Journal of Surgical Oncology 39:119-121 (1988)

Radiotherapy and 1-Triiodothyronine in the Treatment of High-Grade Astrocytoma

PEDRO MORALES, MD, ANTONIO BOSCH, MD, RICARDO LOPEZ, MD, CRlSTlNA NEW, MD,

FREDDY BORRAS, MD, AND MARIO ROSA, MD

from the Departments of Radiotherapy (P.M., A.B., R.L.), Pathology (C.N.), and Nuclear Medicine (M. R.), 1. Gonzalez Martinez Oncologic Hospital, and the Department of

Neurosurgery, University of Puerto Rico (f. B.), San luan, Puerto Rico

From January 1983 to March 1984, eight patients with high-grade astro- cytoma received postoperative irradiation concomitantly with triiodothy- ronine at the Radiation Therapy Department of the I. Gonzilez Martinez Oncologic Hospital in San Juan, Puerto Rico. There were no complica- tions related to treatment. One patient is alive without evidence of disease at 39 months and seven patients died with disease, one of whom lived for 3 yr. The survival curve for these patients is similar to the survival curve of 18 patients treated at the University of Chicago by surgery, radiation, and triiodothyronine. The value of triiodothyronine as an adjuvant in the treatment of high grade astrocytoma should be further investigated.

KEY WORDS: glioblastoma multiforme, surgery

INTRODUCTION High-grade malignant astrocytomas account for over

25% of all intracraneal tumors, and the main cause of death for patients suffering from these malignant tumors is failure to control the primary. In spite of much work done in the search of treatment modalities that would lead to a substantial increase in the survival of these patients, results remain uniformly disappointing.

The incidence of malignant brain tumors in Puerto Rico is 2.7 per 100,OOO people, and the mortality rate due to these tumors is 1.4 per 100,OOO people [ 11. The most common method of treatment in Puerto Rico is extensive surgical resection of the tumor mass, whenever possible, and postoperative irradiation.

In 1976 Yung et al. [2] reported their results in a group of 18 patients with glioblastoma multiforme treated with radiation and triiodothyronine. In this communication, the group at the University of Chicago analyzed the outcome of 117 patients with glioblastoma multiforme, 24 of whom did not receive treatment. The remaining 93 patients were treated as follows: 10 patients received radiation only; 24 patients received surgery only; 33 patients received surgery, radiation, and colchicine, and 18 patients received surgery, radiation, and triiodothy- ronine. By far the best survival was obtained with the group treated by surgery, radiation, and triiodothyronine.

0 1988 Alan R. Liss, Inc.

To the best of our knowledge this study on the treatment of astrocytoma with the combination of surgery, radia- tion, and triiodothyronine has not been repeated.

In an effort to reproduce and confirm the results ob- tained by Yung et al. [2], the Department of Radiother- apy at the I. Gonzilez Martinez Oncologic Hospital and the Neurosurgery Department at the University of Puerto Rico decided in 1983 to consider patients with high-grade astrocytoma for treatment with surgery, radiation, and triiodothyronine. Following the recommendation of our Medical Endocrinology Department, the protocol of the University of Chicago was not strictly followed; lower doses of triiodothyronine were given, and doses of radia- tion higher than the 4,000 rad employed by Yung et al. were utilized. This paper reports on the outcome of eight patients treated with this combined therapy.

MATERIALS AND METHODS From January 1983 to March 1984, eight patients with

high-grade astrocytoma received postoperative irradia- tion concomitantly with triiodothyronine. The clinical data of these eight patients are shown in Table 1. There

Accepted for publication November 11, 1987. Address reprint requests to Pedro Morales, MD, Oncologic Hospital, Department of Radiotherapy, P.O. Box 1811, Hato Rey, Puerto Rico 00919-1811.

120 Morales et al.

TABLE I. Clinical Data

Patient Tumor Postoperative Pathology Type of Triiodothyronine Survival N O . - -. .- site - __ _- Sex/age - - pathologic - - diagnosis review surgery daily dose in fig Status in months

I Temporal E’/5 I GM GM Subtotal 200 DWD 18

2 Frontal MI72 CiM GM Subtotal 200 DWD 8

3 Frontal MI34 CiM GM Subtotal 300 DWD 13

excision

excision

excision

excision

excision

excision

excision

excision

4 Frontoparietal MI39 CiM GM Subtotal 200 DWD I 1

S Parietal F/S4 Ast. Gr. 11-111 GM Gross total 200 DWD 36

h Ternproparietal F/49 Ast. Gr. Ill GM Subtotal 300 DWD 9

7 Tcmpiroparietal MI39 GM Anap. Ast. Subtotal 400 NED 39

x ‘lernporoparietal MI45 Ast. Gr. 111 Anap. Ast. Gross total 400 DWD 4

GM, glioblastorna multiforrne; Ast. Gr., astrocytoma grade; DWD, dead with disease; Anap. Ast., anaplastic astrocytorna; NED, no evidence of disease

were four males and four females. The youngest patient was 34 and the oldest was 72. The median age of these patients was 47 yr. The location of the eight tumors was as follows: three in the temporoparielal area, two in the frontal lobe, one in the frontoparietal area, one in the parietal lobe, and one in the temporal lobe. All surgical procedures were performed outside our hospital, and the patients were referred to our Radiotherapy Department after surgery. All histologic material was reviewed by the same pathologist, and classification of the tumors was based on the criteria described by Burger and Vogel 131. Six tumors were classified as glioblastorna rnultiforrne and the other two were reported as anaplastic astrocytoma.

Prior to initiation of postoperative irradiation, all pa- tients underwent cardiovascular evaluation at the Car- diology Service. All patients were euthyroid with normal values of T3. T4, and TSH, and all had normal thyroid scans. Patients were hospitalized while the hyperthyroid state was induced with the administration of L-triiodoth- yronine. Tablets of 25 pg were used and doses between 200 and 400 pg were administered daily. The L-triio- dothyronine was started on the first day of irradiation and continued during the entire treatment course. The whole brain was irradiated with a 6 MEV Linear Accel- erator to a tumor dose of 40 Gy with daily fractions of 2 Gy and 5 fractions per week. The primary tumor re- ceived an additional boost of 16 Gy. The L-triiodothyron- ine was discontinued immediately after completion of the irradiation course, and the patient was discharged from the hospital.

RESULTS At the time of the review of the medical records for

analysis of the data (September 1986) seven of the eight

I00

80 1 3 5 Lz 3 cn 60 I- z W u [L W a

40

20 UNlV CHICAGO I8 PATIENTS

~ - - - - 4 O N C O L O G I C MOSPlTbL 8 PATIENTS

I I 1 1 I 1 1

12 24 36 48 60 72 84

TIME IN WEEKS

Fig. I . Survival of patients treated at the University of Chicago and at the I . Gonzalcz Martinez Oncologic Hospital in San Juan, Pucrto Rico.

patients had died (Table I). The survival rate for these seven patients ranged from 4-36 months. One patient is alive and well 39 months after surgery. The main cause of death in these patients was failure to control the pri- mary tumor, except in one case where the patient died of septicemia secondary to urinary tract infection due to pseudomonas (patient 8). Two cases underwent a second

craniotomy with biopsy-proven recurrent glioblastoma multiforme. Treatment was well tolerated and no compli- cations related to treatment were reported.

The percent survival of the eight patients in our study plotted against the percent survival of the 18 cases treated by surgery, radiation, and triiodothyronine by the group at the University of Chicago [4] is shown in Figure 1.

DISCUSSION The grim outlook for patients with malignant astrocy-

toma is due to failure to control local disease. Local persistence or recurrence after radiotherapy has often been attributed to the presence of hypoxic cells. Attempts to offset the effects of hypoxia have included radiation sensitizers, heavy particle radiotherapy, unconventional fractionation, interstitial brachytherapy, and hyperther- mia; but no significant difference in survival has been demonstrated.

Chemotherapy in the treatment of these tumors has been hampered by lack of therapeutic specificity, exces- sive toxicity to normal tissues, and problems related to drug delivery such as low tumor blood flow and the blood-brain barrier.

For many years triiodothyronine has been investigated as a possible modifier of the radiation reaction. The hyperthyroid state has been shown to hasten mortality in mice given acute lethal doses of total body irradiation [5,6]. Sundell-Bergman and Johanson [7] reported on the impaired repair capacity of DNA strand breaks induced by ’251-triiodothyronine in Chinese hamster cells. Glicks- man et al. [8] demonstrated beneficial effects of triiodoth- yronine in skin ulceration, necrosis, and postirradiation fibrosis. Griem and Stein [9] and Griem et al. [lo] re- ported increased irradiation sensitivity in vivo of certain tumors when radiation was given concomitantly with triiodothyronine and increased radiosensitivity of tissues when animals were treated by subcutaneous injection of triiodothyronine. Caldwell et al. [ 11 J found enhancement of radiation nephritis in rabbits irradiated while on in- duced thyrotoxicosis.

The reason for using triiodothyronine as a radiosensi- tizing agent has been discussed by Griem and Stein [9], and the fact that tissue doses between 40 Gy and 60 Gy rad were used in their study for treatment of glioblastoma

XRT and TJ in High-Grade Astrocytoma Ul

multiforme further suggests the increased radiosensitivity of this tumor in the induced hyperthyroid state.

Triiodothyronine might cause metabolic change in tis- sue oxygenation at the cellular level, an increase in blood flow to the tumor tissue, and recruitment of cells into the cell cycle, therefore increasing the number of cells sus- ceptible to radiation.

The small number of patients in this study precludes any definite conclusion, but the close resemblance of the survival curve in our experience with that of the Univer- sity of Chicago is encouraging.

ACKNOWLEDGMENTS The authors wish to express their gratitude to the sup-

port of Dr. Jose Eugenio Lbpez, former Professor and Head of the Department of Internal Medicine of the San Juan City Hospital, for his careful cardiovascular evalu- ation of the patients considered for this study.

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Caldwell WL, Thomassen RW, Bosch A: Effects of triiodo- thyronine in altering the response of kidneys to Cobalt-60 radia- tion. Radiology 81:657-663, 1963.

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