Volume 45, Number 2

March 2015

Guest Editorial


esearch into the detection and consequences of hypoxia in solid tumors continues to advance at a rapid pace and on multiple fronts. This collection of outstanding review articles presents the state-of-the-art development in both research and clinical settings while highlighting several areas of concordance and controversy in the field. Tumor hypoxia is defined at the molecular level as an insufficiency of molecular oxygen, and as such, its noninvasive visualization truly justifies the term “molecular imaging.” However, it is clear from the articles presented in this issue that the “concept” of tumor hypoxia can represent different things depending on one's viewpoint—hypoxia can be regarded as a biochemical, cellular, microregional, or a whole-tumor phenomenon, each with particular characteristics that influence the interpretation of the observations being made. For example, the article by Span and Bussink1 in this issue provides an excellent overview of the consequences of hypoxia at the metabolic, molecular, and cellular levels. This is a quickly moving field, providing frequent new insights into adaptive tumor biology and uncovering many potential targets for therapeutic intervention. The clinical potential of novel pharmaceutical treatments that target these largely tumor-specific cellular processes is huge, and noninvasive hypoxia imaging will certainly play an important future role in patient selection and management. It is essential, therefore, that the various imaging modalities be continually examined and refined to ensure that the underlying physiological processes are accurately reflected. The molecular response to hypoxia is both rapid and complex, creating the activation of a number of signal transduction pathways and gene regulatory mechanisms believed to those that select for aggressive and metastatic tumor cell genotypes. Although basic biology research is rapidly uncovering the molecular chain of events that lead to the resistant tumor phenotype, almost separately and in parallel, clinical researchers have sought methods to visualize and quantify hypoxia in clinical tumors for more than two decades. The early work with Eppendorf probes established a relationship between the number of hypoxic measurement points and the treatment outcome.2 Although Eppendorf probes allow direct point measurements of the partial oxygen 98

http://dx.doi.org/10.1053/j.semnuclmed.2014.10.007 0001-2998/& 2015 Elsevier Inc. All rights reserved.

pressure, they are difficult to use, require the tumor to be accessible to the probe, provide only a limited number of point measurements and normally need to be performed in the surgical setting. Nuclear imaging of hypoxia began with the pioneering work at the University of Washington,3 where a 20 nitroimidazole, misonidazole, was first labeled with fluorine18; misonidazole, having been used as oxygen-mimetic radio sensitizer in radiotherapy, trails at the time. Although misonidazole had been proven neurotoxic at therapeutic concentrations, the amount of radiolabeled misonidazole to image hypoxia required just tracer levels that are several orders of magnitude below those resulting in toxicity. Rajendran and Krohn are part of the University of Washington group that pioneered the field of hypoxia imaging, and in an article entitled “FMISO Imaging Tumor Hypoxia: Imaging the Microenvironment for Personalized Cancer Therapy,” they summarize the continuing importance of this radiotracer in nuclear medicine. Citing from their article “By virtue of extensive clinical utilization, FMISO remains the lead candidate for imaging and quantifying hypoxia,” Rajendran and Krohn4 provide a detailed description of the optimal properties required to be an ideal hypoxia radiotracer and demonstrate how the properties of fluoromisonidazole (FMISO) so aptly meet these requirements. These authors also state their preference for a simple reliable method for quantifying hypoxia using FMISO akin to the success of standardized uptake value (SUV) in FDG-PET scans and have made extensive efforts to define tumor-to-blood (or tumor to muscle) ratios that serve as thresholds to identify hypoxic tissue. Such operational threshold values provide an invaluable tool for hypoxia quantification and are the most widely used nuclear medicine approach to define a hypoxic tumor volume, as might be needed in the context of a resistant radiotherapy target subvolume. However, immunohistochemical (IHC) studies such as described by Span and Bussink1 do illustrate that every PET image voxel within a tumor contains an admixture of normoxic, hypoxic, and necrotic tissue and thus is not readily reduced to a binary “hypoxic” or “nonhypoxic” classification. Similarly, the detailed description of three different hypoxia “types” (chronic, cycling, and macroscopic regional) in the article by Koch and Evans5 provides a further physiological division of the hypoxic compartment, with the

Guest Editorial suggestion by the authors that “that the capability to independently measure blood flow is very important in dissecting ‘types’ of hypoxia.” Composite hypoxia-blood flow measurements such as this may become more common following the introduction of combined PET/MR scanners into the clinic, and there will be an increasing need for the validation of appropriate dual-modality metrics. Compartmental models that try to quantify the rate of irreversible trapping of the PET tracer may result in a more accurate estimation of tumor hypoxia, but at the cost of a considerable effort that does not lend itself to widespread use at the current time. Such models have highlighted example patients in which there exists contradictory information between hypoxic voxels defined by the threshold methods vs parametric maps of the rate of irreversible trapping (k3) derived from compartmental analysis. The key questions to be asked are: How often do these contradictions occur? Does the threshold method work in most cases to render the compartmental approach not worth the additional effort? More work clearly needs to be done to answer this question. The importance of getting the hypoxic tumor subvolume accurately contoured is highly relevant for radiotherapy dose painting as it may serve as a target for a radiotherapy boost. However, a number of other hypoxia management strategies such as carbogen breathing or hypoxia-activated prodrugs do not require accurate spatial definition of the hypoxic tumor subvolume. In these instances, a method to stratify patients according to whether they have more or less hypoxia may be all that is needed in patient selection to receive such treatment. However, as described by Span and Bussink,1 the quite distinct cellular responses observed at pO2 below 15, 10, and 1 mm Hg may ultimately govern response to these agents, and the role of hypoxia imaging in the context of treatment response evaluation remains to be fully established. Among the shortcomings of FMISO is the relatively poor contrast images achieved when compared with those with 18FFDG and has lead to the development of a wide range of alternate compounds for hypoxia imaging. The comprehensive review provided by Kumar et al6 describes the synthetic routes of a great number of nitroaromatic radiotracers developed for hypoxia imaging. The availability of a relatively large number of small-molecule hypoxia tracers developed for nuclear imaging presents many opportunities along with some difficulties. Although the diverse chemical characteristics of these compounds may potentially allow for fine-tuning of hypoxia selectivity or pharmacokinetic characteristics, the task of evaluating and comparing each, even using preclinical models, is challenging and costly, with no guarantee of a positive outcome. As a result, most studies have been conducted using only a few compounds (FMISO, copper (II) diacetyl-bis (N4)-methylthiosemicarbazone [Cu-ATSM], nitroimidazole [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentaflouropropyl) acetamide [EF5], or fluoroazomycin arabinoside [FAZA], each of which is given an expert, in-depth description in this issue), and only a handful of these directly compare different tracers side by side. The ability to

99 comparatively assess the properties of hypoxia tracers during their development would greatly benefit from the standardization of preclinical model systems and experimental methods. One chemical characteristic of the 20 -nitroimidazole compounds that has been studied in detail is the partition coefficient, which describes the relative hydrophilicity of the compound. This property governs many aspects of the in vivo behavior of the compound, including volume of distribution, routes of excretion and blood circulation time. Although the majority of 20 -nitroimidazole tracers are relatively hydrophilic, the trifluorinated and pentafluorinated nitroimidazole derivatives EF3 [2-(2-nitroimidazol-1H-yl)-N-(3,3,3-trifluoropropyl) acetamide] and EF5 are significantly more lipophilic. The specific properties and benefits of a lipophilic nitroimidazole tracer are well summarized by the developers of these compounds.5 Despite extensive clinical studies using unlabeled EF5 as an IHC hypoxia marker, the number of studies employing 18F-EF5-PET has grown relatively slowly, possibly due to the more demanding conditions required for radiofluorination resulting in restricted availability. However, Chitneni and colleagues7 have recently reported on a simplified synthesis of 18F-EF5, which may overcome this limitation and, combined with the general improvements in distribution of fluorinated radiopharmaceuticals, may increase the use of this tracer in a general clinical setting. One of the great advantages of the 2-(2-nitroimidazol-1H-yl)-N-(3,3,3-trifluoropropyl)acetamide or EF5 pair is the availability of antibodies for IHC detection of bioreduced adducts. After coadministration of 18Flabeled and cold compounds, this allows for direct comparison of PET data with those obtained from autoradiography and IHC using a chemically identical compound. A recent preclinical study from the group at Duke University has highlighted the benefits of such an approach in interpreting PET data.8 In the 1990s, a new hypoxia imaging agent emerged that was not one of the 20 -nitroimidazole family, Cu-ATSM that exhibited a high membrane permeability and low redox potential.9 The authors Lapi et al10 have been pioneers in exploring the clinical utility of Cu-ATSM and in their article summarizing the numerous clinical studies with this hypoxia radiotracer, not only for the detection of hypoxia in oncology but also in coronary artery disease and oxidative stress in neurologic disorders such as stroke and because of mitochondrial dysfunction in Parkinson disease. Enthusiasm for this hypoxia radiotracer is threefold: (1) the ability to select copper isotopes of differing half-lives, which includes the short-lived 60 Cu (23.4 minutes), 61Cu (3.4 hours), and 62Cu (9.7 minutes) and the longer-lived 64Cu (10.64 hours) allowing shipment of the radiotracer to hospitals not equipped within close proximity of a cyclotron, but also flexibility in the PET imaging time after injection, (2) the significantly high SUVs and tumorbackground ratios relative to the 20 -nitroimidazole radiotracers, and (3) the accumulation of clinical data suggesting a correlation between 64Cu-ATSM uptake and poor prognosis. The authors discuss the controversy surrounding the non– hypoxia-associated uptake of Cu-ATSM in certain tumor models, such as prostate cancer, a purported consequence of fatty acid synthase expression, and acknowledge the lack of

S. Carlin and J. Humm

100 universality of Cu-ATSM, or indeed any other single compound, as a tracer that is equally effective in all tumor types. The variable kinetics of Cu-ATSM uptake between tumor models both in vitro and in vivo suggests more studies are warranted to determine the mechanisms of Cu-ATSM uptake and metabolism. The high SUVs obtained with Cu-ATSM suggest an alternative mechanism of uptake that is not hypoxia related that could contribute to its apparent prognostic success. The high Cu-ATSM uptake values are a conundrum for the following reason. In vitro data from several tumor cell lines suggest both Cu-ATSM and the 20 -nitroimidazole radiotracers exhibit about an eightfold greater uptake under a pO2 of 0.5% oxygen (3.8 mm Hg) vs 20% oxygen. IHC study of human tumors suggests typical hypoxic fractions between 10% and 30%. Thus a 5  5  5 mm3 tumor volume, containing 20% hypoxia, would be expected to result in a corresponding PET voxel signal of 0.2  8 ¼ 1.4 relative to an entirely normoxic PET voxel. The study by McCall et al11 suggests a selective uptake of 64Cu-ATSM in tumor cells regardless of their hypoxia status relative to the normal tissue stroma that may account for the correlation between Cu-ATSM uptake and poor prognosis. The identification of robust IHC correlates of Cu-ATSM distribution would greatly aid in the interpretation of the behavior of this compound. Dhani et al in their article show that the clinical relevance of hypoxia in treatment response and its correlation to metastatic spread is indisputable in several cancers, which include those of the head and neck, cervix, prostate, pancreas, and possibly others. Their contribution provides a detailed summary of what they refer to as “observational studies,” in which measurement of tumor hypoxia was correlated with outcome, and “therapeutic studies,” in which the effect of hypoxiatargeted treatment on outcome is reviewed. Dhani et al highlight the emergence of hypoxia signatures from genomic analyses that may have the ability to separate patients into those who might benefit from hypoxia-targeted treatments and those who may not. The importance of imaging will remain; however, because of its potential ability to assess the heterogeneity of hypoxia throughout the patient's entire disease burden and its ability to study changes in hypoxia resulting from intervention as well as to track changes during and after treatment. The considerable effort invested in the development and investigation of hypoxia PET tracers is now coming to fruition in the clinic, and the growing number of hypoxia PET studies is well highlighted in this issue. The specific role of hypoxia imaging in patient stratification, treatment planning, and monitoring of response is becoming increasingly clear. An essential component of this role is the validation of noninvasive assessments at the microscopic level using patient-derived tissue specimens where possible, and clinical research protocols should aim to include this type of sampling as a matter of course. The routine coadministration of unlabeled nitroimidazole compounds (pimonidazole or EF5) as part of these

protocols would also provide a unique opportunity to simultaneously observe macroscopic and molecular events in the same patient. In conclusion, the field of hypoxia imaging can truly be seen as an outstanding example of the type of cross-disciplinary interaction required for successful translation of molecular imaging strategies. The articles presented in this issue together highlight what is achieved when broad expertise converges on a single goal and emphasize the benefits of an ongoing interaction between basic science, preclinical and clinical investigators. It is this interaction that will ensure that this unique hallmark of cancer is fully exploited in routine cancer treatment and management. Sean Carlin, PhD Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY John Humm, PhD Department of Radiology and Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY

References 1. Span PN, Bussink J: Biology of hypoxia. Semin Nucl Med 2014;45 (2):101-109 2. Hockel M, Knoop C, Schlenger K, et al: Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 1993;26 (1):45-50 3. Grunbaum Z, Freauff SJ, Krohn KA, et al: Synthesis and characterization of congeners of misonidazole for imaging hypoxia. J Nucl Med 1987;28 (1):68-75 4. Rajendran JG, Krohn KA: F-18 fluoromisonidazole for imaging tumor hypoxia: Imaging the microenvironment for personalized cancer therapy. Semin Nucl Med 2014;45(2):151-162 5. Koch CJ, Evans SM: Optimizing hypoxia detection and treatment strategies. Semin Nucl Med 2014;45(2):163-176 6. Kumar P, Bacchu V, Wiebe LI: The chemistry and radiochemistry of hypoxia-specific, radiohalogenated nitroaromatic imaging probes. Semin Nucl Med 2014;45(2):137-150 7. Chitneni SK, Bida GT, Dewhirst MW, et al: A simplified synthesis of the hypoxia imaging agent 2-(2-Nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-[18F] pentafluoropropyl)-acetamide ([18F]EF5). Nucl Med Biol 2012;39 (7):1012-1018 8. Chitneni SK, Bida GT, Zalutsky MR, et al: Comparison of the hypoxia PET tracer 18F-EF5 to immunohistochemical marker EF5 in 3 different human tumor xenograft models. J Nucl Med 2014;55(7):1192-1197 9. Fujibayashi Y, Taniuchi H, Yonekura Y, et al: Copper-62-ATSM: A new hypoxia imaging agent with high membrane permeability and low redox potential. J Nucl Med 1997;38(7):1155-1160 10. Lapi SE, Lewis JS, Dehdashti F: Evaluation of hypoxia with copper-labeled diacetyl-bis(N-methylthiosemicarbazone). Semin Nucl Med 2014;45(2): 177-185 11. McCall KC, Humm JL, Bartlett R, et al: Copper-64-diacetyl-bis(N(4)methylthiosemicarbazone) pharmacokinetics in FaDu xenograft tumors and correlation with microscopic markers of hypoxia. Int J Radiat Oncol Biol Phys 2012;84(3):e393-e399

Hypoxia imaging. Guest editorial.

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