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The British Journal of Radiology Jan 2019The concept of tumour hypoxia as a cause of radiation resistance has been prevalent for over 100 years. During this time, our understanding of tumour hypoxia has matured... (Review)
Review
The concept of tumour hypoxia as a cause of radiation resistance has been prevalent for over 100 years. During this time, our understanding of tumour hypoxia has matured with the recognition that oxygen tension within a tumour is influenced by both diffusion and perfusion mechanisms. In parallel, clinical strategies to modify tumour hypoxia with the expectation that this will improve response to radiation have been developed and tested in clinical trials. Despite many disappointments, meta-analysis of the data on hypoxia modification confirms a significant impact on both tumour control and survival. Early trials evaluated hyperbaric oxygen followed by a generation of studies testing oxygen mimetics such as misonidazole, pimonidazole and etanidazole. One highly significant result stands out from the use of nimorazole in advanced laryngeal cancer with a significant advantage seen for locoregional control using this radiosensitiser. More recent studies have evaluated carbogen and nicotinamide targeting both diffusion related and perfusion related hypoxia. A significant survival advantage is seen in muscle invasive bladder cancer and also for locoregional control in hypopharygeal cancer associated with a low haemoglobin. New developments include the recognition that mitochondrial complex inhibitors reducing tumour oxygen consumption are potential radiosensitising agents and atovaquone is currently in clinical trials. One shortcoming of past hypoxia modifying trials is the failure to identify oxygenation status and select those patient with significant hypoxia. A range of biomarkers are now available including histological necrosis, immunohistochemical intrinsic markers such as CAIX and Glut 1 and hypoxia gene signatures which have been shown to predict outcome and will inform the next generation of hypoxia modifying clinical trials.
Topics: Animals; Cell Hypoxia; Female; Humans; Male; Misonidazole; Neoplasms; Niacinamide; Oxygen Consumption; Radiation-Sensitizing Agents; Randomized Controlled Trials as Topic; Risk Assessment; Survival Analysis; Treatment Outcome; Tumor Hypoxia
PubMed: 29979089
DOI: 10.1259/bjr.20170966 -
Current Radiopharmaceuticals 2020FDG PET/CT imaging has an established role in lung cancer (LC) management. Whilst it is a sensitive technique, FDG PET/CT has a limited specificity in the... (Review)
Review
BACKGROUND
FDG PET/CT imaging has an established role in lung cancer (LC) management. Whilst it is a sensitive technique, FDG PET/CT has a limited specificity in the differentiation between LC and benign conditions and is not capable of defining LC heterogeneity since FDG uptake varies between histotypes.
OBJECTIVE
To get an overview of new radiopharmaceuticals for the study of cancer biology features beyond glucose metabolism in LC.
METHODS
A comprehensive literature review of PubMed/Medline was performed using a combination of the following keywords: "positron emission tomography", "lung neoplasms", "non-FDG", "radiopharmaceuticals", "tracers".
RESULTS
Evidences suggest that proliferation markers, such as 18F-Fluorothymidine and 11CMethionine, improve LC staging and are useful in evaluating treatment response and progression free survival. 68Ga-DOTA-peptides are already routinely used in pulmonary neuroendocrine neoplasms (NENs) management and should be firstly performed in suspected NENs. 18F-Fluoromisonidazole and other radiopharmaceuticals show a promising impact on staging, prognosis assessment and therapy response in LC patients, by visualizing hypoxia and perfusion. Radiolabeled RGD-peptides, targeting angiogenesis, may have a role in LC staging, treatment outcome and therapy. PET radiopharmaceuticals tracing a specific oncogene/signal pathway, such as EGFR or ALK, are gaining interest especially for therapeutic implications. Other PET tracers, like 68Ga-PSMA-peptides or radiolabeled FAPIs, need more development in LC, though, they are promising for therapy purposes.
CONCLUSION
To date, the employment of most of the described tracers is limited to the experimental field, however, research development may offer innovative opportunities to improve LC staging, characterization, stratification and response assessment in an era of increased personalized therapy.
Topics: Acetates; Carbon Radioisotopes; Dideoxynucleosides; Fluorodeoxyglucose F18; Gallium Isotopes; Gallium Radioisotopes; Humans; Lung Neoplasms; Methionine; Misonidazole; Neoplasm Staging; Neuroendocrine Tumors; Peptides; Peptides, Cyclic; Positron Emission Tomography Computed Tomography; Quinolines; Radiopharmaceuticals; Sensitivity and Specificity
PubMed: 31868150
DOI: 10.2174/1874471013666191223151402 -
The British Journal of Radiology Jan 2019Nitroimidazoles have been extensively explored as hypoxic cell radiosensitizers but have had limited clinical success, with efficacy restricted by toxicity. However,... (Review)
Review
Nitroimidazoles have been extensively explored as hypoxic cell radiosensitizers but have had limited clinical success, with efficacy restricted by toxicity. However, they have proven clinically useful as probes for tumour hypoxia. Both applications, and probably much of the dose-limiting toxicities, reflect the dominant chemical property of electron affinity or ease of reduction, associated with the nitro substituent in an aromatic structure. This single dominant property affords unusual, indeed extraordinary flexibility in drug or probe design, suggesting further development is possible in spite of earlier limitations, in particular building on the benefit of hindsight and an appreciation of errors made in earlier studies. The most notable errors were: the delay in viewing cellular thiol depletion as a likely common artefact in testing ; slow recognition of pH-driven concentration gradients when compounds were weak acids and bases; and a failure to explore the possible involvement of pH and ascorbate in influencing hypoxia probe binding. The experience points to the need to involve a wider range of expertise than that historically involved in many laboratories when studying the effects of chemicals on radiation response or using diagnostic probes.
Topics: Animals; Cell Hypoxia; Cell Survival; Dose-Response Relationship, Drug; Humans; Misonidazole; Oxygen Consumption; Radiation-Sensitizing Agents; Sensitivity and Specificity; Tumor Hypoxia
PubMed: 29303355
DOI: 10.1259/bjr.20170915 -
The British Journal of Radiology Aug 2017Oxygen distribution is a major determinant of treatment success in radiotherapy, with well-oxygenated tumour regions responding by up to a factor of three relative to... (Review)
Review
Oxygen distribution is a major determinant of treatment success in radiotherapy, with well-oxygenated tumour regions responding by up to a factor of three relative to anoxic volumes. Conversely, tumour hypoxia is associated with treatment resistance and negative prognosis. Tumour oxygenation is highly heterogeneous and difficult to measure directly. The recent advent of functional hypoxia imaging modalities such as fluorine-18 fluoromisonidazole positron emission tomography have shown promise in non-invasively determining regions of low oxygen tension. This raises the prospect of selectively increasing dose to hypoxic subvolumes, a concept known as dose painting. Yet while this is a promising approach, oxygen-mediated radioresistance is inherently a multiscale problem, and there are still a number of substantial challenges that must be overcome if hypoxia dose painting is to be successfully implemented. Current imaging modalities are limited by the physics of such systems to have resolutions in the millimetre regime, whereas oxygen distribution varies over a micron scale, and treatment delivery is typically modulated on a centimetre scale. In this review, we examine the mechanistic basis and implications of the radiobiological oxygen effect, the factors influencing microscopic heterogeneity in tumour oxygenation and the consequent challenges in the interpretation of clinical hypoxia imaging (in particular fluorine-18 fluoromisonidazole positron emission tomography). We also discuss dose-painting approaches and outline challenges that must be addressed to improve this treatment paradigm.
Topics: Cell Hypoxia; Humans; Hypoxia; Misonidazole; Neoplasms; Positron-Emission Tomography; Radiation-Sensitizing Agents; Radiotherapy Dosage
PubMed: 28540739
DOI: 10.1259/bjr.20160939 -
British Journal of Cancer Apr 2017Pathological angiogenesis involves complex and dynamic interactions between tumour cells and other lineages existing in the microenvironment of the tumour. Preclinical... (Review)
Review
Pathological angiogenesis involves complex and dynamic interactions between tumour cells and other lineages existing in the microenvironment of the tumour. Preclinical and clinical data suggest that tumours can show dual, different adaptive responses against antiangiogenic agents: one successful adaptation is vascular normalisation, whereas the second adaptation is elicited through vascular trimming and increased hypoxia. These phenomena depend on the type of tumour and the type of agent. The classical approach for investigating acquired resistance against antiangiogenic agents is to identify compensatory signalling pathways emerging in response to VEGF blockade, which has led to the development of highly effective drugs; however, ultimately these drugs fail. Here we review how the dual stromal adaptive patterns determine the mechanisms of escape that go beyond the reprogramming of signal transduction pathways, which obliges us to investigate the tumour as an ecosystem and to develop uni- and multicompartmental models that explain drug resistance involving metabolic and immune reprogramming. We also propose a method for facilitating personalised therapeutic decisions, which uses 18F-fluoromisonidazole-positron emission tomography to monitor the dual stromal response in tumours of individual patients.
Topics: Angiogenesis Inhibitors; Cell Hypoxia; Drug Resistance, Neoplasm; Humans; Misonidazole; Neovascularization, Pathologic; Precision Medicine; Stromal Cells; Tumor Microenvironment; Vascular Endothelial Growth Factor A
PubMed: 28301873
DOI: 10.1038/bjc.2017.69 -
SAGE Open Medicine 2020In this study, we evaluated the use and the contribution of radiopharmaceuticals to the field of lung neoplasms imaging using positron emission tomography/computed... (Review)
Review
INTRODUCTION
In this study, we evaluated the use and the contribution of radiopharmaceuticals to the field of lung neoplasms imaging using positron emission tomography/computed tomography.
METHODS
We conducted review of the current literature at PubMed/MEDLINE until February 2020. The search language was English.
RESULTS
The most widely used radiopharmaceuticals are the following:Experimental/pre-clinical approaches: (18)F-Misonidazole (18F-MISO) under clinical development, D(18)F-Fluoro-Methyl-Tyrosine (18F-FMT), 18F-FAMT (L-[3-18F] (18)F-Fluorothymidine (18F-FLT)), (18)F-Fluoro-Azomycin-Arabinoside (18F-FAZA), (68)Ga-Neomannosylated-Human-Serum-Albumin (68Ga-MSA) (23), (68)Ga-Tetraazacyclododecane (68Ga-DOTA) (as theranostic agent), (11)C-Methionine (11C-MET), 18F-FPDOPA, αβ integrin, Ga-RGD, Cu-DOTA-RGD, F-Alfatide, Folate Radio tracers, and immuno-positron emission tomography radiopharmaceutical agents.Clinically approved procedures/radiopharmaceuticals agents: (18)F-Fluoro-Deoxy-Glucose (18F-FDG), (18)F-sodium fluoride (18F-NaF) (bone metastases), and (68)Ga-Tetraazacyclododecane (68Ga-DOTA). The quantitative determination and the change in radiopharmaceutical uptake parameters such as standard uptake value, metabolic tumor volume, total lesion glycolysis, FAZA tumor to muscle ratio, standard uptake value tumor to liver ratio, standard uptake value tumor to spleen ratio, standard uptake value maximum ratio, and the degree of hypoxia have prognostic and predictive (concerning the therapeutic outcome) value. They have been associated with the assessment of overall survival and disease free survival. With the positron emission tomography/computed tomography radiopharmaceuticals, the sensitivity and the specificity of the method have increased.
CONCLUSION
In terms of lung cancer, positron emission tomography/computed tomography may have clinical application and utility (a) in personalizing treatment, (b) as a biomarker for the estimation of overall survival, disease free survival, and (c) apply a cost-effective patient approach because it reveals focuses of the disease, which are not found with the other imaging methods.
PubMed: 33062275
DOI: 10.1177/2050312120961594 -
The British Journal of Radiology Feb 2020The aim of the study was to assess the feasibility of multitracer positron emission tomography (PET) imaging before and during chemoradiation and to evaluate the...
OBJECTIVE
The aim of the study was to assess the feasibility of multitracer positron emission tomography (PET) imaging before and during chemoradiation and to evaluate the predictive value of image-based factors for outcome in locally advanced head and neck cancers treated with chemoradiation.
METHODS
In the week prior to the treatment [F]-2-flu-2-deoxy-D-glucose (FDG), [F]-3'-flu-3'deoxythymidine (FLT) and [F]-flumisonidazole (FMISO) imaging was performed. FLT scans were repeated at 14 and 28 Gy and FMISO at 36 Gy. Overall survival, disease-free survival and local control were correlated with subvolume parameters, and with tumour-to-muscle ratio for FMISO. For every tracer, total metabolic tumour volume was calculated.
RESULTS
33 patients were included. No correlation was found between pre-treatment maximum standardised uptake value for FDG, FLT, FMISO and outcomes. Tumour volume measured on initial CT scans and initial FLT volume correlated with disease-free survivall ( = 0.007 and 0.04 respectively). FDG and FLT metabolic tumour volumes correlated significantly with local control ( = 0.005 and 0.02 respectively). In multivariate Cox analysis only individual initial TMRmax correlated with overall survival.
CONCLUSION
PET/CT imaging is a promising tool. However, various aspects of image analysis need further clinical validation in larger multicentre study employing uniform imaging protocol and standardisation, especially for hypoxia tracer.
ADVANCES IN KNOWLEDGE
Monitoring of biological features of the tumour using multitracer PET modality seems to be a feasible option in daily clinical practice.Evaluation of hypoxic subvolumes is more patient dependent; thus, exploration of individual parameters of hypoxia is needed. tumour-to-muscle ratio seems to be the most promising so far.
Topics: Aged; Antineoplastic Agents; Biomarkers, Tumor; Chemoradiotherapy; Cisplatin; Dideoxynucleosides; Disease-Free Survival; Drug Administration Schedule; Feasibility Studies; Female; Fluorodeoxyglucose F18; Head and Neck Neoplasms; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Misonidazole; Positron Emission Tomography Computed Tomography; Prospective Studies; Radiation-Sensitizing Agents; Treatment Outcome; Tumor Hypoxia
PubMed: 31860336
DOI: 10.1259/bjr.20180781 -
Computational and Mathematical Methods... 2015The innovation of computational techniques serves as an important step toward optimized, patient-specific management of cancer. In particular, in silico simulation of... (Review)
Review
The innovation of computational techniques serves as an important step toward optimized, patient-specific management of cancer. In particular, in silico simulation of tumour growth and treatment response may eventually yield accurate information on disease progression, enhance the quality of cancer treatment, and explain why certain therapies are effective where others are not. In silico modelling is demonstrated to considerably benefit from information obtainable with PET and PET/CT. In particular, models have successfully integrated tumour glucose metabolism, cell proliferation, and cell oxygenation from multiple tracers in order to simulate tumour behaviour. With the development of novel radiotracers to image additional tumour phenomena, such as pH and gene expression, the value of PET and PET/CT data for use in tumour models will continue to grow. In this work, the use of PET and PET/CT information in in silico tumour models is reviewed. The various parameters that can be obtained using PET and PET/CT are detailed, as well as the radiotracers that may be used for this purpose, their utility, and limitations. The biophysical measures used to quantify PET and PET/CT data are also described. Finally, a list of in silico models that incorporate PET and/or PET/CT data is provided and reviewed.
Topics: Cell Proliferation; Coordination Complexes; Dideoxynucleosides; Diffusion; Fluorodeoxyglucose F18; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glucose; Humans; Hydrogen-Ion Concentration; Hypoxia; Misonidazole; Models, Theoretical; Multimodal Imaging; Neoplasms; Neovascularization, Pathologic; Organometallic Compounds; Oxygen; Positron-Emission Tomography; Radiopharmaceuticals; Thiosemicarbazones; Tomography, X-Ray Computed
PubMed: 25788973
DOI: 10.1155/2015/415923 -
Frontiers in Chemistry 2019Photoionization mass spectrometry, photoelectron-photoion coincidence spectroscopic technique, and computational methods have been combined to investigate the...
Photoionization mass spectrometry, photoelectron-photoion coincidence spectroscopic technique, and computational methods have been combined to investigate the fragmentation of two nitroimidazole derived compounds: the metronidazole and misonidazole. These molecules are used in radiotherapy thanks to their capability to sensitize hypoxic tumor cells to radiation by "mimicking" the effects of the presence of oxygen as a damaging agent. Previous investigations of the fragmentation patterns of the nitroimidazole isomers (Bolognesi et al., 2016; Cartoni et al., 2018) have shown their capacity to produce reactive molecular species such as nitric oxide, carbon monoxide or hydrogen cyanide, and their potential impact on the biological system. The results of the present work suggest that different mechanisms are active for the more complex metronidazole and misonidazole molecules. The release of nitric oxide is hampered by the efficient formation of nitrous acid or nitrogen dioxide. Although both metronidazole and misonidazole contain imidazole ring in the backbone, the side branches of these molecules lead to very different bonding mechanisms and properties.
PubMed: 31157205
DOI: 10.3389/fchem.2019.00329 -
European Journal of Nuclear Medicine... Aug 2023Tumor hypoxia and other microenvironmental factors are key determinants of treatment resistance. Hypoxia positron emission tomography (PET) and functional magnetic...
PURPOSE
Tumor hypoxia and other microenvironmental factors are key determinants of treatment resistance. Hypoxia positron emission tomography (PET) and functional magnetic resonance imaging (MRI) are established prognostic imaging modalities to identify radiation resistance in head-and-neck cancer (HNC). The aim of this preclinical study was to develop a multi-parametric imaging parameter specifically for focal radiotherapy (RT) dose escalation using HNC xenografts of different radiation sensitivities.
METHODS
A total of eight human HNC xenograft models were implanted into 68 immunodeficient mice. Combined PET/MRI using dynamic [18F]-fluoromisonidazole (FMISO) hypoxia PET, diffusion-weighted (DW), and dynamic contrast-enhanced MRI was carried out before and after fractionated RT (10 × 2 Gy). Imaging data were analyzed on voxel-basis using principal component (PC) analysis for dynamic data and apparent diffusion coefficients (ADCs) for DW-MRI. A data- and hypothesis-driven machine learning model was trained to identify clusters of high-risk subvolumes (HRSs) from multi-dimensional (1-5D) pre-clinical imaging data before and after RT. The stratification potential of each 1D to 5D model with respect to radiation sensitivity was evaluated using Cohen's d-score and compared to classical features such as mean/peak/maximum standardized uptake values (SUV) and tumor-to-muscle-ratios (TMR) as well as minimum/valley/maximum/mean ADC.
RESULTS
Complete 5D imaging data were available for 42 animals. The final preclinical model for HRS identification at baseline yielding the highest stratification potential was defined in 3D imaging space based on ADC and two FMISO PCs ([Formula: see text]). In 1D imaging space, only clusters of ADC revealed significant stratification potential ([Formula: see text]). Among all classical features, only ADC showed significant correlation to radiation resistance ([Formula: see text]). After 2 weeks of RT, FMISO_c1 showed significant correlation to radiation resistance ([Formula: see text]).
CONCLUSION
A quantitative imaging metric was described in a preclinical study indicating that radiation-resistant subvolumes in HNC may be detected by clusters of ADC and FMISO using combined PET/MRI which are potential targets for future functional image-guided RT dose-painting approaches and require clinical validation.
Topics: Humans; Animals; Mice; Diffusion Magnetic Resonance Imaging; Positron-Emission Tomography; Misonidazole; Magnetic Resonance Imaging; Head and Neck Neoplasms; Hypoxia; Radiopharmaceuticals
PubMed: 37148296
DOI: 10.1007/s00259-023-06254-9