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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 -
International Journal of Radiation... Apr 2015
Topics: Anemia; Blood Transfusion; Carcinoma, Squamous Cell; Cell Hypoxia; Clinical Trials as Topic; Erythropoietin; Etanidazole; Female; Head and Neck Neoplasms; Humans; Male; Misonidazole; Radiation-Sensitizing Agents; Receptors, Erythropoietin; Treatment Failure; Uterine Cervical Neoplasms
PubMed: 25832683
DOI: 10.1016/j.ijrobp.2015.01.041 -
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 -
PET Clinics Jul 2014The recent development and introduction of new hybrid imaging devices combining positron emission tomography (PET) technology with magnetic resonance imaging (MRI) opens... (Review)
Review
The recent development and introduction of new hybrid imaging devices combining positron emission tomography (PET) technology with magnetic resonance imaging (MRI) opens up new perspectives in clinical molecular imaging. Combining MRI and fluorine-18 choline PET would theoretically produce valuable clinical data in a single imaging session, which can be used for staging, prognosis, and assessment of treatment response. Fluorine-18-sodium fluoride (18F-NaF) is a highly sensitive PET tracer used as a marker of osteoblastic abnormalities. PET imaging with (68)Ga-DOTATATE or DOTATOC has demonstrated promising results for locating metastatic lesions, occasionally with superior sensitivity than whole-body MRI. l-DOPA PET adds data regarding l-DOPA metabolism, which may increase the specificity and sensibility of the study itself. Fluoromisonidazole is known to be not only a useful tracer for determining hypoxic cells but also an efficient hypoxic radiosensitizer.
Topics: Carbon Radioisotopes; Choline; Fluorine Radioisotopes; Humans; Levodopa; Magnetic Resonance Imaging; Misonidazole; Octreotide; Organometallic Compounds; Positron-Emission Tomography; Radiation-Sensitizing Agents; Radiopharmaceuticals; Sodium Fluoride
PubMed: 25030398
DOI: 10.1016/j.cpet.2014.03.010 -
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 -
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 -
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 -
Recent Results in Cancer Research.... 2016Tumor hypoxia is a clinically relevant cause of radiation resistance. Direct measurements of tumor oxygenation have been performed predominantly with the Eppendorf... (Review)
Review
Tumor hypoxia is a clinically relevant cause of radiation resistance. Direct measurements of tumor oxygenation have been performed predominantly with the Eppendorf histograph and these have defined the reduced prognosis after radiotherapy in poorly oxygenated tumors, especially head-and-neck cancer, cervix cancer and sarcoma. Exogenous markers have been used for immunohistochemical detection of hypoxic tumor areas (pimonidazole) or for positron-emission tomography (PET) imaging (misonidazole). Overexpression of hypoxia-related proteins such as hypoxia-inducible factor-1α (HIF-1α) has also been linked to poor prognosis after radiotherapy and such proteins are considered as potential endogenous hypoxia markers.
Topics: Biomarkers, Tumor; Disease-Free Survival; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms; Osteopontin; Precision Medicine; Prognosis; Radiation Oncology
PubMed: 27318684
DOI: 10.1007/978-3-662-49651-0_6 -
International Journal of Clinical... Aug 2016Tumor hypoxia is associated with tumor progression and resistance to various treatments. Noninvasive imaging using positron emission tomography (PET) and F-18-labeled... (Review)
Review
Tumor hypoxia is associated with tumor progression and resistance to various treatments. Noninvasive imaging using positron emission tomography (PET) and F-18-labeled fluoromisonidazole (FMISO) was recently introduced in order to define and quantify tumor hypoxia. The FMISO uptake was closely correlated with pimonidazole immunohistochemistry and hypoxia-inducible factor 1 expression in basic studies. Tumor hypoxia in head and neck cancers and other tumors in a clinical setting may also indicate resistance to radiation and/or chemotherapy. Hypoxic imaging may thus play a new and important role for suitable radiation planning, including dose escalation and dose reduction based on the image findings. Such radiation-dose painting based on the findings of hypoxia may require high-performance PET imaging to provide high target-to-background ratio images and an optimal quantitative parameter to define the hypoxic region. A multicenter prospective study using data from a large number of patients is also warranted to test the clinical value of hypoxic imaging.
Topics: Biomarkers; Head and Neck Neoplasms; Humans; Hypoxia-Inducible Factor 1; Misonidazole; Positron-Emission Tomography; Radiation Tolerance; Radiopharmaceuticals; Tumor Hypoxia
PubMed: 26577447
DOI: 10.1007/s10147-015-0920-6 -
Seminars in Nuclear Medicine Jan 2021Head and neck cancers are commonly encountered malignancies in the United States, of which the majority are attributed to squamous cell carcinoma. F-FDG-PET/CT has been... (Review)
Review
Head and neck cancers are commonly encountered malignancies in the United States, of which the majority are attributed to squamous cell carcinoma. F-FDG-PET/CT has been well established in the evaluation, treatment planning, prognostic implications of these tumors and is routinely applied for the management of patients with these cancers. Many alternative investigational PET radiotracers have been extensively studied in the evaluation of these tumors. Although these radiotracers have not been able to replace F-FDG-PET/CT in routine clinical practice currently, they may provide important additional information about the biological mechanisms of these tumors, such as foci of tumor hypoxia as seen on hypoxia specific PET radiotracers such as F-Fluoromisonidazole (F-FMISO), which could be useful in targeting radioresistant hypoxic tumor foci when treatment planning. There are multiple other hypoxia-specific PET radiotracers such as F-Fluoroazomycinarabinoside (FAZA), F-Flortanidazole (HX4), which have been evaluated similarly, of which F-Fluoromisonidazole (F-FMISO) has been the most investigated. Other radiotracers frequently studied in the evaluation of these tumors include radiolabeled amino acid PET radiotracers, which show increased uptake in tumor cells with limited uptake in inflammatory tissue, which can be useful especially in differentiating postradiation inflammation from residual and/or recurrent disease. F-Fluorothymidine (FLT) is localized intracellularly by nucleoside transport and undergoes phosphorylation thereby being retained within tumor cells and can serve as an indicator of tumor proliferation. Decrease in radiotracer activity following treatment can be an early indicator of treatment response. This review aims at synthesizing the available literature on the most studied non-FDG-PET/CT in head and neck cancer.
Topics: Azoles; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Head and Neck Neoplasms; Humans; Misonidazole; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radiopharmaceuticals
PubMed: 33246541
DOI: 10.1053/j.semnuclmed.2020.07.008