Oxygen microbubbles may improve efficacy of radiation therapy

John Eisenbrey

Surfactant-shelled oxygen microbubbles injected via IV may improve response to radiation therapy, according to study results.

Previous findings for systemic delivery of oxygen before radiation therapy failed to show sufficient efficacy. However, in this study, John Eisenbrey, PhD, assistant professor of radiology at Thomas Jefferson University, and colleagues demonstrated in murine models that this approach consistently produced a 20-mmHg increase in breast tumor oxygenation levels, which appeared significantly greater than the response for saline or untriggered oxygen microbubbles used in controls (P < .001).

Oxygen delivery remained independent of hemoglobin transport, which the researchers suggested allows for oxygen to be delivered to avascular regions of the tumor. In addition, overcoming hypoxia led to a nearly threefold improvement in radiosensitivity, which yielded approximately 30 days of improved tumor control, along with significantly improved tumor growth and survival outcomes in mice (P < .03).

A first-in-human trial of a similar microbubble approach for hepatocellular carcinoma is underway.

HemOnc Today spoke with Eisenbrey about the mechanisms, efficacy and safety of the microbubble approach, as well as what investigators will assess in the first-in-human trial.

Question: H ow does the microbubble approach work ?

Answer: Ultrasound contrast agents are gas-filled microbubbles that circulate systemically after IV injection. We can use noninvasive ultrasound to cause either stable or inertial bubble cavitation within a localized area in the body. Although commercial imaging agents use low-solubility gases for stability, our group has developed a stable oxygen-filled bubble. By focusing ultrasound energy on the tumor and initiating microbubble destruction, we can locally deliver the oxygen within the core of the bubbles as they circulate through the tumor blood supply. This is important because tumor hypoxia has been shown to limit tumor sensitivity to radiation. By locally delivering oxygen with this approach prior to radiation therapy, we improve the sensitivity of breast tumors to radiation.

Q: Do the bubbles need to be filled with oxygen, or might other gases work?

A: Oxygen is an ideal gas core because it overcomes hypoxia-associated radiotherapy resistance. However, it also has been shown that inertial microbubble cavitation alone with commercial ultrasound contrast agents provides some radiotherapy sensitization. Our work demonstrated this with improved tumor control using a nitrogen-filled bubble as a control. Other groups have shown this in bladder and prostate cancers. We also have shown that liver cancer becomes more sensitive to radiation therapy following localized cavitation of commercial ultrasound contrast agents. Although not as effective as an oxygen-filled microbubble, this approach is attractive because it allows for faster clinical translation given that the commercial microbubbles are already approved for contrast-enhanced ultrasound imaging. This led us to start a clinical trial using microbubble cavitation to sensitize liver tumors to radiation.

Q: How did you measure efficacy ?

A: In our animal studies, we judged efficacy by the delay in tumor growth and improved animal survival. Our oxygen approach tripled the sensitivity of tumors to radiation and roughly doubled overall animal survival. In our pilot clinical trial, we are randomly assigning patients to either standard radiation therapy or their standard of care combined with microbubble cavitation. We are following liver function as an indicator of safety, as well as tumor response over a 6-month period and OS.

Q: Are there any safety concerns?

A: Safety concerns are relatively minor given the extent of sensitization. We saw no adverse events in our animals that received oxygen microbubbles, and previous toxicology studies with similar-shelled microbubbles showed they are very well tolerated. In our preclinical work examining microbubble cavitation to sensitize liver tumors to radiation, we saw no significant differences in liver function or side effects between groups that received radiation alone or microbubbles with radiation. To date, our human data has also shown this. Safety concerns with the microbubbles are minimal given that they are extensively used for diagnostic imaging.

Q: What are the potential clinical implications of this approach for hematology and oncology ?

A: Our clinical trial using microbubble cavitation in hepatocellular carcinoma is underway. We expect this approach to be applicable to a wide variety of solid tumors being treated with radiation therapy. We are encouraged by our results with oxygen microbubbles in breast cancer and are exploring ways to proceed with this formulation toward an FDA investigational new drug application to hopefully begin human trials within the next few years. – by Rob Volansky

Reference:

Eisenbrey JR, et al. Int J Radiat Oncol Biol Phys. 2018;doi:10.1016/j.ijrobp.2018.01.042.

For more information:

John Eisenbrey, PhD, can be reached at Thomas Jefferson University, Department of Radiology, 132 South 10th St., Philadelphia, PA, 19107; email: john.eisenbrey@jefferson.edu.

Disclosure: Eisenbrey reports research, equipment and drug support from GE Healthcare; equipment support from Siemens, SonoScape and Toshiba; and drug support from Lantheus Medical Imaging.