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1
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Mokoala KMG, Sathekge MM. Non-FDG hypoxia tracers. Semin Nucl Med 2024; 54:827-844. [PMID: 39510855 DOI: 10.1053/j.semnuclmed.2024.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 10/01/2024] [Indexed: 11/15/2024]
Abstract
Hypoxia plays a critical role in tumor biology, influencing cancer progression, treatment resistance, and patient prognosis. While 18-Fluorine fluoredeoxyglucose ([18F]F-FDG) PET imaging has been the standard for metabolic assessment, its limitations in accurately depicting hypoxic tumor regions necessitate the exploration of non-FDG hypoxia tracers. This review aims to evaluate emerging non-FDG radiotracers, such as nitroimidazole derivatives, copper-based agents, gallium-based agents and other innovative compounds, highlighting their mechanisms of action, biodistribution, and clinical applications. We will discuss the advantages and challenges associated with hypoxia imaging, as well as recent advancements in imaging techniques that enhance the assessment of tumor hypoxia. By synthesizing current research, this review seeks to provide insights into the potential of non-FDG hypoxia tracers for improving cancer diagnosis, treatment planning, and monitoring, ultimately contributing to more personalized and effective cancer care.
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Affiliation(s)
- Kgomotso M G Mokoala
- University of Pretoria, Pretoria, ZA-GP, South Africa; Nuclear Medicine Research Infrastructure (NuMeRI), Pretoria, ZA-GP, South Africa.
| | - Mike M Sathekge
- University of Pretoria, Pretoria, ZA-GP, South Africa; Nuclear Medicine Research Infrastructure (NuMeRI), Pretoria, ZA-GP, South Africa
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2
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Perez RC, Kim D, Maxwell AWP, Camacho JC. Functional Imaging of Hypoxia: PET and MRI. Cancers (Basel) 2023; 15:3336. [PMID: 37444446 DOI: 10.3390/cancers15133336] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/22/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Molecular and functional imaging have critical roles in cancer care. Existing evidence suggests that noninvasive detection of hypoxia within a particular type of cancer can provide new information regarding the relationship between hypoxia, cancer aggressiveness and altered therapeutic responses. Following the identification of hypoxia inducible factor (HIF), significant progress in understanding the regulation of hypoxia-induced genes has been made. These advances have provided the ability to therapeutically target HIF and tumor-associated hypoxia. Therefore, by utilizing the molecular basis of hypoxia, hypoxia-based theranostic strategies are in the process of being developed which will further personalize care for cancer patients. The aim of this review is to provide an overview of the significance of tumor hypoxia and its relevance in cancer management as well as to lay out the role of imaging in detecting hypoxia within the context of cancer.
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Affiliation(s)
- Ryan C Perez
- Florida State University College of Medicine, Tallahassee, FL 32306, USA
| | - DaeHee Kim
- Department of Diagnostic Imaging, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Aaron W P Maxwell
- Department of Diagnostic Imaging, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Juan C Camacho
- Department of Clinical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
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3
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Gouel P, Decazes P, Vera P, Gardin I, Thureau S, Bohn P. Advances in PET and MRI imaging of tumor hypoxia. Front Med (Lausanne) 2023; 10:1055062. [PMID: 36844199 PMCID: PMC9947663 DOI: 10.3389/fmed.2023.1055062] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 01/30/2023] [Indexed: 02/11/2023] Open
Abstract
Tumor hypoxia is a complex and evolving phenomenon both in time and space. Molecular imaging allows to approach these variations, but the tracers used have their own limitations. PET imaging has the disadvantage of low resolution and must take into account molecular biodistribution, but has the advantage of high targeting accuracy. The relationship between the signal in MRI imaging and oxygen is complex but hopefully it would lead to the detection of truly oxygen-depleted tissue. Different ways of imaging hypoxia are discussed in this review, with nuclear medicine tracers such as [18F]-FMISO, [18F]-FAZA, or [64Cu]-ATSM but also with MRI techniques such as perfusion imaging, diffusion MRI or oxygen-enhanced MRI. Hypoxia is a pejorative factor regarding aggressiveness, tumor dissemination and resistance to treatments. Therefore, having accurate tools is particularly important.
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Affiliation(s)
- Pierrick Gouel
- Département d’Imagerie, Centre Henri Becquerel, Rouen, France,QuantIF-LITIS, EA 4108, IRIB, Université de Rouen, Rouen, France
| | - Pierre Decazes
- Département d’Imagerie, Centre Henri Becquerel, Rouen, France,QuantIF-LITIS, EA 4108, IRIB, Université de Rouen, Rouen, France
| | - Pierre Vera
- Département d’Imagerie, Centre Henri Becquerel, Rouen, France,QuantIF-LITIS, EA 4108, IRIB, Université de Rouen, Rouen, France
| | - Isabelle Gardin
- Département d’Imagerie, Centre Henri Becquerel, Rouen, France,QuantIF-LITIS, EA 4108, IRIB, Université de Rouen, Rouen, France
| | - Sébastien Thureau
- QuantIF-LITIS, EA 4108, IRIB, Université de Rouen, Rouen, France,Département de Radiothérapie, Centre Henri Becquerel, Rouen, France
| | - Pierre Bohn
- Département d’Imagerie, Centre Henri Becquerel, Rouen, France,QuantIF-LITIS, EA 4108, IRIB, Université de Rouen, Rouen, France,*Correspondence: Pierre Bohn,
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4
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Han K, Fyles A, Shek T, Croke J, Dhani N, D'Souza D, Lee TY, Chaudary N, Bruce J, Pintilie M, Cairns R, Vines D, Pakbaz S, Jaffray D, Metser U, Rouzbahman M, Milosevic M, Koritzinsky M. A Phase II Randomized Trial of Chemoradiation with or without Metformin in Locally Advanced Cervical Cancer. Clin Cancer Res 2022; 28:5263-5271. [PMID: 36037303 DOI: 10.1158/1078-0432.ccr-22-1665] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/13/2022] [Accepted: 08/25/2022] [Indexed: 01/24/2023]
Abstract
PURPOSE Tumor hypoxia is associated with poor response to radiation (RT). We previously discovered a novel mechanism of metformin: enhancing tumor RT response by decreasing tumor hypoxia. We hypothesized that metformin would decrease tumor hypoxia and improve cervical cancer response to RT. PATIENTS AND METHODS A window-of-opportunity, phase II randomized trial was performed in stage IB-IVA cervical cancer. Patients underwent screening positron emission tomography (PET) imaging with hypoxia tracer fluoroazomycin arabinoside (FAZA). Only patients with FAZA uptake (hypoxic tumor) were included and randomized 2:1 to receive metformin in combination with chemoRT or chemoRT alone. A second FAZA-PET/CT scan was performed after 1 week of metformin or no intervention (control). The primary endpoint was a change in fractional hypoxic volume (FHV) between FAZA-PET scans, compared using the Wilcoxon signed-rank test. The study was closed early due to FAZA availability and the COVID-19 pandemic. RESULTS Of the 20 consented patients, 6 were excluded due to no FAZA uptake and 1 withdrew. FHV of 10 patients in the metformin arm decreased by an average of 10.2% (44.4%-34.2%) ± SD 16.9% after 1 week of metformin, compared with an average increase of 4.7% (29.1%-33.8%) ± 11.5% for the 3 controls (P = 0.027). Those with FHV reduction after metformin had significantly lower MATE2 expression. With a median follow-up of 2.8 years, the 2-year disease-free survival was 67% for the metformin arm versus 33% for controls (P = 0.09). CONCLUSIONS Metformin decreased cervical tumor hypoxia in this trial that selected for patients with hypoxic tumor. See related commentary by Lyng et al., p. 5233.
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Affiliation(s)
- Kathy Han
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Anthony Fyles
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Tina Shek
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Quantitative Imaging for Personalized Cancer Medicine, Techna Institute, University Health Network, Toronto, Ontario, Canada
| | - Jennifer Croke
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Neesha Dhani
- Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - David D'Souza
- London Regional Cancer Program, London Health Sciences Centre, Department of Oncology, Western University, London, Ontario, Canada
| | - Ting-Yim Lee
- London Regional Cancer Program, London Health Sciences Centre, Department of Oncology, Western University, London, Ontario, Canada
| | - Naz Chaudary
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Jeffrey Bruce
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Melania Pintilie
- Department of Biostatistics, University Health Network, Toronto, Ontario, Canada
| | - Rob Cairns
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Douglass Vines
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Sara Pakbaz
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - David Jaffray
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Ur Metser
- Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Marjan Rouzbahman
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Michael Milosevic
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Marianne Koritzinsky
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
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5
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PET imaging of hypoxia and apoptosis. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00205-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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6
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Narva SI, Seppänen MP, Raiko JRH, Forsback SJ, Orte KJ, Virtanen JM, Hynninen J, Hietanen S. Imaging of Tumor Hypoxia With 18F-EF5 PET/MRI in Cervical Cancer. Clin Nucl Med 2021; 46:952-957. [PMID: 34619699 DOI: 10.1097/rlu.0000000000003914] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
PURPOSE OF THE REPORT The aim of this study was to evaluate the distribution of hypoxia using 18F-EF5 as a hypoxia tracer in cervical cancer patients with PET/MRI. We investigated the association between this 18F-EF5-PET tracer and the immunohistochemical expression of endogenous hypoxia markers: HIF1α, CAIX, and GLUT1. PATIENTS AND METHODS Nine patients with biopsy-proven primary squamous cell cervix carcinoma (FIGO 2018 radiological stages IB1-IIIC2r) were imaged with dual tracers 18F-EF5 and 18F-FDG using PET/MRI (Int J Gynaecol Obstet. 2019;145:129-135). 18F-EF5 images were analyzed by calculating the tumor-to-muscle ratio to determine the hypoxic tissue (T/M ratio >1.5) and further hypoxic subvolume (HSV) and percentage hypoxic area. These 18F-EF5 hypoxic parameters were correlated with the size and localization of tumors in 18F-FDG PET/MRI and the results of hypoxia immunohistochemistry. RESULTS All primary tumors were clearly 18F-FDG and 18F-EF5 PET positive and heterogeneously hypoxic with multiple 18F-EF5-avid areas in locally advanced cancer and single areas in clinically stage I tumors. The location of hypoxia was detected mainly in the periphery of tumor. Hypoxia parameters 18F-EF5 max T/M ratio and HSV in primary tumors correlated independently with the advanced stage (P = 0.036 and P = 0.040, respectively), and HSV correlated with the tumor size (P = 0.027). The location of hypoxia in 18F-EF5 imaging was confirmed with a higher hypoxic marker expression HIF1α and CAIX in tumor fresh biopsies. CONCLUSIONS The 18F-EF5 imaging has promising potential in detecting areas of tumor hypoxia in cervical cancer.
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7
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Datta A, West C, O'Connor JPB, Choudhury A, Hoskin P. Impact of hypoxia on cervical cancer outcomes. Int J Gynecol Cancer 2021; 31:1459-1470. [PMID: 34593564 DOI: 10.1136/ijgc-2021-002806] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 09/14/2021] [Indexed: 01/22/2023] Open
Abstract
The annual global incidence of cervical cancer is approximately 604 000 cases/342 000 deaths, making it the fourth most common cancer in women. Cervical cancer is a major healthcare problem in low and middle income countries where 85% of new cases and deaths occur. Secondary prevention measures have reduced incidence and mortality in developed countries over the past 30 years, but cervical cancer remains a major cause of cancer deaths in women. For women who present with Fédération Internationale de Gynécologie et d'Obstétrique (FIGO 2018) stages IB3 or upwards, chemoradiation is the established treatment. Despite high rates of local control, overall survival is less than 50%, largely due to distant relapse. Reducing the health burden of cervical cancer requires greater individualization of treatment, identifying those at risk of relapse and progression for modified or intensified treatment. Hypoxia is a well known feature of solid tumors and an established therapeutic target. Low tumorous oxygenation increases the risk of local invasion, metastasis and treatment failure. While meta-analyses show benefit, many individual trials targeting hypoxia failed in part due to not selecting patients most likely to benefit. This review summarizes the available hypoxia-targeted strategies and identifies further research and new treatment paradigms needed to improve patient outcomes. The applications and limitations of hypoxia biomarkers for treatment selection and response monitoring are discussed. Finally, areas of greatest unmet clinical need are identified to measure and target hypoxia and therefore improve cervical cancer outcomes.
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Affiliation(s)
- Anubhav Datta
- Division of Cancer Sciences, The University of Manchester Faculty of Biology Medicine and Health, Manchester, UK
- Clinical Radiology, The Christie NHS Foundation Trust, Manchester, UK
| | - Catharine West
- Division of Cancer Sciences, The University of Manchester Faculty of Biology Medicine and Health, Manchester, UK
| | - James P B O'Connor
- Division of Cancer Sciences, The University of Manchester Faculty of Biology Medicine and Health, Manchester, UK
- Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
| | - Ananya Choudhury
- Division of Cancer Sciences, The University of Manchester Faculty of Biology Medicine and Health, Manchester, UK
- Clinical Oncology, The Christie Hospital NHS Trust, Manchester, UK
| | - Peter Hoskin
- Division of Cancer Sciences, The University of Manchester Faculty of Biology Medicine and Health, Manchester, UK
- Clinical Oncology, Mount Vernon Cancer Centre, Northwood, Middlesex, UK
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8
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Huang Y, Fan J, Li Y, Fu S, Chen Y, Wu J. Imaging of Tumor Hypoxia With Radionuclide-Labeled Tracers for PET. Front Oncol 2021; 11:731503. [PMID: 34557414 PMCID: PMC8454408 DOI: 10.3389/fonc.2021.731503] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 08/19/2021] [Indexed: 01/27/2023] Open
Abstract
The hypoxic state in a solid tumor refers to the internal hypoxic environment that appears as the tumor volume increases (the maximum radius exceeds 180-200 microns). This state can promote angiogenesis, destroy the balance of the cell’s internal environment, and lead to resistance to radiotherapy and chemotherapy, as well as poor prognostic factors such as metastasis and recurrence. Therefore, accurate quantification, mapping, and monitoring of hypoxia, targeted therapy, and improvement of tumor hypoxia are of great significance for tumor treatment and improving patient survival. Despite many years of development, PET-based hypoxia imaging is still the most widely used evaluation method. This article provides a comprehensive overview of tumor hypoxia imaging using radionuclide-labeled PET tracers. We introduced the mechanism of tumor hypoxia and the reasons leading to the poor prognosis, and more comprehensively included the past, recent and ongoing studies of PET radiotracers for tumor hypoxia imaging. At the same time, the advantages and disadvantages of mainstream methods for detecting tumor hypoxia are summarized.
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Affiliation(s)
- Yuan Huang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Junying Fan
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yi Li
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Shaozhi Fu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Department of Oncology, Academician (Expert) Workstation of Sichuan Province, Luzhou, China
| | - Yue Chen
- Department of Oncology, Academician (Expert) Workstation of Sichuan Province, Luzhou, China.,Nuclear Medicine and Molecular Imaging key Laboratory of Sichuan Province, Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jingbo Wu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Department of Oncology, Academician (Expert) Workstation of Sichuan Province, Luzhou, China
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9
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A Systematic Review and Meta-Analysis of the Prognostic Impact of Pretreatment Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Parameters in Patients with Locally Advanced Cervical Cancer Treated with Concomitant Chemoradiotherapy. Diagnostics (Basel) 2021; 11:diagnostics11071258. [PMID: 34359345 PMCID: PMC8304455 DOI: 10.3390/diagnostics11071258] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/07/2021] [Accepted: 07/07/2021] [Indexed: 12/02/2022] Open
Abstract
Backgrounds: The purpose of this paper is to investigate the prognostic value of fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) parameters in patients treated with concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC). Methods: Studies that met the following criteria were retrieved from PubMed and Embase: patients treated with CCRT for LACC; FDG PET/CT scans performed before CCRT treatment; and a detected relationship between the parameters of FDG PET/CT and the prognosis of patients. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate the overall survival (OS) or event-free survival (EFS). Results: In total, 14 eligible studies with 1313 patients were included in this meta-analysis. Patients with a high maximum standardized uptake value (SUVmax) have a shorter OS than those with a low SUVmax (HR = 2.582, 95% = CI 1.936–3.443, p < 0.001). Primary tumor SUVmax values (HR = 1.938, 95% CI = 1.203–3.054, p = 0.004) were significantly correlated with EFS, with a relatively high heterogeneity (I2 = 84% and I2 = 69.4%, respectively). Based on the limited data, the combined HR for EFS with the highest primary tumor total lesion glycolysis (TLG) and metabolic tumor volume (MTV) was 1.843 (95% CI = 1.100–3.086, p = 0.02) and 2.06 (95% CI = 1.21–3.51, p = 0.007), respectively. Besides, the combined HR for OS with the highest nodal SUVmax was 2.095 (95% CI = 2.027–2.166, p < 0.001). Conclusion: A high primary SUVmax has a significant correlation with the OS and EFS of patients treated with CCRT for LACC and may therefore serve as a prognostic predictor. Due to the limited data, to explore the correlation between survival and TLG, MTV, and nodal SUVmax, further large-scale prospective studies are needed.
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10
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Abstract
Over the last few years, cancer immunotherapy experienced tremendous developments and it is nowadays considered a promising strategy against many types of cancer. However, the exclusion of lymphocytes from the tumor nest is a common phenomenon that limits the efficiency of immunotherapy in solid tumors. Despite several mechanisms proposed during the years to explain the immune excluded phenotype, at present, there is no integrated understanding about the role played by different models of immune exclusion in human cancers. Hypoxia is a hallmark of most solid tumors and, being a multifaceted and complex condition, shapes in a unique way the tumor microenvironment, affecting gene transcription and chromatin remodeling. In this review, we speculate about an upstream role for hypoxia as a common biological determinant of immune exclusion in solid tumors. We also discuss the current state of ex vivo and in vivo imaging of hypoxic determinants in relation to T cell distribution that could mechanisms of immune exclusion and discover functional-morphological tumor features that could support clinical monitoring.
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11
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Waller J, Onderdonk B, Flood A, Swartz H, Shah J, Shah A, Aydogan B, Halpern H, Hasan Y. The clinical utility of imaging methods used to measure hypoxia in cervical cancer. Br J Radiol 2020; 93:20190640. [PMID: 32286849 PMCID: PMC7336054 DOI: 10.1259/bjr.20190640] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 03/18/2020] [Accepted: 04/07/2020] [Indexed: 12/13/2022] Open
Abstract
While it is well-established that hypoxia is a major factor that affects clinical outcomes in cervical cancer, widespread usage of clinically available methods to detect and evaluate hypoxia during the course of treatment have not been established. This review compares these methods, summarizes their strengths and weaknesses, and assesses the pathways for their useful employment to alter clinical practice. We conducted a search on PubMed for literature pertaining to imaging hypoxic cervical cancer, and implemented keywords related to oxygen measurement tools to improve the relevance of the search results.Oxygenation level-dependent applications of MRI have demonstrated hypoxia-induced radioresistance, and changes in cervix tumor oxygenation from hyperoxic therapy.The hypoxic areas within tumors can be indirectly identified in dynamic contrast-enhanced images, where they generally display low signal enhancement, and diffusion-weighted images, which demonstrates areas of restricted diffusion (which correlates with hypoxia). Positron emmision tomography, used independently and with other imaging modalities, has demonstrated utility in imaging hypoxia through tracers specific for low oxygen levels, like Cu-ATSM tracers and nitroimidazoles. Detecting hypoxia in the tumors of patients diagnosed with cervical cancer via medical imaging and non-imaging tools like electron paramagnetic resonance oximetry can be utilized clinically, such as for guiding radiation and post-treatment surveillance, for a more personalized approach to treatment. The merits of these methods warrant further investigation via comparative effectiveness research and large clinical trials into their clinical applications.
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Affiliation(s)
- Joseph Waller
- Drexel College of Medicine, 2900 W Queen Ln, PA 19129, United States
| | - Benjamin Onderdonk
- Department of Radiation and Cellular Oncology, The University of Chicago, 5758 S Maryland Ave, IL 60637, United States
| | - Ann Flood
- Department of Radiology, Dartmouth Geisel School of Medicine, 1 Rope Ferry Rd, NH 03755, United States
| | - Harold Swartz
- Department of Radiology, Dartmouth Geisel School of Medicine, 1 Rope Ferry Rd, NH 03755, United States
| | - Jaffer Shah
- Drexel College of Medicine, 2900 W Queen Ln, PA 19129, United States
| | - Asghar Shah
- Brown University, Providence, RI 02912, United States
| | - Bulent Aydogan
- Department of Radiation and Cellular Oncology, The University of Chicago, 5758 S Maryland Ave, IL 60637, United States
| | - Howard Halpern
- Department of Radiation and Cellular Oncology, The University of Chicago, 5758 S Maryland Ave, IL 60637, United States
| | - Yasmin Hasan
- Department of Radiation and Cellular Oncology, The University of Chicago, 5758 S Maryland Ave, IL 60637, United States
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12
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13
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Han K, Shek T, Vines D, Driscoll B, Fyles A, Jaffray D, Keller H, Metser U, Pintilie M, Xie J, Yeung I, Milosevic M. Measurement of Tumor Hypoxia in Patients With Locally Advanced Cervical Cancer Using Positron Emission Tomography with 18F-Fluoroazomyin Arabinoside. Int J Radiat Oncol Biol Phys 2018; 102:1202-1209. [PMID: 29680257 DOI: 10.1016/j.ijrobp.2018.02.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/11/2018] [Accepted: 02/20/2018] [Indexed: 01/25/2023]
Abstract
PURPOSE To assess cervical tumor hypoxia using the hypoxia tracer 18F-fluoroazomycin arabinoside (18F-FAZA) and compare different reference tissues and thresholds for quantifying tumor hypoxia. METHODS AND MATERIALS Twenty-seven patients with cervical cancer were studied prospectively by positron emission tomography (PET) imaging with 18F-FAZA before starting standard chemoradiation. The hypoxic volume was defined as all voxels within a tumor (T) with standardized uptake values (SUVs) greater than 3 standard deviations from the mean gluteus maximus muscle SUV value (M) or SUVs greater than 1 to 1.4 times the mean SUV value of the left ventricle, a blood (B) surrogate. The hypoxic fraction was defined as the ratio of the number of hypoxic voxels to the total number of tumor voxels. RESULTS A 18F-FAZA-PET hypoxic volume could be identified in the majority of cervical tumors (89% when using T/M or T/B > 1.2 as threshold) on the 2-hour static scan. The hypoxic fraction ranged from 0% to 99% (median 31%) when defined using the T/M threshold and from 0% to 78% (median 32%) with the T/B > 1.2 threshold. Hypoxic volumes derived from the different thresholds were highly correlated (Spearman's correlation coefficient ρ between T/M and T/B > 1-1.4 were 0.82-0.91), as were hypoxic fractions (0.75-0.85). Compartmental analysis of the dynamic scans showed k3, the FAZA accumulation constant, to be strongly correlated with hypoxic fraction defined using the T/M (Spearman's ρ=0.72) and T/B > 1.2 thresholds (0.76). CONCLUSIONS Hypoxia was detected in the majority of cervical tumors on 18F-FAZA-PET imaging. The extent of hypoxia varied markedly between tumors but not significantly with different reference tissues/thresholds.
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Affiliation(s)
- Kathy Han
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
| | - Tina Shek
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Quantitative Imaging for Personalized Cancer Medicine, Techna Institute, University Health Network, Toronto, Ontario, Canada
| | - Douglass Vines
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Quantitative Imaging for Personalized Cancer Medicine, Techna Institute, University Health Network, Toronto, Ontario, Canada
| | - Brandon Driscoll
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Quantitative Imaging for Personalized Cancer Medicine, Techna Institute, University Health Network, Toronto, Ontario, Canada
| | - Anthony Fyles
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - David Jaffray
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Quantitative Imaging for Personalized Cancer Medicine, Techna Institute, University Health Network, Toronto, Ontario, Canada
| | - Harald Keller
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Quantitative Imaging for Personalized Cancer Medicine, Techna Institute, University Health Network, Toronto, Ontario, Canada
| | - Ur Metser
- Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, Canada; Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada
| | - Melania Pintilie
- Department of Biostatistics, University Health Network, Toronto, Ontario, Canada
| | - Jason Xie
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Ivan Yeung
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Quantitative Imaging for Personalized Cancer Medicine, Techna Institute, University Health Network, Toronto, Ontario, Canada
| | - Michael Milosevic
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
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Bonnitcha P, Grieve S, Figtree G. Clinical imaging of hypoxia: Current status and future directions. Free Radic Biol Med 2018; 126:296-312. [PMID: 30130569 DOI: 10.1016/j.freeradbiomed.2018.08.019] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 07/30/2018] [Accepted: 08/14/2018] [Indexed: 12/20/2022]
Abstract
Tissue hypoxia is a key feature of many important causes of morbidity and mortality. In pathologies such as stroke, peripheral vascular disease and ischaemic heart disease, hypoxia is largely a consequence of low blood flow induced ischaemia, hence perfusion imaging is often used as a surrogate for hypoxia to guide clinical diagnosis and treatment. Importantly, ischaemia and hypoxia are not synonymous conditions as it is not universally true that well perfused tissues are normoxic or that poorly perfused tissues are hypoxic. In pathologies such as cancer, for instance, perfusion imaging and oxygen concentration are less well correlated, and oxygen concentration is independently correlated to radiotherapy response and overall treatment outcomes. In addition, the progression of many diseases is intricately related to maladaptive responses to the hypoxia itself. Thus there is potentially great clinical and scientific utility in direct measurements of tissue oxygenation. Despite this, imaging assessment of hypoxia in patients is rarely performed in clinical settings. This review summarises some of the current methods used to clinically evaluate hypoxia, the barriers to the routine use of these methods and the newer agents and techniques being explored for the assessment of hypoxia in pathological processes.
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Affiliation(s)
- Paul Bonnitcha
- Northern and Central Clinical Schools, Faculty of Medicine, Sydney University, Sydney, NSW 2006, Australia; Chemical Pathology Department, NSW Health Pathology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia; Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales 2065, Australia.
| | - Stuart Grieve
- Sydney Translational Imaging Laboratory, Heart Research Institute, Charles Perkins Centre and Sydney Medical School, University of Sydney, NSW 2050, Australia
| | - Gemma Figtree
- Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales 2065, Australia; Cardiology Department, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia
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Marcu LG, Moghaddasi L, Bezak E. Imaging of Tumor Characteristics and Molecular Pathways With PET: Developments Over the Last Decade Toward Personalized Cancer Therapy. Int J Radiat Oncol Biol Phys 2018; 102:1165-1182. [PMID: 29907486 DOI: 10.1016/j.ijrobp.2018.04.055] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 04/09/2018] [Accepted: 04/19/2018] [Indexed: 02/08/2023]
Abstract
PURPOSE Improvements in personalized therapy are made possible by the advances in molecular biology that led to developments in molecular imaging, allowing highly specific in vivo imaging of biological processes. Positron emission tomography (PET) is the most specific and sensitive imaging technique for in vivo molecular targets and pathways, offering quantification and evaluation of functional properties of the targeted anatomy. MATERIALS AND METHODS This work is an integrative research review that summarizes and evaluates the accumulated current status of knowledge of recent advances in PET imaging for cancer diagnosis and treatment, concentrating on novel radiotracers and evaluating their advantages and disadvantages in cancer characterization. Medline search was conducted, limited to English publications from 2007 onward. Identified manuscripts were evaluated for most recent developments in PET imaging of cancer hypoxia, angiogenesis, proliferation, and clonogenic cancer stem cells (CSC). RESULTS There is an expansion observed from purely metabolic-based PET imaging toward antibody-based PET to achieve more information on cancer characteristics to identify hypoxia, proangiogenic factors, CSC, and others. 64Cu-ATSM, for example, can be used both as a hypoxia and a CSC marker. CONCLUSIONS Progress in the field of functional imaging will possibly lead to more specific tumor targeting and personalized treatment, increasing tumor control and improving quality of life.
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Affiliation(s)
- Loredana Gabriela Marcu
- Faculty of Science, University of Oradea, Oradea, Romania; Cancer Research Institute and School of Health Sciences, University of South Australia, Adelaide SA, Australia
| | - Leyla Moghaddasi
- GenesisCare, Tennyson Centre, Adelaide SA, Australia; Department of Physics, University of Adelaide, Adelaide SA, Australia
| | - Eva Bezak
- Cancer Research Institute and School of Health Sciences, University of South Australia, Adelaide SA, Australia; Department of Physics, University of Adelaide, Adelaide SA, Australia.
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Kalshetty A, Basu S. Non- 18F-2-Fluoro-2-Deoxy-d-Glucose PET/Computed Tomography in Gynecologic Oncology: An Overview of Current Status and Future Potential. PET Clin 2018; 13:239-248. [PMID: 29482752 DOI: 10.1016/j.cpet.2017.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The current status and future potential targets of non-18F-2-fluoro-2-deoxy-d-glucose (FDG) PET/computed tomography (CT) in 3 major gynecologic malignancies are discussed. Estrogen receptor-based 16alpha-18F-fluoro-17beta-estradiol (18F-FES) PET/CT has been investigated in (a) Uterine malignancies (both endometrial and myometrial pathologies) and (b) ovarian carcinoma. For uterine tumors, FDG/FES standardized uptake value and/or uptake ratio showed a positive correlation with malignant transformation (ie, endometrial carcinoma and uterine sarcoma) and higher malignant grades, whereas higher 18F-FES uptake was documented in benign pathologies (ie, endometrial hyperplasia and leiomyoma). For epithelial ovarian carcinomas, 18F-FES PET/CT can predict the response to antiestrogen therapy in platinum-resistant cases.
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Affiliation(s)
- Ashwini Kalshetty
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe Building, Jerbai Wadia Road, Parel, Mumbai 400 012, India; Homi Bhabha National Institute, Mumbai, India
| | - Sandip Basu
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe Building, Jerbai Wadia Road, Parel, Mumbai 400 012, India; Homi Bhabha National Institute, Mumbai, India.
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Challapalli A, Carroll L, Aboagye EO. Molecular mechanisms of hypoxia in cancer. Clin Transl Imaging 2017; 5:225-253. [PMID: 28596947 PMCID: PMC5437135 DOI: 10.1007/s40336-017-0231-1] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 04/21/2017] [Indexed: 02/07/2023]
Abstract
PURPOSE Hypoxia is a condition of insufficient oxygen to support metabolism which occurs when the vascular supply is interrupted, or when a tumour outgrows its vascular supply. It is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. This review provides an overview of hypoxia imaging with Positron emission tomography (PET), with an emphasis on the biological relevance, mechanism of action, highlighting advantages, and limitations of the currently available hypoxia radiotracers. METHODS A comprehensive PubMed literature search was performed, identifying articles relating to biological significance and measurement of hypoxia, MRI methods, and PET imaging of hypoxia in preclinical and clinical settings, up to December 2016. RESULTS A variety of approaches have been explored over the years for detecting and monitoring changes in tumour hypoxia, including regional measurements with oxygen electrodes placed under CT guidance, MRI methods that measure either oxygenation or lactate production consequent to hypoxia, different nuclear medicine approaches that utilise imaging agents the accumulation of which is inversely related to oxygen tension, and optical methods. The advantages and disadvantages of these approaches are reviewed, along with individual strategies for validating different imaging methods. PET is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. CONCLUSION Even though hypoxia could have significant prognostic and predictive value in the clinic, the best method for hypoxia assessment has in our opinion not been realised.
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Affiliation(s)
- Amarnath Challapalli
- Department of Clinical Oncology, Bristol Cancer Institute, Horfield Road, Bristol, United Kingdom
| | - Laurence Carroll
- Department of Surgery and Cancer, Imperial College, GN1, Commonwealth Building, Hammersmith Hospital, Du Cane Road, London, W120NN United Kingdom
| | - Eric O. Aboagye
- Department of Surgery and Cancer, Imperial College, GN1, Commonwealth Building, Hammersmith Hospital, Du Cane Road, London, W120NN United Kingdom
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18
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Lyng H, Malinen E. Hypoxia in cervical cancer: from biology to imaging. Clin Transl Imaging 2017; 5:373-388. [PMID: 28804704 PMCID: PMC5532411 DOI: 10.1007/s40336-017-0238-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 06/24/2017] [Indexed: 12/14/2022]
Abstract
PURPOSE Hypoxia imaging may improve identification of cervical cancer patients at risk of treatment failure and be utilized in treatment planning and monitoring, but its clinical potential is far from fully realized. Here, we briefly describe the biology of hypoxia in cervix tumors of relevance for imaging, and evaluate positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques that have shown promise for assessing hypoxia in a clinical setting. We further discuss emerging imaging approaches, and how imaging can play a role in future treatment strategies to target hypoxia. METHODS We performed a PubMed literature search, using keywords related to imaging and hypoxia in cervical cancer, with a particular emphasis on studies correlating imaging with other hypoxia measures and treatment outcome. RESULTS Only a few and rather small studies have utilized PET with tracers specific for hypoxia, and no firm conclusions regarding preferred tracer or clinical potential can be drawn so far. Most studies address indirect hypoxia imaging with dynamic contrast-enhanced techniques. Strong evidences for a role of these techniques in hypoxia imaging have been presented. Pre-treatment images have shown significant association to outcome in several studies, and images acquired during fractionated radiotherapy may further improve risk stratification. Multiparametric MRI and multimodality PET/MRI enable combined imaging of factors of relevance for tumor hypoxia and warrant further investigation. CONCLUSIONS Several imaging approaches have shown promise for hypoxia imaging in cervical cancer. Evaluation in large clinical trials is required to decide upon the optimal modality and approach.
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Affiliation(s)
- Heidi Lyng
- Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Eirik Malinen
- Department of Medical Physics, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Department of Physics, University of Oslo, Oslo, Norway
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19
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Zegers CML, Hoebers FJP, van Elmpt W, Bons JA, Öllers MC, Troost EGC, Eekers D, Balmaekers L, Arts-Pechtold M, Mottaghy FM, Lambin P. Evaluation of tumour hypoxia during radiotherapy using [ 18F]HX4 PET imaging and blood biomarkers in patients with head and neck cancer. Eur J Nucl Med Mol Imaging 2016; 43:2139-2146. [PMID: 27251643 PMCID: PMC5047929 DOI: 10.1007/s00259-016-3429-y] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 05/19/2016] [Indexed: 01/31/2023]
Abstract
Background and purpose Increased tumour hypoxia is associated with a worse overall survival in patients with head and neck squamous cell carcinoma (HNSCC). The aims of this study were to evaluate treatment-associated changes in [18F]HX4-PET, hypoxia-related blood biomarkers, and their interdependence. Material and methods [18F]HX4-PET/CT scans of 20 patients with HNSCC were acquired at baseline and after ±20Gy of radiotherapy. Within the gross-tumour-volumes (GTV; primary and lymph nodes), mean and maximum standardized uptake values, the hypoxic fraction (HF) and volume (HV) were calculated. Also, the changes in spatial uptake pattern were evaluated using [18F]HX4-PET/CT imaging. For all patients, the plasma concentration of CAIX, osteopontin and VEGF was assessed. Results At baseline, tumour hypoxia was detected in 69 % (22/32) of the GTVs. During therapy, we observed a significant decrease in all image parameters. The HF decreased from 21.7 ± 19.8 % (baseline) to 3.6 ± 10.0 % (during treatment; P < 0.001). Only two patients had a HV > 1 cm3 during treatment, which was located for >98 % within the baseline HV. During treatment, no significant changes in plasma CAIX or VEGF were observed, while osteopontin was increased. Conclusions [18F]HX4-PET/CT imaging allows monitoring changes in hypoxia during (chemo)radiotherapy whereas the blood biomarkers were not able to detect a treatment-associated decrease in hypoxia. Electronic supplementary material The online version of this article (doi:10.1007/s00259-016-3429-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Catharina M L Zegers
- Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastro Clinic, Dr. Tanslaan 12, 6229ET, Maastricht, The Netherlands.
| | - Frank J P Hoebers
- Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastro Clinic, Dr. Tanslaan 12, 6229ET, Maastricht, The Netherlands
| | - Wouter van Elmpt
- Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastro Clinic, Dr. Tanslaan 12, 6229ET, Maastricht, The Netherlands
| | - Judith A Bons
- Central Diagnostic Laboratory, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Michel C Öllers
- Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastro Clinic, Dr. Tanslaan 12, 6229ET, Maastricht, The Netherlands
| | - Esther G C Troost
- Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastro Clinic, Dr. Tanslaan 12, 6229ET, Maastricht, The Netherlands.,Helmholtz Zentrum Dresden-Rossendorf, Dresden, Germany.,OncoRay, Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Daniëlle Eekers
- Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastro Clinic, Dr. Tanslaan 12, 6229ET, Maastricht, The Netherlands
| | - Leo Balmaekers
- Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastro Clinic, Dr. Tanslaan 12, 6229ET, Maastricht, The Netherlands
| | - Marlies Arts-Pechtold
- Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastro Clinic, Dr. Tanslaan 12, 6229ET, Maastricht, The Netherlands
| | - Felix M Mottaghy
- Department of Nuclear Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands.,Department of Nuclear Medicine, RWTH Aachen University, University Hospital, Aachen, Germany
| | - Philippe Lambin
- Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastro Clinic, Dr. Tanslaan 12, 6229ET, Maastricht, The Netherlands
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20
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Prognostic Implications of the SUVmax of Primary Tumors and Metastatic Lymph Node Measured by 18F-FDG PET in Patients With Uterine Cervical Cancer. Clin Nucl Med 2016; 41:34-40. [DOI: 10.1097/rlu.0000000000001049] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Fleming IN, Manavaki R, Blower PJ, West C, Williams KJ, Harris AL, Domarkas J, Lord S, Baldry C, Gilbert FJ. Imaging tumour hypoxia with positron emission tomography. Br J Cancer 2015; 112:238-50. [PMID: 25514380 PMCID: PMC4453462 DOI: 10.1038/bjc.2014.610] [Citation(s) in RCA: 240] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 09/30/2014] [Accepted: 11/10/2014] [Indexed: 01/02/2023] Open
Abstract
Hypoxia, a hallmark of most solid tumours, is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. Given its prominent role in oncology, accurate detection of hypoxia is important, as it impacts on prognosis and could influence treatment planning. A variety of approaches have been explored over the years for detecting and monitoring changes in hypoxia in tumours, including biological markers and noninvasive imaging techniques. Positron emission tomography (PET) is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. This review provides an overview of imaging hypoxia with PET, with an emphasis on the advantages and limitations of the currently available hypoxia radiotracers.
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Affiliation(s)
- I N Fleming
- Aberdeen Biomedical Imaging Centre, Lilian Sutton Building, Foresterhill, Aberdeen AB25 2ZD, UK
| | - R Manavaki
- Department of Radiology, School of Clinical Medicine, University of Cambridge, Box 218-Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
| | - P J Blower
- Division of Imaging Sciences and Biomedical Engineering, St Thomas' Hospital, King's College London, 4th Floor, Lambeth Wing, London SE1 7EH, UK
| | - C West
- Manchester Academic Health Science Centre, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
| | - K J Williams
- Manchester Pharmacy School, Faculty of Medical and Human Sciences, University Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
- EPSRC and CRUK Cancer Imaging Centre in Cambridge and Manchester, Cambridge, UK
| | - A L Harris
- Molecular Oncology Laboratories, University Department of Medical Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
| | - J Domarkas
- Centre for Cardiovascular and Metabolic Research, Respiratory Medicine, Hull-York Medical School, University of Hull, Hull HU16 5JQ, UK
| | - S Lord
- Molecular Oncology Laboratories, University Department of Medical Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
| | - C Baldry
- Division of Imaging Sciences and Biomedical Engineering, St Thomas' Hospital, King's College London, 4th Floor, Lambeth Wing, London SE1 7EH, UK
| | - F J Gilbert
- Department of Radiology, School of Clinical Medicine, University of Cambridge, Box 218-Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
- EPSRC and CRUK Cancer Imaging Centre in Cambridge and Manchester, Cambridge, UK
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Verwer EE, Boellaard R, Veldt AAMVD. Positron emission tomography to assess hypoxia and perfusion in lung cancer. World J Clin Oncol 2014; 5:824-844. [PMID: 25493221 PMCID: PMC4259945 DOI: 10.5306/wjco.v5.i5.824] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Revised: 04/29/2014] [Accepted: 07/15/2014] [Indexed: 02/06/2023] Open
Abstract
In lung cancer, tumor hypoxia is a characteristic feature, which is associated with a poor prognosis and resistance to both radiation therapy and chemotherapy. As the development of tumor hypoxia is associated with decreased perfusion, perfusion measurements provide more insight into the relation between hypoxia and perfusion in malignant tumors. Positron emission tomography (PET) is a highly sensitive nuclear imaging technique that is suited for non-invasive in vivo monitoring of dynamic processes including hypoxia and its associated parameter perfusion. The PET technique enables quantitative assessment of hypoxia and perfusion in tumors. To this end, consecutive PET scans can be performed in one scan session. Using different hypoxia tracers, PET imaging may provide insight into the prognostic significance of hypoxia and perfusion in lung cancer. In addition, PET studies may play an important role in various stages of personalized medicine, as these may help to select patients for specific treatments including radiation therapy, hypoxia modifying therapies, and antiangiogenic strategies. In addition, specific PET tracers can be applied for monitoring therapy. The present review provides an overview of the clinical applications of PET to measure hypoxia and perfusion in lung cancer. Available PET tracers and their characteristics as well as the applications of combined hypoxia and perfusion PET imaging are discussed.
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Bittner MI, Grosu AL. Hypoxia in Head and Neck Tumors: Characteristics and Development during Therapy. Front Oncol 2013; 3:223. [PMID: 24010122 PMCID: PMC3755323 DOI: 10.3389/fonc.2013.00223] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 08/13/2013] [Indexed: 11/23/2022] Open
Abstract
Cancers of the head and neck are a malignancy causing a considerable health burden. In head and neck cancer patients, tumor hypoxia has been shown to be an important predictor of response to therapy and outcome. Several imaging modalities can be used to determine the amount and localization of tumor hypoxia. Especially PET has been used in a number of studies analyzing this phenomenon. However, only few studies have reported the characteristics and development during (chemoradio-) therapy. Yet, the characterization of tumor hypoxia in the course of treatment is of great clinical importance. Successful delineation of hypoxic subvolumes could make an inclusion into radiation treatment planning feasible, where dose painting is hypothesized to improve the tumor control probability. So far, hypoxic subvolumes have been shown to undergo changes during therapy; in most cases, a reduction in tumor hypoxia can be seen, but there are also differing observations. In addition, the hypoxic subvolumes have mostly been described as geographically rather stable. However, studies specifically addressing these issues are needed to provide more data regarding these initial findings and the hypotheses connected with them.
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Maharjan S, Sharma P, Patel CD, Sharma DN, Dhull VS, Jain SK, Thulkar S, Malhotra A, Kumar R. Prospective evaluation of qualitative and quantitative ¹⁸F-FDG PET-CT parameters for predicting survival in recurrent carcinoma of the cervix. Nucl Med Commun 2013; 34:741-748. [PMID: 23676840 DOI: 10.1097/mnm.0b013e3283622f0d] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate the prognostic significance of qualitative and quantitative F-fluorodeoxyglucose (F-FDG) PET-computed tomography (PET-CT) parameters in patients with recurrent cervical carcinoma. METHODS Twenty-six patients (age: 44 ± 10.1 years) with histologically proven recurrent carcinoma of the cervix (squamous, 21; adenocarcinoma, five) were prospectively enrolled and they underwent F-FDG PET-CT before salvage therapy. The qualitative parameters included for analysis were vaginal involvement, regional nodal metastasis, and distant metastasis on PET-CT. The quantitative PET-CT parameters included were standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Cutoff values were determined using receiver operating characteristic curve analysis. A Kaplan-Meier analysis was carried out to compare survival among groups. Impact of PET-CT parameters on progression-free survival (PFS) and overall survival (OS) was evaluated using Cox proportional hazard regression. RESULTS On PET-CT, vaginal involvement was seen in 16 patients, regional nodal metastasis in 12 patients, and distant metastasis (node and lung) in 11 patients. The mean SUVmax was 6.8 ± 4, MTV was 8.2 ± 12.8 ml, and TLG was 49.6 ± 108.4 ml. On multivariate analysis, SUVmax of up to 4.9 [hazard ratio (HR): 0.026, confidence interval (CI): 0.002-0.268, P=0.002] and distant metastasis (HR: 18.88, CI: 2.14-166.24, P=0.008) were independent predictors of PFS. On multivariate analysis, SUVmax greater than 9 (HR: 19.25, CI: 2.15-172.17, P=0.008) and distant metastasis (HR: 33.88, CI: 2.17-526.61, P=0.012) were also independent predictors of OS. MTV, TLG, and regional node involvement evaluated using PET-CT were found to be significant on univariate analysis but not on multivariate analysis. CONCLUSION SUVmax and the presence of distant metastasis on F-FDG PET-CT are independent predictors of PFS and OS in patients with recurrent cervical carcinoma.
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Affiliation(s)
- Sagar Maharjan
- Departments of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
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