The role of hypoxia as a key determinant of outcome for human cancers has encouraged efforts to noninvasively detect and localize regions of poor oxygenation in tumors. In this review, we will summarize existing and developing techniques for imaging tumoral hypoxia. A brief review of the biology of tumor oxygenation and its effect on tumor cells will be provided initially. We will then describe existing methods for measurement of tissue oxygenation status. An overview of emerging molecular imaging techniques based on radiolabeled hypoxic markers such as misonidazole or hypoxia-related genes and proteins will then be given, and the usefulness of these approaches toward targeting hypoxia directly will be assessed. Finally, we will evaluate the clinical potential of oxygen- and molecular-specific techniques for imaging hypoxia, and discuss how these methods will individually and collectively advance oncology.
The problem of tumoral hypoxia and hypoxic cells has been recognized for more than a half-century. Likewise, its negative influence on patient outcome and the prognostic significance of hypoxia markers have been established. Clinical prognostic methods such as tumor size, stage, and the presence of anemia have not been effective predictors of hypoxia and its negative influence on patient outcome, necessitating more specific methods to evaluate hypoxia that go beyond the clinically used nonspecific imaging methods (eg, 18F-fluorodeoxyglucose positron-emission tomography [FDG-PET]).[1,2]
Due largely to recent technologic advances, noninvasive methods including molecular imaging are being actively studied and promise to build on the foundation laid by earlier invasive hypoxia-imaging methods. After extensive validation,
F-fluoromisonidazole (FMISO)-PET remains one of the most widely used noninvasive methods for the evaluation of hypoxia. The availability of scanners combining PET and computed tomography (CT) has further strengthened the role of this technique in clinical practice.
Explosive Growth in Understanding
Most earlier attempts to overcome the cure-limiting ability of hypoxia focused on the "oxygen effect," and in using methods such as altered fractionation, non-oxygen-dependent radiation, and/or radiosensitizers. However, an explosive growth in our understanding of the biology of hypoxia response will help us go beyond just evaluating the microenvironment, and should enable us to explore new opportunities for targeted therapies.
For example, elucidation of hypoxia-inducible factor (HIF)-1-alpha as the primary factor that controls other downstream factors in cellular hypoxia response has opened up new opportunities. In order to address issues with heterogeneity in hypoxia as well as hypoxia response within or between tumors, an ideal method should be able to image the entire tumor and regional disease, quantify in a repeated fashion, and differentiate from other confounding factors such as blood flow.
Several reports suggest that the varying ability of HIF-1-alpha overexpression to predict prognosis and patient outcome is largely tissue-type-and organ-specific. In addition, HIF-1-alpha stabilization is known to occur under normoxic conditions (eg, in renal cell carcinoma), which further complicates prognostic assessment. These reports suggest that exogenous (eg, pO2 or hypoxia measurement) and endogenous (eg, HIF-1-alpha, carbonic anhydrase [CA] IX) markers of hypoxia look at different aspects of the same process and that they are complementary in nature. All these parameters should be evaluated for the individual patient to maximize the predictive ability for hypoxia.
Currently, immunohistochemistry is commonly used to evaluate the expression of endogenous hypoxia markers on biopsy samples, but heterogeneity in expression can result in sampling errors. In vivo imaging of these markers will have the potential to evaluate the entire tumor and metastatic disease in snapshot fashion. Evaluating and or targeting just one of the pathways or one aspect of the microenvironment will likely not result in a successful outcome, whereas targeting multiple pathways will have a greater chance of success. This is because the various pathways and processes in the cancer cells are interconnected and strongly influenced by microenvironmental factors, including but not limited to hypoxia.
Targeted therapy with anti-HIF-1-alpha or anti-CA IX molecules or antibodies is an attractive proposition, but the limitations of this method need to be considered. What will be the toxic effect of such drugs on normal cells, given the ubiquitous presence of both HIF-1-alpha and CA IX in the body? Targeting HIF by blocking its effect can be a double-edged sword, likely with pronounced toxicities on vital normal organs such as the heart and brain, which require HIF action to survive hypoxia-related damage secondary to ischemia.
Radioimmunotherapy has the following drawbacks: (a) intratumoral heterogeneity in HIF-1-alpha expression, (b) compromised blood supply to the tumor itself, coupled with poor antibody penetration, resulting in reduced delivery of the radioimmunoconjugate, and (c) the historic lack of success of radioimmunotherapy in solid tumors. Some of these challenges can be circumvented by using smaller molecules/fragments or novel targeting methods and by combining conventional therapies with novel therapies. Nevertheless, opportunities provided by these compounds that target HIF or CA IX deserve further investigations to establish their roles in clinical cancer management.
The real strength of molecular imaging is in our ability to identify vital cellular pathways as well as evaluate the tumor microenvironment, and to use that information in a collective fashion to tailor therapy for the individual patient. The concept of biologic target volume that would incorporate the phenotypic information obtained from several such molecular methods (eg, PET, magnetic resonance imaging) was introduced a few years ago in connection with solid tumor radiation therapy. This should go beyond just the physical transfer of biologic information to radiation treatment planning images.
Radiation therapy will continue to play a key role in the management of several solid tumors and will retain the ability to escalate dose to hypoxic subvolumes (within the limits of clinically achievable dose levels). In this process, it will be helped by hypoxia-specific drug therapy that includes hypoxic cell cytotoxins and anti-HIF-1-alpha or anti-CA IX agents. To be successful, hypoxia therapy should target multiple pathways of hypoxia response as well as the microenvironment by using multiple modalities to overcome the cure-limiting ability of hypoxia.
Graves et al have reviewed the problem of tumor hypoxia and the biology of hypoxia response. They have summarized available methods to evaluate hypoxia and described techniques that will go beyond imaging. The future of cancer management will depend not only on our ability to characterize the microenvironment but also on the biology of cancer cells, including the genotype, phenotype, and, more importantly, the host (ie, the patient). The next step will be to apply that information to select and tailor treatment that will result in the optimal therapeutic ratio for individual patients.
Joseph G. Rajendran, MD
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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