D. M. Prescott

Changes in plasma TGFβ levels during pulmonary radiotherapy as a predictor of the risk of developing radiation pneumonitis

PURPOSE To determine whether plasma transforming growth factor-beta (TGF-beta) levels measured before and during radical radiotherapy for lung cancer could be used to predict patients at risk for the development of radiation pneumonitis. METHODS AND MATERIALS The first eight patients with lung cancer (nonsmall cell: seven, small cell: one) enrolled in a prospective study designed to evaluate physiological and molecular biologic correlates of radiation induced normal tissue injury are described. The study began in June 1991. All patients were treated with radiotherapy with curative intent. Plasma transforming growth factor-beta levels were obtained before, weekly during, and at each follow-up after treatment. Pretreatment pulmonary function tests and single photon emission computed tomography scans were obtained to assess baseline lung function and were repeated at follow-up visits. Dose-volume histogram analyses were performed to determine the volume of lung which received > or = 30 Gy. Patients were assessed at each follow-up visit for signs and symptoms of pneumonitis. RESULTS Five patients developed signs and/or symptoms of pulmonary injury consistent with pneumonitis and three patients did not. In all three patients not developing pneumonitis, plasma TGF-beta levels normalized by the end of radiotherapy. In contrast, four out of five patients who suffered pneumonitis had persistently elevated plasma TGF-beta levels by the end of therapy. This finding appeared to be independent of the volume of irradiated lung. CONCLUSIONS These results suggest that plasma TGF-beta levels during treatment may be useful to determine which patients are at high risk of developing symptomatic pneumonitis following thoracic radiotherapy. This finding may have implications when planning additional therapy (either chemotherapy or radiotherapy) which may have potentially adverse consequences on the lung.

Magnetic Resonance Thermometry During Hyperthermia for Human High-Grade Sarcoma

PURPOSE To determine the feasibility of measuring temperature noninvasively with magnetic resonance imaging during hyperthermia treatment of human tumors. METHODS The proton chemical shift detected using phase-difference magnetic resonance imaging (MRI) was used to measure temperature in phantoms and human tumors during treatment with hyperthermia. Four adult patients having high-grade primary sarcoma tumors of the lower leg received 5 hyperthermia treatments in the MR scanner using an MRI-compatible radiofrequency heating applicator. Prior to each treatment, an average of 3 fiberoptic temperature probes were invasively placed into the tumor (or phantom). Hyperthermia was applied concurrent with MR thermometry. Following completion of the treatment, regions of interest (ROI) were defined on MR phase images at each temperature probe location, in bone marrow, and in gel standards placed outside the heated region. The median phase difference (compared to pretreatment baseline images) was calculated for each ROI. This phase difference was corrected for phase drift observed in standards and bone marrow. The observed phase difference, with and without corrections, was correlated with the fiberoptic temperature measurements. RESULTS The phase difference observed with MRI was found to correlate with temperature. Phantom measurements demonstrated a linear regression coefficient of 4.70 degrees phase difference per degree Celsius, with an R2 = 0.998. After human images with artifact were excluded, the linear regression demonstrated a correlation coefficient of 5.5 degrees phase difference per degree Celsius, with an R2 = 0.84. In both phantom and human treatments, temperature measured via corrected phase difference closely tracked measurements obtained with fiberoptic probes during the hyperthermia treatments. CONCLUSIONS Proton chemical shift imaging with current MRI and hyperthermia technology can be used to monitor and control temperature during treatment of large tumors in the distal lower extremity.

1H MRI phase thermometry in vivo in canine brain, muscle, and tumor tissue

The temperature sensitivity of the chemical shift of water (approximately 0.01 ppm/degree C) provides a potential method to monitor temperature changes in vivo or in vitro through the changes in phase of a gradient-echo magnetic resonance (MR) image. This relation was studied at 1.5 T in gel materials and in vivo in canine brain and muscle tissue, heated with a radio frequency (rf) annular phased array hyperthermia antenna. The rf fields associated with heating (130 MHz) and imaging (64 MHz) were decoupled using bandpass filters providing isolation in excess of 100 dB, thus allowing simultaneous imaging and rf heating without deterioration of the MR image signal-to-noise ratio. In a gel, temperature sensitivity of the MR image phase was observed to be (4.41 +/- 0.02) phase degrees/degree C for Te = 20 ms, which allowed temperature changes of 0.22 degree C to be resolved for a 50-mm3 region in less than 10 s of data acquisition. In vivo, for Te = 20 ms, the temperature sensitivity was (3.2 +/- 0.1) phase degrees/degree C for brain tissue, (3.1 +/- 0.1) phase degrees/degree C for muscle, and (3.0 +/- 0.2) phase degrees/degree C for a muscle tumor (sarcoma), allowing temperature changes of 0.6 degree C to be resolved in a 16-mm3 volume in less than 10 s of data acquisition. We conclude that, while the technique is very sensitive to magnetic field inhomogeneity, stability, and subject motion, it appears to be useful for in vivo temperature change measurement.

Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment

PURPOSE The objectives of this study were to evaluate effects of hyperthermia on tumor oxygenation, extracellular pH (pHe), and blood flow in 13 dogs with spontaneous soft tissue sarcomas prior to and after local hyperthermia. METHODS AND MATERIALS Tumor pO2 was measured using an Eppendorf polarographic device, pHe using interstitial electrodes, and blood flow using contrast-enhanced magnetic resonance imaging (MRI). RESULTS There was an overall improvement in tumor oxygenation observed as an increase in median pO2 and decrease in hypoxic fraction (% of pO2 measurements <5 mm Hg) at 24-h post hyperthermia. These changes were most pronounced when the median temperature (T50) during hyperthermia treatment was less than 44 degrees C. Tumors with T50 > 44 degrees C were characterized by a decrease in median PO2 and an increase in hypoxic fraction. Similar thermal dose-related changes were observed in tumor perfusion. Perfusion was significantly higher after hyperthermia. Increases in perfusion were most evident in tumors with T50 < 44 degrees C. With T50 > 44 degrees C, there was no change in perfusion after hyperthermia. On average, pHe values declined in all animals after hyperthermia, with the greatest reduction seen for larger T50 values. CONCLUSION This study suggests that hyperthermia has biphasic effects on tumor physiologic parameters. Lower temperatures tend to favor improved perfusion and oxygenation, whereas higher temperatures are more likely to cause vascular damage, thus leading to greater hypoxia. While it has long been recognized that such effects occur in rodent tumors, this is the first report to tie such changes to temperatures achieved during hyperthermia in the clinical setting. Furthermore, it suggests that the thermal threshold for vascular damage is higher in spontaneous tumors than in more rapidly growing rodent tumors.

Radiation plus local hyperthermia versus radiation plus the combination of local and whole-body hyperthermia in canine sarcomas

PURPOSE The purpose of this study was to assess the effect of increasing intratumoral temperatures by the combination of local hyperthermia (LH) and whole body hyperthermia (WBH) on the radiation response of canine sarcomas. METHODS AND MATERIALS Dogs with spontaneous soft tissue sarcomas and no evidence of metastasis were randomized to be treated with radiation combined with either LH alone or LH + WBH. Dogs were accessioned for treatment at two institutions. The radiation dose was 56.25 Gy, given in 25 2.25 Gy daily fractions. Two hyperthermia treatments were given; one during the first and one during the last week of treatment. Dogs were evaluated after treatment for local recurrence, metastasis, and complications. RESULTS Sixty-four dogs were treated between 1989 and 1993. The use of LH+WBH resulted in statistically significant increases in the low and middle regions of the temperature distributions. The largest increase was in the low temperatures with median CEM 43 T90 values of 4 vs. 49 min for LH vs. LH + WBH, respectively (p<0.001). There was no difference in duration of local tumor control between hyperthermia groups (p = 0.59). The time to metastasis was shorter for dogs receiving LH + WBH (p = 0.02); the hazard ratio for metastatic disease for dogs in the LH + WBH group was 2.4 (95% confidence interval, 1.2-5.4) with respect to dogs in the LH group. Complications were greater in larger tumors and in tumors treated with LH + WBH, CONCLUSION: The combination of LH + WBH with radiation therapy, as described herein, was not associated with an increase in local tumor control in comparison to use of LH with radiation therapy. The combination of LH + WBH also appeared to alter the biology of the metastatic process and was associated with more complications than LH. We identified no rationale for further study of LH + WBH in combination with radiation for treatment of solid tumors.

Therapy monitoring in human and canine soft tissue sarcomas using magnetic resonance imaging and spectroscopy

PURPOSE The goals of this study were to determine whether magnetic resonance parameters (a) can identify early during therapy those patients most likely to respond to hyperthermia and radiotherapy, (b) can provide prior to or early during therapy information about the temperature distributions which can be obtained in patients receiving hyperthermia, and (c) can provide an understanding of the effects of hyperthermia on tumor metabolic status. METHODS AND MATERIALS Twenty-one human patients and 10 canine patients with soft tissue sarcomas treated with preoperative hyperthermia and radiation had a series of magnetic resonance imaging and phosphorous spectroscopy studies done. To address the goals for both the human and canine populations, changes in mean T2 relaxation times, pH, and various phosphometabolite ratios from the pretreatment (Study 1) to the post first hyperthermia study (Study 2) were correlated with treatment outcome; pretreatment magnetic resonance parameters and changes in magnetic resonance parameters (Study 2-Study 1) were compared with various cumulative thermal descriptors; and thermal descriptors of the first hyperthermia were compared with changes in magnetic resonance phosphometabolite ratios. RESULTS A decrease in adenosine triphosphate/phosphomonoester from study 1 to study 2 is associated with a greater chance of > or = 95% necrosis in surgical resected tumors from human patients, but no significant relationships were observed between changes in tumor pH or phosphometabolite ratios and time to local failure in dogs. Pretreatment magnetic resonance parameters correlated with various thermal dose descriptors in canines but not in humans. Change in adenosine triphosphate/inorganic phosphate and phosphomonoester signal to noise ratio correlated with cumulative thermal descriptors in dogs and humans, respectively. In dogs only, increases in thermal dose resulted in decreases in high energy phosphometabolites. CONCLUSION Changes in magnetic resonance parameters early during therapy may be predictive of treatment outcome. Pretreatment and changes in magnetic resonance parameters appear to predict how well a tumor will be heated during hyperthermia. Magnetic resonance spectroscopy also appears to be a useful tool to study the effects of various thermal doses on tumor metabolic status.

Use of nitroprusside to increase tissue temperature during local hyperthermia in normal and tumor-bearing dogs

The present study investigates the effects of nitroprusside, a potent vasodilating agent, on tissue temperature during local hyperthermia in five normal and five tumor-bearing dogs. Caudal thigh muscles were heated in normal dogs and muscle temperatures were recorded during hyperthermia. Tumor-bearing dogs received two hyperthermia treatments during a course of radiation therapy. Temperatures were recorded in tumor and surrounding normal tissues. Mean arterial pressure was decreased by approximately 40-45% during nitroprusside infusion and was associated with a compensatory increase in heart rate and increases in tissue temperature. In normal dogs, muscle temperatures increased an average of 1.7 degrees C with nitroprusside administration. When nitroprusside was administered at the beginning of local hyperthermia to induce step-down heating, approximately 48% of the measured positions in caudal thigh muscle achieved a temperature greater than or equal to 43 degrees C, sufficient to induce step-down heating, during the hyperthermia episode. In tumor-bearing dogs, there was a significant increase in tumor and normal tissue temperatures during nitroprusside administration. Estimated T90 and T50 descriptors increased by 0.9 degrees C and 1.6 degrees C, respectively, for tumor tissue and by 0.4 degrees C and 1.2 degrees C, respectively, for normal tissue. Despite the increase in normal tissue temperatures no toxicity was observed in these dogs. Nitroprusside may be a useful agent for manipulation of tumor temperatures during the entire hyperthermia treatment or for a short time period at the initiation of treatment to induce step-down heating.

Estimation of cell survival in tumours heated to nonuniform temperature distributions

UNLABELLED A stochastic model describing the probability of cell survival as a function of thermal exposure was developed and fit to data arising from studies of CHO cell survival under hyperthermic conditions. This model characterizes the separate risks of temperature-induced cell death and induction of thermotolerance during heating. Tumour cells are assumed to be affected independently of each other by hyperthermia. Tumour geometry, perfusion and power deposition affect hyperthermia-induced temperature distributions in tumours, producing nonuniform temperatures. Two tumours may respond to hyperthermia slightly differently because of differences in tumour geometry, perfusion, power deposition, or by chance alone and the approach presented here incorporates chance and these other factors explicitly. THE RESULTS (1) the time-temperature history is important for estimating tumour cell survival; (2) tumour temperature heterogeneity leaves more surviving cells at a given T90 temperature than would be expected if the entire tumour were uniformly heated to that same temperature; and (3) changes in the shape of the temperature distribution because of tumour geometry and perfusion distribution greatly influence cell survival between tumours, even when the standard temperature descriptors, such as T90, are fixed. The simulations also showed a modest effect on cell kill attributable to varying the lengths of the warm-up and the cool-down periods. These simulations indicate that these types of sensitivity studies can be used to investigate relationships between various modifiers of temperature distributions achieved when treating tumours with hyperthermia and to assess their potential therapeutic impact in clinical trials.

Manipulation of intra- and extracellular pH in spontaneous canine tumours by use of hyperglycaemia

We evaluated the use of hyperglycaemia to reduce tumour pH in dog with spontaneous tumours. Dogs were randomized to two groups: control and glucose. Intravenous administration of 20% glucose was used to induce and maintain hyperglycaemia. Extra- and intracellular tumour pH were measured using interstitial pH microelectrodes and 31P-MRS, respectively. During the administration of glucose, the mean (+/- SEM) blood glucose concentration was 419.8 (+/- 32.8) and 121.1 (+/- 8.0) mg/dl for the glucose and control groups, respectively. The mean extracellular tumour pH before and following 90 min of hyperglycaemia was 7.15 (+/- 0.08) and 7.15 (+/- 0.09). During consecutive measurements, intracellular tumour pH did not change significantly for the control group or the group subjected to hyperglycaemic manipulation. In contradistinction to previous rodent studies, our results demonstrate that hyperglycaemia alone is not sufficient to manipulate either intra- (pHi) or extracellular (pHe) hydrogen ion concentration in spontaneous canine soft tissue tumours.

Application of new technology in clinical hyperthermia

Two areas of technical progress related to hyperthermic oncology are presented: (1) numerical modelling of absorbed power and temperature distributions; and (2) non-invasive thermometry using magnetic resonance imaging. The results represent achievements made during the past 5 years at Duke University Medical Centers Departments of Radiation Oncology and Radiology. They represent examples of progress in the technology of hyperthermia that have potential for greatly improving the delivery, monitoring and assessment of clinical hyperthermia.