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• W3213307083 abstract "HomeRadiologyVol. 302, No. 2 PreviousNext Reviews and CommentaryFree AccessEditorialThe Lung-to-Tumor Interface for the Evaluation of Tumor HypoxiaDavid J. Murphy , David T. RyanDavid J. Murphy , David T. RyanAuthor AffiliationsFrom the Department of Radiology, St Vincent’s University Hospital, Dublin, Ireland.Address correspondence to D.J.M. (e-mail: [email protected]).David J. Murphy David T. RyanPublished Online:Nov 16 2021https://doi.org/10.1148/radiol.2021211926MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In See also the article by Dewaguet et al in this issue.Dr David J. Murphy is a consultant radiologist specializing in cardiothoracic and PET imaging in the Department of Radiology, St Vincent’s University Hospital and an associate clinical professor of radiology in University College Dublin in Dublin, Ireland. His main research interests are in quantitative CT and MRI evaluation of thoracic malignancies, interstitial lung disease, diffuse cystic lung disease, inflammatory cardiomyopathies, and nonmalignant cardiothoracic applications of PET.Download as PowerPointOpen in Image Viewer Dr David T. Ryan is a 4th-year radiology resident in the Department of Radiology, St Vincent’s University Hospital, Dublin, Ireland. His main areas of interest include musculoskeletal and cardiothoracic imaging, with a special focus on interventional techniques along with research in cardiac MRI and radiomics.Download as PowerPointOpen in Image Viewer The treatment of non–small cell lung cancer (NSCLC) is on the basis of combinations of surgery, chemotherapy, radiation therapy, and targeted therapies. Treatment failure is a major problem in NSCLC, and tumor hypoxia is one of the driving forces of treatment failure. The rapid and uncontrolled growth of solid tumors leads to imbalances between oxygen supply and consumption, which often exhibits substantial temporal variability (intermittent/cycling hypoxia). The resulting hypoxia promotes an alternate means of energy production via anaerobic glycolysis.Hypoxia has an aggressive effect on the tumor microenvironment, promoting genomic instability, further abnormal proliferation, enhanced local invasion, and new blood vessel formation (1). This environment of altered gene expression can ultimately promote metastatic spread and confer therapy resistance (2). Hypoxia is also an attractive therapeutic target if successfully exploited because it is almost only found in cancer cells, giving it a favorable therapeutic ratio. Identifying hypoxic tumors allows recognition of more aggressive lung cancers and may eventually inform therapeutic decision making. Accurate identification of hypoxic tumors with noninvasive imaging is currently difficult because of the complexity of the tumor microenvironment.In this issue of Radiology, Dewaguet et al (3) reported on the use of dual-energy CT (DECT) perfusion to assess for tumor hypoxia in NSCLC, with a particular emphasis on the perfusion profile of the invading tumor front. This is the outer layer of the tumor at the interface with surrounding lung parenchyma and is a part of the tumor that demonstrates active endothelial proliferation. This prospective study examined tumor perfusion in 49 patients with NSCLC (37 adenocarcinomas, 12 squamous cell carcinomas) before surgical resection by using a dual-phase DECT protocol. Resected pathologic specimens were examined for expression of a marker of tumor hypoxia, membranous carbonic anhydrase (mCA) IX. Tumor perfusion was evaluated at DECT by measuring iodine concentration and normalized iodine uptake at both first pass and on delayed-phase acquisitions throughout the tumor as a whole and in three 2-mm-thick peripheral layers that were automatically segmented by proprietary software. These three layers encompassed the rim of the lung parenchyma surrounding the tumor, the intermediate rim at the frontier between the tumor and the lung parenchyma (the invading tumor front), and the most peripheral rim of the tumor. Comparisons of iodine concentration between the two DECT phases were used to profile tumor neovascularization as either functional or nonfunctional. If the iodine concentration value on the delayed phase was greater than that at the first pass, the neovascularization was classified as nonfunctional (ie, composed of porous vessels), and the converse pattern was deemed functional neovascularization.Thirty-three tumors (67%) were positive for mCA IX (hypoxic), with no differences between adenocarcinomas and squamous cell carcinomas. At the DECT perfusion analysis, at the level of the invading tumor front, the iodine concentration and normalized iodine uptake were higher on the first-pass acquisitions of mCA IX–positive NSCLCs compared with mCA IX–negative tumors (0.53 vs 0.21 mg/mL and 0.04 vs 0.02 mg/mL, respectively; P = .03 for both). Delayed iodine concentration in the central part of the tumors was higher in mCA IX–negative tumors (1.68 vs 1.28 mg/mL; P = .02). Otherwise, there were no differences in iodine concentration and normalized iodine uptake between hypoxic and nonhypoxic NSCLCs in the tumor as a whole or in the outer or inner peripheral layers. Twenty-nine tumors (59%) exhibited a profile of functional neovascularization at the invasive tumor front. These tumors had a higher median mCA IX score than NSCLCs with a nonfunctional neovascularization profile (P = .03). 70% of hypoxic tumors exhibited a functional neovascularization profile at this intermediate rim, compared with 40% of nonhypoxic tumors (P = .05). These findings suggest that hypoxic NSCLCs have a greater proliferation of new blood vessels at the level of the invading tumor front than nonhypoxic tumors and that this neovascularization tends to be composed of well-formed capillaries.Perfusion-based imaging, in the form of dynamic contrast-enhanced (DCE) CT, has been previously assessed as a noninvasive indirect marker of tumor hypoxia. DCE CT tumor perfusion studies have shown that increases in regional tumor blood volume and permeability surface area occur as the tumor adapts to a hypoxic microenvironment. Therefore, comparisons of regional tumor blood flow and blood volume measurements may serve as a surrogate marker of tumor hypoxia (4). However, DCE CT perfusion has generally failed to transition from trials to routine clinical use. The reasons behind this are likely related to several factors, including a lack of standardization of techniques across different vendors and relatively high radiation dose and breathing-related artifacts because of the multiple sequential CT acquisitions required. The method used by Dewaguet et al (3) is on the basis of a similar principle to DCE CT, with tumor perfusion as an indirect marker of hypoxia. This technique measures perfusion by quantifying tumor iodine concentration at two points from iodine maps generated with DECT by using the material decomposition principle. This two-phase DECT protocol is straightforward to perform and does not have the same radiation dose penalty as earlier DCE CT techniques. The first-pass CT acquisition measures maximal tumor arterial perfusion and the 50-second delayed-phase measures contrast agent leak from tumor neovasculature into the interstitium. Of the measurements performed, normalized iodine uptake standardizes the iodine concentration measured within a volume to the iodine concentration in the aorta. This makes it the more robust and reproducible measurement of iodine content because it helps correct for differences in scan timing, cardiovascular status, and administered contrast agent dose.Previous DECT perfusion studies in NSCLC have shown usefulness in assessing tumor grade (5) and local tumor invasion (6). Li et al (7) found a correlation between lung cancer microvessel density, a marker of neoangiogenesis, and both iodine concentration and normalized iodine concentration at DECT perfusion, with a significant association between iodine concentration on the venous phase and both tumor grade and necrosis. Interestingly, these parameters were not associated with nodal metastasis or TNM stage at the time of diagnosis. DECT perfusion has also been evaluated in NSCLC treatment response assessment; Baxa et al (8) measured whole-tumor vascularity in patients with NSCLC on anti–epidermal growth factor receptor–targeted therapy by using DECT perfusion, demonstrating that treatment responders showed a reduction in overall tumor vascularity. These lung cancer DECT perfusion studies evaluated perfusion by considering the tumor as a whole single homogenous entity, but we know that this does not often reflect tumor biology. NSCLCs are complex, heterogeneous biologic environments. Therefore, the approach taken in the study by Dewaguet et al (3) to subdivide tumors into distinct central and distinct peripheral zones enables an evaluation of regional tumor perfusion that is likely to be more representative of underlying tumor biology. Their results demonstrate differences in tumor perfusion and profile of neoangiogenesis at the invading tumor front between hypoxic and nonhypoxic NSCLCs. This is an important advance in our knowledge because it begins to provide an insight into the biology of probably the most active portion of the invading lung cancer.There are a number of unanswered questions that merit further exploration. The authors performed DECT with a dual-source DECT system from a single vendor. Validation of this technique would therefore need to be performed with other available DECT systems from different vendors. As an exploratory study, Dewaguet et al (3) only included patients with operable NSCLC. However, the type of tumor perfusion and hypoxia evaluation discussed in the study is most likely to be beneficial in treatment decisions for patients with inoperable disease. Therefore, any future studies should focus on patients with inoperable NSCLC, preferentially by encompassing different centers and including all NSCLC histologic subtypes. We also do not know the prognostic significance of characteristics at the invading tumor front because this was not evaluated with DECT perfusion, which would be of interest in future projects. CT is not the only noninvasive imaging technique that may depict tumor hypoxia. Oxygen-enhanced MRI techniques (9) and hypoxia-specific PET tracers, such as nitroimidazole-based fluorine 18–labeled radiotracers (10), have shown efficacy in depicting tumor hypoxia. However, widespread use of both of these modalities for tumor hypoxia evaluation is currently limited by cost, availability, and the level of expertise required. It would be interesting to evaluate how DECT perfusion performs relative to MRI or PET as a noninvasive marker of lung tumor hypoxia. However, given its widespread availability, any CT technique that provides clinically relevant information regarding tumor biology should be explored. Nearly every patient with lung cancer who chooses to be treated will undergo CT at some point in their clinical course. Advancing the assessment that radiologists can offer beyond morphologic structure into tumor biology will hopefully advance patient care.Disclosures of Conflicts of Interest: D.J.M. No relevant relationships. D.T.R. No relevant relationships.References1. Salem A, Asselin MC, Reymen B, et al. Targeting Hypoxia to Improve Non-Small Cell Lung Cancer Outcome. J Natl Cancer Inst 2018;110(1)14–30. Crossref, Google Scholar2. Ziółkowska-Suchanek I. Mimicking Tumor Hypoxia in Non-Small Cell Lung Cancer Employing Three-Dimensional In Vitro Models. Cells 2021;10(1):141. Crossref, Medline, Google Scholar3. Dewaguet J, Copin MC, Duhamel A, et al. Dual-Energy CT Perfusion of Invasive Tumor Front in Non–Small Cell Lung Cancers. Radiology 2021. https://doi.org/10.1148/radiol.2021210600. Published online November 16, 2021. Link, Google Scholar4. Miles KA, Lee TY, Goh V, et al. Current status and guidelines for the assessment of tumour vascular support with dynamic contrast-enhanced computed tomography. Eur Radiol 2012;22(7):1430–1441. Crossref, Medline, Google Scholar5. Iwano S, Ito R, Umakoshi H, Ito S, Naganawa S. Evaluation of lung cancer by enhanced dual-energy CT: association between three-dimensional iodine concentration and tumour differentiation. Br J Radiol 2015;88(1055):20150224. Crossref, Medline, Google Scholar6. Shimamoto H, Iwano S, Umakoshi H, Kawaguchi K, Naganawa S. Evaluation of locoregional invasiveness of small-sized non-small cell lung cancers by enhanced dual-energy computed tomography. Cancer Imaging 2016;16(1):18. Crossref, Medline, Google Scholar7. Li Q, Li X, Li XY, Huo JW, Lv FJ, Luo TY. Spectral CT in Lung Cancer: Usefulness of Iodine Concentration for Evaluation of Tumor Angiogenesis and Prognosis. AJR Am J Roentgenol 2020;215(3):595–602. Crossref, Medline, Google Scholar8. Baxa J, Matouskova T, Krakorova G, et al. Dual-Phase Dual-Energy CT in Patients Treated with Erlotinib for Advanced Non-Small Cell Lung Cancer: Possible Benefits of Iodine Quantification in Response Assessment. Eur Radiol 2016;26(8):2828–2836. Crossref, Medline, Google Scholar9. O’Connor JPB, Robinson SP, Waterton JC. Imaging tumour hypoxia with oxygen-enhanced MRI and BOLD MRI. Br J Radiol 2019;92(1095):20180642. Crossref, Medline, Google Scholar10. Peeters SGJA, Zegers CML, Lieuwes NG, et al. A comparative study of the hypoxia PET tracers [18F]HX4, [18F]FAZA, and [18F]FMISO in a preclinical tumor model. Int J Radiat Oncol Biol Phys 2015;91(2):351–359. Crossref, Medline, Google ScholarArticle HistoryReceived: July 29 2021Revision requested: Aug 11 2021Revision received: Aug 13 2021Accepted: Aug 16 2021Published online: Nov 16 2021Published in print: Feb 2022 FiguresReferencesRelatedDetailsAccompanying This ArticleDual-Energy CT Perfusion of Invasive Tumor Front in Non–Small Cell Lung CancersNov 16 2021RadiologyRecommended Articles Dual-Energy CT Perfusion of Invasive Tumor Front in Non–Small Cell Lung CancersRadiology2021Volume: 302Issue: 2pp. 448-456Pseudoprogression during Immune Checkpoint Inhibitor Therapy for Solid Tumors: Clarity Amidst Rapid EvolutionRadiology2020Volume: 297Issue: 1pp. 97-98Pulmonary Functional Imaging: Part 2—State-of-the-Art Clinical Applications and Opportunities for Improved Patient CareRadiology2021Volume: 299Issue: 3pp. 524-538Advances in Thoracic Imaging: Key Developments in the Past Decade and Future DirectionsRadiology2023Volume: 306Issue: 2Is the Cyst-Airway Communicating Index a Possible Tool to Differentiate Cystic Lung Diseases?Radiology: Cardiothoracic Imaging2020Volume: 2Issue: 2See More RSNA Education Exhibits Pitfalls in Interpreting FDG PET Findings Related to Lung Cancer Except StagingDigital Posters2020Spectral CT in Cardiothoracic Imaging: Potential Applications that Radiologists Should KnowDigital Posters2022Wait, You Can See Motion on Chest Radiographs?! 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