JUNE 2003

Angiogenesis reveals cancer

CT, MR, and PET all play roles

By: Paula Gould

For generations, a canary in a cage warned miners of the presence of poisonous gases while they still had time to dash to safety. Now, angiogenesis-the ability of cancers to produce blood vessels-is playing a similar role in oncology. Diagnostic tests measuring this cellular behavior show promise for faster diagnosis and earlier reports on the effectiveness of therapy.

A focus session at the 2003 European Congress of Radiology in March considered the roles that diagnostic imaging can potentially play.

Functional CT is a way to obtain accurate, reproducible data on tumor physiology that correlates well with angiogenic behavior, according to Dr. Ken Miles, an adjunct professor of medical physics at Queensland University of Technology in Brisbane, Australia. The protocol involves contrast-enhanced rapid scanning of the targeted site and pixel-by-pixel analysis of resulting data to map the tumor's functional behavior.

Semiquantitative parameters such as enhancement rate, peak tissue enhancement, and time to peak enhancement can be transformed into absolute physiological measurements, namely, perfusion and transfer time, Miles said. A standard perfusion value (SPV), which relates tumor perfusion to average whole-body perfusion, can then be used to track microvessel density, a known histological method of assessing angiogenesis. This is similar in concept to the standard uptake value (SUV) used to assess FDG uptake in PET studies. Calculation of SPV distinguishes genuine reductions in microvessel density from changes in cardiac output when monitoring tumor regression.

While some studies suggest a direct correlation between increased perfusion (or angiogenesis) and higher FDG uptake, the relationship may be more complex, Miles said. He showed an example of lung cancer in which SUV and SPV levels both increased up to stage III. At stage IV, however, the SUV/SPV ratio decreased, as the tumor became rapidly aggressive and perfusion levels correspondingly soared.

"It's also possible to hypothesize that a situation where we have a metabolic demand but very few blood vessels means that the tumor is supply-limited and, therefore, unable to be excessively metabolically active," he said. "The CT perfusion measurements combined with FDG-PET in one examination may give us a handle on some of these concepts."

Dynamic contrast-enhanced MRI (DCE-MRI) of angiogenesis can aid tumor localization and staging, according to Dr. Jelle Barentsz, a professor of radiology at Nijmegen University Hospital in the Netherlands. Using images of bladder, prostate, and breast cancer, Barentsz explained how DCE-MRI and MR spectroscopy can be combined in a signal imaging session to define tumors' metabolic and vascular characteristics. The combination can reveal a complete picture of functional anatomy, including information on vessel fusion and leakage.

"Microvessel density alone is not a reliable indicator of the outcome of chemotherapy. You should look also at the surface of the vessels, and not only in 2D, but in 3D too," he said.

MRI at 3T has potential for imaging tumor neovascularity because of its high spatial resolution and ability to distinguish enhancing tumor clearly from surrounding tissue, Barentsz said. The Nijmegen University group is investigating the ability of 3T MRI to characterize the vascularity of prostate cancers but has yet to publish results.

DCE-MRI techniques also factor into drug development, said Dr. Anwar Padhani, lead MRI researcher at the Paul Strickland Scanner Centre at Mount Vernon Hospital in Northwood, U.K. Tumor angiogenesis depends on internal secretion of chemicals that stimulate new blood vessel growth. Identification of angiogenic substances such as vascular endothelial growth factor (VEGF) has led to experimental drug treatments targeting tumor vascularity directly.

Proof-of-concept investigations at a number of U.K. centers have shown DCE-MR capable of quickly differentiating between pharmaceutical winners and losers, he said. In each study, patients receiving an escalating dose of an anti-VEGF drug underwent MR scanning before, shortly after, and a few weeks following each treatment session. Reduction of vascular permeability was taken as a marker of treatment efficacy and could also be used to determine the biologically active dose.

Data collection and analysis techniques must be standardized if DCE-MRI is to be used in larger scale antiangiogenic drug efficacy studies, Padhani said. Future investigations are likely to include a combination of cancer therapies and involve multicenter collaboration, making the establishment of quality assurance programs all the more important.