Glenn E. Sheline

THERAPEUTIC IRRADIATION AND BRAIN INJURY

Abstract This is a review and reanalysis of the literature on adverse effects of therapeutic irradiation on the brain. Reactions have been grouped and considered according to time of appearance. The emphasis of the analysis is on delayed reactions, especially those that occur from a few months to several years after irradiation. Over 100 such cases are reported in the literature. Eighty cases were identified in which the patient was given a single course of radiation therapy and in which reasonable estimates of the time-dose-fractionation regimen could be made. Eleven of these patients had been irradiated for cancer of the skin, 17 for other extracranial tumors, 20 for either a pituitary tumor or a craniopharyngioma and 32 for primary brain tumors. All dose specifications were converted into equivalent megavoltage rads. The data were analyzed in terms of total dose, overall treatment time and number of treatment fractions. The data were also analyzed in terms of time-dose-fractionation (TDF) and nominal standard dose (NSD). NSD calculations were done according to the usual Ellis formula and also according to a modification in which the N exponent was −0.44 and the T exponent −0.06. When total dose was plotted against number of fractions, a line with slope 0.44 fitted well with the lower dose limits at which brain necrosis has been reported. Also discussed were acute radiation reactions, early delayed radiation reactions, somnolence and leukoencephalopathy post-irradiation/chemotherapy and combined effects of radiation and chemotherapy.

An analysis of dose-effect relationship in the radiotherapy of malignant gliomas☆

The relationship between increasing survival and increasing doses of radiotherapy has been examined in 621 patients who were entered into three successive Brain Tumor Study Group protocols between 1966 and 1975. These patients were operated upon and had histologically proven malignant gliomas. The median survival of patients who received no radiotherapy was 18.0 weeks; for those who had ⪯4500 rad, it was 13.5 weeks (p = .346); those who received 5000 rad had a median survival of 28 weeks (p < .001), 5500 rad - 36.0 weeks (p < .001), and 6000 rad - 42.0 weeks (p < .001). The specific relationship between 5000 and 6000 rad indicates a 1.3 times increase in median life span associated with the higher dose (p = .004). A detailed analysis of specific factors which might have significantly biased results indicated that patients who received less than 4500 rad were not comparable to other groups of patients because they had a poorer initial performance status and a greater number died before completion of radiotherapy. Factors of importance including parameters of radiotherapy, pathology distribution, the influence of corticosteroids, and the effect of age, sex, and initial performance status were all comparable within the various other subgroups. No other treatment characteristics or selective factors which might have a direct effect on survival were identified. It was concluded that radiotherapy had a significant influence on the survival of patients with malignant glioma and that a clear-cut dose-effect relationship exists.

Radiation therapy in the treatment of partially resected meningiomas

To address the question of whether radiation therapy is beneficial in the management of partially resected meningiomas, we reviewed the records of all patients admitted to the University of California, San Francisco, between 1968 and 1978 who had a diagnosis of intracranial meningioma. The patients were divided into three groups: 51 patients had gross total resection and did not receive radiation therapy, 30 patients had subtotal resection and no radiation therapy, and 54 patients had subtotal resection followed by radiation therapy. The subtotal resection groups were similar in average age, male:female ratio, and tumor location, which allowed a valid comparison of the effects of irradiation. The recurrence rate in the total resection group was 4% (2 of 51 patients). Among patients in the subtotal resection groups, 60% of nonirradiated patients had a recurrence, compared with only 32% of the irradiated patients. The median time to recurrence was significantly longer in the irradiated group than in the nonirradiated group (125 vs. 66 months, P less than 0.05). There was no complication related to irradiation. These results provide convincing evidence that radiation therapy is beneficial in the treatment of partially resected meningiomas.

Radiation tolerance of the spinal cord

A series of nine cases of radiation myelopathy seen at the University of California, San Francisco (UCSF) is reviewed, and their treatment data converted into nominal single doses (NSD) and equivalent single doses (ED). The 1% incidence level of myelopathy in the thoracic cord is 1015 rets (ED), and the 50% incidence level is 1476 rets (ED). Caution should be used when utilizing a rapid fractionation schedule; it appears that 2000 rads in 5 fractions and 3000 rads in 10 fractions is a safe regimen for the thoracic spinal cord.

Radiation injury to the nervous system

Part 1 Response of normal tissue to ionizing radiation: cellular and molecular targets in normal tissue radiation injury biochemical response of normal tissues to ionizing radiation early and late effects of radiation on normal tissues influence of fractionation on normal tissue tolerance influence of dose rate on normal tissue tolerance. Part 2 Tolerance of the nervous system to ionizing radiation - experimental results: central nervous system radiation injury in small and large animal models experimental central nervous system injury from fast neutrons and from implanted isotopes the pathology of central nervous system radiation injury. Part 3 Tolerance of the nervous system to ionzing radiation - clinical experience: diagnostic imaging of central nervous system radiation injury tolerance of the brain and spinal cord to conventional irradiation factors affecting radiation injury after interstitial brachytherapy for brain tumors treatment of radiation necrosis of the brain tolerance of the visual apparatus to conventional therapeutic irradiation radiation and the hypothalamic-pituitary axis changes in intellect associated with cranial radiation therapy injury to the central nervous system after high LET radiation drug/radiation interactions and central nervous system injury radiation injury to peripheral and cranial nerves. Part 4 Tolerance of the nervous system to ionizing radiation - related issues: the effects of heat on the nervous system prospects for radioprotection of the nervous system radiation-induced tumors of the nervous system.

Radiation therapy of brain tumors

Results of radiation therapy obtained at the University of California, San Francisco, over approximately the past 20 years for various histologic types of brain tumors are presented. Included are astrocytomas, malignant gliomas, medulloblastomas, ependymomas, oligodendrogliomas, and brain stem tumors. Degree of malignancy and tendency to disseminate within the central nervous system are also reviewed. For each tumor type and grade considered, the survival rate appeared improved when incomplete resection was followed by irradiation. The increase in survival rate for glioblastomas was only evident for 1–2 years, but for the remainder the improvement extends to 5–10 years. Since many patients were still alive at the time of review, it is possible that permanent control of many intracranial neoplasms may be induced by radiation therapy.

The role of radiation therapy in the treatment of astrocytomas

One hundred forty‐seven patients with astrocytoma were treated between 1942 and 1967. There were 25 postoperative deaths. The 14 patients in whom the tumor was thought to have been completely removed were not irradiated and all survived 5 years or longer. Seventy‐one of the 108 patients with incompletely excised lesions received radiation therapy. The 5‐year survival rate for those with incomplete resection alone was 19%, compared to 46% when irradiation was given. Based on observations up to 20 years, after incomplete removal postoperative irradiation significantly prolonged useful life and may have lead to permanent control in some. There was no evidence of radiation damage. Most of these tumors were fibrillary astrocytomas, and the results apply particularly to this histologic type. Only 1 of 11 patients with gemistocytic astrocytoma survived 5 years. The survival rate for Grade I tumors was appreciably greater than for Grade II lesions; in both grades, it was improved by irradiation.

Radiotherapy of primary intracranial germinomas: The case against routine craniospinal irradiation

A retrospective study was performed on all patients with biopsy-proven intracranial germinomas and unbiopsied suprasellar or pineal region tumors treated during the past 30 years in the Department of Radiation Oncology, University of California, San Francisco. A total of 33 patients were treated: 13 with biopsy-proven germinomas, and 20 others who were unbiopsied. All patients were treated with megavoltage equipment; total dose varied between 40-55 Gy. Only two patients were treated with prophylactic spinal irradiation. No patient received initial or adjuvant chemotherapy. Follow-up times for biopsy-proven patients ranged from 0.5 to 16.7 years with a median 5.3 years. No biopsy-proven patient had a recurrence of the tumor or died; thus, actuarial relapse-free and determinate survivals at 5 years were 100%. Although only one patient in this group received prophylactic spinal irradiation, no patient failed in the spinal axis. The 20 unbiopsied patients had follow-up times ranging from 0.1 to 27.5 years with a median of 5.5 years. Six unbiopsied patients died: two from recurrent disease at the primary site, one from distant peritoneal metastases, two from complications of treatment, and one from intercurrent disease. For this group, actuarial relapse-free survival at 5 years was 72%; the corresponding determinate survival was 73%. Nineteen unbiopsied patients were treated without craniospinal irradiation. Only one developed spinal metastases. The results from this and other series indicate that the risk of spinal metastases from intracranial germinoma is too low to warrant routine prophylactic spinal irradiation. However, patients with gross tumor spill causing contamination of the CSF, malignant CSF cytology, or documented subependymal or subarachnoid metastases presumably are at higher risk for leptomeningeal failure. Craniospinal irradiation is recommended for these patients.

Postoperative radiotherapy of primary spinal cord tumors

During the 30 year period from 1957 to 1986, 42 patients with primary tumors arising from the spinal cord or cauda equina received postoperative irradiation at the University of California, San Francisco. Twenty-one patients had ependymomas: 18 were localized to one site, and 3 diffusely involved the cord. There were 12 patients with low grade astrocytomas and 3 with highly anaplastic astrocytoma or glioblastoma multiforme. All astrocytomas were localized at presentation. In 6 cases tissue was insufficient to permit a histologic diagnosis. Thirty-nine patients (93%) received total radiation doses ranging between 45.0-54.7 Gy using standard fractionation. The 10-year actuarial disease-specific survival rate for patients with localized ependymoma was 93%; 33% of these tumors recurred locally. The corresponding rate for diffuse ependymomas was 50%; the spinal disease was controlled in all 3 patients, but one developed a cerebral metastasis despite prophylactic cranial irradiation. Low-grade astrocytoma patients had a 10-year actuarial disease-specific survival rate of 91%, with 33% of these tumors recurring locally. No patient with highly anaplastic astrocytoma or glioblastoma multiforme survived longer than 8 months; all of these tumors recurred locally, and two of the three also developed diffuse craniospinal axis metastases. Local recurrence for ependymoma was delayed as long as 12 years following treatment, while all but one astrocytoma failure occurred within 3 years of treatment. No significant dose-response relationship with respect to local control was noted for either localized ependymomas or low grade astrocytomas. One patient developed radiation myelitis after receiving 50.4 Gy with standard fractionation. These results indicate that patients who undergo postoperative irradiation for low grade spinal astrocytomas and localized spinal ependymomas achieve excellent survival. However, despite treatment with total radiation doses taken to the practical limit of spinal cord tolerance, local failure remains common.

Delayed onset of hypopituitarism: Sequelae of therapeutic irradiation of central nervous system, eye, and middle ear tumors†‡

Four children with short stature who received irradiation to the head in conventional doses had clinical and laboratory evidence of hypothalamic-pituitary hormone deficiencies several years later. Growth hormone was deficient in all. One patient also had evidence of TSH, ACTH, and gonadotropin deficiency. Basal prolactin levels and prolactin response to synthetic TRF were normal in all patients tested. Treatment with human growth hormone significantly increased growth rate. We suggest that children should have the hypothalamic-pituitary area shielded from irradiation. Periodic measurements of hypothalamic-pituitary function should be performed in children who have had irradiation to the head, in order to detect and treat hormonal deficiencies before growth and development are seriously compromised.