interaction between microwave-induced brain hyperthermia and high dose rate radiation in the bt4an...

Journal of Neuro-Oncology 27: 205-214, 1996. © 1996 Kluwer Academic Publishers. Printed in the Netherlands.

Laboratory Investigation

Interaction between microwave-induced brain hyperthermia and high dose rate radiation in the BT4An brain glioma in rats

BMd Kronen Krossnes, ~ Baard-C. Schem, j Britt Nygaard, 20lav Dahl 1 and Olav Mella 1 1 Department ofOncology, Haukeland Hospital, University of Bergen, N-5021 Bergen, Norway; 2 Department of Radiophysics, Haukeland Hospital, University of Bergen, N-5021 Bergen, Norway

Key words: BT~An, glioma, hyperthermia, microwave, radiotherapy

Summary

The cerebral BT4An glioma model in BD IX rats was used to study the effect of hyperthermia given in combination with radiotherapy (thermoradiotherapy) in the treatment of brain tumours. A single treatment with high dose rate radiation was given to a local brain field. Local brain hyperthermia was given at 42.4 ° C for 45 min by externally applied microwaves (700 MHz), immediately before radiotherapy (10 Gy).

In a pilot study, thermoradiotherapy increased the median life span with 20 days compared to controls, which was significantly better than that observed after radiotherapy alone (7 days). In an extended experiment the corresponding figures for thermoradiotherapy, hyperthermia alone and radiotherapy alone were 12.5, 3.5, and 3.5 days, respectively. Thermoradiotherapy was significantly better than radiotherapy and hyperthermia alone. There was no acute mortality in these experiments. Neurological side-effects were infre- quent, of slight degree and reversible. The present study shows that a survival benefit of adding hyperthermia to radiotherapy can be achieved without unacceptable neurological side-effects in an animal glioma model.

Introduction

Radiotherapy has a documented effect on aggres- sive gliomas, but does not prevent a poor outcome of the disease [1]. Hyperthermia acts as a radiosen- sitiser in both rodent [2] and human [3] glioma cell lines in vitro, the most important mechanism probably being inhibition of repair of radiation induced DNA-damage. Hyperthermia itself is cytotoxic, es- pecially affecting cells in a nutrient deprived envi- ronment with a low pH, which may exist near ne- crotic areas in turnouts [4].

The therapeutic effect of hyperthermia given in combination with radiotherapy (thermoradiotherapy) in the treatment of human brain tumours, has been evaluated in several clinical trials during the

last decade [5-11]. The results have so far been in- conclusive, but a trend towards improved survival when a homogenous and good tumour heating is achieved suggests that hyperthermia may be of benefit in prolonging local control of brain tumours [5, 11].

A particular problem associated with hyperthermic treatment of brain tumours is the low tolerance for heat in the normal brain tissue. Detailed knowledge about human brain tolerance is still lacking [12], but animal studies indicate that significant brain injury can be induced if the temperature exceeds 42-42.5°C for 40-60 min or 43°C for 30 min [13-16]. Whether there is a therapeutic gain of adding hyperthermia to other treatment modalities can therefore only be examined when the glio-

Presented in part at the meeting of the European Society for Hyperthermic Oncology (ESHO), Brussels, June 17, 1993

206

ma is located in the vulnerable brain tissue. Thus studies in cerebral animal glioma models may be an important link between in vitro studies and clinical studies.

We have previously described a transplantable, glioblastoma-like brain tumour in syngeneic BD IX rats [17]. Earlier studies in this model have shown a prolongation of survival with moderate side-effects, in animals given hyperthermia to the tumour- bearing part of the brain, together with i.p. BCNU [18] and ACNU infused intravenously or intraarte- rially to the brain [19, 20]. The purpose of the present study was to examine if a survival benefit can be achieved without unacceptable side-effects by adding local hyperthermia to a single dose of radiation, administered at a high dose rate in the cerebral glioma model.

Materials and methods

Animals, tumour and anaesthetics

Male rats of the inbred strain BD IX were used. The tumour implantation procedure has been published earlier [18]. Briefly, exponentially growing BT4Cn cells were harvested from cell culture, stained with trypan blue (0.4%), and counted in a Btirker cham- ber. A volume of 5 gl containing 0.5 x 10 s viable cells diluted in 1% methylcellulose, was manually injected with a Hamilton syringe 3 mm into the right frontal lobe.

Before tumour implantation, radiotherapy, hyperthermia and sham treatment, the animals were given the compound anaesthetic midazolam/fentanyl/fluanisone s.c. in a dosage of midazolam 1.25 mg/kg, fentanyl 0.05 mg/kg, and fluanisone 2.5 mg/kg. When prolonged anaesthesia was necessary, half the initial dose was given with 20 min interval.

Radiotherapy

Radiotherapy to the brain was given by a field mea- suring 2.3 x 2.3 cm, with shielding of the cerebellum and part of the left hemisphere. Photon radiation

(4 MV) was given at a dose rate of 3 Gy/min. A 2 cm scalp skin incision was made along the sagittal suture on the anaesthetised animal, exploring the implantation hole. The animal was then fixed in a restrainment frame, with the field centre at the implantation hole. To achieve full dosage at the skin level a one cm bolus (Superflab) was fixed to the rat head. Six thermoluminescent dosimetry measure- ments, each with three LiF rods encapsulated in perspex, were performed in sacrificed rats to con- firm that the brain just beneath the cranium re- ceived the prescribed dose.

Hyperthermia

Hyperthermia was given by externally applied microwaves (700 MHz). The basic equipment was the BSD-1000 clinical hyperthermia system (BSD Med- ical Corporation), connected to a locally built applicator with a physical aperture of 2 x 3 cm as described earlier [18]. The applicator was circulated with deionised, thermostatically controlled water (31.4 ° C, range 31.2-31.6 ° C) for surface cooling.

Before treatment, the scalp skin was incised and the rat fixed in the same way as during radiotherapy. Atropine 0.06 mg/kg was given subcutaneously before hyperthermia to prevent respiratory distress. The animal was placed on a heating pad to keep the rectal temperature between 36 and 38°C during treatment. In the survival experiments a single Bowman probe was inserted at a 45 ° angle with the horizontal plane, 4 mm length in a lateral to medial direction through the burr hole used for tumour implantation. The temperature sensitive tip was then located at 2.5 to 3 mm depth into the brain, near the medial periphery of the tumours. This probe will from now on be referred to as the control probe. The applicator was placed in good contact with the scalp, with the field centre at the burr hole.

Hyperthermia was given for 45 min at 42.4 ° C. Brain, rectal and cooling water temperature was registered during the hyperthermia treatment, and average temperatures were calculated with the BSD-1000 software package, as was induction time and average power after achievement of the desired temperature.

Immediately after treatment the animals were given 0.90mg betamethason subcutaneously to prevent cerebral oedema. The steroid solution (Ce- leston Chronodose, R. Schering-Plough) contains a fast acting component and a salt with prolonged ac- tion. Earlier studies with this model have shown that this steroid dose has no influence on the survival time of sham treated tumour-inoculated animals (unpublished results).

Temperature profile mapping during hyperthermia treatment

The main disadvantage with rat brain models is the small animal size, which greatly restricts probe in- sertion for thermometry. In the survival experiments, only one probe was used in order to limit brain trauma. To get a more detailed knowledge about the temperature profile in the brain during the hyperthermia treatment, fifteen rats without turnout were used for temperature profile mapping. In these experiments a second temperature probe (mapping probe) was inserted into the brain in addition to the control probe, which was placed as described above. Five animals were used for measure- ments with the mapping probe in each of three positions, A, B and C, as illustrated in Fig. 1. As in the survival experiments the BSD system was pro- grammed to keep the brain temperature measured by the control probe at 42.4 ° C. The temperatures measured by the mapping probe, after 10 min stabilisation, were compared statistically with the control probe temperature by the Mann-Whitney test. The animals were sacrificed after the experiment.

Evaluation of tumour size on day 7post-implantation

In a separate experiment, ten rats were given sham hyperthermia treatment 7 days after tumour implantation. India ink was used to mark the tip of the temperature probe in 6 of the animals. After the sham treatment, the brains of these six animals were examined macroscopically for assessment of the tumour size and the spatial relationship be-

207

tween the tumour and the temperature probe, and microscopically to document the presence of an in- vasive tumour.

Survival experiments

The survival experiments were performed 7 days after tumour implantation. In all experiments the animals were stratified after implantation order, and then randomised to the different treatment groups. The average body-weight was 363 g, with minor variation between the different experiments.

In Exp. 1, the dose-response relationship for radiotherapy alone was established. Fifty rats were given sham procedure (fixation in restrainment frame), 8 Gy, 12 Gy, 16 Gy, or 20 Gy radiotherapy to the brain. The maximal dose of 20 Gy was chosen after a dose escalation study on rats without turnout, showing 100% 12 months survival of 10 rats after 20 Gy to the brain, whereas 6 of 10 rats given 24 Gy died within a month, probably because of acute oral/pharyngeal side effects.

In a pilot study on thermoradiotherapy (Exp. 2a), 16 animals were given sham procedure, radiotherapy alone (10 Gy) or thermoradiotherapy. In Exp. 2b, a hyperthermia alone group was included, and a total of 40 rats were given sham procedure, hyperthermia alone, radiotherapy alone (10 Gy) or thermoradiotherapy. To make the interval between the two treatment modahties as short as possible, radiotherapy was given after hyperthermia in the thermoradiotherapy group. The gap between the two treatments never exceeded 2 min. Sham hyperthermia treatment was given to the control and radiotherapy alone groups by inserting the temperature probe into the brain and placing the applicator for 2 min. All animals in Exp. 2 were given betamethason after treatment as described above.

The rats were observed and weighed daily. At signs of tumour recurrence, like passivity, weight loss, or reduced co-ordination of movement, the rats were sacrificed. 'The brain was removed, and the presence of a large tumour in the right hemisphere resulting in mid-line shift to the left was con- firmed by macroscopic examination. The relative weight at nadir after treatment (the lowest weight

208

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before stabilisation or weight regain) was calculated as a measure of treatment related weight loss. Survival was defined as time from tumour implantation to sacrifice. Weight loss, and treatment parameters in the different groups were compared statistically by the Mann-Whitney test. The Mann- Whitney test could also be used in the analysis of survival as there were no censored observations.

Results

Temperature profile mapping during hyperthermia treatment

The temperature probe positions during temperature profile mapping are illustrated in Fig. 1. In position A, which corresponds to the tumour centre, the median temperature was 43.7 ° C (range 43.5 to

209

N Mapping

Applicator Control I ~ I I [

i m p l a P i ~ o / ~ I /mfrantation { / Mapping

[ 5 mm ~ / probe hole ~ C r a n i u ~ ; < 5 m m / , ~ ' - ~ - ~ " '

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C I Procedure viewed from above II Parasagittal section through the implantation hole

Fig. 1, Temperature profile mapping during hyperthermia. Mapping was performed in three different positions A, B, and C. As in the survival experiments, the temperature at the control probe was kept stable at 42.4 ° C. In position A the tip of the mapping probe was located 3 mm into the brain beneath the implantation hole, which corresponds to the tumour centre. In position B, the tip of the mapping probe was located 3 mm lateral to the site of tumour implantation, which corresponds to the lateral periphery of the tumours. In position C, the tip of the mapping probe was located 5 mm into the brain beneath the implantation hole.

44.8 ° C), which was significantly higher than the control probe tempera ture of 42.4 ° C (p < 0.01).

In position B, which corresponds to the lateral periphery of the turnouts, the median tempera ture was 42.8 ° C (range 42.3-43.4 ° C), which did not differ significantly f rom the control probe temper-

ature. In position C, at 5 m m depth beneath the implan-

tation hole (2 m m deeper than position A) the median tempera ture was 43.6 ° C (range 42.7- 44.3 ° C), which was significantly higher than the control probe tempera ture (p < 0.01).

Evaluation of tumour size on day 7 after implantation

All six animals had macroscopically visible tumour seven days after tumour implantation, with a median diameter of 2 m m (range 1.5-4 mm). The tip of the tempera ture probe was located at a depth of 2.5-3 m m into the brain, near the medial periphery of the tumours. Microscopic examination con-

firmed the presence of an infiltratively growing tumour in all six brains.

Survival experiments

Experiment 1: Radiotherapy alone The survival of animals following single dose radiotherapy is shown in Fig. 2. The median survival t ime (MST) was 17 days in the control group, 21.5 days in the 8 Gy group, 24.5 days in the 12 Gy group, 27

days in the 16 Gy group, and 40.5 days in the group given 20 Gy. All groups given radiotherapy had a longer MST than the control group (p < 0.01, all groups).

The relative weight at nadir after t reatment was significantly lower in the 20 Gy group than in the control group (0.84 and 0.98 on an average respectively, p < 0.01). The weight loss in the other groups did not differ significantly f rom that in the control group. Post-mortem ,examination of all the brains showed large expansive tumours with mid-line shift.

210

EXPERIHENT 1: RADIOTHERAPY ALONE

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Fig. 2. Survival of rats with BT4An brain tumours after single dose radiotherapy given on day 7 after tumour implantation.

Experiment 2a: A pilot study on thermo radiotherapy There was no treatment related mortality. One animal given thermoradiotherapy developed a tendency to rotate on the day after treatment, when elevat- ed from the ground. The rat did however walk nor- mally in the cage. The rotation tendency faded off

after a few days. The weight loss and the hyperthermia treatment parameters are given in Table 1. There was no significant difference in weight loss between the three groups.

The survival after tumour implantation in this experiment is shown in Fig. 3. The MST was 16.5 days

Table 1. Parameters registered in the thermoradiotherapy experiments. Mean values; range given in parenthesis

Treatment Number Relative weight Regain of Average brain Rectal temp. Induction time Power at group of rats at nadir after pretreatment control temp. (° C) (rain : s) control

treatment weight (o C) temp. (W)

Experiment 2a Control 4 0.89 0/4

(0.85-0.91) Radiotherapy 6 0.89 0/6 alone (0.88-0.90) Thermoradio- 6 0.86 3/6 therapy (0.85-0.88)

Experiment 2b Control 10 0.89 1/10

(0.83-0.99) Radiotherapy 10 0.90 1/10 alone (0.85-0.96) Hyperthermia 10 0.87 0/10 alone (0.82-0.95) Thermoradio- 10 0.87 4/10 therapy (0.85-0.92)

42.3 37.7 1:04 64 (42.3-42.3) (37.3-38.2) (0:40-1:50) (61-68)

42.3 37.8 1:23 67.2 (42.2-42.3) (37.5-38.2) (0:30-2:40) (62-86) 42,3 38.1 1:20 69.8 (42.3-42.3) (37.3-38.8) (0:30-2:30) (60-82)

EXPERIMENT 20:PILOT STUDY ON THERHORADIOTHERAPY

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211

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Fig. 3. Survival of rats with BT4An brain tumours after radiotherapy (RT), hyperthermia (HT), thermoradiotherapy (HT + RT) or sham treatment (control) given on day 7 after turnout implantation.

in the control group, 23.5 days in the 10 Gy alone group and 36.5 days in the thermoradiotherapy group. Thermoradiotherapy thereby increased the life span by 20 days, as compared with controls, whereas the corresponding figure for radiotherapy alone was 7 days (p < 0.01, both groups). The animals in the thermoradiotherapy group lived significantly longer than those given radiotherapy alone (p < 0.01). Post-mortem examination of all the

brains showed large expansive tumours with mid- line shift.

Experiment 2b: Thermoradiotherapy There was no treatment related mortality. One rat given hyperthermia alone developed adduction of the left forelimb upon elevation from the ground, two days after treatment. This sign disappeared in two days. The weight loss and the hyperthermia

212

treatment parameters are given in Table 1. There was no significant difference in weight loss between the four treatment groups. There was no significant difference in any of the hyperthermia treatment parameters between the hyperthermia alone group and the thermoradiotherapy group.

The survival after tumour implantation in this experiment is shown in Fig. 3. The MST was 15 days in the control group, 18.5 days in the radiotherapy group, 18.5 days in the hyperthermia alone group and 27.5 days in the thermoradiotherapy group. Thermoradiotherapy thereby increased the median life span by 12.5 days compared to controls, whereas the corresponding figure was 3.5 days both for hyperthermia alone and radiotherapy alone (p < 0.01, all groups). The animals in the thermoradiotherapy group lived significantly longer than those given hyperthermia or radiotherapy alone (p < 0.01, both groups).

All rats except one were sacrificed because of signs of tumour recurrence, the post-mortem examination showing expansive tumours in the right hemisphere with midline-shift. The longest living rat in the thermoradiotherapy group had to be sacrificed after 58 days because of a large subcutaneous tumour above the implantation hole. Examin- ation of the brain revealed a small scar beneath the implantation hole. No cerebral tumour was seen on microscopic examination.

Discussion

In the present study, a dose-dependent prolongation of survival after single doses of radiation (8- 20 Gy) to the brain was found in the BT4An cerebral glioma model. The prolongation of survival, compared to controls, at the different radiation dose levels in this model is comparable to that re- ported by Henderson et al. [21], from experiments with the 9L gliosarcoma model. The dose-dependent response to radiotherapy indicates that the BTgAn glioma model is suitable for radiotherapy research.

In two independent experiments, we have shown that the addition of hyperthermia to single dose radiation increases the life span of rats with BT4An

gliomas above that achieved after radiation alone. Thermoradiotherapy gave, in Exp. 2b, a prolongation of the median survival compared to controls, which was more than three times longer than that observed after each of the two treatment modalities alone. Of particular interest is the occurrence of long-time survivors in the thermoradiotherapy group in both experiments, which was not found in any of the other groups. One rat was probably cured of the cerebral tumour, but had to be sacrificed due to a subcutaneous relapse on the vertex. In this rat, tumour cells unintentionally seeded near the implantation hole may have survived the thermoradiotherapy due to cooling of the scalp by the applicator during hyperthermia. Subcutaneous tumours at the vertex were also found at sacrifice in some of the other long time survivors. This strongly suggests that immunological mechanisms have not contrib- uted significantly to the prolongation of survival after thermoradiotherapy. The fact that there is 100 % tumour-take in this model and that preimmunisa- tion does not alter the symptom-free period after intracerebral implantation of low numbers of tumour cells also indicate a low immunogenicity of the BT4An tumour [17].

In the present experiments, the more than additive effect on survival when combining radiation and hyperthermia indicates that thermal radiosen- sitisation in part is responsible for the encouraging effect of thermoradiotherapy. Although the data are strongly suggestive of a several log cell kill by thermoradiotherapy [17], alterations in cell kinetics may also contribute to the increased life span [22].

To our knowledge a survival benefit of thermoradiotherapy over radiotherapy alone has not been shown previously in a cerebral glioma model. Tam- ura et al. [23] found a life prolonging effect of both high dose rate radiotherapy (8 Gy) and interstitial microwave hyperthermia (44-45 ° C at the surface of the inserting probe for 30 rain) in the G-XII rat glioma model, but no significant increase in survival when the two modalities were combined (hyperthermia before radiation), compared to each modality alone. Bromodeoxyuridine labelling in the same model showed, however, an additive effect of hyperthermia and radiotherapy on tumour cell growth [24].

The encouraging effect of thermoradiotherapy on survival in the BT4An glioma model, was achieved without unacceptable side-effects. Neur- ological side effects were of slight degree, reversible, and seen only in one rat given hyperthermia alone (Exp. 2b) and one rat given thermoradiotherapy (Exp. 2a). The weight loss was not greater in the thermoradiotherapy group than in the other groups. The high proportion of animals given thermoradiotherapy reaching their pretreatment weight before signs of tumour recurrence (Table 1), also indicate the view that the thermoradiotherapy was tolerated well.

Thermoradiotherapy has, however, potential dangers. In dose escalation studies in rats without tumour we found that a radiation dose of 16 Gy led to an unacceptable acute mortality when combined with hyperthermia, whereas 12 Gy and hyperthermia was tolerated well. To further reduce the risk of animal morbidity we decided to give 10 Gy in the thermoradiotherapy experiments. A prolongation of the hyperthermia treatment time to 60 min led to an unacceptable mortality when combined with 10 Gy. The single exposure thermoradiotherapy given in Experiment 2 (hyperthermia for 45 min followed by 10 Gy radiotherapy) is therefore probably near the normal brain tissue tolerance in BD IX rats.

The thermal mapping (Fig. 1) showed that a cylinder of brain tissue about 6 mm in diameter, and at least 5 mm high, is heated to a temperature at or above the desired control probe temperature of 42.4 ° C during hyperthermic treatment in this model. Given a correct applicator positioning, the macroscopically visible part of the tumour, which is up to 4 mm in diameter, is confined to this area and thereby heated to at least 42.4 ° C. Outside the maximally heated cylinder of brain tissue the temperature rapidly declines. We have earlier measured a temperature of 40 ° C 8 mm posterior to the control probe [18]. We can therefore conclude that the brain hyperthermia in these experiments was fairly localised.

Even if an encouraging prolongation of the survival was seen after adding hyperthermia to radiotherapy it is worth noting that the survival after 20 Gy radiation alone in Exp. 1 was longer than af-

213

ter thermoradiotherapy in both Exp. 2a and 2b. It is, however, important to realize that we here are comparing different experiments. In the first thermoradiotherapy experiment (Exp. 2a) the survival of controls and the effect of radiotherapy alone was similar to that found in Exp. 1. When comparing these experiments it is found that the survival after thermoradiotherapy (36.5 days) was very near that after 20 Gy radiation (40.5 days). In Exp. 2b the survival after the combined treatment was shorter, but in this experiment the control animals died earlier, indicating a larger tumour on the treatment day, probably resulting in a poorer heating of the tumour periphery.

As the maximally tolerable radiation dose of 20 Gy and the maximally tolerable thermoradiotherapy (42.4 ° C for 45 min 10 Gy +) resulted in a similar prolongation of survival one may argue that there is no therapeutic advantage of adding hyperthermia to radiotherapy in this model. Even if no neurological side effects were recognised in rats without tumour given 20 Gy as single dose high dose rate radiotherapy, this treatment obviously would result in an unacceptable toxicity if given to patients. The question regarding therapeutic gain of adding hyperthermia to radiotherapy must therefore be evaluated in experiments where clin- ically relevant radiation doses are given in a frac- tionated schedule. In hyperthermic treatment in the clinic a more selective heating of the tumour than achieved in this animal model is possible. This will probably be a necessary strategy to avoid increased normal tissue damage after thermoradiotherapy.

Acknowledgements

The authors gratefully acknowledge the expert technical assistance of Bente Kartvedt. The work was supported by the Norwegian Cancer Society.

References

1. Kristiansen K, Hagen S, Kollevold T, Torvik A, Holme I, Nesbakken R, Hatlevoll R, Lindgren M, Brun A, Lindgren S, Notter G, Andersen AR Elgen K: Combined modality

214

Therapy of operated astrocytomas grade III and IV. Confir- mation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time. Cancer 47: 649- 652, 1981

2. Ross-Riveros R Leith JT: Response of 9L Tumor cells to hyperthermia and X irradiation. Radiation Research 78: 296- 311, 1979

3. Raaphorst GR Feeley MM, Chu GL, Dewey WC: A com- parison of the enhancement of radiation sensitivity and DNA polymerase inactivation by hyperthermia in human glioma cells. Radiation Research 134(3): 331-336, 1993

4. Overgaard J: The current and potential role of hyperthermia in radiotherapy. Int J Radiation Oncology Biol Phys 16: 535-549, 1989

5. Sneed PK, Gutin PH, Stauffer PR, Phillips TL, Prados MD, Weaver KA, Suen S, Lamb SA, Ham B, Ahn DK, Lamborn K, Larson DA, Wara WM: Thermoradiotherapy of recur- rent malignant brain tumors. Int J Radiation Oncology Biol Phys 23(4): 853-861, 1992

6. Stea B, Kittelson J, Kittelson J, Cassady JR, Hamilton A, Guthkelch N, Lulu B, Obbens E, Rossman K, Shapiro W, Shetter A, Cetas T: Treatment of malignant gliomas with interstitial irradiation and hyperthermia. Int J Radiation On- cology Biol Phys 24(4): 657-667, 1992

7. Guthkelch AN, Carter LR Cassady JR, Hynynen KH, Iacono RR Johnson PC, Obbens EAMT, Roemer RB, Seeg- er JF, Shimm DS, Stea B: Treatment of malignant brain tumors with focused ultrasound hyperthermia and radiation: Results of a phase I trial. Journal of Neuro-Oncology 10(3): 271-284,1991

8. Roberts DW, Strohbehn JW, Coughlin CT, Ryan TR Lyons BE, Douple E: Iridium-192 Brachytherapy in combination with interstitial microwave-induced hyperthermia for malignant glioma. Appl Neurophysio150: 287-291, 1987

9. Tanaka R, Kim CH, Yamada N, Saito Y: Radiofrequency hyperthermia for malignant brain tumors: Preliminary results of clinical trials. Neurosurgery 21(4): 478-483, 1987

10. Marchosky JA, Garcia DM, Moran CJ, Nussbaum G, De- Ford JA, Welsh DM: High-dose-rate brachytherapy combined with long-duration hyperthermia for the treatment of malignant glioma (Abstract). In: Gerner EW (ed.) Hyper- thermic Oncology 1992, Vol 1. (Proceedings of the 6th In- ternational Congress on Hyperthermic Oncology, Tucson, Arizona, April 27-May 1, 1992) p 390

11. Nakajima T, Roberts DW, Ryan TR Hoopes PJ, Coughlin CT, Trembly BS, Strohbehn JW: Pattern of response to interstitial hyperthermia and brachytherapy for malignant in- tracranial tumour: a CT analysis. Int J Hyperthermia 9(4): 491-502, 1993

12. Fike JR, Gobbel GT, Satoh T, Stauffer PR: Normal brain

response after interstitial microwave hyperthermia. Int J Hyperthermia 7(5): 795-808,1991

13. Lyons BE, Britt RH, Strohbehn JW: Localized hyperthermia in the treatment of malignant brain tumors using an interstitial microwave antenna array. IEEE Transactions on Biomedical Engineering 31(1): 53-62, 1984

14. Lyons BE, Obana WG, Borcich JK, Kleinman R, Singh D, Britt RH: Chronic histological effects of ultrasonic hyperthermia on normal feline brain tissue. Radiation Research 106: 234-251,1986

15. Sminia R Van der Zee J, Wondergem J, Haveman J: Effect of hyperthermia on the central nervous system: a review. Int J Hyperthermia 10(1): 1-30, 1994

16. Sneed PK, Matsumoto K, Stauffer PR, Fike JR, Smith V, Gutin PH: Interstitial microwave hyperthermia in a canine brain model. Int J Radiat Oncol Biol Phys 12: 1887-1897, 1986

17. Mella O, Bjerkvig R, Schem BC, Dahl O, La~rum OD: A cerebral glioma model for experimental therapy and in vivo invasion studies in syngeneic BD IX rats. Journal of Neuro- Oncology 9: 93-104, 1990

18. Mella O, Mehus A, Dahl O: Pilot studies of microwave- induced brain hyperthermia and systemic BCNU in a rat glioblastoma model. Recent Results in Cancer Research 107: 188-192, 1988

19. Schem BC, Krossnes BK: Enhancement of ACNU treatment of the BT4An rat glioma by local brain hyperthermia and intraarterial drug administration. Eur J Cancer 31A(11): 1869-1874, 1995

20. Schem BC, Krossnes BK, Mella O: Thermochemotherapy with intra-arterial ACNU in the BT4An brain tumor model. Accepted for publication in J of Neuro-Oncology

21. Henderson SD, Kimler BE Morantz RA: Radiation therapy of 9L rat brain tumors. Int J Radiation Oncology Biol Phys 7: 497-502, 1981

22. Wheeler KT: Review of factors influencing the response of experimental brain tumors to therapy. Cancer Treatment Reports 65 (Suppl 2): 75-81, 1981

23, Tamura M, Zama A, Kunimine H, Tamaki Y, Niibe H: Effect of hyperthermia in combination with radiation therapy in a rat glioma model. Neurol Surg 16(5): 659-663, 1988

24. Tamura M, Tsukahara T, Kunimine H, Zama A, Tamaki Y, Niibe H: Histopathologic changes and tumor cell kinetics after hyperthermia and/or radiation therapy in a rat glioma model. Bromodeoxyuridine (BUdR) labelling index. Neu- rol Surg 17(6): 555-559, 1989

Address for offprints: B. Kronen Krossnes, Dept. of Oncology, Haukeland Hospital, N-5021 Bergen, Norway

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