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, 18F-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.
1. Rajendran JG, Mankoff DA, O'Sullivan F, et al: Hypoxia and glucose metabolism in malignant tumors: evaluation by [F-18]fluoromisonidazole and [F-18]fluoro-deoxyglucose positron emission tomography imaging. Clin Cancer Res 10:2245-2252, 2004.
2. Dehdashti F, Grigsby PW, Mintun MA, et al: Assessing tumor hypoxia in cervical cancer by positron emission tomography with [Cu-60] Cu-ATSM: Relationship to therapeutic response-a preliminary report. Int J Radiat Oncol Biol Phys 55:1233-1238, 2003.
3. Rajendran JG, Schwartz DL, O'Sullivan J, et al: Tumor hypoxia imaging with [F-18] FMISO PET in head and neck cancer. Clin Cancer Res 12:5435-5441, 2006.
4. Mayer A, Hockel M, Vaupel P: Endogenous hypoxia markers in locally advanced cancers of the uterine cervix: Reality or wishful thinking? Strahlenther Onkol 182:501-510, 2006.
5. Ling CC, Humm J, Larson S, et al: Towards multidimensional radiotherapy (MD-CRT): Biological imaging and biological conformality. Int J Radiat Oncol Biol Phys 47:551-560, 2000.
6. Brown JM: Exploiting the hypoxic cancer cell: Mechanisms and therapeutic strategies. Mol Med Today 6:157-162, 2000.