Med. Oncol. & Tumor Pharmacother. Vol. 2, No. 1, pp. 55-57, 1985 0736--0118/83 $3.(~ + .00 Printed in Great Britain Pergamon Press Ltd.

MEETING REPORT

Fourth Annual Sanrocco International Cancer Symposium

TREATING CANCER WITH HEAT

The meeting, under the protection of the Italian Health Ministry, was kept jointly with the Fifth Annual Meeting of the International Clinical Hyperthermia Society. It was organized by P. Pontiggia, Sanrocco Clinic, and chaired by J. McLaren, Emory University and H. Le Veen, University of South Carolina.

An appreciable portion of the scientific program was devoted to the inter-relationships of hyperthermia and immunocompetence. Other subjects included bioheat transfer mechanisms, thermosensitivity and thermotoler- ance, biological effects of heat, methods to increase the effectiveness of heat, thermometry, specifications and uses of current commercial heat generators and adjuvant clinical applications of hyperthermia to surgery, chemotherapy and radiation. Approximately 50% of those papers presented covered the basic fundamentals of hyperthermia whereas the other 50% was devoted to the clinical applications.

TECHNOLOGY

Data by B. Southcott of London, England, demonstrated modifications in the blood flow through the heated volume, which resulted in alteration of temperature distributions upon subsequent hyperthermia. In contrast to the increased blood flow a tdepth , there was a decrease at superficial levels, which may influence clinical responses during fractionated hyperthermia. Together with K. Gammampila she demonstrated a multi- thermocouple needle probe designed for specific use with a microwave-shielded, computer-based thermometry system used with 434 MHz generators.

P. Dunscombe of Winnipeg, Canada discussed the difficulties of phantom design particularly in relation to absorption patterns of coherent microwave beams and tissue structures.

G. Ibbott of Denver, Colorado, covered the many problems encountered with thermometry, including radiometry, ultrasound and nuclear magnetic resonant imaging, infra-red photography, and techniques for estimation of temperatures within a given volume of tissue based upon the bioheat equation. R. Shupe, Indianapolis, Indiana, summarized the use of metallic temperature probes.

I. Kruzela of Lurid, Sweden discussed the clinical applications of a proportional integrating derivating (PID) computer control based on temperature measurement to regulate optimum power. Decisions are based on feedback, prediction by tangential extrapolation, and interval action. This computer control has been integrated into a clinical microwave hyperthermia system.

I. Brezovich, Birmingham, Alabama, gave an analysis of the three fundamental methods by which microwave electrical fields may be applied to patients (i.e. circumferential, longitudinal, and normal) and related various available commercial units to his idealized models.

Raymond U, Durham, North Carolina presented specifications of the thermatron hyperthemia generator, its isotherm patterns in a phantom, early results in a canine model, and the clinical results obtained by a number of investigators in Japan.

P. Lele of Cambridge, Massachusetts, discussed the various attenuation characteristics of ultrasound, which permit its focusing to a small volume at mid-body plan depths. He also discussed the relative merits of ultrasonic electromagnetic technology under various conditions and the possible obtainable results.

PROSTAGLANDINS AND LYMPHOCYTES

D. Krag, Los Angeles, California, data-correlated levels of prostaglandin (PGE2) with the development of heat resistance in various melanoma cell cultures. Such heat resistance could be reversed by the addition of indomethacin and re-appeared with the addition of prostaglandin.

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Blastogenesis of lymphocytes was adversely affected by increased temperatures, and further reduced at a low pH in data presented by J. McLaren, Atlanta, Georgia. The mixed lymphocyte reaction, applicable to in vivo situations, was inhibited by approximately 50% at 43~ for 30 min. No significant inhibition was found at 42~ for 30 min, but it was found after 90 min. Inhibition was less pH-dependent than blastogenesis. M. Skeen also found that, while exposure of lymphocytes to 41~ or 42~ for 30 min produced no statistically significant inhibition of blastogenesis, incubation at 43~ resulted in a response decrement of approximately 50%.

S. Szmigieiski, Szaserow, Warsaw, showed in mice that whole body microwave hyperthermia resulted in a slight and short-lasting (about 4 days) stimulation of cell-mediated immune functions and NK activity, followed by a dramatic (although transient) reduction. Local microwave heating, in contrast, led to enhancement of the delayed hypersensitivity reaction.

ANIMAL STUDIES

E. Lengfelder, University of Munich, discussed the mechanism of radiotherapy, adriamycin, and bleomycin action via activated oxygen species such as superoxide or hydroxyl radicals. In the xanthine oxidase model, hyperthermia can likewise produce superoxide radicals.

Szmigielsky found, in animals, it was also documented that thermotherapy potentiated radiotherapy anti-tumor effects. This was supported by J. Overgaard, Copenhagen, who had compiled literature response figures in melanoma and various other non-stratified tumors suggesting better effects of radiation plus heat than of radiotherapy alone.

G. Hahn, Stanford University, clearly showed synergism between heat and cytostatics in animal tumors. Cures depend on satisfactory temperatures in the coldest part of the tumor.

CLINICAL STUDIES

N. Hornback, University of Indiana, had reviewed records of 78 patients with primary untreated stage III-B carcinoma of the cervix. Seventeen patients who received heat in combination with radiation had a possibly better local tumor control, but no longer survival. Of 85 malignant melanoma lesions 74 responded to high energy photon, electron, and X-rays, and hyperthermia. Of 21 patients 2 did not respond to treatment.

A. Puthawala, Memorial Medical Center, Long Beach, California, had treated 50 patients with head and neck, pelvis and breast carcinoma with microwave antennae in hollow Teflon guide needles. Tumors were heated to between 41 and 43~ for a period of 60 min. Complete regression was claimed in 85% of the patients who had a minimum follow up period of three months. The rest of the patients had at least 50% or greater tumor regression.

H. Bicher, Los Angeles, California, claimed high tumor response rates among patients with unspecified tumors after 1600-5000 rads plus thermotherapy. Of 144 evaluable patients (total about 300 patients) there were 132 total and 65 partial responses. He presented data demonstrating that hyperthermia produces collapse of the microcirculation and discussed the potential clinical significance of microcirculation.

W. Krueger of Dresden, East Germany, demonstrated effects of inhibition of microcirculation with tumor heating and the importance of pH and temperature upon erythrocyte fragility.

G. Arcangeli, Rome, reviewed different modalities of combinations of heat and radiation (64-87% responses) as compared to heat alone (33-37%), on different, not always strictly comparable lesions in melanoma patients.

F. Storm, UCLA, California, reported on seven U.S.A. institutions who had performed 14,807 phase I-II treatments of magnetic-induction hyperthermia in 1170 adults with advanced tumors. Results in 960 evaluable patients were CR 9% (duration 1-34 months, 7 months median), PR 18% (1-39 months, 4 months median), MR 10% (1-15% months, 3 months median) no change 33% (1-32 months, 3 months median), with pain relief in 30% and improved activity in 21%.

N. Yamanaka, Bio-Dynamics Research Institute, Shinseikai Foundation, Nagoya, had combined, in advanced tumors, a phase I study of chemotherapy, sometimes radiation, and extracorporeally induced total body hyperthermia. Response rates were 43-57%. Several responses were in lymphoma and nasopharyngeal and renal cancer. No control group. Survivals varied between 1 and 12 months. Bone marrow depression and alopecia were observed.

R. Falk, Toronto General Hospital, had given about 150 evaluable and 129 inevaluable patients with liver metastases of various tumors heat plus cytostatics, achieving a tumor temperature of 39.7~ Eighty-six patients

Meeting Report 57

died after 3-76 weeks, while others have been followed for an average of 6 months. Between 16 and 78% of patients in different stages showed a partial response. Toxicity was low. In preliminary results of a prospective, randomized study of colorectal cancer with metastases, chemotherapy alone was less effective than that associated with heat.

N. Estes, Indiana University, had treated four patients with uncontrolled rectal cancer recurrences, who had pain as a major feature, with 5FU in the iliac arteries and microwave hyperthermia. All patients had a partial response and pain relief.

R. Page, Mid-South Cancer Research Foundation, Memphis Tennessee, had also treated 17 metastatic patients with diathermy plus chemotherapy or radiation. Fifteen patients had a partial response. Several similar cases were reported by Le Veen, University of South Carolina.

M. Vaglini, National Tumor Institute, Milan, showed literature data on perfusion hyperthermia combined with melphalan on malignant melanoma lesions on the extremities. Five year survivals were about 40% in stage II and 22% in stage III A and B. He had severe complications in many of his own 15 patients, however, with a temperature of 42~ less at 40-41~ with 42 patients. O f these melanoma patients 25% had partial remissions.

P. Pontiggia, Sanrocco Clinic, Como, had treated 250 patients with inoperable solid tumors with a combination of hyperthermia and chemotherapy (CR 5.1%, PR 42.3%) or immunostimulation (CR 52.8%, PR 12.8%).

CONCLUSIONS

This meeting seems to show that while technical problems connected with heat treatment of deep-seated tumors is being studied with advanced and adequate methods, and while there is some animal evidence for synergism between heat, radiation, and cytostatics, there is not yet convincing evidence that this new form is reproducibly beneficial in the clinical situation. The reason is that it is difficult to distinguish between the effects of heat and those of simultaneously giyen radiation or drugs. However, on-going controlled studies hold promise of answers rather soon.

PETER REIZENSTEIN JOHN McLAREN

CLAUDIO OGIER