role of these spikes of acidity in underpinning the physical chemistry and biology of the “FLASH effect”. Full article
(This article belongs to the Topic Innovative Radiation Therapies)
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13 pages, 1764 KiB  
Article
Mean Heart Dose Prediction Using Parameters of Single-Slice Computed Tomography and Body Mass Index: Machine Learning Approach for Radiotherapy of Left-Sided Breast Cancer of Asian Patients
Curr. Oncol. 2023, 30(8), 7412-7424; https://doi.org/10.3390/curroncol30080537 - 04 Aug 2023
Viewed by 1789
Abstract
Deep inspiration breath-hold (DIBH) is an excellent technique to reduce the incidental radiation received by the heart during radiotherapy in patients with breast cancer. However, DIBH is costly and time-consuming for patients and radiotherapy staff. In Asian countries, the use of DIBH is [...] Read more.
Deep inspiration breath-hold (DIBH) is an excellent technique to reduce the incidental radiation received by the heart during radiotherapy in patients with breast cancer. However, DIBH is costly and time-consuming for patients and radiotherapy staff. In Asian countries, the use of DIBH is restricted due to the limited number of patients with a high mean heart dose (MHD) and the shortage of radiotherapy personnel and equipment compared to that in the USA. This study aimed to develop, evaluate, and compare the performance of ten machine learning algorithms for predicting MHD using a patient’s body mass index and single-slice CT parameters to identify patients who may not require DIBH. Machine learning models were built and tested using a dataset containing 207 patients with left-sided breast cancer who were treated with field-in-field radiotherapy with free breathing. The average MHD was 251 cGy. Stratified repeated four-fold cross-validation was used to build models using 165 training data. The models were compared internally using their average performance metrics: F2 score, AUC, recall, accuracy, Cohen’s kappa, and Matthews correlation coefficient. The final performance evaluation for each model was further externally analyzed using 42 unseen test data. The performance of each model was evaluated as a binary classifier by setting the cut-off value of MHD ≥ 300 cGy. The deep neural network (DNN) achieved the highest F2 score (78.9%). Most models successfully classified all patients with high MHD as true positive. This study indicates that the ten models, especially the DNN, might have the potential to identify patients who may not require DIBH. Full article
(This article belongs to the Topic Innovative Radiation Therapies)
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14 pages, 1103 KiB  
Article
Predicting Overall Survival for Patients with Malignant Mesothelioma Following Radiotherapy via Interpretable Machine Learning
Cancers 2023, 15(15), 3916; https://doi.org/10.3390/cancers15153916 - 01 Aug 2023
Cited by 1 | Viewed by 1398
Abstract
Purpose/Objectives: Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer arising from the cells of the thoracic pleura with a poor prognosis. We aimed to develop a model, via interpretable machine learning (ML) methods, predicting overall survival for MPM following radiotherapy based [...] Read more.
Purpose/Objectives: Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer arising from the cells of the thoracic pleura with a poor prognosis. We aimed to develop a model, via interpretable machine learning (ML) methods, predicting overall survival for MPM following radiotherapy based on dosimetric metrics as well as patient characteristics. Materials/Methods: Sixty MPM (37 right, 23 left) patients treated on a Tomotherapy unit between 2013 and 2018 were retrospectively analyzed. All patients received 45 Gy (25 fractions). The multivariable Cox regression (Cox PH) model and Survival Support Vector Machine (sSVM) were applied to build predictive models of overall survival (OS) based on clinical, dosimetric, and combined variables. Results: Significant differences in dosimetric endpoints for critical structures, i.e., the lung, heart, liver, kidney, and stomach, were observed according to target laterality. The OS was found to be insignificantly different (p = 0.18) between MPM patients who tested left- and right-sided, with 1-year OS of 77.3% and 75.0%, respectively. With Cox PH regression, considering dosimetric variables for right-sided patients alone, an increase in PTV_Min, Total_Lung_PTV_Mean, Contra_Lung_Volume, Contra_Lung_V20, Esophagus_Mean, and Heart_Volume had a greater hazard to all-cause death, while an increase in Total_Lung_PTV_V20, Contra_Lung_V5, and Esophagus_Max had a lower hazard to all-cause death. Considering clinical variables alone, males and increases in N stage had greater hazard to all-cause death; considering both clinical and dosimetric variables, increases in N stage, PTV_Mean, PTV_Min, and esophagus_Mean had greater hazard to all-cause death, while increases in T stage and Heart_V30 had lower hazard to all-cause-death. In terms of C-index, the Cox PH model and sSVM performed similarly and fairly well when considering clinical and dosimetric variables independently or jointly. Conclusions: Clinical and dosimetric variables may predict the overall survival of mesothelioma patients, which could guide personalized treatment planning towards a better treatment response. The identified predictors and their impact on survival offered additional value for translational application in clinical practice. Full article
(This article belongs to the Topic Innovative Radiation Therapies)
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17 pages, 10055 KiB  
Article
Synthesis, Characterization, and Therapeutic Efficacy of 177Lu-DMSA@SPIONs in Nanobrachytherapy of Solid Tumors
Pharmaceutics 2023, 15(7), 1943; https://doi.org/10.3390/pharmaceutics15071943 - 13 Jul 2023
Cited by 2 | Viewed by 1098
Abstract
As an alternative to classical brachytherapy, intratumoral injection of radionuclide-labeled nanoparticles (nanobrachytherapy, NBT) has been investigated as a superior delivery method over an intravenous route for radionuclide therapy of solid tumors. We created superparamagnetic iron oxide nanoparticles (SPIONs) coated with meso-1,2-dimercaptosuccinic acid (DMSA) [...] Read more.
As an alternative to classical brachytherapy, intratumoral injection of radionuclide-labeled nanoparticles (nanobrachytherapy, NBT) has been investigated as a superior delivery method over an intravenous route for radionuclide therapy of solid tumors. We created superparamagnetic iron oxide nanoparticles (SPIONs) coated with meso-1,2-dimercaptosuccinic acid (DMSA) and radiolabeled with Lutetium-177 (177Lu), generating 177Lu-DMSA@SPIONs as a potential antitumor agent for nanobrachytherapy. Efficient radiolabeling of DMSA@SPIONS by 177Lu resulted in a stable bond with minimal leakage in vitro. After an intratumoral injection to mouse colorectal CT-26 or breast 4T1 subcutaneous tumors, the nanoparticles remained well localized at the injection site for weeks, with limited leakage. The dose of 3.70 MBq/100 µg/50 µL of 177Lu-DMSA@SPIONs applied intratumorally resulted in a high therapeutic efficacy, without signs of general toxicity. A decreased dose of 1.85 MBq/100 µg/50 µL still retained therapeutic efficacy, while an increased dose of 9.25 MBq/100 µg/50 µL did not significantly benefit the therapy. Histopathology analysis revealed that the 177Lu-DMSA@SPIONs act within a limited range around the injection site, which explains the good therapeutic efficacy achieved by a single administration of a relatively low dose without the need for increased or repeated dosing. Overall, 177Lu-DMSA@SPIONs are safe and potent agents suitable for intra-tumoral administration for localized tumor radionuclide therapy. Full article
(This article belongs to the Topic Innovative Radiation Therapies)
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12 pages, 808 KiB  
Systematic Review
Stereotactic Radiotherapy for Critically Located Pancreatic and Biliary Targets: A Review on Simultaneous Integrated Protection and Other Dose-Painting Strategies to Minimize Dose to Critical Organs at Risk
Radiation 2023, 3(2), 98-109; https://doi.org/10.3390/radiation3020009 - 16 May 2023
Cited by 1 | Viewed by 1164
Abstract
Background: Stereotactic Radiotherapy (SRT) in pancreatic and biliary tract cancer (PBC) suffers from proximity to any organ(s) at risk (OARs). Some strategies to manage this issue have previously been proposed, such as Simultaneous Integrated Protection (SIP), with the aim of maintaining a biological [...] Read more.
Background: Stereotactic Radiotherapy (SRT) in pancreatic and biliary tract cancer (PBC) suffers from proximity to any organ(s) at risk (OARs). Some strategies to manage this issue have previously been proposed, such as Simultaneous Integrated Protection (SIP), with the aim of maintaining a biological effective dose prescription while reducing toxicities. We performed a systematic review of the literature about SRT techniques applied in patients with tumor in proximity to OARs, with the aim of testing safety and efficacy. Methods: using PRISMA guidelines, we selected studies from a pool of more than 25,000 articles published from 2010 to 30 January 2023 that explored the use of SRT to deliver targeted treatment for PBC. We then selected the ones referring to decreases in prescription doses (for SRT only) in the area of overlap between planning target volume (PTV) and OARs. Local control (LC) and toxicities being detailed were exclusion criteria for articles. Results: 9 studies were included in our review, considering 368 patients. One-year LC probability ranges between 67% and 98.3% were reported. Late G3 toxicities ranged between 0% and 5.3%, while G4-G5 late toxicities were both reported as 0.3%. Conclusion: prioritizing critical OAR constraints limits severe toxicities while preserving LC in PBC SRT. Improving in-study reporting is essential to confirm these promising results. Full article
(This article belongs to the Topic Innovative Radiation Therapies)
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16 pages, 6745 KiB  
Article
Orthovoltage X-ray Minibeam Radiation Therapy for the Treatment of Ocular Tumours—An In Silico Evaluation
Cancers 2023, 15(3), 679; https://doi.org/10.3390/cancers15030679 - 21 Jan 2023
Cited by 1 | Viewed by 1787
Abstract
(1) Background: Radiotherapeutic treatments of ocular tumors are often challenging because of nearby radiosensitive structures and the high doses required to treat radioresistant cancers such as uveal melanomas. Although increased local control rates can be obtained with advanced techniques such as proton therapy [...] Read more.
(1) Background: Radiotherapeutic treatments of ocular tumors are often challenging because of nearby radiosensitive structures and the high doses required to treat radioresistant cancers such as uveal melanomas. Although increased local control rates can be obtained with advanced techniques such as proton therapy and stereotactic radiosurgery, these modalities are not always accessible to patients (due to high costs or low availability) and side effects in structures such as the lens, eyelids or anterior chamber remain an issue. Minibeam radiation therapy (MBRT) could represent a promising alternative in this regard. MBRT is an innovative new treatment approach where the irradiation field is composed of multiple sub-millimetric beamlets, spaced apart by a few millimetres. This creates a so-called spatial fractionation of the dose which, in small animal experiments, has been shown to increase normal tissue sparing while simultaneously providing high tumour control rates. Moreover, MBRT with orthovoltage X-rays could be easily implemented in widely available and comparably inexpensive irradiation platforms. (2) Methods: Monte Carlo simulations were performed using the TOPAS toolkit to evaluate orthovoltage X-ray MBRT as a potential alternative for treating ocular tumours. Dose distributions were simulated in CT images of a human head, considering six different irradiation configurations. (3) Results: The mean, peak and valley doses were assessed in a generic target region and in different organs at risk. The obtained doses were comparable to those reported in previous X-ray MBRT animal studies where good normal tissue sparing and tumour control (rat glioma models) were found. (4) Conclusions: A proof-of-concept study for the application of orthovoltage X-ray MBRT to ocular tumours was performed. The simulation results encourage the realisation of dedicated animal studies considering minibeam irradiations of the eye to specifically assess ocular and orbital toxicities as well as tumour response. If proven successful, orthovoltage X-ray minibeams could become a cost-effective treatment alternative, in particular for developing countries. Full article
(This article belongs to the Topic Innovative Radiation Therapies)
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15 pages, 3093 KiB  
Article
Effects of Microbeam Irradiation on Rodent Esophageal Smooth Muscle Contraction
Cells 2023, 12(1), 176; https://doi.org/10.3390/cells12010176 - 31 Dec 2022
Cited by 1 | Viewed by 1524
Abstract
Background: High-dose-rate radiotherapy has shown promising results with respect to normal tissue preservation. We developed an ex vivo model to study the physiological effects of experimental radiotherapy in the rodent esophageal smooth muscle. Methods: We assessed the physiological parameters of the esophageal function [...] Read more.
Background: High-dose-rate radiotherapy has shown promising results with respect to normal tissue preservation. We developed an ex vivo model to study the physiological effects of experimental radiotherapy in the rodent esophageal smooth muscle. Methods: We assessed the physiological parameters of the esophageal function in ex vivo preparations of the proximal, middle, and distal segments in the organ bath. High-dose-rate synchrotron irradiation was conducted using both the microbeam irradiation (MBI) technique with peak doses greater than 200 Gy and broadbeam irradiation (BBI) with doses ranging between 3.5–4 Gy. Results: Neither MBI nor BBI affected the function of the contractile apparatus. While peak latency and maximal force change were not affected in the BBI group, and no changes were seen in the proximal esophagus segments after MBI, a significant increase in peak latency and a decrease in maximal force change was observed in the middle and distal esophageal segments. Conclusion: No severe changes in physiological parameters of esophageal contraction were determined after high-dose-rate radiotherapy in our model, but our results indicate a delayed esophageal function. From the clinical perspective, the observed increase in peak latency and decreased maximal force change may indicate delayed esophageal transit. Full article
(This article belongs to the Topic Innovative Radiation Therapies)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: New Radiation Oncology Optimization Principles Based on In Vivo Predictive Assay and Recent Developments in Molecular Radiation Biology
Authors: Anders Brahme
Affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Abstract: The recent understanding that most TP53-intact normal tissues are low-dose hypersensitive (LDHS) and low-dose apoptotic (LDA) implies that the well-known fractionation window at ≈ 2 Gy/Fr defines the optimal tolerance level for most organs at risk and not at all the tumor dose when using IMRT. This necessitates new approaches to biologically optimized radiation therapy, requiring that the maximum dose to organs at risk should be ≤2.3 Gy/Fr, and especially that it should be of low ionization density or LET. The fractionation window is due to low-dose initiation of full DNA repair capability in normal tissues at ≈½ Gy, and we should use this acquired repair advantage to its full extent up to ≈2.3 Gy where otherwise the high dose apoptosis (HDA) may set in. Thus biologically optimized treatments should be focused on the application of a low number of high tumor-dose intensity- and/or radiation quality-modulated photon, electron or lower LET light ion beams. Doing so, reduces the total dose and the risk for secondary cancers and generating a real tumor cure without risk for subsequent caspase-3-induced accelerated tumor cell repopulation. The light ions should truly have the lowest possible LET in normal tissues to retain the fractionation window property but still have a high LET only in the gross tumor region to simultaneously maximize tumor cell inactivation. This necessitates the use of the lightest ions, from helium to ≈boron, as this fractionation advantage is practically lost for carbon and heavier ions. This unique property of the lightest ions is combined with the highest possible apoptosis and senescence in front of the Bragg peak and can best be characterized as allowing molecular radiation therapy since surrounding normal tissues are only exposed to a low dose and LET that causes easily repairable low dose damage. Many other new associated ideas are also discussed, such as optimal use of IMRT, molecular tumor imaging with MRSI, PET-CT and phase contrast X-rays, TP53 cell survival radiation biology, biologically optimized radiation therapy: BIOART, quantum biology of curative radiation therapy, 4D-space-time radiation therapy optimization, the influence of microdosimetric heterogeneity on the dose response relation, optimal time dose fractionation, accounting for tumor hypoxia, biologically optimal radiation quality, secondary cancer risks, mutant TP53 reactivation, and optimal dose delivery techniques since they are all involved directly or indirectly in these new principles for true optimization of radiation therapy.

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