Article a b s t r a c t I t is generally acknowledged that radiation therapy (RT)provides effective palliative treatment for the majority of patients with brain metastases. It is less well known that RT can be “curative.” In 10 years, we examined five patients with brain metastases treated with whole-brain radiotherapy and with no residual tumor in the brain at autopsy. These five patients represented about 3 percent (5 of 187) of patients treated for brain metastases and later examined at autopsy. Some metastatic brain tumors are eradicated by RT, and all nonterminal patients should be offered such treatment. NEUROLOGY 29: 1195-1202,September 1979
Sterilization of cerebral metastases by radiation therapy J. Gregory Cairncross, M.D., Norman L. Chernik, M.D., Jae-Ho Kim, M.D., a n d Jerome B. Posner, M.D.
Central nervous system (CNS) complications of cancer are common. Brain metastases are present at autopsy i n 12 percent of patients with systemic cancer.’ F u r t h e r m o r e , at Memorial S l o a n Kettering Cancer Center (MSKCC), 65 to 75 percent of patients with CNS metastatic disease suffer major neurologic symptoms during life.2 For the most part, the management of CNS metastases is palliative radiation therapy, which relieves neurologic s y m p t o m s in a b o u t t w o - t h i r d s of patients.3-5 Radiation therapy (RT) is delivered to the whole brain. The dose and fractionation procedures vary from center t o center, b u t have not been shown to make a substantial difference i n the outcome of the rap^.^ Despite initial improvement, many p a t i e n t s soon relapse, and median survivals are usually less than 6 months. A few long-term survivors have been reported, but in some of them the original diagnosis may have been incorrect, since there was no histologic verification of the lesion before or after therapy. No pathologic reports published to date verify the sterilization of metastatic brain tumor by RT alone. In the 10 years between 1968 and 1977, we encountered five patients with cerebral metastatic tumor, treated with whole brain RT, and with no evidence of residual intracranial tumor at autopsy. Case reports. Patient 1. At age 57 in 1963,this patient underwent a radical mastectomy for anaplastic carcinoma. Pleural and bone metastases were found in 1968. T r a n s f r o n t a l craniotomy w a s performed for
hypophysectomy, but extensive metastatic tumor was found infiltrating the right frontal lobe. A brain biopsy confirmed intraparenchymal metastatic carcinoma (figure 1).No attempt was made t o extirpate the tumor. Postoperatively she remained asymptomatic, and 3500 rads of RT was given t o the whole brain. Fifteen months later, in October 1969, she noted right-sided weakness, numbness, and clumsiness. There was mild cognitive impairment, normal speech, right lower facial weakness, mild right arm and leg weakness, brisk tendon reflexes with sustained clonus at the right ankle, a right extensor plantar response, and an unsteady gait. Skull roentgenograms revealed multiple calvarial metastases. An isotope brain scan disclosed multiple areas of increased uptake within the calvarium but no intraparenchymal lesions. She was treated with steroids and an additional 2400 rads of RT to the whole brain. The neurologic symptoms and signs rapidly improved and did not recur. She died 8 months later, 23 months after the original treatment of the cerebral metastasis. General postmortem examination revealed metastatic tumor involving the lungs, pleura, mediastinal and abdominal lymph nodes, adrenals, and ovaries. Neuropathologic examination followed formalin fixation of the brain. A thick, gelatinous, grayish-colored membrane covered the subdural surface of both cerebral hemispheres. The meninges over both cerebral convexities were thick, opaque, and granular in appearance. The vessels a t the base of the brain and over the lateral convexities were unremarkable. There was an area of brownish discoloration and cavitation measuring 3 by 2 cm involving the dorsolateral aspect of the right frontal pole. The brainstem, cerebellum, and spinal cord were unremarkable. On serial section of the cerebral hemispheres, the lesion in the right frontal pole extended into the central white matter and exhibited the typical appearance of a cystic infarct (figure 2). A
From the Departments of Neurology, Pathology, and Radiation Therapy, Memorial Sloan-Kettering Cancer Center; and the Departments of Neurology and Pathology, Cornell University Medical College, New, York, New York. Presented a t the thirty-first Annual Meeting of the American Academy of Neurology, Chicago, Illinois, April, 1979 Accepted for publication February 6,1979
Address reprint requests to Dr. Posner, 1275 York Avenue, New York, NY 10021.
September I979 NEUROLOGY 29 1195
Figure 1. (Patient 1 ) Photomicrograph of brain biopsy demonstrating infiltrating adenocarcinoma of the breast. Hematoxylin-eosin, x 50. second cystic lesion, measuring 2 by 1cm, was found in the caudal aspect of the left putamen. This lesion extended across the posterior limb of the internal capsule to the wall of the lateral ventricle. Transverse sections of the brainstem and cerebellum were unremarkable. The lateral ventricles were moderately dilated. Microscopic examination of 15 sections through various parts of the right frontal lesion demonstrated a relatively uniform picture without evidence of tumor cells. Surrounding the cavitation was a loosely structured hypercellular fibrillary matrix with large numbers of gemistocytic and fibrillary astrocytes (figure 3). Numerous macrophages, some pigmented, and occasional reactive giant cells were identified. The overlying meninges were thickened and hypercellular. Multiple sections of the left putamen demonstrated an area of central cavitation surrounded by a loosely structured fibrillary matrix containing large numbers of gemistocytic astrocytes and nonpigmented macrophages. No tumor cells were identified. Review of the biopsy specimen from 1968 confirmed the initial report of extensive tumor infiltration of the dura, underlying meninges, and cerebral cortex. In the cortical segments of the biopsy, the parenchyma surrounding the tumor nodules showed moderate disruption of the neuropil, ischemic changes in the neurons, and moderate numbers of gemistocytic astrocytes.
Patient 2. A 62-year-old man with widely metastatic
1196 NEUROLOGY 29 September 1979
oat cell carcinoma of the lung died in June 1968. He had been admitted to the hospital in September 1967 after 3 weeks of right frontal headache and 1 week of progressive left-sided weakness, gait unsteadiness, and emotional lability. He was lethargic, with striking impairment of all cognitive functions. Funduscopic examination revealed dilated, tortuous retinal veins with absent venous pulsations. Left lower facial weakness and a mild left hemiparesis were noted. Rapid alternating movements, fine finger movements, and finger-to-nose testing were poorly performed on the left. Cortical sensory modalities were impaired in the left hand. Tendon reflexes were brisk throughout, with bilateral extensor plantar responses. Primitive reflexes were prominent. Skull roentgenograms were unremarkable. An echoencephalogram demonstrated a midline shift from right to left. An isotope brain scan disclosed a right frontoparietal area of increased uptake. A right retrograde brachial angiogram revealed a large, anterior suprasylvian mass containing tumor vessels. He was treated with steroids and received 3000 rads of RT to the whole brain. Cerebrospinal fluid (CSF) pressure (140 mm KO) and contents were normal. The neurologic symptoms and signs rapidly improved. One month after RT was completed, he was free of headache, intellectually intact, and complained only of mild left arm weakness. A follow-up brain scan demonstrated a much smaller area of increased uptake in the right frontoparietal region. A t the time of his final admission, 9
months after metastasis, the treatment of the cerebral neurologic examination was normal. The general postmortem examination revealed metastatic tumor involving the liver, adrenals, and bone marrow. Fibrosis and radiation changes were seen in the lower lobe of the right lung, but no residual tumor was found in the right main stem bronchus or its branches. On serial section of the cerebral hemispheres, a large necrotic lesion was found in the central white matter of the right frontal lobe. Transverse sections of the brainstem and cerebellum were unremarkable. On microscopic examination, multiple sections from the right frontal cavitation showed the lining of the cavity to consist of a fibrillary matrix containing a dense collection of macrophages and gemistocytic astrocytes. Several large vessels, some with markedly thickened collagenous walls, were seen, In the adjacent parenchyma, multiple, irregular, smooth-walled cystic spaces were noted. Some of these were filled with macrophages, and others were empty. The intervening parenchyma was characterized by dense gliosis, with gemistocytic and fibrillary forms, and groups of macrophages with occasional reactive giant cells. No hemosiderin pigment was observed. In all sections, there were extensive mineral deposits forming perivascular and mural droplets and rings as well as large parenchymal plaque formations. Sections of the basal ganglia and dentate nucleus of the cerebellum showed similar extensive mineraliza-
tion. The meninges over the cerebral cortex were thickened. No tumor cells were identified.
Patient 3. A 26-year-old man with diffuse histiocytic lymphoma died in June 1969, 16 months after diagnosis. He was admitted in September 1968after 1week of morning headache, vomiting, and lethargy, and 2 days of diplopia. Examination revealed papilledema, nystagmus on lateral and vertical gaze, ocular dysmetria, and poor rapid alternating movements and finger-to-nose testing in the left arm. Tendon reflexes were brisk and symmetric, with flexor plantar responses. No weakness, sensory disturbance, or gait abnormality was noted. Skull roentgenograms were unremarkable. An electroencephalogram (EEG) demonstrated bilateral slowing and disorganization. An isotope brain scan disclosed areas of increased uptake in the left cerebellum and right parietal lobe. Cerebral angiography demonstrated bowing of the anterior cerebral arteries, indicating ventricular enlargement, and raised the suspicion of a left posterior fossa mass. Pneum.oencephalogramrevealed a cerebellar mass lesion with partial obstruction of the fourth ventricle and aqueduct. He was treated with steroids and RT to the whole brain. At discharge, he was much improved, with only mild left-sided cerebellar signs persisting. His subsequent neurologic course was unremarkable, and future admissions were related to the systemic disease. A follow-up isotope brain scan 6
Figure 2 . (Patient 1 ) Coronal section demonstrating the necrotic lesion in the right frontal lobe in the area where the metastasis had been. September 1979 NEUROLOGY 29 1197
bT,er111ZatlOn of Cerebral metastases
Figure 3. (Patient 1 ) Photomicrograph of a section from the lesion in figure 2 demonstrating an area of cavitation surrounded by a hypercellular fibrillary matrix containing abundant gemistocytic and fibrillary astrocytes and lipid-laden macrophnges. Hernatoxylin-eosin, x 12.5.
months after completion of therapy was normal. He died 3 months later. General postmortem examination revealed widely disseminated lymphoma involving the lungs, heart, mesentery, adrenals, kidneys, pancreas, and testis. The dura, meninges, and blood vessels were unremarkable. The external appearance of the cerebral hemispheres and brainstem were unremarkable. A small area of brownish discoloration was seen on the inferior surface of the left cerebellar hemisphere. Serial sections of the cerebral hemispheres revealed mild, diffuse edema of the central white matter. The ventricles were normal in size. Transverse sections of the brainstem were unremarkable. Serial sections of the cerebellum disclosed a 1-by-1-cmbrownish, indurated lesion in the inferior aspect of the left hemisphere. Multiple sections were taken from the left cerebellar lesion. The normal cellular detail was replaced by fibrillary gliosis and scattered areas of partial liquefaction. The latter area contained numerous hemosiderin-laden macrophages. Penetrating blood vessels with thickened collagenous walls and areas of mineralization were noted in the adjacent parenchyma. The overlying meninges were markedly thickened. No tumor cells were found.
Patient 4. A 36-year-old man with embryonal cell carcinoma died in July 1977. He had presented 15 months
1198 NEUROLOGY 29 September 1979
earlier with superior vena caval obstruction. The diagnosis was established by mediastinoscopy. In April 1977 he was admitted for management of bilateral malignant pleural effusions. Neurologic examination was normal on admission. Two weeks later, he was lethargic, disoriented, and unable to correctly perform simple tests of cognitive function. Funduscopic examination revealed slight blurring of the right disk margin. The visual fields and ocular movements were full. Right lower facial weakness and mild right arm and leg weakness were noted. Tendon reflexes were brisk and symmetric, with a right extensor plantar response. There was no language or sensory disturbance. CSF pressure and contents were normal. Computed tomography (CT) revealed a left parietooccipital contrast-enhancing mass lesion with a small, central area of increased density prior to contrast administration (figure 4). He was treated with steroids and received 3900 rads of RT to the whole brain. Rapid clinical improvement ensued, and 1 month after completion of RT, the neurologic examination was normal. He died 4 months later with widespread systemic disease. General postmortem examination revealed metastatic tumor involving the lungs, pleura, mediastinal lymph nodes, pericardium, mesentery, liver, kidney, and bone marrow. The dura, meninges, blood vessels, and external appearance of the brain were unremark-
able. Transverse sections of the brainstem and cerebellum were unremarkable. On serial sectioning of the cerebral hemispheres, a 1-by-1-cmarea of softening and brownish discoloration was found in the left occipital lobe. The ventricles were normal in size. There was no evidence of mass effect or herniation. Multiple sections were taken from the lesion. Microscopic examination revealed an area of liquefactive and coagulative necrosis surrounded by a dense connective tissue capsule and gliosis. Numerous hemosiderin-laden macrophages and gemistocytic astrocytes were seen (figure 5). The center of the lesion contained, in addition to necrotic debris, cholesterol crystals and hemosiderin pigment. However, no residual tumor was found within the lesion or infltrating the surrounding parenchyma.
Figure 4 (Patient 4 ) Computed tomographic scan following intravenous contrast demonstrating a left parietooccipital metastasis.
Patient 5. A 32-year-old inan with choriocarcinoma died in August 1977,ll months after diagnosis. He was admitted in June 1977 after 3 weeks of right parietal headaches, visual blurring to the left, and difficulty in reading. Neurologic examination was remarkable for a left inferior homonymous quadrantanopia and a left extensor plantar response. CT demonstrated multiple contrast-enhancing lesions, the largest in the right occipitoparietal region. Additional lesions were seen in the left parietal lobe and both frontal lobes. He was treated with steroids and 3000 rads of RT to the whole brain. Rapid clinical improvement ensued. He died 2 months later with widespread systemic disease and acute bronchopneumonia. Forty-eight hours prior to his death, CSF pressure and contents were normal; no
Table 1. Clinical findings in patients with “sterilized” cerebral metastases
Patient age a n d
bn%h of survival
Symptoms and signs
Diagnostic
sex
Primary tumor
studies
RT dose
64.F
Breast
Asymptomatic 1968 Right hemiparesis 1969
Brain biopsy: metastatic carcinoma
3500 rads in Remission Septicemia 23 mos. 24 days (1968) 2400 rads in 8 mos 16 days (1969)
62,M
Lung (oat cell)
Headaches, confusion, left hemiparesis
Angiogram: 3000 rads right frontal mass in 23 with tumor vessels days
Remission Septicemia
9 mos.
Cystic lesion, right frontal lobe
Lymphoma
Headaches, vomiting, lethargy, diplopia
Pneumwncephalogram: left cerebellar mass
2000 rads in 10 days
Remission Uremia
9 mw.
Necrotic lesion, left cerebellum
Embryonal carcinoma
Confusion, right hemiparesis
CT scan:
3900 rads in 19 days
Remission Respiratory failure
4 mos.
Necrotic lesion. left occipital lobe
Choriocarcinoma
Headaches, visual blurring
CT scan: multiple contrastenhancing lesions
3000 rads in 14 days
Remission Septicemia
2 mw.
Necrotic lesions, frontal and parietal lobes
26,M
(DHL)
36,M
32.M
left parieb occipital mass
Clinical courw
Causeof death
Pathology Cystic lesions, right frontal lobe and leR putamen
September 1970 NEUROLOGY 29 1198
Sterilization of cerebral metastases malignant cells were found. Simultaneous human chorionic gonadotropin (HCG) beta subunit determinations on serum and CSF were 175,000ng per milliliter and 900 ng per milliliter, respectively, a finding suggesting absence of CNS metastasis.6 General postmortem examination revealed metastatic tumor involving the lungs, mediastinal lymph nodes, and liver. The dura, meninges, blood vessels, and external appearance of the brain were unremarkable, Transverse sections of cerebellum and brainstem were unremarkable. Serial coronal sections of the cerebral hemispheres disclosed multiple discrete areas of softening and brownish discoloration in the frontal and parietal lobes bilaterally. The largest of the lesions was found in the right parietal lobe. The ventricles were normal in size. Multiple sections were taken from the lesions. Microscopic examination revealed areas of liquefactive and coagulative necrosis surrounded by dense gliotic capsules containing numerous hemosiderin-laden macrophages and gemistocytic astrocytes. The center of the lesions contained in addition to necrotic debris, large amounts of hemosiderin pigment, and areas of hemorrhage. No tumor cells were identified.
Discussion. In the 10 years between January 1968 and December 1977, intracerebral metas-
tases were found a t autopsy in 485 patients. Patients with extradural, subdural, or leptomeningeal metastases not invading the underlying brain were excluded. Two hundred two of the 485 patients had received a full course of RT to the whole brain. Among these were 15 patients in whom RT was preceded by surgical resection of a solitary metastatic tumor; 187 patients were treated solely with RT. In five of these patients (table l), no evidence of residual metastatic tumor could be found at autopsy. In a further nine patients, only rare scattered tumor cells were seen, usually at the periphery of necrotic or cystic lesions, previously the site of large symptomatic metastatic tumors. Residual tumor was found in all but 1 of the 15 surgically treated patients. Prior to RT, an unequivocal diagnosis of metastatic brain tumor was made in only the first of the five p a t i e n t s p r e s e n t e d . I n t h a t case, a n asymptomatic right frontal metastasis was discovered during a transfrontal hypophysectomy. In the others, a presumptive diagnosis was based on clinical observation and diagnostic tests. Since no brain tumor was found at autopsy, the accuracy of the diagnostic evaluation must be substantiated in
Figure 5. (Patient 4 ) Photomicrograph o f a section from the lesion shown i n figure 4 demonstrating a single thickened blood vessel, numerous lipid-filled macrophages, and the intense astrocytic response surrounding the necrotic lesion. Hematoxylin-eosin, x 25.
1200 NEUROLOGY 29 September 1979
Table 2. Survival after therapy in patients living longer than 30 days Survival Number Cases Whole-brain radiation therapy
Median (months)
Mean (months)
One-year
91
4
5.6
10%
14
5
8.7
14%
Whole-brain radiation therapy (sterilized-metastases) Surgery and whole-brain radiation therapy
the four patients who were not biopsied. Posner reviewed the autopsy records at Memorial SloanKettering Cancer Center of patients radiated for brain metastasis and previously reported in two large series.’ In the first series, before neurologic consultation was a routine part of the diagnostic evaluation, 48 of 138 patients so treated did not have intracranial lesions at autopsy. The diagnostic error rate was 35 percent. In later series, where careful diagnostic evaluation preceded treatment, there was one error in 54 patients, less than 2 percent. Since CT scans became available the error rate is even lower. Thus, reports of sterilization of cerebral metastasis by RT must be viewed with suspicion unless there is a n unequivocal pretreatment diagnosis. We believe the history and the clinical and radiologic findings clearly established the diagnosis in the patients reported here. Furthermore, at autopsy a lesion was found at the site of the suspected brain metastasis, and the pathologic findings were similar in all patients, supporting the pretreatment diagnosis of metastatic brain tumors. The lesions were discrete, well-circumscribed necrotic areas with surrounding gliosis. The astrocytic response was typically intense, with many large fibrillary and gemistocytic astrocytes. Numerous macrophages, some pigmented, and occasional reactive giant cells were identified. In two cases, blood vessels adjacent to the lesions were markedly thickened and the nearby parenchyma contained numerous mineral deposits. Where the lesions were near the cortical surface, the overlying meninges were thickened and hypercellular. Multiple sections from all lesions were carefully examined, but no tumor cells were found. The combination of the clinical and pathologic findings strongly supports the original diagnosis of brain metastasis in all our patients. These five patients represented about 3 percent (5 of 187) of patients treated for brain metastasis and examined at autopsy. This figure is certainly an underestimate, in part because patients were included only if multiple sections of the lesion were taken (not done in every case), and in part because
patients whose brain tumors are sterilized live longer and thus are often lost to follow-up or do not die in the hospital. The length of survival from the onset of treatment could be determined accurately in all cases. The 30-day mortality in our patients was extremely high. In this series, 96 of the patients (51 percent) died within l month of the start of RT. The very high 30-day mortality can be explained in part by the tendency at this center to treat all patients, including those who are critically ill, and in part by the tendency for an autopsy series to select patients who respond less well. If we consider only the 91 patients who lived longer than 30 days, the median survival was 4 months (mean, 5.6 months), a figure comparable to that reported in other s t u d i e ~ . ~ - :By ’ . ~comparison, -~~ the median survival was 9 months in the five patients in whom RT appeared to sterilize the metastatic lesions, and 5 months in the surgically treated group. The 1-year survival rate in this autopsy series was 5 percent in the ,medicallytreated group and 13 percent in the small surgical group. If we eliminate the patients who died within the first 30 days, the 1-year survival rates were 10 percent and 14 percent, respectively (table 2). Median survival for the “cured patients was 9 months, as compared to 1 month for all patients treated medically and 5 months for the surgical group. Multiple biological factors influence the local radiocurability of a tumor. The radiosensitivity of metastatic cancers varies with the cell of origin. Small-cell carcinomas of thte lung (oat cell) and the lymphomas are considered highly radiosensitive. On the other hand, adenocarcinoma of the breast and nonseminomatous testicular tumors such as embryonal cell carcinoma and choriocarcinoma are only moderately responsive to radiation therapy and usually require a tumor dose of 4000 rads or more for adequate control of the lesion for a significant period of time. The wide range of radiosensitivities seen among various human tumors cannot be explained by inherent cellular factors, at least as measured by in vitro x-ray sur-
September 1979 NEUROLOGY 29 1201
Sterilization of cerebral metastases
viva1 and DNA repair.l5 In addition to the histology of the tumor, other factors influence tumor survival after RT. The number of tumor cells and the proportion of hypoxic cells are important factors in determining the radiation dose required to eradicate a cancer.16-18Large tumors containing large numbers of hypoxic cells are less sensitive to irradiation than smaller, well-oxygenated lesions. Metastatic brain tumors frequently contain foci of necrotic tissue, impairing radioresponsiveness. However, the present documentation that metastatic cancer to the brain can be sterilized by fractionated RT points out the importance of wholebrain irradiation and justifies aggressive radiation in an attempt to achieve a high rate of tumor control. What are the implications of this study? We find two: First, RT alone delivered to brain metastases, particularly those from radiosensitive primaries (as in our patients), may be more than palliative, and all nonterminal patients should be offered such treatment. Second, if some brain metastases can be eradicated by the palliative doses of RT used in these patients, it is likely that more patients will be sterilized by higher, “curative” doses. Thus, we have changed our treatment of brain metastasis to a course of 3900 rads in 11 doses over 17 days (500 rads x 3 consecutive days; 4-day rest; 300 rads x 8 week days) in the hope of achieving a larger number of sterilized cerebral metastases. References 1. Posner JB: Management of central nervous system metastases. Semin Oncol4:81-91, 1977 2. Posner JB, Shapiro WR: Brain tumor: Current status of treatment and its complications. Arch Neurol 32:781-784, 1975
1202 NEUROLOGY 29 September 1879
3. Hendrickson FR: Radiation therapy of metastatic tumors. Semin Oncol 2:43-46, 1975 4. Young DF, Posner JB, Chu F, e t al: Rapid-course radiation therapy of cerebral metastases: Results and complications. Cancer 34:1069-1076, 1974 5. Order SE, Hellman S, Von Essen CF, e t al: Improvement in quality of survival following whole-brain irradiation for brain metastases. Radiology 91:149-153, 1968 6. Schold SC, Vugrin D, Golbey RE, e t al: Central nervous system metastases from germ cell carcinoma of testis. Semin Oncol (In press) 7. Posner JB: Diagnosis and treatment of metastases to the brain. Clin Buli 4:47-57, 1974 8. Hindo WA. DeTrana FA 111. Lee M-S. e t al: Laree dose increment irradiation i n the treatment of cerebrarmetastases. Cancer 26:138-141, 1970 9. Horton J , Baxter DH, Olson KB: The management of metastases to the brain by irradiation and corticosteroids. Am J Roentgenol 111:33336, 1971 10. Nisce LZ, Hilaris BS, Chu FCH: A review of experience with irradiation of brain metastasis. Am J Roentgenol 111: 329-333, 1971 11. Montana GS, Meacham WF, Caldwell W L Brain irradiation for metastic disease of lung origin. Cancer 29:14771480,1972 12. Hazra T, Mullins GM, Lott S : Management of cerebral metastasis from bronchogenic carcinoma. Johns Hopkins Med J 130:377-383, 1972 13. Gottlieb JA, Frei E 111, Luce JK: An evaluation of the management of patients with cerebral metastases from malignant melanoma. Cancer 29:701-705, 1972 14. Shehata WM, Hendrickson FR, Hindo WA: Rapid fractionation technique and retreatment of cerebral metastases by irradiation. Cancer 34:257-261, 1974 15. Weichselbaum RR, Epstein J , Little JB, e t al: Inherent cellular radiosensitivity of human tumors of varying clinical curability. Am J Roentgenol 127:1027-1032, 1976 16. Gray LH: Radiobiologic basis of oxygen as a modifying factor in radiation therapy. Am J Roentgenol 85803-815, 1961 17. Thomlinson RH: Changes of oxygenation in tumors in relation to irradiation, Front Radiation “her Onc 3:109-121, 1968 18. Fletcher GH: Clinical dose-response curves of human malignant epithelial tumors. Br J Radio1 461-12, 1973
Sterilization of cerebral metastases by radiation therapy J. Gregory Cairncross, Norman L. Chernik, Jae-Ho Kim, et al. Neurology 1979;29;1195 DOI 10.1212/WNL.29.9_Part_1.1195 This information is current as of September 1, 1979 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1979 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Sterilization of cerebral metastases by radiation therapy J. Gregory Cairncross, M.D., Norman L. Chernik, M.D., Jae-Ho Kim, M.D., a n d Jerome B. Posner, M.D.
Central nervous system (CNS) complications of cancer are common. Brain metastases are present at autopsy i n 12 percent of patients with systemic cancer.’ F u r t h e r m o r e , at Memorial S l o a n Kettering Cancer Center (MSKCC), 65 to 75 percent of patients with CNS metastatic disease suffer major neurologic symptoms during life.2 For the most part, the management of CNS metastases is palliative radiation therapy, which relieves neurologic s y m p t o m s in a b o u t t w o - t h i r d s of patients.3-5 Radiation therapy (RT) is delivered to the whole brain. The dose and fractionation procedures vary from center t o center, b u t have not been shown to make a substantial difference i n the outcome of the rap^.^ Despite initial improvement, many p a t i e n t s soon relapse, and median survivals are usually less than 6 months. A few long-term survivors have been reported, but in some of them the original diagnosis may have been incorrect, since there was no histologic verification of the lesion before or after therapy. No pathologic reports published to date verify the sterilization of metastatic brain tumor by RT alone. In the 10 years between 1968 and 1977, we encountered five patients with cerebral metastatic tumor, treated with whole brain RT, and with no evidence of residual intracranial tumor at autopsy. Case reports. Patient 1. At age 57 in 1963,this patient underwent a radical mastectomy for anaplastic carcinoma. Pleural and bone metastases were found in 1968. T r a n s f r o n t a l craniotomy w a s performed for
hypophysectomy, but extensive metastatic tumor was found infiltrating the right frontal lobe. A brain biopsy confirmed intraparenchymal metastatic carcinoma (figure 1).No attempt was made t o extirpate the tumor. Postoperatively she remained asymptomatic, and 3500 rads of RT was given t o the whole brain. Fifteen months later, in October 1969, she noted right-sided weakness, numbness, and clumsiness. There was mild cognitive impairment, normal speech, right lower facial weakness, mild right arm and leg weakness, brisk tendon reflexes with sustained clonus at the right ankle, a right extensor plantar response, and an unsteady gait. Skull roentgenograms revealed multiple calvarial metastases. An isotope brain scan disclosed multiple areas of increased uptake within the calvarium but no intraparenchymal lesions. She was treated with steroids and an additional 2400 rads of RT to the whole brain. The neurologic symptoms and signs rapidly improved and did not recur. She died 8 months later, 23 months after the original treatment of the cerebral metastasis. General postmortem examination revealed metastatic tumor involving the lungs, pleura, mediastinal and abdominal lymph nodes, adrenals, and ovaries. Neuropathologic examination followed formalin fixation of the brain. A thick, gelatinous, grayish-colored membrane covered the subdural surface of both cerebral hemispheres. The meninges over both cerebral convexities were thick, opaque, and granular in appearance. The vessels a t the base of the brain and over the lateral convexities were unremarkable. There was an area of brownish discoloration and cavitation measuring 3 by 2 cm involving the dorsolateral aspect of the right frontal pole. The brainstem, cerebellum, and spinal cord were unremarkable. On serial section of the cerebral hemispheres, the lesion in the right frontal pole extended into the central white matter and exhibited the typical appearance of a cystic infarct (figure 2). A
From the Departments of Neurology, Pathology, and Radiation Therapy, Memorial Sloan-Kettering Cancer Center; and the Departments of Neurology and Pathology, Cornell University Medical College, New, York, New York. Presented a t the thirty-first Annual Meeting of the American Academy of Neurology, Chicago, Illinois, April, 1979 Accepted for publication February 6,1979
Address reprint requests to Dr. Posner, 1275 York Avenue, New York, NY 10021.
September I979 NEUROLOGY 29 1195
Figure 1. (Patient 1 ) Photomicrograph of brain biopsy demonstrating infiltrating adenocarcinoma of the breast. Hematoxylin-eosin, x 50. second cystic lesion, measuring 2 by 1cm, was found in the caudal aspect of the left putamen. This lesion extended across the posterior limb of the internal capsule to the wall of the lateral ventricle. Transverse sections of the brainstem and cerebellum were unremarkable. The lateral ventricles were moderately dilated. Microscopic examination of 15 sections through various parts of the right frontal lesion demonstrated a relatively uniform picture without evidence of tumor cells. Surrounding the cavitation was a loosely structured hypercellular fibrillary matrix with large numbers of gemistocytic and fibrillary astrocytes (figure 3). Numerous macrophages, some pigmented, and occasional reactive giant cells were identified. The overlying meninges were thickened and hypercellular. Multiple sections of the left putamen demonstrated an area of central cavitation surrounded by a loosely structured fibrillary matrix containing large numbers of gemistocytic astrocytes and nonpigmented macrophages. No tumor cells were identified. Review of the biopsy specimen from 1968 confirmed the initial report of extensive tumor infiltration of the dura, underlying meninges, and cerebral cortex. In the cortical segments of the biopsy, the parenchyma surrounding the tumor nodules showed moderate disruption of the neuropil, ischemic changes in the neurons, and moderate numbers of gemistocytic astrocytes.
Patient 2. A 62-year-old man with widely metastatic
1196 NEUROLOGY 29 September 1979
oat cell carcinoma of the lung died in June 1968. He had been admitted to the hospital in September 1967 after 3 weeks of right frontal headache and 1 week of progressive left-sided weakness, gait unsteadiness, and emotional lability. He was lethargic, with striking impairment of all cognitive functions. Funduscopic examination revealed dilated, tortuous retinal veins with absent venous pulsations. Left lower facial weakness and a mild left hemiparesis were noted. Rapid alternating movements, fine finger movements, and finger-to-nose testing were poorly performed on the left. Cortical sensory modalities were impaired in the left hand. Tendon reflexes were brisk throughout, with bilateral extensor plantar responses. Primitive reflexes were prominent. Skull roentgenograms were unremarkable. An echoencephalogram demonstrated a midline shift from right to left. An isotope brain scan disclosed a right frontoparietal area of increased uptake. A right retrograde brachial angiogram revealed a large, anterior suprasylvian mass containing tumor vessels. He was treated with steroids and received 3000 rads of RT to the whole brain. Cerebrospinal fluid (CSF) pressure (140 mm KO) and contents were normal. The neurologic symptoms and signs rapidly improved. One month after RT was completed, he was free of headache, intellectually intact, and complained only of mild left arm weakness. A follow-up brain scan demonstrated a much smaller area of increased uptake in the right frontoparietal region. A t the time of his final admission, 9
months after metastasis, the treatment of the cerebral neurologic examination was normal. The general postmortem examination revealed metastatic tumor involving the liver, adrenals, and bone marrow. Fibrosis and radiation changes were seen in the lower lobe of the right lung, but no residual tumor was found in the right main stem bronchus or its branches. On serial section of the cerebral hemispheres, a large necrotic lesion was found in the central white matter of the right frontal lobe. Transverse sections of the brainstem and cerebellum were unremarkable. On microscopic examination, multiple sections from the right frontal cavitation showed the lining of the cavity to consist of a fibrillary matrix containing a dense collection of macrophages and gemistocytic astrocytes. Several large vessels, some with markedly thickened collagenous walls, were seen, In the adjacent parenchyma, multiple, irregular, smooth-walled cystic spaces were noted. Some of these were filled with macrophages, and others were empty. The intervening parenchyma was characterized by dense gliosis, with gemistocytic and fibrillary forms, and groups of macrophages with occasional reactive giant cells. No hemosiderin pigment was observed. In all sections, there were extensive mineral deposits forming perivascular and mural droplets and rings as well as large parenchymal plaque formations. Sections of the basal ganglia and dentate nucleus of the cerebellum showed similar extensive mineraliza-
tion. The meninges over the cerebral cortex were thickened. No tumor cells were identified.
Patient 3. A 26-year-old man with diffuse histiocytic lymphoma died in June 1969, 16 months after diagnosis. He was admitted in September 1968after 1week of morning headache, vomiting, and lethargy, and 2 days of diplopia. Examination revealed papilledema, nystagmus on lateral and vertical gaze, ocular dysmetria, and poor rapid alternating movements and finger-to-nose testing in the left arm. Tendon reflexes were brisk and symmetric, with flexor plantar responses. No weakness, sensory disturbance, or gait abnormality was noted. Skull roentgenograms were unremarkable. An electroencephalogram (EEG) demonstrated bilateral slowing and disorganization. An isotope brain scan disclosed areas of increased uptake in the left cerebellum and right parietal lobe. Cerebral angiography demonstrated bowing of the anterior cerebral arteries, indicating ventricular enlargement, and raised the suspicion of a left posterior fossa mass. Pneum.oencephalogramrevealed a cerebellar mass lesion with partial obstruction of the fourth ventricle and aqueduct. He was treated with steroids and RT to the whole brain. At discharge, he was much improved, with only mild left-sided cerebellar signs persisting. His subsequent neurologic course was unremarkable, and future admissions were related to the systemic disease. A follow-up isotope brain scan 6
Figure 2 . (Patient 1 ) Coronal section demonstrating the necrotic lesion in the right frontal lobe in the area where the metastasis had been. September 1979 NEUROLOGY 29 1197
bT,er111ZatlOn of Cerebral metastases
Figure 3. (Patient 1 ) Photomicrograph of a section from the lesion in figure 2 demonstrating an area of cavitation surrounded by a hypercellular fibrillary matrix containing abundant gemistocytic and fibrillary astrocytes and lipid-laden macrophnges. Hernatoxylin-eosin, x 12.5.
months after completion of therapy was normal. He died 3 months later. General postmortem examination revealed widely disseminated lymphoma involving the lungs, heart, mesentery, adrenals, kidneys, pancreas, and testis. The dura, meninges, and blood vessels were unremarkable. The external appearance of the cerebral hemispheres and brainstem were unremarkable. A small area of brownish discoloration was seen on the inferior surface of the left cerebellar hemisphere. Serial sections of the cerebral hemispheres revealed mild, diffuse edema of the central white matter. The ventricles were normal in size. Transverse sections of the brainstem were unremarkable. Serial sections of the cerebellum disclosed a 1-by-1-cmbrownish, indurated lesion in the inferior aspect of the left hemisphere. Multiple sections were taken from the left cerebellar lesion. The normal cellular detail was replaced by fibrillary gliosis and scattered areas of partial liquefaction. The latter area contained numerous hemosiderin-laden macrophages. Penetrating blood vessels with thickened collagenous walls and areas of mineralization were noted in the adjacent parenchyma. The overlying meninges were markedly thickened. No tumor cells were found.
Patient 4. A 36-year-old man with embryonal cell carcinoma died in July 1977. He had presented 15 months
1198 NEUROLOGY 29 September 1979
earlier with superior vena caval obstruction. The diagnosis was established by mediastinoscopy. In April 1977 he was admitted for management of bilateral malignant pleural effusions. Neurologic examination was normal on admission. Two weeks later, he was lethargic, disoriented, and unable to correctly perform simple tests of cognitive function. Funduscopic examination revealed slight blurring of the right disk margin. The visual fields and ocular movements were full. Right lower facial weakness and mild right arm and leg weakness were noted. Tendon reflexes were brisk and symmetric, with a right extensor plantar response. There was no language or sensory disturbance. CSF pressure and contents were normal. Computed tomography (CT) revealed a left parietooccipital contrast-enhancing mass lesion with a small, central area of increased density prior to contrast administration (figure 4). He was treated with steroids and received 3900 rads of RT to the whole brain. Rapid clinical improvement ensued, and 1 month after completion of RT, the neurologic examination was normal. He died 4 months later with widespread systemic disease. General postmortem examination revealed metastatic tumor involving the lungs, pleura, mediastinal lymph nodes, pericardium, mesentery, liver, kidney, and bone marrow. The dura, meninges, blood vessels, and external appearance of the brain were unremark-
able. Transverse sections of the brainstem and cerebellum were unremarkable. On serial sectioning of the cerebral hemispheres, a 1-by-1-cmarea of softening and brownish discoloration was found in the left occipital lobe. The ventricles were normal in size. There was no evidence of mass effect or herniation. Multiple sections were taken from the lesion. Microscopic examination revealed an area of liquefactive and coagulative necrosis surrounded by a dense connective tissue capsule and gliosis. Numerous hemosiderin-laden macrophages and gemistocytic astrocytes were seen (figure 5). The center of the lesion contained, in addition to necrotic debris, cholesterol crystals and hemosiderin pigment. However, no residual tumor was found within the lesion or infltrating the surrounding parenchyma.
Figure 4 (Patient 4 ) Computed tomographic scan following intravenous contrast demonstrating a left parietooccipital metastasis.
Patient 5. A 32-year-old inan with choriocarcinoma died in August 1977,ll months after diagnosis. He was admitted in June 1977 after 3 weeks of right parietal headaches, visual blurring to the left, and difficulty in reading. Neurologic examination was remarkable for a left inferior homonymous quadrantanopia and a left extensor plantar response. CT demonstrated multiple contrast-enhancing lesions, the largest in the right occipitoparietal region. Additional lesions were seen in the left parietal lobe and both frontal lobes. He was treated with steroids and 3000 rads of RT to the whole brain. Rapid clinical improvement ensued. He died 2 months later with widespread systemic disease and acute bronchopneumonia. Forty-eight hours prior to his death, CSF pressure and contents were normal; no
Table 1. Clinical findings in patients with “sterilized” cerebral metastases
Patient age a n d
bn%h of survival
Symptoms and signs
Diagnostic
sex
Primary tumor
studies
RT dose
64.F
Breast
Asymptomatic 1968 Right hemiparesis 1969
Brain biopsy: metastatic carcinoma
3500 rads in Remission Septicemia 23 mos. 24 days (1968) 2400 rads in 8 mos 16 days (1969)
62,M
Lung (oat cell)
Headaches, confusion, left hemiparesis
Angiogram: 3000 rads right frontal mass in 23 with tumor vessels days
Remission Septicemia
9 mos.
Cystic lesion, right frontal lobe
Lymphoma
Headaches, vomiting, lethargy, diplopia
Pneumwncephalogram: left cerebellar mass
2000 rads in 10 days
Remission Uremia
9 mw.
Necrotic lesion, left cerebellum
Embryonal carcinoma
Confusion, right hemiparesis
CT scan:
3900 rads in 19 days
Remission Respiratory failure
4 mos.
Necrotic lesion. left occipital lobe
Choriocarcinoma
Headaches, visual blurring
CT scan: multiple contrastenhancing lesions
3000 rads in 14 days
Remission Septicemia
2 mw.
Necrotic lesions, frontal and parietal lobes
26,M
(DHL)
36,M
32.M
left parieb occipital mass
Clinical courw
Causeof death
Pathology Cystic lesions, right frontal lobe and leR putamen
September 1970 NEUROLOGY 29 1198
Sterilization of cerebral metastases malignant cells were found. Simultaneous human chorionic gonadotropin (HCG) beta subunit determinations on serum and CSF were 175,000ng per milliliter and 900 ng per milliliter, respectively, a finding suggesting absence of CNS metastasis.6 General postmortem examination revealed metastatic tumor involving the lungs, mediastinal lymph nodes, and liver. The dura, meninges, blood vessels, and external appearance of the brain were unremarkable, Transverse sections of cerebellum and brainstem were unremarkable. Serial coronal sections of the cerebral hemispheres disclosed multiple discrete areas of softening and brownish discoloration in the frontal and parietal lobes bilaterally. The largest of the lesions was found in the right parietal lobe. The ventricles were normal in size. Multiple sections were taken from the lesions. Microscopic examination revealed areas of liquefactive and coagulative necrosis surrounded by dense gliotic capsules containing numerous hemosiderin-laden macrophages and gemistocytic astrocytes. The center of the lesions contained in addition to necrotic debris, large amounts of hemosiderin pigment, and areas of hemorrhage. No tumor cells were identified.
Discussion. In the 10 years between January 1968 and December 1977, intracerebral metas-
tases were found a t autopsy in 485 patients. Patients with extradural, subdural, or leptomeningeal metastases not invading the underlying brain were excluded. Two hundred two of the 485 patients had received a full course of RT to the whole brain. Among these were 15 patients in whom RT was preceded by surgical resection of a solitary metastatic tumor; 187 patients were treated solely with RT. In five of these patients (table l), no evidence of residual metastatic tumor could be found at autopsy. In a further nine patients, only rare scattered tumor cells were seen, usually at the periphery of necrotic or cystic lesions, previously the site of large symptomatic metastatic tumors. Residual tumor was found in all but 1 of the 15 surgically treated patients. Prior to RT, an unequivocal diagnosis of metastatic brain tumor was made in only the first of the five p a t i e n t s p r e s e n t e d . I n t h a t case, a n asymptomatic right frontal metastasis was discovered during a transfrontal hypophysectomy. In the others, a presumptive diagnosis was based on clinical observation and diagnostic tests. Since no brain tumor was found at autopsy, the accuracy of the diagnostic evaluation must be substantiated in
Figure 5. (Patient 4 ) Photomicrograph o f a section from the lesion shown i n figure 4 demonstrating a single thickened blood vessel, numerous lipid-filled macrophages, and the intense astrocytic response surrounding the necrotic lesion. Hematoxylin-eosin, x 25.
1200 NEUROLOGY 29 September 1979
Table 2. Survival after therapy in patients living longer than 30 days Survival Number Cases Whole-brain radiation therapy
Median (months)
Mean (months)
One-year
91
4
5.6
10%
14
5
8.7
14%
Whole-brain radiation therapy (sterilized-metastases) Surgery and whole-brain radiation therapy
the four patients who were not biopsied. Posner reviewed the autopsy records at Memorial SloanKettering Cancer Center of patients radiated for brain metastasis and previously reported in two large series.’ In the first series, before neurologic consultation was a routine part of the diagnostic evaluation, 48 of 138 patients so treated did not have intracranial lesions at autopsy. The diagnostic error rate was 35 percent. In later series, where careful diagnostic evaluation preceded treatment, there was one error in 54 patients, less than 2 percent. Since CT scans became available the error rate is even lower. Thus, reports of sterilization of cerebral metastasis by RT must be viewed with suspicion unless there is a n unequivocal pretreatment diagnosis. We believe the history and the clinical and radiologic findings clearly established the diagnosis in the patients reported here. Furthermore, at autopsy a lesion was found at the site of the suspected brain metastasis, and the pathologic findings were similar in all patients, supporting the pretreatment diagnosis of metastatic brain tumors. The lesions were discrete, well-circumscribed necrotic areas with surrounding gliosis. The astrocytic response was typically intense, with many large fibrillary and gemistocytic astrocytes. Numerous macrophages, some pigmented, and occasional reactive giant cells were identified. In two cases, blood vessels adjacent to the lesions were markedly thickened and the nearby parenchyma contained numerous mineral deposits. Where the lesions were near the cortical surface, the overlying meninges were thickened and hypercellular. Multiple sections from all lesions were carefully examined, but no tumor cells were found. The combination of the clinical and pathologic findings strongly supports the original diagnosis of brain metastasis in all our patients. These five patients represented about 3 percent (5 of 187) of patients treated for brain metastasis and examined at autopsy. This figure is certainly an underestimate, in part because patients were included only if multiple sections of the lesion were taken (not done in every case), and in part because
patients whose brain tumors are sterilized live longer and thus are often lost to follow-up or do not die in the hospital. The length of survival from the onset of treatment could be determined accurately in all cases. The 30-day mortality in our patients was extremely high. In this series, 96 of the patients (51 percent) died within l month of the start of RT. The very high 30-day mortality can be explained in part by the tendency at this center to treat all patients, including those who are critically ill, and in part by the tendency for an autopsy series to select patients who respond less well. If we consider only the 91 patients who lived longer than 30 days, the median survival was 4 months (mean, 5.6 months), a figure comparable to that reported in other s t u d i e ~ . ~ - :By ’ . ~comparison, -~~ the median survival was 9 months in the five patients in whom RT appeared to sterilize the metastatic lesions, and 5 months in the surgically treated group. The 1-year survival rate in this autopsy series was 5 percent in the ,medicallytreated group and 13 percent in the small surgical group. If we eliminate the patients who died within the first 30 days, the 1-year survival rates were 10 percent and 14 percent, respectively (table 2). Median survival for the “cured patients was 9 months, as compared to 1 month for all patients treated medically and 5 months for the surgical group. Multiple biological factors influence the local radiocurability of a tumor. The radiosensitivity of metastatic cancers varies with the cell of origin. Small-cell carcinomas of thte lung (oat cell) and the lymphomas are considered highly radiosensitive. On the other hand, adenocarcinoma of the breast and nonseminomatous testicular tumors such as embryonal cell carcinoma and choriocarcinoma are only moderately responsive to radiation therapy and usually require a tumor dose of 4000 rads or more for adequate control of the lesion for a significant period of time. The wide range of radiosensitivities seen among various human tumors cannot be explained by inherent cellular factors, at least as measured by in vitro x-ray sur-
September 1979 NEUROLOGY 29 1201
Sterilization of cerebral metastases
viva1 and DNA repair.l5 In addition to the histology of the tumor, other factors influence tumor survival after RT. The number of tumor cells and the proportion of hypoxic cells are important factors in determining the radiation dose required to eradicate a cancer.16-18Large tumors containing large numbers of hypoxic cells are less sensitive to irradiation than smaller, well-oxygenated lesions. Metastatic brain tumors frequently contain foci of necrotic tissue, impairing radioresponsiveness. However, the present documentation that metastatic cancer to the brain can be sterilized by fractionated RT points out the importance of wholebrain irradiation and justifies aggressive radiation in an attempt to achieve a high rate of tumor control. What are the implications of this study? We find two: First, RT alone delivered to brain metastases, particularly those from radiosensitive primaries (as in our patients), may be more than palliative, and all nonterminal patients should be offered such treatment. Second, if some brain metastases can be eradicated by the palliative doses of RT used in these patients, it is likely that more patients will be sterilized by higher, “curative” doses. Thus, we have changed our treatment of brain metastasis to a course of 3900 rads in 11 doses over 17 days (500 rads x 3 consecutive days; 4-day rest; 300 rads x 8 week days) in the hope of achieving a larger number of sterilized cerebral metastases. References 1. Posner JB: Management of central nervous system metastases. Semin Oncol4:81-91, 1977 2. Posner JB, Shapiro WR: Brain tumor: Current status of treatment and its complications. Arch Neurol 32:781-784, 1975
1202 NEUROLOGY 29 September 1879
3. Hendrickson FR: Radiation therapy of metastatic tumors. Semin Oncol 2:43-46, 1975 4. Young DF, Posner JB, Chu F, e t al: Rapid-course radiation therapy of cerebral metastases: Results and complications. Cancer 34:1069-1076, 1974 5. Order SE, Hellman S, Von Essen CF, e t al: Improvement in quality of survival following whole-brain irradiation for brain metastases. Radiology 91:149-153, 1968 6. Schold SC, Vugrin D, Golbey RE, e t al: Central nervous system metastases from germ cell carcinoma of testis. Semin Oncol (In press) 7. Posner JB: Diagnosis and treatment of metastases to the brain. Clin Buli 4:47-57, 1974 8. Hindo WA. DeTrana FA 111. Lee M-S. e t al: Laree dose increment irradiation i n the treatment of cerebrarmetastases. Cancer 26:138-141, 1970 9. Horton J , Baxter DH, Olson KB: The management of metastases to the brain by irradiation and corticosteroids. Am J Roentgenol 111:33336, 1971 10. Nisce LZ, Hilaris BS, Chu FCH: A review of experience with irradiation of brain metastasis. Am J Roentgenol 111: 329-333, 1971 11. Montana GS, Meacham WF, Caldwell W L Brain irradiation for metastic disease of lung origin. Cancer 29:14771480,1972 12. Hazra T, Mullins GM, Lott S : Management of cerebral metastasis from bronchogenic carcinoma. Johns Hopkins Med J 130:377-383, 1972 13. Gottlieb JA, Frei E 111, Luce JK: An evaluation of the management of patients with cerebral metastases from malignant melanoma. Cancer 29:701-705, 1972 14. Shehata WM, Hendrickson FR, Hindo WA: Rapid fractionation technique and retreatment of cerebral metastases by irradiation. Cancer 34:257-261, 1974 15. Weichselbaum RR, Epstein J , Little JB, e t al: Inherent cellular radiosensitivity of human tumors of varying clinical curability. Am J Roentgenol 127:1027-1032, 1976 16. Gray LH: Radiobiologic basis of oxygen as a modifying factor in radiation therapy. Am J Roentgenol 85803-815, 1961 17. Thomlinson RH: Changes of oxygenation in tumors in relation to irradiation, Front Radiation “her Onc 3:109-121, 1968 18. Fletcher GH: Clinical dose-response curves of human malignant epithelial tumors. Br J Radio1 461-12, 1973
Sterilization of cerebral metastases by radiation therapy J. Gregory Cairncross, Norman L. Chernik, Jae-Ho Kim, et al. Neurology 1979;29;1195 DOI 10.1212/WNL.29.9_Part_1.1195 This information is current as of September 1, 1979 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1979 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
