F-18 Fluoromisonidazole for Imaging Tumor Hypoxia: Imaging the Microenvironment for Personalized Cancer Therapy

https://doi.org/10.1053/j.semnuclmed.2014.10.006Get rights and content

Hypoxia in solid tumors is one of the seminal mechanisms for developing aggressive trait and treatment resistance in solid tumors. This evolutionarily conserved biological mechanism along with derepression of cellular functions in cancer, although resulting in many challenges, provide us with opportunities to use these adversities to our advantage. Our ability to use molecular imaging to characterize therapeutic targets such as hypoxia and apply this information for therapeutic interventions is growing rapidly. Evaluation of hypoxia and its biological ramifications to effectively plan appropriate therapy that can overcome the cure-limiting effects of hypoxia provides an objective means for treatment selection and planning. Fluoromisonidazole (FMISO) continues to be the lead radiopharmaceutical in PET imaging for the evaluation, prognostication, and quantification of tumor hypoxia, one of the key elements of the tumor microenvironment. FMISO is less confounded by blood flow, and although the images have less contrast than FDG-PET, its uptake after 2 hours is an accurate reflection of inadequate regional oxygen partial pressure at the time of radiopharmaceutical administration. By virtue of extensive clinical utilization, FMISO remains the lead candidate for imaging and quantifying hypoxia. The past decade has seen significant technological advances in investigating hypoxia imaging in radiation treatment planning and in providing us with the ability to individualize radiation delivery and target volume coverage. The presence of widespread hypoxia in the tumor can be effectively targeted with a systemic hypoxic cell cytotoxin or other agents that are more effective with diminished oxygen partial pressure, either alone or in combination. Molecular imaging in general and hypoxia imaging in particular will likely become an important in vivo imaging biomarker of the future, complementing the traditional direct tissue sampling methods by providing a snap shot of a primary tumor and metastatic disease and in following treatment response and will serve as adjuncts to personalized therapy.

Introduction

Several novel targeted anticancer agents and modalities have been introduced for personalized cancer therapy, providing new opportunities for molecular imaging in localizing and characterizing targets. Molecular imaging has the potential to be an in vivo “biopsy” as it has the ability to noninvasively image the targets in primary and metastatic lesions in a snap-shot fashion.1 Intratumoral heterogeneity remains one of the major challenges facing personalized cancer therapy both in the identification of targets and instituting therapy against them. However, the ultimate goal of personalized therapy remains to achieve cure by blocking the multiple pathways of cancer development and proliferation.2 Hypoxia, one of the major microenvironmental factors, was described by Thomlinson and Gray in 1955 and still remains a stubborn and intriguing problem in cancer management.3 The dawn of molecular imaging coupled with the availability of an expanding array of molecular probes is augmenting the role of molecular medicine in the treatment of cancer.4 This is complemented by technological advances in radiation delivery such as intensity-modulated radiotherapy (IMRT) and the availability of novel therapeutic agents,5 making personalized cancer therapy a real possibility.6, 7, 8, 9, 10

Development of hypoxia in the tumor microenvironment is a dynamic process that is primarily dictated by abnormal vasculature and results in changes in metabolism and cellular proliferation. A clear understanding of the role of these processes and the interactions between them is important when considering personalized cancer therapy.4 Typically, focal areas of hypoxia develop in many solid tumors (generally in the center of the tumor) as they grow and because of direct consequences of unregulated cellular growth that results in a greater demand of oxygen (as well as other nutrients) for energy metabolism. Hypoxia response is one of the many derepression “atavistic” traits exhibited by multicellular organisms in an attempt to express primitive unicellular characteristics as a means of “cellular survivalism.”11 Cancer cells revert back to primitive protozoanlike functions that exist quiescently in any normal cell but can be derepressed by carcinogenic transformation. The ability to survive the lack of oxygen or hypoxia is one such trait, and hypoxia response itself is a characteristic prephotosynthesis biological trait when there was lack of molecular oxygen in the atmosphere; this response trait is evolutionarily highly conserved in nature, as exemplified by the stabilization mechanism of hypoxia-inducible factor (HIF)1α under hypoxic conditions.

Section snippets

Hypoxia-Induced Changes in Tumor Behavior

A number of hypoxia-related genes have been found to be responsible for the genomic changes, and associated downstream transcription factors have been identified,12, 13 for example, expression of endothelial cytokines such as vascular endothelial growth factor (VEGF) and signaling molecules such as IL-1, tumor necrosis factor (TNF) alpha, and transforming growth factor (TGF) beta, and selection of cells with mutated p53 expression14 and increased glucose transporter activity.15 The paradoxical

Hypoxia-Inducible Factor

The seminal mechanism for cellular oxygen sensing and response appears to be mediated by a heme-protein that uses O2 as a substrate to catalyze hydroxylation of proline in a segment of HIF1α,19, 20, 21 leading to its degradation. In the absence of O2, it survives and becomes an important transcription factor, regulating proteins that promote survival of There are hypoxia-directed therapies including reagents against HIF1α itself.18, 22, 23, 24

Tumor Hypoxia and Clinical Outcome

Negative influence of hypoxia on response to radiation therapy (XRT) has long been recognized by radiobiologists with the understanding that oxygen is necessary for “fixing,” in the sense of making permanent, the radiation-induced products in tissues.25 Clinical and laboratory experience indicate that it can take three times as much photon radiation dose to cause the same cytotoxic effect in hypoxic cells as in normoxic cells.26 Boost radiation to a hypoxic subvolume (HV) could be effectively

Hypoxia as a Prognostic Marker

Fluoromisonidazole (FMISO) uptake in a solid tumor reflects the degree of hypoxia and hence the changes affecting the biology of cancer. Noninvasively identifying tumors with significant hypoxia in the tumor microenvironment along with other molecular markers of tumor biology, aggressiveness, and treatment resistance, for example, glucose metabolism and cellular proliferation, will help us in selecting the appropriate therapy early in the process as a personalized approach.17, 56, 57, 58

PET has

Methods for Evaluating Hypoxia

Currently available assays for tumor hypoxia can be largely categorized as in vivo (invasive and noninvasive) or ex vivo (invasive biopsy).8, 59 To be clinically useful, an assay must distinguish normoxic regions from the ones that are hypoxic at a level relevant to cancer—oxygen partial pressure (PO2) in the 5 mm Hg range. Beginning with clinical evaluation and polarographic electrode measurements, several methods of evaluation have been attempted but they all have been shown to have weaknesses

Heterogeneity Issues

Spatial heterogeneity in the distribution of hypoxia requires an assay that provides locoregional evaluation of the tumor in its entirety. Hypoxia that is heterogeneously distributed should benefit from a differential delivery of radiation dose to a subvolume by dose painting based on semiquantitative measures of hypoxia and radiosensitivity maps.39, 62, 63 Imaging, in general and PET in particular, has all of these advantages to overcome these limitations and to be effectively used in the

FMISO History

Hypoxia imaging was developed in our laboratory as an outgrowth of the development of radiosensitizers, which were pioneered in the 1970s to improve response of tumors to XRT.64 Radiation oncologists were searching for a compound that was not consumed like O2 and could therefore diffuse farther than O2 and radiosensitize the poorly perfused hypoxic cells.65, 66 This oxygen mimetic might reach tissue regions where PO2 was insufficient to elicit the maximal cytotoxic effect of ionizing radiation.

The Hypoxia-Glucose Metabolism Connection

Increased glucose metabolism in cancer because of aerobic glucolysis, the “Warburg effect,” is ubiquitous and has a major role in clinical oncologic imaging using F-18 FDG-PET tracer. Anerobic glycolysis can also occur and so FDG has also been suggested as an indirect marker for hypoxia.87 Because glucose metabolism is increased in cancer cells even in the presence of oxygen, FDG should not be as accurate as FMISO in reflecting the degree of tumor hypoxia. As FMISO and FDG look at two

Robust Quantification for Clinical Use

Although the tumor-to-background ratio image does not show high contrast, this does not compromise image interpretation. Hypoxia images can be interpreted in several ways, both qualitatively or quantitatively. Qualitative interpretations have been used with a scoring system to grade the uptake in a tumor compared with adjacent normal tissue.41 After extensive validation studies, we have preferred a simple but accurate quantitation method using a venous blood sample drawn during the imaging

Clinical Applications of FMISO

After extensive preclinical and clinical trials, FMISO has remained as the most highly investigated and used PET tracer for the evaluation of tumor hypoxia. Pretherapy hypoxia and FMISO uptake in predicting prognosis has been confirmed in several human studies—glioblastoma multiforme, head and neck cancer,53, 56, 58, 101, 102 lung cancer,103, 104 breast cancer,105 pancreatic cancer,9 gynecologic cancers—cervical cancer,106 and sarcoma,107 as demonstrated in the following images (Figure 4,

Summary

Our ability to use molecular imaging to characterize therapeutic targets and apply this information for therapeutic interventions is growing rapidly.40, 42, 94, 108, 109 Evaluation of hypoxia and its biological ramifications to effectively plan appropriate therapy that can overcome the cure-limiting effects of hypoxia provides an objective means for treatment selection and planning. FMISO-PET imaging of tumor hypoxia continues to be the lead radiopharmaceutical for the evaluation,

Acknowledgments

We thank Ms Lanell Peterson for her help in preparing this manuscript and numerous colleagues who have been active in developing hypoxia imaging.

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