Rival hypoxia agents vie for premier treatment role

Two PET radiopharmaceuticals are competing to become the preferred noninvasive tools to identify the presence and extent of hypoxia. The state of diminished tissue oxygenation saps therapies of their cancer-killing powers, paving the way to disease progression and death.

Clinically relevant levels of hypoxia are detected in more than half of all solid tumors, regardless of their size and histopathological features, according to Dr. Farrokh Dehdashti, a professor of radiology at the Mallinckrodt Institute of Radiology in St. Lou is. Hypoxia is an infamously bad actor, known to activate angiogenesis, promote tumor progression and metastasis, and fend off therapy. An invasive device involving oxygen electrodes that directly measures pO2 was the method of choice for mapping hypoxia until the advent of noninvasive PET agents.

Dehdashti has investigated a radioactive copper-labeled probe, diacetyl-bis (N4-methylthiosemicarbazone), also known as ATSM. In vivo and in vitro animal studies have shown that copper-60 ATSM accumulates selectively in hypoxic cells, clears rapidly from the blood, and rapidly washes out of normoxic cells. It is well suited for pelvic organ imaging because of its minimal excretion by the urinary tract, according to Dehdashti. Cu-60 and Cu-64 are short-lived isotopes, however, that require an onsite cyclotron for practical administration.

The other probe, fluorine-18 fluoromisonidazole (FMISO), has been more thoroughly researched than ATSM, especially for head-and-neck cancers. It was developed and validated in the early 2000s by Dr. Kenneth A. Krohn and colleagues in the radiology department at the University of Washington. A positive accumulation of FMISO closely correlates with the extent of hypoxia. Its use of fluorine-18, a widely available positron-emitting isotope with a half-life of six hours, makes it a potentially practical choice for use in community-based hospitals.

Two separate American College of Radiology Imaging Network trials will help determine if one or both agents can be trusted to identify cancer patients who will respond poorly to radiotherapy.

In a written analysis, Dehdashti has faulted FMISO for its relatively poor contrast between hypoxic and normal tissue and poor clearance compared with ATSM. She noted that in vitro studies of tumor cells in culture have shown better uptake characteristics for ATSM than FMISO. In vitro studies of tumor cells in culture established that the uptake of Cu-64 ATSM correlates inversely with the oxygen concentrate of the medium.

ACRIN 6684 is a multicenter phase II assessment of tumor hypoxia in glioblastoma. Dr. A. Gregory Sorensen, director of the Center for Biomarkers in Imaging at Massachusetts General Hospital, is the principal investigator. The study of hypoxia associated with glioblastoma will aim at correlating the tumor-to-blood ratio of F-18 FMISO and hypoxic volume with a physiological MR parameter of Ktrans and cerebral blood volume and patient survival and disease progress over three years.