Inr. J Radmim Oncolo~j’ RIOI Phl.7, Vol. Printed in the U.S.A. All nghts reserved.

0 Hyperthermia

0360.3016192 $5.00 t .oO Copyright 0 I992 Pergamon Press Ltd.

24. PP. 657-661

Original Contribution

TREATMENT OF MALIGNANT GLIOMAS WITH INTERSTITIAL IRRADIATION AND HYPERTHERMIA BALDASSARRE STEA, PH.D. M.D.,’ JOHN KITTELSON, M.S.,’ J. ROBERT CASSADY, M.D.,l ALLAN HAMILTON, M.D.,3 NORMAN GUTHKELCH, M.D.,3 BRUCE LULU, PH.D.,’ EUGENIE OBBENS, M.D., PH.D.,~ KENT ROSSMAN, M.D.,4 WILLIAM SHAPIRO, M.D.,4 ANDREW SHETTER, M.D.4 AND THOMAS CETAS, PH.D.’ Depts. of ‘Radiation Oncology, ‘Neurology and 3Division of Neurosurgery, University of Arizona Health Sciences Center, Tucson,

AZ; and 4Barrow Neurological

Institute,

Phoenix,

AZ

Phase I study of interstitial thermoradiotherapy for high-grade supratentorial gliomas has been completed. The objective of this trial was to test the feasibility and toxicity of hyperthermia induced by ferromagnetic implants in

A

the treatment of intracranial tumors. The patient population consisted of 16 males and 12 females, with a median age of 44 years and a median Karnofsky score of 90. Nine patients had anaplastic astrocytoma while 19 had glioblastoma multiforme. Twenty two patients were treated at the time of their initial diagnosis with a course of external beam radiotherapy (median dose 48.4 Gy) followed by an interstitial implant with Ir-192 (median dose 32.7 Gy). Six patients with recurrent tumors received only an interstitial implant (median dose 40 Gy). Median implant volume for all patients was 55.8 cc and median number of treatment catheters implanted per tumor was eighteen. A 60-minute hyperthermia treatment was given through these catheters just before and right after completion of brachytherapy. Time-averaged temperatures of all treatments were computed for sensors located within the core of (> 5 mm from edge of implant), and at the periphery of the implant (outer 5 mm). The percentage of sensors achieving an average temperature > 42°C was 61% and 35%, respectively. Hyperthermia was generally well tolerated; however, there have been 11 minor toxicities, which resolved with conservative management, and one episode of massive edema resulting in the death of a patient. In addition, there were three major complications associated with the surgical implantation of the catheters. Preliminary survival analysis shows that 16 of the 28 patients have died, with a median survival of 20.6 months from diagnosis. We conclude that interstitial hyperthermia of brain tumors with ferromagnetic implants is feasible and carries significant but acceptable morbidity given the extremely poor prognosis of this patient population. Gliomas, Interstitial irradiation, Hyperthermia.

Despite advances in microsurgical techniques (16), innovations in the delivery of radiotherapy (36,44) and the advent of new chemotherapeutic agents (23, 28, 35), the prognosis for patients afflicted by high-grade gliomas remains extremely poor. Malignant gliomas are characterized by the presence of intrinsically radioresistant cells (9); regions of necrosis (4) harboring hypoxic cells; and the presence of isolated tumor cells outside of the contrastenhancing mass on either computed tomography (CT) or magnetic resonance imaging (MRI) scans (4, 17). During

the past two decades, several studies have demonstrated a clear dose-response relationship of external beam radiotherapy in the treatment of this disease (33, 4 1). This modality, however, is limited by obvious normal tissue tolerance of the unaffected brain. Interstitial irradiation has a substantial appeal in the treatment of intracranial gliomas because it allows precise delivery of higher doses of radiation directly to the tumor while sparing normal brain tissue (11,22,32). This technique is useful in boosting the bulky portion of the tumor which accounts for the great majority of the recurrences after external beam radiotherapy (RT) (42). However, despite early encour-

Reprint requests to: Baldassarre Stea, Ph.D., M.D. Dept. of Radiation Oncology, Univ. of Arizona Health Sciences Ctr., Tucson, AZ 85724. Acknowledgements-The authors would like to thank Anne Fletcher and Dennis Anhalt, M.S. for technical assistance during hyperthermia treatments; Christine Arvizu for data collection; Peter Johnson, M.D. for histopathological analysis; Joachim Seeger, M.D. for radiological evaluations; and Wendell Lutz,

Ph.D. for stereotactic implant technique and stimulating discussions. Supported by American Cancer Society Grant PDT3 10; NC1 grants CA 29653 and CA 39468; Cancer Center Core Grant CA 23074; and Arizona Disease Control Research Commission Grant 8277-OOOOOO-1-0-YR-930 1. Dr. Stea is a recipient of an American Cancer Society Oncology Career Development Award. Accepted for publication 17 April 1992.

INTRODUCTION

65-t

658

I. J. Radiation Oncology 0 Biology 0 Physics

aging results with interstitial irradiation, local recurrences continue to be the most common mode of failure. It is in this context that hyperthermia, as an adjunct to interstitial irradiation, became an appealing treatment modality with the goal of improving the local control rate and, thereby, the survival of patients with malignant brain tumors. In addition to the well known biological rationale (7) numerous clinical studies (30), including several randomized trials ( 1,34,40), lend support to the use of combined heat and radiation in treating radioresistant tumors. The evidence is even more compelling when studies utilizing interstitial thermoradiotherapy are considered (2). Thus, from 1988 to 1990, a Phase I clinical trial of interstitial irradiation and hyperthermia for supratentorial high-grade gliomas was conducted at the University of Arizona. The objective of this trial was to study the feasibility of hyperthermia induced by ferromagnetic implants (FMI) and evaluate the toxicity associated with interstitial thermoradiotherapy in the treatment of brain tumors. In a preliminary report (39), we described the technique and early toxicities associated with this treatment modality. This paper addresses the final results of this clinical trial including analysis of thermometric data, survival, and mode of failure in 28 patients. METHODS

AND MATERIALS

Patient selection Between March 1988 and October 1990, patients with a biopsy-proven diagnosis of either anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) were enrolled in this Phase I trial. Selection criteria included size and location of the tumor; following our initial experience (39) we have limited the implant volumes to I 100 cm3; tumors located in the posterior/fossa brain stem or multicentric tumors were excluded from this study. Patients had to have a Karnofsky performance status of at least 50; have a life expectancy of 2 3 months; be at least 21 years of age; and be able to give informed consent. This protocol was approved by the University of Arizona Human Subjects Committee. Interstitial catheters implantation The operative technique of catheter implantation has been previously described in detail (39). Briefly, multiple afterloading plastic catheters were stereotactically implanted into tumors with the help of a template attached to the arc of the stereotactic system* (24). The most commonly used template was the one with an intercatheter spacing of 1.2 cm. Preoperative treatment planning was performed as previously described (24, 39). The target volume boundary was outlined on a Lexidata terminal using the CT scan obtained on the morning of the pro-

* Brown-Roberts-Wells lington, MA.

stereotactic

system; Radionics,

Bur-

Volume 24, Number 4, 1992

cedure. A margin of up to 15mm outside the contrastenhancing edge of the tumor was used whenever possible. Attempts were made to encompass within the target boundary as much of the peritumoral edema seen on CT scan as possible, but always within the constraints imposed by adjacent normal structures. Therefore, margins were necessarily smaller when the tumor abutted the skull, ventricles or other critical structures such as the motor strip. Approach direction, depth of catheter placement, source positioning, and strength were all planned prospectively, and implants were generally performed within 4-5 hr of obtaining the CT scan, In addition to treatment catheters, 3-5 thermometry catheters were implanted in the center and in the periphery of the implant (outside of the ring of contrast enhancement). During the initial phase of the study (first 14 patients), an orthogonal pair of radiographs with dummy sources was taken through a fiducial marker box mounted on the head ring of the stereotactic system. Because of the high concordance between plans based on post-implant orthogonal radiographs and pre-implant CT-based plans, simulation films with dummy seeds were not felt to add significantly to the precision of dose distribution and, therefore, were not done during the second half of the study. Interstitial hyperthermia Hyperthermia was given by means of inductivelyheated, thermally-regulating ferromagnetic implants (FMI) afterloaded into the stereotactically-placed catheters. The heating of tissues by FM1 is based upon the absorption of energy by the seeds from the applied radiofrequency (RF) field. In particular, the RF magnetic field induces eddy currents within the seeds, and these currents heat the seeds resistively. The heated implants then raise the temperature of the surrounding tissues by thermal conduction. The final temperature achieved in the implanted tissue depends on the properties of the implant, the level of blood flow, the seed spacing, and the strength of the magnetic field (12). The complete hyperthermia system consists of three components: the FMI, the magnetic induction system, and the data acquisition system. The FM1 used in the study are alloys of nickel and silicon with Curie points in the range of 50-65°C (Curie point is the temperature at which ferromagnetism disappears and the seeds no longer absorb power (Fig. 1) (5). In the initial phase of the study (39) we used FM1 in the form of ribbons containing a specified number of cylindrical seeds (10 mm long by 1 mm in diameter), with higher Curie point than those used in the latter part of the study. The seeds were replaced by multi-stranded wire bundles (1.4 mm o.d.) which have a greater efficiency of power absorption (12). The length of the strands used in each implant was individually selected to conform to the

659

Interstitial irradiation and hyperthermia 0 B. STEA et a/.

from completion of hyperthermia). A second hyperthermia treatment was planned within 60 minutes following source removal. Patients were monitored with continuous vital signs and frequent neurological examinations (every 5- 10 min) during the hyperthermia treatments.

‘.*;

20 25 30 35 40 45 50 55 60 65 70 Temperature [Celsius]

75

Fig. 1. Power absorption versus temperature characteristic of a typical ferromagnetic implant used in this study. The symbols represent measured permeability data that have been converted to relative power absorption properties. The smooth curve is an analytical characterization of these data according to the formulation of Haider et al. ( 12). The Curie point for this material is 53”C, the slope of the transition region is l/P X dP/dt = -I l%/“C. thickness of the target volume. The magnetic induction system consists of a generator-amplifier power source connected through a matching network to an induction coil (Fig. 2). The coil used in the second half of the study, has an aperture of 30 cm in diameter and operates at frequencies of 80- 100 KHz which produces a field strength of 1500-2000 A/m. Heating is accomplished by placing the head of the patient in or near the coil. Temperatures are continuously monitored by means of multisensor thermocouple probes (each containing seven sensors at 1 cm intervals) or fiberoptic thermometers+ (each containing four sensors also at 1 cm intervals). These probes are inserted into independent catheters (3-5 per patient) stereotactically implanted along the same axis of the treatment catheters. Thermometry data were collected with a computercontrolled data acquisition system’ and time-averaged mean temperatures were then computed for each sensor. Hyperthermia was delivered for 60 min after the first intratumoral sensor(s) achieved a temperature > 42°C (39), with the goal of heating as much of the implant volume as possible to temperatures between 42-45°C. Occasional sensors were allowed to reach temperatures > 45 “C when they were located in the “core” of the implant (i.e., in poorly perfused areas of the tumor). Heating was performed just before interstitial irradiation (radioactive sources were usually afterloaded within 30-60 minutes

+ Luxtron Model 3000 fluoroptic thermometers, Mountain View.

Luxtron,

Radiation therapy Patients with previously untreated tumors received a course of external beam radiotherapy to partial brain volumes using a margin of 3 cm around the contrast-enhancing region on CT scans or 1.5-2 cm around the area of increased signal intensity on the T2-weighted MRI images (whichever was the larger). Doses of 40-54 Gy (median dose:48.4 Gy) at conventional fractionation of 1.82.0 Gy, 5 days per week, were delivered by appropriate portal arrangements that spared as much normal brain tissue as possible. Two to 4 weeks after completion of external beam RT, patients underwent an interstitial im-

Fig. 2. Magnetic Induction System. The picture shows the head of a mannequin (with a simulated implant) positioned inside a 30 cm. i.d. magnetic induction coil. The cooling water lines are shown at the top. This coil operates at a frequency of - 100 KHz when connected to a resonating capacitance tank circuit. The coil produces a magnetic field of 1500 A/m with an applied power of 200 W.

* Hewlett-Packard

Model 3852.

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I. J. Radiation Oncology 0 Biology 0 Physics

plant with Iridium-192. The implant delivered an additional dose of 26-41 Gy (median dose: 32.7 Gy). Source strength and distribution were optimized so that the target boundary (usually located 15 mm outside the contrastenhancing margin on CT scans) could receive the prescribed dose at a rate of 35-70 cGy/hr. Six patients were treated at the time of recurrence, after having received tolerance doses of external beam radiotherapy. These patients received only an interstitial implant which delivered doses of 13.9-50 Gy (median dose: 40 Gy). In one patient, interstitial irradiation had to be terminated prematurely (13.9 Gy) due to the insurgence of complications (i.e., edema and deterioration of neurological status). Computerized dosimetry, with display of the isodose lines in multiple planes, was carried out for each patient to insure that the chosen isodose line fully encompassed the contrast-enhancing volume in every plane. Follow-up evaluation Patients were evaluated every 4-6 weeks with a neurological exam and every 2 months with either a CT or an MRI study. Survival analyses were done from the date of diagnosis or from the date of implant (for the patients treated at the time of recurrence). Representation of the probability of survival was obtained by the method of Kaplan and Meier (20). RESULTS Twenty-nine patients with high-grade supratentorial gliomas were enrolled in this study; 28 were able to complete the prescribed treatment. One patient developed an intracranial hemorrhage at the time of the surgical implantation of the catheters and underwent emergency evacuation of the hematoma with complete recovery. A second attempt to implantation was not considered safe for this patient and, therefore, she completed her treatment with external beam RT. This patient was included in toxicity evaluation but excluded from survival analysis since FM1 heating was never attempted. Details of the patient population, tumor characteristics, and treatment parameters are shown in Table 1. In brief, there were 16 males and 12 females with a median age of 44 years (range: 21-79 years) and a median KPS of 90 (range: 50-90). Nineteen patients had a diagnosis of GBM while 9 had AA. Twenty-two patients were treated at the time of their initial diagnosis (“up-front” group). Following debulking surgery, they were treated first with external beam RT (median dose 48.4 Gy, range: 40-54 Gy), followed by an interstitial implant (median dose 32.7 Gy, range: 26-4 1.4 Gy) in conjunction with FMI-induced hyperthermia. During the course of the study, the external beam dose was escalated from 40-41 Gy to 50-54 Gy; and the implant dose was reduced from 40 Gy to 30 Gy, thus, keeping the combined total dose constant in the range of 75-85 Gy. This change was made when early autopsy results showed that failures tended to occur at the margins of the

Volume 24, Number 4, I992

implant. Six patients (4 GBM, 2 AA) were treated at the time of recurrence and received an interstitial implant (median dose 40 Gy, range: 13.9-50 Gy) with hyperthermia but no external radiation therapy. The interval between the original diagnosis and retreatment for this group of patients ranged between 6- 15 months (median: 9 mos). All six patients had been treated previously with subtotal resection, external beam RT (59.4-65 Gy), implant (1 patient), and chemotherapy (1 patient). Recurrence was documented histologically in all cases by stereotactic biopsy. The median implant volume (volume encompassed by the prescribed isodose line) for all patients was 55.8 cc (range 9.9-l 32 cc). The median number of interstitial catheters implanted per patient was 18 (range: 4-33). Among the 22 patients treated “up-front”, nine received chemotherapy either in an adjuvant mode (6 patients) or at the time of recurrence (3 patients). Chemotherapeutic regimens varied according to the preference of the treating physicians and available protocols (Table 1). Furthermore, 14 of the 22 patients in the “up-front” group required reoperation of the original tumor site between 1 and 12 months post-implant (median time to reoperation: 6.5 months); two patients underwent a second reoperation (patient no. 4 at 23 months; patient no. 29 at 10 months) due to tumor progression. Reoperations were performed when either there was an increase in the region of contrast enhancement on serial CT scans or when patients developed significant neurological symptoms in spite of increasing steroid medications. Histopathological evaluation of the specimens obtained at reoperation showed the presence of massive necrosis (with or without scattered tumor cells) in seven patients; persistent or recurrent glioma at the treatment site in six patients; and a marginal recurrence in one patient. Because of the inability to distinguish between necrosis and tumor growth on various imaging studies (including PET scans), survival was used as the ultimate endpoint in this study. Sixteen of the 28 patients entered on this trial have died (median survival: 20.6 months): fourteen patients from locally recurrent tumors, one patient from complications of treatment, and one patient (patient 16 in Table 1) died within 24 hr of being admitted for “acute respiratory failure” although he was neurologically stable at the time (autopsy not performed). The presumed cause of death for this patient was pulmonary embolus. The Kaplan-Meier representation of survival for the 28 patients entered on the study is shown in Figure 3a. Although it is not standard practice in Phase I studies, patient survival was analyzed because our techniques remained essentially constant throughout the study, and the patients entered in this trial have characteristics which should be similar to patients in future studies. Survival was measured from the date of diagnosis for all patients, although six of them were treated at the time of recurrence; survival from the time of retreatment with thermoradiotherapy (for patients with recurrent tumors) is shown in Table 1. The median survival for the six patients with recurrent tumors

2

68, 69, 51, 21, 39, 25, 50, 58, 37, 65, 51, 64, 65, 44, 32, 71, 53, 48, 43, 22, 53, 32, 26, 32, 79, 41, 36, 44,

F F F F M F M F F F M M F F F M M M M M M M M M M M F M

Age/Sex

50 90 60 90 90 90 90 90 90 90 70 70 IO 90 90 90 90 90 90 90 90 90 90 90 90 90 80 90

KPS”

GBM GBM AA AA GBM AA GBM GBM AA GBM GBM GBM GBM GBM GBM GBM GBM GBM GBM AA GBM AA AA GBM GBM AA

Histology Recurrent Primary Recurrent Primary Primary Primary Recurrent Primary Primary Primary Primary Primary Recurrent Recurrent Primary Primary Primary Primary Primary Primary Primary Primary Recurrent Primary Primary Primary Primary Primary

Stage h

R, L, R, R, R, L, R, R, L, L, L, L, R, R, R, L, L, R, R, L, L R, L R, L L

Th T T/P F FIT O/T/P P F T P 0 T/P F P P/O P/O F F P F/P T TIP p/o F p TIP

R, F/P L p/o

Tumor locationC 42 14 13 45 42 II 61 36 90 10 70 21 41 60 75 35 90 45 10 20 50 75 60 50 70 20 34 57

Vo1.d

41.4 41 41.4 41 40 41 41.4 41 41.4 41.4 41.4 50 54 50.4 50.4 50 46.8 50 50 50 50 50.4

parameters

13.9 32.2 35.5 32 33.2 40 50 35.7 39.8 40 40 40.2 40 49.6 38.5 39.9 30.1 26 30 35 30 30 40 30 35 32.1 30 30

Dose (Gy) impl.

treatment

Rad. ext.

I. Patient characteristics,

313 l/3 o/o 218 013 415 213 617 ND’ 212 ND’ 112 414 212 314 212 313 l/4 114 416 3/3 313 313 o/o 214 214 313 215

Sensorse > 42” Chemo’

status

N N N N BCNU N N N N N BCNU N N N BCNU, PCV N BCNU, CDDP PCV PCV N BCNU, CDDP N N N N N BCNU, CDDP BCNU

and survival

Y Y

Y

N

Y

N N N Y Y Y

N

N Y Y Y N N N Y N

N

N N N Y Y Y

Reop

a Kamofky Performance Score. b Primary = Hyperthermia at time of diagnosis; Recurrent = Hyperthermia at recurrence. ’ Tumor location: R = Right hemisphere; L = Left hemisphere; F = Frontal; P = Parietal; T = Temporal; 0 = Occipital; Th = thalamus. d Tumor volume (cm3) corresponds to the volume of constrast enhancement on CT scans. e Proportion of sensors exceeding 42” within the “core” of the implant (best treatment). ‘Chemotherapy: BCNU = Carmustine; PCV = Procarbazine; CCNU = Lomustine, vincristine; CDDP = Cisplatin; N = None. g DOD = Dead of disease; DOC = Dead of complications. h Survival time in weeks from diagnosis (Dx) for primary patients and from retreatment (ReTx) for patients with recurrent disease. ’ND = no data, due to early termination of heat treatment beacuse of seizures. j Patient died within 24 hrs of admission for “acute respiratory failure” but neurologically stable.

2 3 4 5 6 I 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

1

Pt. no.

Table

DOD DOD DOD Alive DOD Alive DOD DOC DOD DOD Alive DOD DOD DOD Alive Dead’ DOD DOD DOD Alive Alive Alive Alive Alive DOD Alive Alive Alive

Statusg

31 41 71 190+ 166 178+ 90 11 24 65 137+ 65 30 91 129+ 63 44 53 58 98+ 86+ 80+ 111+ 73+ 41 71+ 68+ 63+

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Fig. 4. Spatial temperature distribution for one patient. Monitored sensors were localized with respect to the implant margin outlined on a planning CT scan (see methods). The sensors located in the outer 5 mm zone of the implant were defined as being in the periphery. Those located > 5 mm from the edge were defined as being located in the core of the implant. Time-averaged (over 60 min) mean temperatures are plotted as a function of their

location within the implant. patient survival in this study. None of the other factors showed a significant association with survival after adjusting for patient age. Analysis

qfthermometric data

,patients had at least one attempt at the hyperthermia treatment. Two patients had partial treatment due to development of seizure activity. Furthermore, 17 patients received a second heat treatment post-brachytherapy. Eleven patients received only one heat treatment for a variety of reasons: development of seizures during first treatment, development of edema (either from catheter implantation or hyperthermia), and patient anxiety. Thus, a total of 43 full hyperthermia treatments were given to 26 patients. Temperature analysis was performed on a total of 679 sensors monitored during 39 heat sessions in these 26 patients. Since stereotactic techniques were used to place all treatment and thermometry catheters, accurate reconstruction of the ferromagnetic seed implant geometry was possible. Specifically, the coordinates of each ferromagnetic seed and each temperature sensor were calculated in three dimensions, and were used to accurately compute the distance between each sensor and the closest edge of the implant (Fig. 4). To describe the adequacy of heating with ferromagnetic seed hyperthermia, sensors were categorized according to their location as follows: (a) outside of the implant (i.e., sensors in scalp, skull, or intervening normal brain): (b) at the periphery of the implant (i.e., from 0 to 5 mm from the edge of the implant); (c) within the core of the implant (i.e., more than 5 mm inside of the implant). With this classification, 127 of the 679 sensors were in the core, 380 All 28

were in the periphery, and 172 were outside of the implant. The temperature for each sensor was averaged over the treatment interval so that a time-averaged temperature distribution within each region could be constructed (Fig. 5). The results show that 6 1% of the core sensors, 35.0% of the peripheral sensors, and 3.5% of the sensors in normal tissue exceeded 42°C. For each treatment the temperature exceeded by 90% of the sensors (T& was computed for each of these regions, Considering all treatments, median TgOin the core was 41.4”C (range: 37.2”C to 44.O”C) while median Tso in the periphery was 39.2”C (range: 37.3”C to 41.9”C). For each patient, the best Tgo in the core region was used for analysis of survival. Hyperthermia was generally well tolerated. Only two patients (in the early part of the study) were unable to complete at least one heat session due to development of focal seizures. This proved to be the most common side effect associated with hyperthermia, occurring in 6/28 patients (all of these patients had had history of seizures prior to hyperthermia). Seizures were always focal in nature, lasting approximately 30-90 set and, in all cases, resolved with intravenous administration of diazepam: other minor side effects encountered were transient brain edema and neurological deficits (four patients) which responded to conservative medical management (steroids). One patient developed increased arm weakness postoperatively. In addition, there have been three major complications: one case of hydrocephalus secondary to edema from catheter implantation; one patient developed pneumoencephalos from failure to suture all of the stab wounds on the scalp after removal of the interstitial catheters; one patient developed an intracranial hemorrhage at the time

664

1. J. Radiation Oncology 0 Biology0 Physics

I

I

38

40

Volume 24. Number 4, 1992

42 T-index

I

I

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44

46

48

50

(‘C)

Fig. 5. Time-averaged temperature distributions for all patients monitored, plotted as a function ofsensors’ location within the implant. The percent of sensors that attained a temperature > 42°C was 61%, 35%, and 3.5% for the core, the periphery of the implant, and normal tissues outside of the implant, respectively.

of catheter implantation. All of these complications resolved with appropriate surgical intervention. Finally, one patient died from complications of treatment in the early phase of the study, as described in detail in our previous publication (39). DISCUSSION High-grade brain gliomas, and GBM in particular, represent a major therapeutic challenge for neurosurgeons, radiation oncologists, and neuroncologists (6). With the advent of CT scans and stereotactic equipment, it has become possible to deliver an interstitial boost to the enhancing lesions. A recently published study from the University of California at San Francisco (UCSF) points out the major benefits from an interstitial implant ( 19). When compared with matched control patients treated only with external beam RT, those who received an implant had a longer median survival (52 vs. 95 weeks for patients with GBM). The value of an implant in the treatment of malignant gliomas is now being tested prospectively by the Brain Tumor Cooperative Group in a randomized trial (protocol 87-O 1) of external beam RT with or without an interstitial boost with I- 125. In an attempt to further improve the local control of brain tumors, hyperthermia is being evaluated at several institutions as an adjunct to interstitial irradiation (31, 38, 43). Several animal studies have shown that the tolerance of normal brain tissue to hyperthermia is in the range of 42.2-43°C for 30-60 min (15,25, 37). Therefore, a narrow therapeutic index exists in brain tissue since temperatures > 42°C are necessary for direct hyperthermic cytotoxicity; however, thermoradiosensitization can occur even at temperatures of 4 1 “C (3, 14). Thus, in order

to achieve a therapeutic gain, hyperthermia and interstitial irradiation have to be delivered in a very precise manner. An important consideration to make in brain tumor hyperthermia is the volume that needs to be heated at therapeutic temperatures. Since tumor cells are known to infiltrate adjacent normal brain tissue for several centimeters around the contrast-enhancing mass (4, 17) we have attempted, in our study, to implant a volume that extends beyond the contrast-enhancing margins by approximately 1.5 cm. This approach also ensured that higher temperatures would be achieved in the core of the implant (i.e., in the region of contrast enhancement) which is thought to harbor hypoxic and nutritionally deprived cells. When we analyzed our thermometry data (Fig. 5), we found that the temperatures in the core were indeed higher than in the periphery (outer 5mm zone of the implant). The core temperatures were very similar to those obtained in a recent study from UCSF where hyperthermia was induced with microwave antennae operating at 915 MHz (38). The inability to adequately heat the periphery of the implant is due to increased thermal conduction from tumor to normal brain and also to higher blood flow (i.e., higher thermal convection). This is a limitation common to all interstitial methods of heat delivery and may account for the still high rate of loco-marginal failures encountered in this and other studies (38). Other techniques of heat delivery such as scanned focused ultrasound (SFUS) could, in theory, overcome heat losses at the periphery since with this technique the focussed US beam can be scanned at high speed under computer guidance through the tumor volume, and the applied power is continuously adjusted in different regions of the tumor based on measured temperatures. This technique is currently under investigation in our department, and, in a recently published

Interstitial irradiation and hyperthermia 0 B. STEAet al.

clinical trial of 15 patients with brain tumors treated with SFUS (lo), the percentage of sensors within the scanned volume attaining a temperature 2 42°C was on the average 66%. Another consideration to be made in brain tumor hyperthermia is that of thermal dose. There is good evidence from animal studies (8) and human studies (29) that the minimum thermal dose (a function of time and temperature) correlates with treatment outcome. In this study, we did not find a correlation between minimum core temperature (T& and survival. Possible explanations for this finding include: (a) insufficient variation in the observed range of Tso’s to demonstrate a dose-response relationship (the range was narrow because the study was not designed to assess the effect of different thermal doses): (b) delivery of subtherapeutic thermal doses; or (c) incomplete coverage of the entire target volume by therapeutic isotherms (i.e., presence of “cold spots” within the target volume). The latter possibility is currently being investigated in our department by tridimensional dosimetry. Other investigators have addressed the issue of thermal dose by using alternative fractionation schemes of heat delivery, such as continuous hyperthermia for 72 hr by means of electrically heated catheters (26) or multiple heat treatment for 45-60 min twice a week for several weeks by means of permanently implanted ferromagnetic seeds (IS). Although both groups have reported encouraging preliminary results, no conclusions can yet be drawn about dose-response relationship in brain tumor hyperthermia. Analysis of tissues obtained at reoperation showed that 7/ 14 specimens contained residual or recurrent gliomas at the treatment site (within the target volume) or at the margins of the implant. This finding suggests that the thermal dose and/or radiation dose used in this study were not sufficient to completely sterilize the site of bulky tumor. Future developments in the field of brain tumor hyperthermia may involve simultaneous heat and radiation during the course of the implant. Both cellular and animal studies have shown a significantly higher thermal enhancement ratio when the two modalities are delivered simultaneously (27, 30). The preliminary survival results achieved in this study (median survival of 20.6 months for the entire group and

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14.9 months for patients with GBM) are encouraging, and the toxicity associated with the implantation of multiple catheters (median of 18 treatment catheters and four thermometry catheters per patient) was acceptable. Furthermore, side effects associated with the heating sessions were reasonable in the context of this disease (six focal seizures, five patients with transient increase in edema or neurological deficits) and patient tolerance has been excellent (only one patient refused a second heat treatment because of anxiety). Half of the patients entered in this trial underwent reoperation for increasing mass effect or worsening neurological symptoms. This rate of reoperation is similar to that observed in other trials employing only interstitial irradiation ( 11, 22) and, as in those trials, the reoperated group had significantly longer survival than the group that did not have a reoperation. We note this result in order to emphasize the dangers of inferring causality when the factor is confounded with the outcome. Here, reoperation is only considered if the patient is well enough to tolerate the procedure. This obviously happens most frequently in patients who live longer. Thus, we have no way of knowing (based on this kind of data) if the reoperation causes patients to survive longer. or if longer survival causes patients to have reoperations. The factor is hopelessly confounded with the outcome: hence, no conclusions can be drawn regarding association between the two. The technique of heat delivery used in this study (FMI) offers several advantages: (a) relative ease of operation, since FM1 are afterloaded in the same catheters used for irradiation and require no electrical connection; (b) safety; since FM1 are intrinsically thermo-regulating, and power is deposited directly into the seeds within the implant, the heating pattern is more predictable and easier to control than with other methods. The major drawback of this technique is the relatively high density of implanted catheters as efficient heating requires an intercatheter spacing of 1.0-1.2 cm (39). In summary, this study demonstrates that interstitial hyperthermia of brain tumors with FM1 is feasible and generally safe to perform as long as certain volume limitations are not exceeded. It offers considerable promise as an adjunct to interstitial irradiation and deserves further evaluation in larger cooperative studies.

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