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The objectives of this study were to compare the effects of two vasodilators, sodium nitroprusside (SNP) and calcitonin gene-related peptide (CGRP) on mean arterial pressure (MAP), heart rate (HR) and temperatures in tumour and surrounding normal tissue during local hyperthermia treatment. Eleven tumour-bearing pet dogs with spontaneous soft tissue sarcomas were given SNP intravenously during local hyperthermia. The drug infusion rate was adjusted to maintain a 20% decrease in MAP. The median (95% CI) increase in the temperature distribution descriptors T(90) and T(50) was 0.2 degrees C (0.0-0.4 degrees C, p = 0.02) and 0.4 degrees C (0.1-0.7 degrees C, p = 0.02), respectively, in tumour. Normal subcutaneous tissue temperatures were mildly increased but remained below the threshold for thermal injury. The effects of CGRP were investigated in six tumour-bearing dogs following a protocol similar to that used for SNP. The median (interquartile (IQ) range) decrease in mean arterial pressure was 19% (15-26%) after CGRP administration and a significant increase was seen in tumour but not normal subcutaneous tissue temperatures. The median (95% CI) increase in the temperature distribution descriptors T(90) and T(50) was 0.5 degrees C (0.1-1.6 degrees C, p = 0.03) and 0.8 degrees C (0.1-1.6 degrees C, p = 0.13), respectively. Administration of SNP or CGRP did not result in local or systemic toxicity in tumour-bearing dogs. However, the magnitude of increase in tumour temperatures was not sufficient to improve the likelihood of increased response rates. Therefore, there is little justification for translation of this approach to human trials using conventional local hyperthermia.

The adverse prognostic impact of tumor hypoxia has been demonstrated in human malignancy. We report the effects of radiotherapy and hyperthermia (HT) on soft tissue sarcoma oxygenation and the relationship between treatment-induced changes in oxygenation and clinical treatment outcome. Patients receiving preoperative radiotherapy and HT underwent tumor oxygenation measurement pretreatment after the start of radiation/pre-HT and one day after the first HT treatment. The magnitude of improvement in tumor oxygenation after the first HT fraction relative to pretreatment baseline was positively correlated with the amount of necrosis seen in the resection specimen. Patients with90% resection specimen necrosis experienced longer disease-free survival than those withor = 90% necrosis. Increasing levels of tumor hypoxia were also correlated with diminished metabolic status as measured by P-31 magnetic resonance spectroscopy.

Using a regional annular microwave array it was possible to produce a systemic temperature of 42 degrees C in approximately 80 min with applied net power levels of approximately 150 W. Resulting temperature distributions were non-uniform. Sites within the array were above systemic temperature during heating but approximated systemic temperature during the plateau phase. Sites outside of the array were lower than systemic temperature during heating and plateau phases. Dogs allowed to recover from the procedure experienced severe toxicity consisting of lumbar muscle haemorrhage, pain and swelling, and pelvic limb paralysis. Histologically, there was severe myopathy and haemorrhage and oedema in neural tissue in the caudal lumbar spine. Acute necrosis of lymphoid tissue was observed in all dogs. Temperatures in muscle reached 43-46 degrees C and were higher than at other measured sites. Spinal canal temperatures were essentially equal to rectal temperature, approximating 42-43 degrees C during heating and plateau phases. These data suggest regionally induced whole-body hyperthermia may result in: (1) power deposition non-uniformity leading to muscle and spinal canal temperatures which exceed systemic temperature and which are sufficient to cause serious toxicity; (2) systemic temperature non-uniformity which is undesirable for systemic thermochemotherapy; and (3) possible immunological dysfunction associated with lymphoid necrosis. Extreme caution must be exercised in administering energy to localized regions of human patients with the intent of elevating systemic temperature.

Clinical quality assurance guidelines are established for RTOG hyperthermia protocols in which unfocused planar ultrasound may be used to administer hyperthermia. Measurement of temperature at a few fixed points is no longer considered to be adequate. Thermal mapping is required to obtain profiles of the temperature across the tumor dimensions, including margins of normal tissue. The thermometry strategies established for microwaves are to be adhered to with oblique insertion of the probes recommended. Two types of errors arise which are generally not present with microwaves. A measurement error, commonly referred to as a temperature artifact, arises because of absorption and/or viscous heating of the probe. Another error arises when thermocouples are used due to the conduction of heat along the wire leads, especially the copper wire. Several thermometry systems are evaluated with regard to the expected artifact and conduction errors. Acceptable systems include: a) indexing a polyurethane sheathed single sensor thermocouple in a polyurethane catheter, b) indexing a fiberoptic probe in a steel needle, c) indexing a single sensor thermocouple in a steel needle, and d) use of manganin-constantan multisensor thermocouples. Unacceptable systems include: a) fixed or static probes that do not provide profiles of the temperature across the tumor dimensions, b) copper-constantan multisensor thermocouples, and c) teflon sheathed thermocouples inserted into a teflon catheter.

M. W. DEWHIRST, D.V.M., PH.D.,* T. L. PHILLIPS, M.D.,+ T. V. SAMULSKI, PH.D.,+ P. STAUFFER, MSEE,? P. SHRIVASTAVA, PH.D.,+ B. PALIWAL, PH.D.,+ T. PAJAK, PH.D.,+ M. GILLIM, PH.D.,+ M. SAPOZINK, M.D., PH.D.,+ R. MYERSON, M.D., PH.D.,+ F. M. WATERMAN, PH.D.,+ S. A. SAPARETO, PH.D.,+ P. CORRY, PH.D.,+ T. C. CETAS, PH.D.,+ D. B. LEEPER, PH.D.,+ P. FESSENDEN, PH.D.,+ D. KAPP, M.D., PH.D.,+ J. R. OLESON, M.D., PH.D.+ AND B. EMAMI, M.D.*

Since September 1983, five patients with head and neck cancers and five patients with pelvic or perineal recurrences of colorectal neoplasms received 192Ir interstitial implants through flexible afterloading catheters that were modified to allow RF hyperthermia treatments of the tumor within 1 hr pre- and post-brachytherapy. Local control in the implant volume was obtained in three of the patients with head and neck cancers (base tongue--2/4; floor of mouth--1/1) with follow-up of 9 to 42 months. Two patients had local recurrences after disease-free periods of 8 and 24 months. Two of the five patients treated for pelvic recurrences had complete responses lasting less than 3 months; prolonged stabilization (12 months) of a presacral mass in a third patient also occurred, but the neoplasm eventually regrew. Average temperatures of 39.2 degrees C to 43.7 degrees C were obtained in the implant volumes of these patients during the 45 minute heating periods which took place prior to loading, and just after removal, of the 192Ir seeds in each patient. No instances of intra or post-operative hemorrhage or necrosis of bone or soft tissues occurred in these patients. However, one individual required a permanent tracheostomy for persistent epiglottic edema after implantation as part of a base-tongue brachytherapy procedure. Interstitial RF hyperthermia in conjunction with brachytherapy appears to be a relatively safe and effective modality, but must be tested prospectively to compare its efficacy to interstitial irradiation alone.

The delivery of local and regional therapeutic hyperthermia in clinical practice proves to be a difficult challenge. The objective is to elevate the temperature of malignant tissue to a uniform level in excess of some minimum therapeutic temperature (e.g., 42.0 °C) for a period on the order of 30–60 min. At the same time, normal tissue temperatures should be maintained at subtherapeutic levels. This objective is seldom achieved. The difficulty is associated not so much with excessive heating of normal tissue (normal tissue toxicity is thus far reportedly low) as with achieving a minimum, uniform therapeutic temperature in the target tissue volume. It is known that thermal cytotoxicity is very temperature dependent [1]. In addition, thermal tolerance, the ability of cells to become resistant to elevated temperature, is another phenomenon that is highly dependent on temperature and exposure time and may be therapeutically relevant [1,2].

1 Thermometry in Therapeutic Hyperthermia.- 1.1 Introduction.- 1.2 Clinical Considerations.- 1.2.1 Practical Applications.- 1.2.2 Temperature Control.- 1.3 Available Technologies.- 1.3.1 Thermocouple Thermometry.- 1.3.2 Electrical Resistance Thermometry.- 1.3.3 Gallium Arsenide Optical Thermometry.- 1.3.4 Photoluminescent Thermometry.- 1.4 Measurement Errors and Artifacts.- 1.4.1 Calibration and Drift.- 1.4.2 Thermal Smearing.- 1.4.3 Electromagnetic Artifacts.- 1.4.4 Ultrasound Artifacts.- 1.5 Future Developments.- 1.5.1 Noninvasive Thermometers.- 1.5.2 Mathematical Modeling.- 1.6 Summary.- References.- 2 Noninvasive Control of Hyperthermia.- 2.1 Introduction.- 2.2 General Considerations Regarding Imaging Technique Performances.- 2.2.1 Presentation.- 2.2.2 Expected Performances for Noninvasive Control of Hyperthermia.- 2.2.3 Classification of Imaging Modalities.- 2.2.4 Analysis of Image Content.- 2.2.5 Usual Criteria of Image Quality.- 2.2.6 Temperature Dependence of Images.- 2.2.7 Other Practical Considerations.- 2.2.8 Optimization of Performances.- 2.3 Electromagnetic Radiometric Techniques.- 2.3.1 Presentation.- 2.3.2 Natural Limitations.- 2.3.3 Recent Developments.- 2.3.4 Discussion.- 2.4 X-Ray Tomodensitometry.- 2.4.1 Presentation.- 2.4.2 Fundamentals.- 2.4.3 Image Quality.- 2.4.4 Temperature Dependence of CT Numbers.- 2.4.5 Some Results.- 2.4.6 Discussion.- 2.5 NMR Tomography.- 2.5.1 Fundamentals.- 2.5.2 Image Quality.- 2.5.3 Temperature Dependence of NMR Imaging Parameters.- 2.5.4 Some Results.- 2.5.5 Discussion.- 2.6 Imaging of Dielectric Properties.- 2.6.1 Presentation.- 2.6.2 Fundamentals.- 2.6.3 Salient Features of Dielectric Properties of Living Tissues.- 2.6.4 Electrical Impedance Tomography.- 2.6.5 Microwave Imaging.- 2.6.6 Radiofrequency Inverse Scattering Techniques.- 2.6.7 Conclusion.- 2.7 Ultrasonic Techniques.- 2.7.1 Presentation.- 2.7.2 Sensitivity of Living Tissue Characteristics to Temperature.- 2.7.3 Active Modalities.- 2.7.4 Ultrasound Radiometry.- 2.7.5 Thermo-induced Acoustic Imaging.- 2.7.6 Discussion.- 2.8 Discussion, Synthesis, and Prospects.- References.- 3 Use of Microwave Radiometry for Hyperthermia Monitoring and as a Basis for Thermal Dosimetry.- 3.1 Introduction.- 3.2 Measurement of Thermal Radiation.- 3.2.1 Physical Principles: The Black Body Radiation.- 3.2.2 Thermal Power Collected by an Antenna: Nyquist's Formula.- 3.2.3 Thickness of Medium and Radiometric Measurement.- 3.2.4 Reflection Effects at the Air-Medium Interface.- 3.2.5 Characteristics of the Radiometric Method for Temperature Measurement.- 3.3 Microwave Radiometric Systems.- 3.3.1 The Dicke Radiometer: Principle and Limitations.- 3.3.2 The Modified Radiometer.- 3.3.3 Description and Performances of the Radiometer Used for Medical Applications Performances of the Applicator Antenna.- 3.4 Control of Hyperthermia by Microwave Radiometry.- 3.4.1 Principles and Problems.- 3.4.2 Design of the Microwave Systems.- 3.4.3 Performances and Possibilities: Examples of Experiments on Phantoms, Animals, and Patients.- 3.4.4 Use of Microwave Radiometry to Control Radiofrequency Hyperthermia.- 3.5 Thermal Dosimetry for Microwave Hyperthermia Based on Microwave Radiometry.- 3.5.1 Principles of the Method.- 3.5.2 Computation of the Radiometric Signal.- 3.5.3 Computation of Thermal Profile Using the Bioheat Transfer Equation.- 3.5.4 The Inverse Process.- 3.5.5 Examples of Results Obtained with These Programs: Theory-Experiment Comparisons.- 3.6 Conclusion.- References.

A photoluminescent thermometer, based on the transient emission response of a europium-activated calcium sulphide phosphor, is described in detail. This optical thermometry system has special advantages for temperature measurements in microwave and RF fields and potential application in electromagnetically induced clinical hyperthermia. A laboratory system has been constructed which utilises a fibreoptic probe with external diameter 0.8 mm. A system temperature resolution of 0.1 degrees C has been achieved in the range 37-47 degrees C.

Hyperthermia has little hope of progressing as a clinical modality without accurate assessment of the temperature distributions obtained. At the present time only direct, invasive temperature-measuring techniques are possible, posing severe limitations. Established techniques for clinical temperature measurement have developed over the past few years, and for both ultrasound and electromagnetic hyperthermia it is possible to get temperature-time profiles at a large number of spatial points. Position uncertainty, thermal conduction smearing, and artifactual heating limit the accuracy to about 0.2 degrees (electromagnetic) or 0.5 degrees (ultrasound), but this is probably less of a hindrance than the inadequate percentage of tumor and normal tissue volume for which achieved temperatures can be documented.

A photoluminescent thermometer, based on the transient emission response of a europium-activated calcium sulphide phosphor, is described in detail. This optical thermometry system has special advantages for temperature measurements in microwave and RF fields and potential application in electromagnetically induced clinical hyperthermia. A laboratory system has been constructed which utilises a fibreoptic probe with external diameter 0.8 mm. A system temperature resolution of 0.1 degree C has been achieved in the range 37-47 degrees C.

The clinical application of hyperthermia in the treatment of deep-seated tumors remains an empirical science. The pleomorphic nature of the neoplasms and the great diversity in the anatomy and physiology of the individual tumor locations make the treatment of nearly every neoplasm a unique challenge. A wide variety of devices is required, both for the administration of hyperthermia and for the measurement of the temperatures achieved. At Stanford University, these include the BSD Medical Corp. annular phased array system, an isospherical ultrasound device, and interstitial radiofrequency for deep heating. Ultrasound transducers and a variety of microwave applicators are used for superficial hyperthermia. Six illustrative case studies, selected from the 91 patients treated in our program since October 1981, are presented, with discussion and comparison of treatment devices. Difficulties in deep heating were encountered in several instances, believed secondary to the thickness of the s.c. fat, the relatively high heat-induced tumor blood flow, and the presence of adjacent bone. It is suggested that ultimate improvement in clinical results will be possible once a better understanding is achieved of such anatomical and physiological factors.

Nitric oxide synthase (NOS) inhibitors have been investigated as potential cytotoxic agents to treat tumors lacking p53 function. Furthermore, their ability to reduce tumor blood flow can be combined with drugs that are specifically designed to kill cells that are hypoxic or to improve temperatures during local heat (hyperthermia) treatment of tumors. This paper reports the unexpected development of acute pancreatitis in two tumor-bearing pet dogs that were treated with the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) during administration of local hyperthermia.Prior to the use of L-NAME in tumor-bearing dogs, purpose-bred beagles were studied. Following induction of inhalation anesthesia, local hyperthermia was applied to either normal thigh muscle (beagles) or tumors (tumor-bearing dogs). Once a thermal steady state was achieved, L-NAME was administered and temperature monitoring continued. Animals were observed after treatment for evidence of toxicity.The beagles tolerated the treatment well, with no side effects noted either clinically or by routine CBC or blood chemistry analyses. In contrast, the first two tumor-bearing dogs accrued onto the phase I study developed acute pancreatitis in the immediate post-treatment period which necessitated hospitalization and intensive care. The trial was stopped. Both dogs had intercurrent risk factors which predisposed them to development of pancreatitis, although neither had a history of symptoms of pancreatitis at the time the hyperthermia + L-NAME treatment was given.We conclude that caution should be exercised when considering NOS inhibition for cancer treatment. Careful evaluation of history and health status as well as recognition of potential risk factors may be key in avoiding potentially fatal complications. This study demonstrates the value of performing potentially harmful treatments in tumor-bearing dogs prior to introduction into the human clinic.