The response of tumors to cytotoxic therapies, especially ionizing radiation, is critically dependent on pO2
]. In vitro
studies indicate that cells in hypoxic environments are approximately 3-times less sensitive to radiation than cells that are well oxygenated. Accordingly, tumor hypoxia is a major limiting factor in the application of radiation therapy and its efficacy. It is also important to recognize that tumor pO2
is not static, especially during the course of treatment when changes in O2
consumption, interstitial pressure, and perfusion are expected. If available, direct knowledge of tumor pO2
could be used to optimize treatment on an individual basis through the application of drugs or procedures that increase tumor oxygenation and/or the optimizations of both temporal and spatial patterns of irradiation to maximize the therapeutic ratio.
Building off of instrumental and methodological developments and previous successes in animal model systems, we are now pursuing the development of EPR oximetry in a clinical setting to meet this need and demonstrate the feasibility of these measurements within the clinical setting. We have performed measurements on tumors in 10 subjects, including 7 with melanoma lesions and metastases, and others with basal cell, soft-tissue sarcoma, and lymphoma tumors. For several subjects, measurements in more than one tumor, or more than one site, have been possible. The distribution of measurement sites is shown in , which illustrates the capability of making measurements with the current in vivo EPR spectrometer at a wide variety of locations, from head to toe.
Fig. 1 (A) Tumor pO2 has been measured for 10 volunteers with different tumor locations from head to toe. (B) Tumor pO2 was monitored in melanoma metastases at two sites, in the scalp and neck, during the course of radiation treatment. Spectra were recorded (more ...)
We have previously described the ability of the EPR measurements to measure baseline levels of tumor pO2
and the response to the inspiration of 100% O2
]. In both of these instances, including melanoma and lymphoma tumors, baseline pO2
values were observed to be quite low (13 and 4 mmHg, respectively) and the application of inhaled oxygen led to dramatic increases in tumor pO2
. Similar measurements have been made with additional subjects, and serial measurements during the course of radiation treatment have been performed. One such set of serial measurement was performed at 2 sites within separate metastatic melanoma tumors during a course of radiation treatment where a total of 36 Gy was applied using 6 Gy × 6 doses (). The tumors were located in the upper right scalp and on the right side of the neck just below the ear. Similar pO2
levels were observed at each site immediately before and after each fraction, but differences were observed between the sites and during the course of treatment. In the tumor located in the neck, consistently low, nearly anoxic, values were recorded with a small upward trend as the therapy progressed. In the scalp, considerably higher values of pO2
were observed, ranging from approximately 3–10 mmHg.
It is especially important to note that in vivo EPR oximetry has been used successfully in the clinical setting to make repeated non-invasive direct measurements of tumor pO2. We have observed that the tumor pO2 values have varied among the patients studied and over the courses of treatment and that different responses of tumor pO2 to increased fractions of inhaled oxygen are observed. Based on the measurements to date, we believe that it is feasible that in vivo EPR oximetry could be used to monitor tumor pO2 in the clinical setting and guide the optimal application of strategies to enhance tumor oxygenation at the time of treatment.
Peripheral Vascular Disease (PVD) is a major cause of morbidity and mortality in diabetics, where a local low tissue pO2
due to poor perfusion can lead to the development of chronic wounds, which often necessitates amputation. The direct measurement of tissue pO2
would facilitate the rational development of treatments for PVD and could be applied on individual bases to monitor the development of the disease and guide the application of interventions. The development of in vivo
EPR oximetry of subcutaneous tissue aimed at assessment of PVD has begun with measurements in healthy subjects to develop the necessary procedures and to observe the short- and long-term oxygen dynamics present in a controlled population. We have made measurements at 14 sites in 9 healthy volunteers, dating back to Oct. 2002. The earliest studies have been described previously [4
]. In the current studies, measurements of pO2
are being performed on a monthly basis at both the dorsal and plantar surfaces of the foot under baseline conditions, as well as with inhalation of increased oxygen and temporary interruption of perfusion of the tissue. Consistent with prior measurements, we have observed that there appears to be a period of decreased pO2
in the weeks following injection, with a gradual increase back to values near 20–30 mmHg. The nature of this apparent decrease is a matter of ongoing investigation. In all studies, we have consistently observed narrowing of the EPR signal following interruption of perfusion, consistent with consumption driving tissue pO2
to near anoxic values. Similarly, we see general, but less consistent, increases in tissue pO2
following the administration of inhaled O2
. Following each of these interventions, we generally observe tissue pO2
returning to the baseline levels. These patterns of oxygenation are demonstrated in the data included in , which describes measurements in the dorsal surfaces of the feet of 4 of the most recent research subjects.
Fig. 2 Tissue pO2 in the dorsal surface is shown for baseline, inspired O2, recovery following O2, compression, and compression recovery periods. For all subjects (A–D) the baseline O2 values rise gradually in the weeks after ink injection. Baseline (more ...)