Enhancing therapy of tumors       

The concentration or partial pressure of oxygen (pO₂) is a crucial factor affecting the response of tumors to irradiation and other cytotoxic treatments. Over the past decade, clinical studies using oxygen microelectrodes have demonstrated the potential value of measuring the pO₂ in tumors in order to determine the probability that the tumors will respond to conventional radiation therapy. While these studies have demonstrated the clinical potential for such measurements, they also have shown the limitations of doing these measurements with oxygen electrodes. Such electrodes are difficult to use, involve a significant degree of invasiveness, have limited sensitivity, and, importantly, cannot be used for repeated measurements. As has been demonstrated in animals, EPR oximetry can overcome all of these limitations; therefore, it may be the clinical tool of choice for such measurements. Establishment of EPR oximetry as a clinical tool for the evaluation of prognosis and treatment of human tumors will be a multi-step process. Initial evaluation of the EPR technique will be made in superficial tumors arising in skin, soft tissues of the extremities, or superficial lymph nodes (such as of the head and neck). These measurements will rely on tissue implantation techniques using India ink or perhaps encapsulated other particulates. These inert substances are well tolerated within the implanted tissues, are not reactive to most oxidizing and reducing agents, and are resistant to large changes in pH. They are especially sensitive to the low pO₂ levels that may be found in tumors.

One particular advantage for EPR, the capacity to provide detailed pO₂ information from the same area of tumor over an extended period of time, would make it ideal for repeated measurements over a course of radiation treatment. Time interval correlation of tumor pO₂ levels over the course of radiation therapy would provide novel, detailed clinical information on changes in oxygen status within human tumors in response to treatment. This approach may be especially useful in measuring the response to therapeutic interventions, such as the periodic administration of chemotherapeutic agents or anti-angiogenic and vascular targeting approaches and approaches that lead to a transient increase of oxygen before radio or chemotherapy.

Other potential important applications of in vivo EPR oximetry include:

-- the extent and timing of effects of chemotherapy on oxygen in tumors;

-- the effects on tumor and tissue oxygen of clinically utilized alterations of respiration that are employed to minimize displacements of tissue during the delivery of therapy;

-- the effects of hyperbaric oxygen treatment on oxygenation within the tumor and surrounding normal tissues;

-- the effects of altered dose/fraction on tumor O₂;

-- the effects of altered dose rates in brachytherapy;

-- the effects of high dose therapy with high intensity implants;

-- the effects of immunotherapy and alterations in cell signaling.

With the development of approved implantable micro-resonators we will extend EPR oximetry to include more deep-seated tumors.

The use of in vivo EPR to evaluate tumor hypoxia relative to the surrounding tissue may improve the ability to target radiation therapy to the tumor, improving the probability that the use of higher doses is done with knowledge of the oxygenation in the tumor and thus avoiding unneeded dose escalation that could increase damage to the surrounding normal tissue.

At this time there are approved protocols for making measurements in superficial tumors, using India Ink as the oxygen-sensitive paramagnetic material. In the near future, when the implantable resonator is more fully developed, a protocol for studies in deeper tumors will be developed.

EPR Center for the Study of Viable Systems