Thaddeus Samulski

RTOG quality assurance guidelines for clinical trials using hyperthermia.

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.*

RTOG QUALITY ASSURANCE GUIDELINES FOR CLINICAL TRIALS USING HYPERTHERMIA ADMINISTERED BY ULTRASOUND

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.

Serious toxicity associated with annular microwave array induction of whole-body hyperthermia in normal dogs

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.

Feasibility of estimating the temperature distribution in a tumor heated by a waveguide applicator

The feasibility of using a 2-dimensional (2D) modeling approach for retrospectively describing complete temperature distributions in the midplane of a tumor during a clinical hyperthermia treatment was tested. An experimental treatment, using a 915-MHz waveguide applicator to heat a large melanoma in a dog, was modeled. Detailed measurements of temperatures were made during the treatment. The steady-state blood flow distribution at the midplane was imaged by positron emission tomography (PET), and these data were used to prescribe the modeled perfusion pattern. A 2D finite element method (FEM) was used to approximate the solution to Maxwells Equations to obtain the specific absorption rate (SAR) distribution. The blood-flow estimates, assumed material properties, SAR distribution, and temperature boundary conditions were then used with the same mesh in a second FEM program to obtain a solution to the bioheat transfer equation. This latter routine was embedded in a state-and-parameter-estimation program that systematically varied selected parameters until the differences between computed and measured temperatures were minimized. Optimizations were performed independently for three subsets of the measured temperature data to assess the sensitivity of the predicted temperature field to the number of measurements. The calculated temperature distributions that resulted were similar to each other, and the predicted temperatures at the sensor points excluded from these optimizations were in reasonable agreement with the measurements. However, lack of unique blood flow values following optimization indicates that the methods of estimating blood flow will need to be improved or that there are problems with model mismatch. This work is a clinical case study of an evolving 2D system of thermal dosimetry which relies on both empirical and theoretical concepts. The methodology is being evaluated for its ability to generate prognostically significant descriptors of the treatment temperature field.

Effect of calcitonin gene related peptide vs sodium nitroprusside to increase temperature in spontaneous canine tumours during local hyperthermia

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%u2009decrease in MAP. The median (95%u2009CI) increase in the temperature distribution descriptors T90 and T50 was 0.2°C (0.0–0.4°C, pu2009=u20090.02) and 0.4°C (0.1–0.7°C, pu2009=u20090.02), 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%u2009(15–26%) after CGRP administration and a significant increase was seen in tumour but not normal subcutaneous tissue temperatures. The median (95%u2009CI) increase in the temperature distribution descriptors T90 and T50 was 0.5°C (0.1–1.6°C, pu2009=u20090.03) and 0.8°C (0.1–1.6°C, pu2009=u20090.13), 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.