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.

A preliminary trial involving 22 glioblastoma patients at the University of Washington confirmed suspicions about the diminished success of radiotherapy when hypoxia permeates a glioblastoma tumor. Tissue was defined as hypoxic when the tumor-to-blood ratio of FMISO uptake was more than 1.2. The study, published in the May 2008 issue of Clinical Cancer Research, found that the presence of hypoxia before radiotherapy was associated with shorter tumor time to progression and patient survival.

ACRIN 6682 is a phase II trial of Cu-64 ATSM-PET/CT assessment of tumor hypoxia in cervical cancer. Dehdashti is the principal investigator. The prospective multicenter trial will assess the relationship between Cu-64 ATSM uptake in the primary cervical tumor and progression-free survival after chemoradiotherapy. One hundred women with invasive squamous cell cervical cancer who are scheduled to undergo radiation therapy and concurrent cisplatin chemotherapy will be examined.

Dehdashti published results of a preliminary study describing experience with 38 patients in 2008 (JNM 2008;49:210). Pretherapy Cu-60 ATSM-PET was performed, measuring tumor-to-muscle ratio before radiotherapy with chemotherapy follow-up in some cases. The response to therapy was followed for up to 79 months.

Hypoxia, measured with ATSM, had a dramatic effect on patient survival. More than 70% of patients with normoxic tumors, having an ATSM tumor-to-muscle ratio of less than 3.5, experienced progression-free survival in the 48 months after therapy. In contrast, only 30% of patients harboring hypoxic tumors, with a T/M ratio of more than 3.5, had not seen their cancers progress in the four-year period.

Cu-60 ATSM-PET has also shown promise in predicting the response and survival of patients undergoing neoadjuvant chemoradiation for advanced renal cancer. A pilot study, led by Dr. David Dietz at The Cleveland Clinic, suggests that ATSM-PET may be able to predict the response to neoadjuvant therapy before it is given. This could allow for tailoring treatment to the patient by perhaps directing likely nonresponders to clinical trials designed to increase the efficacy of standard rotational conformal radio-therapy, according to the authors.

Despite steady progress, both agents remain at a preliminary point in their development, according to Dr. Barry Siegel, chief of the nuclear medicine division at Mallinckrodt.

“We have a way to go, but we are on a path to having a hypoxia-imaging agent in clinical practice eventually,” he said.