F-18 fluoromisonidazole for imaging tumor hypoxia: imaging the microenvironment for personalized cancer therapy

Abstract

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.

Figure 1

In alive cells, the mitochondria are continually leaking electrons that are taken up by the terminal electron acceptor, O₂. In the absence of oxygen, a steady state concentration of the RNO₂ radical anion accumulates and, if reduced by a second electron, it becomes an alkylating agent and is retained in cells at a level inversely related to O₂ concentration. If O₂ is present in adequate concentration, the RN O₂ radical anion gives up its extra electron to the O₂ and is returned in a futile cycle to the original FMISO.

Figure 2

Hypothetical illustration with data from multiple cancers showing the possible scenarios in the correlation between hypoxia and glucose metabolism. Group I - low glucose metabolism and low hypoxia; Group II - low hypoxia and high glucose metabolism; Group III – high hypoxia and high glucose metabolism; Group IV – high hypoxia and low glucose metabolism. (Rajendran JG et al Clin Cancer Res 2004;10(7): 2245–52)

Figure 3

Possible approaches for utilizing information from tumor hypoxia imaging in the various phases in clinical management of solid tumors.

Figure 4

64 year old female patient with large base of tongue carcinoma with extension to anterior tongue. T:Bmax is 2.53 with HV of 110 cc.

Figure 5

69 year old male patient with glioblastoma in the left superior frontal lobe. T2 MR image shows the extent of the whole tumor (Solid red arrow) and FMISO PET image shows a more focal uptake of FMISO predominantly in the posterior and inferior aspect of the tumor (dashed arrow). Fuse image shows localization of hypoxic region within the tumor. Tissue:Blood max of 2.57 and Hypoxic Volume of 35.4cc.

Figure 6

38 year old female patient with Angiosarcoma of the left inguinal region. Axial PET image based on SUV (left) and T:B ratio (right) show FMISO uptake in the tumor and T:B max = 2.3 with Hypoxic Volume = 17.5cc

Figure 7

61 year old female patient with cancer of uterine cervix and a 7cm cervical mass – Solid arrow shows the tumor on CT image and dashed arrow shows areas of FMISO uptake within the tumor on PET image and fused image shows localization of hypoxic regions within the tumor. Max Tissue:Blood ratio = 2.00 with Hypoxic Volume 29.8cc.