Hypoxia Imaging in Oncology
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In cancer patients, tumor cells can become hypoxic, adapting and up-regulating protein production for survival. Hypoxic cells are clinically problematic and tend to be less responsive to standard treatment regimens. The development of an imaging biomarker that selectively identifies hypoxic tumor cells could help radiation oncologists tailor specific treatment options to most efficiently manage this condition.
Clinical Significance
The current hypothesis indicates that hypoxic tissue is more resistant to radiation therapy and chemotherapy. Thus, by identifying tumor entities with high hypoxia fraction, a physician might be able to predict lower sensitivity to radio- and/or chemotherapy, according to Markus Schwaiger, MD, professor of nuclear medicine, at the Technische Universität Munich in Germany. “To overcome these limitations, you could select higher radiation dose based on the areas identified as hypoxic, or if you have proof that there is no significant hypoxia in a given tumor, then standard therapy may provide good results,” he says.
Currently, hypoxia imaging is focused on studying how reproducible these measurements are and how hypoxic regions are affected by therapy, questioning whether starting radiation therapy will increase hypoxic areas or whether it will generate inflammation, which will increase perfusion and tumor growth. It can be used to modify therapy based upon the individual biology of the patient and the tumor, which may lead to improved therapy outcomes. For example, if a tumor has hypoxic areas and a higher radiation dose is given, and a second image shows the tissue has been destroyed, then the therapy has been successful.
“It is a very complex interplay of many biological processes of which hypoxia is only one aspect,” Schwaiger adds. In the overall process, he says the hope of the imaging community is to learn more about the best timing of hypoxic imaging, since most groups apply hypoxia imaging prior to therapy as a prognostic marker. “However, I anticipate that in the future, there will be protocols for longitudinal hypoxia assessment in the tumor as a response marker.”
Currently, there are several clinical trials ongoing that are evaluating hypoxic markers with different compounds; however, Schwaiger says it is really a task for the molecular imaging community to use all the preclinical data to select the best hypoxic marker and use this marker prospectively in a clinical setting.
“There are a number of tracers currently available and each group believes they have the best one, but we haven’t had much direct comparison of the compounds in a comparable situation, which is needed,” he adds.
New hypoxia imaging biomarkers
Hypoxia imaging is of great interest to researchers, and new biomarkers are in development to provide much more specific, biological information about tumor cell growth. One of the first PET tracers that has been developed to assess hypoxia, F-MISO (18 F-fluoromisonidazol), directly correlates with the amount of oxygen in tumor tissue. However, the agent has some limitations, specifically in that it is slow to clear, increasing the wait time to image patients, and with a low signal uptake, it produces poor contrast and images that are hard to read.
With new biomarkers that do a better job of determining whether the tumor is hypoxic, you can gain insight into the biological characteristics of the tumor to create more personalized treatment plans for the patient such as increased radiation therapy dose, dose painting or even use chemotherapy drugs that are activated by hypoxia, says Hartmuth Kolb, PhD, vice president of Siemens Healthcare Biomarker Research.
F-MISO is retained mainly inside hypoxic cells and it has been tested, for example, in brain cancer and lung cancer patients. “F-MISO is the front runner, but it has problems,” Kolb says. “You have to wait 2 to 3 hours post injection to image, because it clears too slowly.”
HX4, a new imaging biomarker developed at Siemens’ Biomarker Research, is like F-MISO, but has a faster clearance time. In a recent trial evaluating the efficacy and safety in humans for the new agent, the compound was found to be stable for imaging at 145 minutes post injection, safely cleared the body through urinary elimination and had very low dose accumulations in major organs. The HX4 imaging biomarker is intended for world-wide distribution by PETNET Solutions, a wholly owned Siemens subsidiary.
Another approach to hypoxia imaging is to target the cell surface protein, carbonic anhydrase IX that is produced in response to low oxygen tension and is linked to poor survival. Pinpointing hypoxic regions in tumors more resistant to radiation will allow oncologists to increase the radiation dose to these areas, potentially reducing the likelihood of recurrent disease.
The promise for the future
In discussing specific biomarkers for molecular imaging of processes like hypoxia, the data must be examined in context with morphology. “Right now, PET/CT is a clinically accepted tool for imaging oncologic patients. Where you can gain is to use CT for morphology and PET for all the molecular imaging,” says Schwaiger. “I am even more excited about future with PET/MR, where you can get additional parameters about tumor physiology and molecular signals.”