John L. Meyer

Stanford University institutional report. Phase I evaluation of equipment for hyperthermia treatment of cancer

From September 16, 1981, through April 4, 1986, a total of 21 radiative electromagnetic (microwave and radiofrequency), ultrasound and interstitial radio-frequency hyperthermia applicators and three types of thermometry systems underwent extensive phantom and clinical testing at Stanford University. A total of 996 treatment sessions involving 268 separate treatment fields in 131 patients was performed. Thermal profiles were obtained in 847 of these treatment sessions by multipoint and/or mapping techniques involving mechanical translation. The ability of these devices to heat superficial, eccentrically located and deep-seated tumours at the major anatomical locations is evaluated and the temperature distributions, acute and subacute toxicities, and chronic complications compared. Average measured tumour temperatures between 42 degrees C and 43 degrees C were obtained with many of the devices used for superficial heating; average tumour temperatures of 39.6 degrees C to 42.1 degrees C were achieved with the three deep-heating devices. When compared to the goal of obtaining minimum tumour temperatures of 43.0 degrees C, all devices performed poorly. Only 14 per cent (118/847) of treatments with measured thermal profiles achieved minimum intratumoural temperatures of 41 degrees C. Fifty-six per cent of all treatments had associated acute toxicity; 14 per cent of all treatments necessitated power reduction resulting in maximum steady-state temperatures of less than 42.5 degrees C. Direct comparisons between two or more devices utilized to treat the same field were made in 67 instances, including 19 treatment fields in which two or more devices were compared at the same treatment session. The analyses from direct comparisons consistently showed that the static spiral and larger area scanning spiral applicators resulted in more favourable temperature distributions. Three fibreoptic thermometry systems (Luxtron single channel, four channel and eight channel multiple [four] probe array), the BSD Bowman thermistor system and a thermocouple system were evaluated with respect to accuracy, stability and artifacts. The clinical reliability, durability, and patient tolerance of the thermometry systems were investigated. The BSD Bowman and third generation Luxtron systems were found clinically useful, with the former meeting all of our established criteria.

Experience with a Multitransducer Ultrasound System for Localized Hyperthermia of Deep Tissues

A system employing six planar ultrasound transducers has been utilized for preclinical and pilot clinical studies with the aim of producing therapeutic heating preferentially at depth. The array consists of six 7 cm diameter PZT-4 disks mounted on a spherical shell section with a 26 cm radius of curvature. The crystals operate at different frequencies a few kilohertz above their fundamental frequencies of approximately 350 kHz for near-field peak suppression, and each has a few percent modulation to minimize standing wave effects. In water, the system can be focused to produce a high intensity region near the isocenter with a full width half maximum of approximately 1.5 cm in all directions. In attenuating tissue, the high intensity region is closer to the array of transducers by a few centimeters. For heating of realistic tumors at depth, small wedges are used to rotate the transducer axes a few degrees away from the radial direction, yielding a waist rather than a single point where the individual beam central axes come closest to each other. The waist is 3-6 cm in diameter, producing, ideally, ellipsoidal shaped temperature distributions centered deep in perfused tissue. Quantitative power deposition profile mapping, as well as qualitative studies using liquid crystal sheets, have been performed in water phantoms to characterize the system for different transducer orientations.

Two or six hyperthermia treatments as an adjunct to radiation therapy yield similar tumor responses: results of a randomized trial.

From March 1984 to February 1988, 70 patients with 179 separate treatment fields containing superficially located (less than 3 cm from surface) recurrent or metastatic malignancies were stratified based on tumor size, histology, and prior radiation therapy and enrolled in prospective randomized trials comparing two versus six hyperthermia treatments as an adjunct to standardized courses of radiation therapy. A total of 165 fields completed the combined hyperthermia-radiation therapy protocols and were evaluable for response. No statistically significant differences were observed between the two treatment arms with respect to tumor location; histology; initial tumor volume; patient age and pretreatment performance status; extent of prior radiation therapy, chemotherapy, hormonal therapy, or immunotherapy; or concurrent radiation therapy. The means for all fields of the averaged minimum, maximum, and average measured intratumoral temperatures were 40.2 degrees C, 44.8 degrees C, 42.5 degrees C, respectively, and did not differ significantly between the fields randomized to two or six hyperthermia treatments. The treatment was well tolerated with an acceptable level of complications. At 3 weeks after completion of therapy, complete disappearance of all measurable tumor was noted in 52% of the fields, greater than or equal to 50% tumor reduction was noted in 7% of the fields, less than 50% tumor reduction was noted in 21% of the fields, and continuing regression (monotonic regression to less than 50% of initial volume) was noted in 20% of the fields. No significant differences were noted in tumor responses at 3 weeks for fields randomized to two versus six hyperthermia treatments (p = 0.89). Cox regression analyses were performed to identify pretreatment or treatment parameters that correlated with duration of local control. Tumor histology, concurrent radiation doses, and tumor volume all correlated with duration of local control. The mean of the minimum intratumoral temperatures (less than 41 degrees C vs. greater than or equal to 41 degrees C) was of borderline prognostic significance in the univariate analysis, and added to the power of the best three covariate model. Neither the actual number of hyperthermia treatments administered nor the hyperthermia protocol group (two versus six treatments) correlated with duration of local control. The development of thermotolerance is postulated to be, at least in part, responsible for limiting the effectiveness of multiple closely spaced hyperthermia treatments.

Parameters predictive for complications of treatment with combined hyperthermia and radiation therapy

Pretreatment and treatment related factors were reviewed for 996 hyperthermia sessions involving 268 separate treatment fields in 131 patients managed with hyperthermia for biopsy confirmed local-regionally advanced or recurrent malignancies to ascertain parameters associated with the development of complications. A subset of 249 fields were identified in which multipoint or mapped temperature data were available for at least one treatment session per field. A total of 198 fields involved superficially located tumors (less than or equal to 3 cm from the surface), whereas 51 fields involved more deeply located tumors. Most of these patients had received extensive prior therapy: 77% had surgery, 75% chemotherapy, 65% radiation therapy and 28% hormonal therapy. They were treated with hyperthermia in conjunction with radiation therapy (244 fields) or hyperthermia alone (5 fields). The hyperthermia treatment objectives were to elevate intratumoral temperatures to a minimum of 43.0 degrees C for 45 minutes while maintaining maximum normal tissue temperatures to less than or equal to 43 degrees C and maximum intratumoral temperatures to less than or equal to 50 degrees C. The hyperthermia was given within 30 to 60 minutes following radiation therapy without the administration of additional analgesics. Hyperthermia treatment regimens using radiative electromagnetic, ultrasound, or radiofrequency interstitial techniques were individualized, with 3 to 4 days between hyperthermia treatments and an average of 3.6 treatments (range 1-14; standard deviation 2.2) utilized per field. A total of 38 complications in 33 treatment fields were noted; an incidence of 27/198 (13.6%) for fields with superficially located tumors, and 6/51 (11.8%) in fields with more deeply located tumors. Univariate analyses demonstrated statistically significant correlations between the maximum tumor temperature (p = 0.0005), average of the maximum tumor temperatures (p = 0.0006), the average of the % tumor temperatures greater than 43.5 degrees C (p = 0.0071), and the average number of hyperthermia treatments (p = 0.033), with the development of complications. The average of the maximum measured tumor temperature for fields without complications was 44.6 degrees C compared with 45.9 degrees C for fields with complications. The complication rate increased from 7.5% (9/120) in fields that received one or two hyperthermia treatments to 18.6% (24/129) in fields that received greater than two hyperthermia treatments. Multivariate logistic regression analyses revealed the best bivariate model predictive of the development of complications included average of the maximum tumor temperature and the number of treatments per field (p = 0.00012 for the bivariate model).(ABSTRACT TRUNCATED AT 400 WORDS)

The significance of thermotolerance after 41°C hyperthermia: In vivo and in vitro tumor and normal tissue investigations☆

Abstract We have investigated the development of thermotolerance in both tumors and normal tissues after 41°C for durations as brief as 15 minutes. The murine RIF tumor, treated by both local radiofrequency and systemic methods, was assayed for thermotolerance by both tumor growth and cell survival analyses. The murine leg and ear, treated by conductive methods, were assayed using pre-defined tissue damage scoring systems. All of these treatments quickly induced substantial levels of thermotolerance. In the tumor studies using local heating, RIF mean diameter doubling time decreased from 17.8 days to a minimum of 13.0 days with a 9 hr interval between 41.0°C for 15 minutes and 44.0°C for 30 minutes (9 hr D 1 –D 2 ); cell survival increased from 1.2 × 10 −2 to 3.4 × 10 −1 (same interval). Both assays showed some degree of tolerance present immediately after 41.0°C for 15, 30 or 60 minutes (0 hr D 1 –D 2 ). In the tumor studies using systemic heating, the kinetic pattern of the induced tolerance was similar to that observed after local heating. In the leg studies, 41.0° for 30 minutes increased the time at 45°C necessary to induce a specified level of tissue damage (mean score of 7) by a maximum of 1.8 times (24 hr D 1 –D 2 ). The kinetic pattern was similar to that for the tumors. In the ear studies, 41.0°C for 30 minutes increased the time at 45°C necessary to induce ear necrosis in 50% of animals by a maximum of 3.5 times (48 hr D 1 –D 2 ). The peak tolerance level occurred later for the ears, which have a lower normal temperature of 28–30°C, than for the tumors or legs. These results indicate that: 1. thermotolerance can begin to appear in tumors during treatment if hyperthermia sessions involve initial low thermal exposures (near 41°C) for 15 minutes or longer; 2. thermotolerance can develop in tumors after systemic heating and occurs with a kinetic pattern similar to that following local heating; and 3. normal tissues also can develop high levels of thermotolerance after similar thermal exposures.

Whole-lung irradiation for Kaposi's sarcoma

Twenty-five patients were treated with whole-lung irradiation for symptomatic pulmonary KS. Treatment was most often given four days per week, 150 cGy per fraction, to 1050–1500 cGy (mean 1224 cGy). No acute toxicity was observed. 89% of patients completing therapy reported improvement in dyspnea. All patients responding symptomatically could reduce (and 78% could eliminate) oxygen use. Chest x-rays showed concurrent improvement in 78% of cases, although this was 50% clearance of infiltrate in only 28%. Symptomatic improvement was prompt, always occurring during the 2–2 1/2 week therapy course. Clinical response was transient in some patients, but 12 weeks after therapy 56% remained symptomatically improved. Pulmonary KS indicated an advanced stage of AIDS and survival was short (mean: 15.7 weeks after completion of therapy). Patients with poor performance status (Karnovsky: 30%) and progression of disease despite chemotherapy had very short survival (mean: 3.2 weeks). For such patients, a supportive care only approach without radiotherapy is suggested. For others, whole-lung irradiation provides prompt symptomatic improvement for most patients, and offers a simple treatment approach with little toxicity for often debilitated patients.

Nasopharyngeal Carcinoma: A Study Examining Asian Patients Treated in the United States

1972 to 1991, 126 Asian patients with nasopharyngeal carcinoma underwent definitive radiation therapy for locoregional disease: 86 men, 40 women. Median age was 50. All patients received external-beam irradiation with cobalt 60 or 4–18 MV x-rays. Local recurrence, regional recurrence, and distant metastases were 22%, 11%, and 23%, respectively. Local recurrence progressively increased with increasing T stage, but doses in those who recurred did not differ from the group as a whole. Regional recurrence was not associated with T or N stage or dose. Patients with N2 disease had the highest distant metastatic rate. The 5− and 10-year overall survival rates were 54% and 38%, respectively. Of age, gender, and histology, only age less then 50 was found to be favorably prognostic. No severe long-term complications were observed, and acute reactions were acceptable. Our survival results are comparable with results found both in Asia and North America. Nonetheless, altered fractionation techniques and/or other radiation modalities should be further explored to improve locoregional control.