APPENDIX I QUALITY ASSURANCE IN THE ADMINISTRATION OF LOCAL AND REGIONAL HYPERTHERMIA: CRITERIA AND PROCEDURES I.

Meaning of the Temperature-Time Specification

The ultimate goal of quality assurance in the administration of local and regional hyperthermia must be the delivery of equivalent thermotherapy to all patients in a given RTOG protocol. The thermal state of the heated tumor and normal tissue should be adequately described. This requires that temperature at several points be meaured and recorded. Proper evaluation and comparison of different clinical protocols employing hyperthermia requires that all patients treated according to a particular protocol be given the same (or _equivalent) thermotherapy. In general, both absorbed power density (w/cm~) and local heat transfer (cal/sec-cm3) will vary considerably over tissue volumes of interest, making it difficult to produce uniform temperature distributions within heated tissues. If satisfactory complience with the temperature-time specification in RTOG protocols is to result in the application of approximately equivalent thermotherapy to all protocol patients, the specified temperature must refer to a "volume-average" temperature, assumed to be at least grossly characteristic of the entire heated volume to which it applies. Accordingly, compliance with protocol specifications will necessitate measurements of temperature at some points within the heated tissue volume. The time indicated in the temperature-time combination of the protocol will refer to the interval during which the heated tissue is kept at the specified temperature (i.e., 43C). II. ProduCtion of t~ieSpecified Temperature-Time Combination A. Heat Generation and Delivery in Vivo Protocol temperature may be produced by radiofrequency currents, microwave radiati~on or ultrasound. B. Information to be recorded 1. Description of physical agent (i.e., microwaves, rf, ultra~sound.) 2. Description of frequency (2450 MHz, 915 MHz microwaves, 2 MHz ultrasound, etc.) 3. Type, shape, size, number and placement of~applicators used. 4. Coupling of the applicator to the tissue surface. 5. Total net power delivered to tissue load. 6. If skin temperature is independently controlled, describe method employed.

III. Thermometry Determination of tissue temperature during the application of local and regional clinical hyperthermia will require the use of invasive thermometers. The temperature probes employed should be carefully calibrated, either by c~nparison with commercially calibrated or NBS calibrated thermometers, or from measurements made in enviroments whose temperature is known (e.g. melting temperature of gallium, transition temperatures of hydrated salts in solution). The probes employed in clinical hyperthermia should be able to measure temperature to both an accura~~ and precision of 0.IC. Therefore, the calibrated thermometers or "fixed point" solutions employed must identify temperature to an accuracy and precision of no less than 0.02C. The probes employed to measure temperature in vivo will have thermistor, thermocouple or optical sensors. Utilization of standard thermistor and thermocouple probes in electromagnetic fields can lead to serious errors in temperature determination due to direct heating of the probes via interaction with such (microwave and rf current) fields. The preferred probes to be used to measure temperature in vivo during clinical hyperthermia are optical probes. Both the sensor and the optical fiber "leads" in a given optical probe are electrical insulators and thus, will not be directly heated in electromagnetic fields. In addition, the optical fiber materials are poorer conductors of heat than metallic leads, thus causing less perturbation of the tissue temperatue being measured. It is strongly recommended that once clinically satisfactory optical probes become commercially available, they be utilized as the primary thermometers in RTOG protocols. A. In every hyperthermia session probes to record temperature will be inserted at the following locations: a. Central axis of the tumor at the greatest possible depth. b. At the same maximum possible plane, on both sides of the central axis within 1 cm. from the lateral margin of the tumor. c. At the surface. A diagram indicating the position of the probes shall be submitted with the treatment records. At the investigators discretion, it is recommended that plastic catheters be impl~nted to allo,~ for the insertion of the measuring probes. This will be particularly important when the thermistors or thermocouples are used with rf or microwave generators.

In every patient the following information shall be recorded: Description of probes used to measure temperature (i.e., thermocouples, thermistors, optical probes, etc.) Position of probes in patient (with diagram). Temperature shall be recorded at all points on the appropriate form every 15 minutes with the power shut off (except for optical probes or ultrasound). The temperature at the surface and the greatest possible depth at the central axis of the tumor should be recorded. In addition, chart records for continuous temperature monitoring shall be recommended. With the generator power off the rate of the decrease of the indicated temperature should be noted. to separate the tissue cooling from the direct probe cooling. Projections of the slope of the tissue cooling cure back to the instant of power removal will identify the actual tissue temperature at that time. If catheters are used, the probes should be removed, the generator power shut off and the temperature measurements made after reinsertion of the probe. Following this the generator power will be reapplied and treatment continued. In this case corrections must be made for the dk of tissue temperature during the time interval between power removal and the temperature measurements. The build up of temperature to the specified level by the protocol should be done as quickly as possible (preferably less than five minutes after the power is shut off). At the end of the treatment, the temperature should be recorded in the tumor and ther normal tissues every minute for a period of five minutes or until the temperature is below 39C.

APPENDIX II SKIN SCORING SYSTEM FOR HYPERTHERMIA TRIAL* Acute Reaction: 0 No visible reaction 1.0 Slight, but definite erythema 2.0 Moderate erythema 3.0 Severe erythema (deep red or pink) 4.0 First sign of dry desquamation 5.0 Dry desquamation in over half of field 6.0 Definite moist desquamation, but over less than half the field. 7.0 Moist desquamation over more than half the field 8.0 Complete breakdown of skin with ulceration 9.0 Skin and/or subcutaneous tissue necrosis 10.0 Other LATE SKIN CHANGES The following should be noted at monthly intervals: The development of skin atrophy, desquamation, telangiectasia, temporary or permanent epilation, and loss of sweating (if the volume treated is large enough to permit such a determination). Subcutaneous fibrosis can be measured by placing india ink tatoos at the corners of the treatment portal, or if a circular portal is used, at the corners of a square inscribed in the circle. Measurements of each side, and of the diagonals should be made initially upon completion of tatooing. Late Effects: 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0

No visible or palpable changes Minimal skin depigmentation (atrophy) Minimal subcutaneous fibrosis Loss of sweating Telangiectasia Complete epilation Moderate subcutaneous fibrosis Severe subcutaneous fibrosis Persistent superficial skin ulceration Skin and!or subcutaneous tissue necrosis Other

*Modified from Catteral et al. "An Investigation into the Clinical Effects of Fast Neutrons: Methods and Early Observations" Brit J Radiol 44:603-611, 1971.