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0364%3016/90 $3.00 + .OO 0 1990 Pel-gamon press PIG
0 Brief Communication CNS TlJMOR INDUCTION BY RADIOTHERAPY: A REPORT OF FOUIR NEW CASES AND ESTIMATE OF DOSE REQUIRED LILLIAN W. CAVIN, M.D.,‘,2 GLENN V. DALRYMPLE, M.D.,~Y~,~ E. LYNN MCGUIRE, ANN W. MANERS, M.D.2,3 AND JOHN R. BROADWATER, M.D.*,2,3 ‘Nuclear University
M.S.,‘>*
Medicine Service, John L. McClellan Veterans Administration Hospital, Little Rock, AR; ‘Radiology Department, the of Arkansas for Medical Sciences, Little Rock, AR; and ‘Central Arkansas Radiation Therapy Institute, Little Rock, AR We have analyzed 60 cases of intra-axial brain tumors associated with antecedent radiation therapy. These include four new cases. The patients had originally received radiation therapy for three reasons: (a) cranial irradiation for acute lymphoblastic leukemia (ALL), (b) definitive treatment of CNS neoplasia, and (c) treatment of benign disease (mostly cutaneous infections). The number of cases reported during the past decade has greatly increased as compared to previous years. Forty-six of the 60 intra-axial tumors have been reported since 1978. The relative risk of induction of an intra-axial brain tumor by radiation therapy is estimated to be more than 100, as compared to individuals who have not had head irradiation. CNS Neoplasms,
Radiation, Tumor-induction,
Radiation therapy, Radiation risk.
cases. This represents some 85% of the total cases reported in the literature. The present report adds four new cases of radiation induced intra-axial tumors.
INTRODUCTION For many years, radiation has been known to induce malignancy. Since the mid 1950’s, some 260 reports of induction of CNS tumors (both intra-axial and extra-axial) by radiation therapy have been published. Of these, 205 were extra-axial (1, 3-6, S-12, 16, 19, 20, 23, 24, 26-30, 32, 37, 38, 43, 45, 47, 49-52, 56, 60, 62, 64, 65, 66, 69, 71-73) and 55 intra-axial(2, 7, 13-15, 17, 18, 21, 22, 25, 31, 33-36, 39-42, 44, 46,48, 53-55, 57-59, 61, 63, 67, 68,70,74,75). Most of tlhe extra-axial tumors were benign meningiomas induced by “soft” X rays used to epilate the scalp of patients with Tineu capatis (1,45). The current report concerns the problem of induction of intra-axial tumors. While the numbers of reported intra-axial tumors are smaller, the significance of the radiation induced intraaxial tumor is much greater. More than 60% of the intraaxial tumors were highly malignant glioblastoma multiforme. The number of reports of radiation induced CNS tumors-especially the intra-axial tumors-is increasing. As late as 1978 Bachman and Ostrow stated that “There are no previous reports of glioblastoma occurring following central nervous system irradiation” (6). While not entirely correct, this does point out that the induction of intraaxial brain tumors was not perceived to be a problem of great importance. Since .l978, there have been 46 reported
METHODS
AND MATERIALS
Patients We have located 60 cases of radiation induced intraaxial tumors-55 are from the world literature, four are the new cases from our institution which are reported here, and one case remains unpublished. From the information provided in the literature, correspondence with the authors of 32 cases, and our own cases, we have enough information for basic statistical evaluation in 42 patients. We do not have enough information on the remaining 18 cases to use these for statistical evaluation. Dosimetry We have combined information from the published reports (where available) together with that gained through correspondence to estimate the brain doses from irradiation. Only two published cases contained actual graphical representations of the original isodose curves (63, 75). Additional data from the original authors was used for the dose reconstruction in 14 cases (4, 13,22, 35,40,44, 53,54,57,58,63). Isodose distributions for our four cases were constructed with a computer. Accepted
* Deceased 11 November 1988. Reprint requests to: Glenn V. Dalrymple, M.D., John L. McClellan Memorial Vetemns Hospital, Slot 115LR, 4300 West Markham, Little Rock, AF: 72205. 399
for publication
9 August
1989.
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For 18 patients information is available from the original reports for Nominal Standard Dose (NSD) calculation and correlation with the anatomic location of the tumor. Nine of these patients were treated for acute lymphoblastic leukemia (ALL) and nine were treated for CNS neoplasia. Fifteen additional ALL patients were given 2400 cGy (we assume this was given as 12 fractions over 16 days) for NSD estimation (2,22,33,42,57). NSD is also estimated for an additional eight patients treated for CNS neoplasia, with estimates based on information in the original reports. Criteria for radiation induction The criteria for considering a neoplasm to be radiation induced were proposed by Cahan et al. (1 l), and later modified by Schrantz and Araoz (60). Briefly restated, the criteria are: 1. The tumor should appear in the irradiated area. 2. The tumor was not present prior to irradiation. 3. A latent period must elapse between irradiation and the appearance of the tumor. 4. The existence of the radiation induced tumor must be histologically proven. A fifth criterion could be applied to virtually all of the cases in our series in which definitive radiation therapy was used to treat a CNS neoplasm. Namely, the radiation induced tumor should be of a different histologic type than the lesion originally treated. Total dose and NSD For 46 cases (42 from the literature and our 4) we have stated the radiation dose in cGy and as the Nominal Standard Dose. For this the Ellis expression was used (2 1). NSD = [D] [N]-“.24 [T]-‘.” where D = dose in cGy for total treatment, N = number of fractions of therapy, T = time over which radiation was given (days). The NSD is given in units of RETS (radiation equivalent therapeutic). The use of NSD allows for comparison of a wide variety of treatment plans with different fractionations and treatment times. We appreciate that the NSD has not enjoyed widespread acceptance in clinical radiation therapy. For comparison of multiple treatment studies, in our view, it has value. Statistical evaluation We have divided the 60 patients into three groups based on the reason for initial irradiation: (a) patients with ALL who received CNS irradiation either prophylactically (251 26) or for CNS leukemia (l/26) (b) patients irradiated for primary CNS neoplasia (including pituitary tumors, medulloblastoma, astrocytoma, meningioma) (c) patients irradiated for benign disease (Tinea capitis, hemangiomas).
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Factors for our analysis are (a) age at irradiation (b) time from irradiation to induced tumor(c) total dose (cGy) (d) NSD (RETS) and (e) the histology of the induced tumor. All three data sets contained missing elements. The situation was improved as a consequence of personal contact with the authors of the published reports. This yielded information for a re-estimation of the isodose distribution to the patient’s brain. Where dose estimates were contained within the published reports, no change from the original value was found. Student’s “t” test was used to compare means of responses. Because of the known problem with multiple comparisons using t tests, the significance levels were appropriately adjusted by the Bonferroni correction (25). Estimate of relative risk of tumor induction for patients with ALL BEIR III defines relative risk (RR) as the ratio of the risk among the exposed to that obtained in the absence of exposure (48). For the patients with ALL (they have had head irradiation), RR is computed as the number of tumors per patient year for patients with ALL divided by the number of tumors per patient year for non-irradiated individuals. The spontaneous incidence of glioblastoma for non-irradiated individuals has been reported to be 5/100,000 patient years for individuals O-l 5 years of age (59). Arkansas ALL cases The charts of all 70 patients treated with cranial irradiation for acute lymphoblastic leukemia were reviewed. In general, the patients were seen at the Arkansas Childrens’ Hospital. All were treated at the Central Arkansas Radiation Therapy Institute (CARTI) in Little Rock, Arkansas. Age at irradiation, date of irradiation, and followup were recorded. This information was then used to calculate the total number of person-years. From 1976 to July 1, 1988, 70 patients, representing 3 10 person-years, have received cranial irradiation for ALL. Case reports Case 1. A 17-month old black male, was diagnosed with ALL August 1977 and placed on chemotherapy (methotrexate, prednisone, vincristine, and intrathecal methotrexate). He went into immediate remission. He developed signs of CNS leukemia and was treated with 2400 cGy (12 fractions, 16 days, 974 RETS; 4 MeV X rays). Whole head irradiation was used (see Fig. 1 for isodose distribution). Except for behavioral problems, he remained in remission and chemotherapy was stopped in October of 198 1. In September 1986 he developed clinical and radiographic evidence of a brain tumor. CT scan showed a mass on the left (see Fig. 1). Brain biopsy revealed glioblastoma multiforme plus recurrence of ALL. He died in September 1987; no autopsy was performed. The time from irradiation to tumor diagnosis was 8 years 11 months.
CNS tumor induction 0 L. W. GAVINef al.
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Fig. 1. Isodose curve (left) and CT scan (right) showing dose of 2000 to 2400 cGy at site of later tumor development (glioblastoma). This child received cranial irradiation for ALL. Case 2. A white female age 3 years 9 months, was diagnosed with ALL in February 1980. Chemotherapy was begun, and prophylactic cranial irradiation of 2400 cGy ( 12 fractions, 16 days, 97,4 RETS; 4 MeV X rays) in March 1980. She went into remission, and remained on chemotherapy, including intrathecal methotrexate, until March 1983. She did relatively well but experienced some difficulty in schoolwork with learning disabilities in math, spelling, and reading, although I.Q. was reported as normal. In August 1987 she developed clinical signs of a brain tumor, and CT scan showed a left fronto-parietal enhancing mass which on craniotomy w,as found to be a glioblastoma. The elapsed time from initial therapy to the induced tumor was 7 years 5 months. The patient remains alive with disease at the time of this communication. Case 3. A 5-year old black male, had a left temporal lobe astrocytoma (grade 2) resected January 1975. Postoperative radiation consisted of 5200 cGy to the left temporal region (26 fractions, 36 days, 1450 RETS; 6oCo teletherapy). He did well for over 112years post treatment. He then developed clinical and radiological signs of a new brain tumor in the left cerebral hemisphere. In March 1987, a glioblastoma multiforme was incompletely resected from the left temporal lobe. Tlhe location of the tumor is shown by an MRI scan (March 1987). Note the location of the tumor as compared with the isodose contours of the initial radiation therapy (Fig. 2). The time from initial radiation therapy to diagnosis of glioblastoma multiforme was 12 years 9 months. The patient remains alive at the time of this communication. Case 4. A 24-year ol’d white female, had incomplete resection of a basophilic adenoma of the pituitary in
March 1977. Postoperatively she received 4500 cGy (25 fractions, 35 days, 6 MeV X rays). The NSD was 1405 RETS. She did well until 1986, when she developed signs of a space occupying intracranial mass. CT scan (Fig. 3) showed a left frontal mass which was partially removed July 1986. Histopathology revealed a glioblastoma multiforme. There was no evidence of recurrence of the pituitary tumor. Note the relationship of the region of initial radiation therapy and the location of the glioblastoma (Fig. 3). The time from radiation therapy to diagnosis of glioblastoma was 9 years 2 months. The patient died April 1987. RESULTS The results for the ALL patients are summarized in the first row of Table 1. A total of 26 cases of radiation induced CNS tumors have been found. This number represents 16 glioblastomas (62%), 8 astrocytomas, 1 neuroectodermal tumor, and 1 ependymoma. The average age at irradiation is 5.0 years and corresponds to the natural history of ALL. Average time to induction of tumor is 7.5 years, with a range from 4.6 to 11 years. The average total dose is 2389 cGy. Average NSD is 952 RETS. The results for the patients irradiated for primary CNS neoplasms are also shown in Table 1. Twenty-four patients comprise this group. Of these, glioblastomas were found in 2 1 (87%). Two astrocytomas and one ependymoma were also found. Average age at irradiation was 18.3 years. This value was higher than that for ALL, as would be expected. Average time to tumor induction was 11.Oyears with a range of 1 year to 26 years, and average total dose was 4544 cGy. Average NSD was also greater than that for ALL patients- 1384 RETS.
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Fig. 2. Isodose curve (left) and MRI scan (right) with left temporal lobe glioblastoma demonstrated area on isodose curve. This patient had been irradiated for an astrocytoma 12 years earlier.
Ten patients form the smallest category, that of patients irradiated for benign disease. In this group one glioblastoma and three astrocytomas were found. In addition, six tumors described only as “malignant brain tumors” occurred in patients originally irradiated for Tinea capitis. No further pathologic information could be obtained for these six cases. Information on the 10 cases in this group is insufficient to estimate NSD. The average age at irradiation was 9.8 years with an average time from irradiation to induced tumor of 9.9 years. The average total dose was 3 13 cGy.
by cross-hatched
A major difficulty in computing risk estimates concerns the actual number of patients who have been irradiated. We have two incidences of patients with ALL who have received head irradiation and who have developed glioblastoma multiforme. Both of these patients were natives of Arkansas and were treated at the Central Arkansas Radiation Therapy Institute (CARTI). Since opening in 1976, 70 patients have received brain irradiation for ALL at CARTI. Through June 1988, they represent 3 10 personyears. Of these 19 are alive without recurrence, 30 died of leukemia, 1 died with glioblastoma multiforme and 1
Fig. 3. Isodose curve (left) and CT scan (right) in a patient previously irradiated for pituitary adenoma. The large enhancing mass on the CT scan was a glioblastoma. Note that dose at the tumor site ranged from 3000-4500 cGy.
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is currently still alive with GM (current report), 2 died of other causes, 1 is alive with disease, and 16 are unknown. (We assume that these patients are alive and well, for purpose of estimating relative risk.) For 3 10 person-years, we anticipate .016 cases. Since two cases have been observed, the relative risk is 125. Table 2 contains the experience of several investigators. The reported relative risk ranges from 20 to 226. Our estimate of 125 falls within this range. DISCUSSION
Animal experimental data A small body of animal experimental data exists, which has a bearing upon the problem of radiation induced CNS tumors in patients. In the early 1960’s, Dalrymple et af. irradiated large numbers of Rhesus monkeys with protons (18). The proton energies ranged from 32 to 2300 MeV. The energies were chosen to simulate the space radiation proton spectrum. The number of glioblastomas (9 animals) observed in the colony of 55 MeV proton survivors (a total of 78 monkeys) is almost 3-fold greater than the total number of other radiation induced tumors (4 monkeys) seen in this group (37, 74). Of the survivors of 800 cGy (surface dose), 33% died of glioblastoma. Later re-evaluation of the dosimetry indicated focal areas of the brain to have received doses as high as 2000 cGy (18). No other cases of glioblastoma have been seen at any other proton energy, after x-irradiation, or in the non-irradiated controls. Since Rhesus monkeys are known to have a very low rate of spontaneous malignancy (68), the very high incidence of glioblastoma after 55 MeV proton irradiation is remarkable. Two other instances of radiation induced glioblastoma in Rhesus monkeys are known (34, 70). The findings of radiation induced glioblastomas in these three groups raised the question whether this phenomenon could occur in humans. Patients with ALL Prophylactic cranial irradiation in patients with ALL has been used extensively since the early 1970’s (31). The combination of chemotherapy (including intrathecal methotrexate) plus radiation greatly reduces the probability of CNS recurrence of ALL. While ALL patients are treated with relatively low radiation doses (approximately 2400 cGy, 975 RETS), they receive total cranial irradiation. The distribution of the radiation induced tumors is also different from the higher dose, definitive therapy group. Of the 26 ALL cases, 24 had radiation induced gliomas (16 glioblastomas, 8 astrocytomas). Average interval from radiation to tumor in this group was 6-8 years, shorter than that of the primary CNS neoplasia group. Some oncologists have reduced prophylactic cranial irradiation in this group, not necessarily from fear of brain tumor induction, but because of possible neurological damage (Albo V, oral personal communication April
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Table 2. Risk of development
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of malignant brain tumors after radiation therauv for ALL
Author
Total dose GY
NSD (RETS)
Number of subjects
Number of tumors observed
Personyears
Number of tumors expected
RR*
Rimm (57) Fontana (22) Albo (2, 17) Cavin (present report)
2400 2400 2400 2400
974 974 974 974
92 37 468 70
1 3 9 2
2500 3800 4700 310
.06 .03 .04 .016
20 100 226 125
* Relative risk = observed cases/expected cases.
1988). Intellectual impairment, post head irradiation, prompted Freeman et al. to explore alternative forms of CNS prophylaxis (46). Both of our reported ALL patients had learning disabilities after irradiation and chemotherapy. Table 2 indicates an increased relative risk of tumor induction by head irradiation. The exact cause of this observed increase is not known, although many authors have implicated a variety of possibilities ranging from altered immune status to interaction of radiotherapy and intrathecal chemotherapy (22). Each of these explanations is possible, but problems arise when looking for common denominators. An interesting aspect is that in a series of 1507 patients with Hodgkin’s disease, no brain tumors were found (67). The key to the development of brain tumors thus seems to be head irradiation. Other tumors were found in the soft tissues, especially in the irradiated areas (67).
Patients with CNS neoplasia Patients irradiated for primary CNS neoplasia were treated with a different radiotherapy program than patients with ALL. For the former group, a relatively small volume of brain receives a high radiation dosage. This is illustrated in Figure 2, where the total dose of 5200 cGy is centered on the tumor bed. While it may be argued that this was the site of a previous astrocytoma and the second tumor might represent malignant degeneration, this rationale assumes a quiescent astrocytoma for a period
of almost 12 years. While this seems unlikely, such a possibility cannot be entirely excluded. No such argument can be espoused in case #4, however, in which a glioblastoma occurred in the radiation field following therapy for pituitary adenoma. Other such cases have been reported where a tumor of glial origin has followed radiotherapy for another tumor type after many years (7, 15, 35, 41, 53, 54, 63). Relative risk cannot be estimated for this group. Unlike patients irradiated for ALL, we do not know how many patients were irradiated but have not shown evidence of a second tumor. Patients with benign disease The patients treated for Tinea capitis and other benign conditions show a very different pattern of radiation induced tumors. These patients, in general, received the lowest radiation doses. Several dose estimates have been published, based upon reconstruction of the actual irradiation conditions. For our purposes, we will assume the total brain dose to be less than 200 cGy. We realize that some parts of the cranial vault, meninges, etc. could have received considerably higher doses, depending upon a number of factors (61). Most of the induced tumors in this group were meningiomas, but a few intra-axial tumors have been reported. One of these cases is a glioblastoma. Risk estimates for tumors following irradiation are not available, except in the cases of radiation induced meningiomas.
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I. J. Radiation Oncology 0 Biology 0 Physics T. Anaplastic astrocytoma following radiation for a glomus jugulare tumor. Cancer 43:2243-2247; 1979. Raffel, C.; Edwards, M. S. B.; Davis, R. L.; Albin, A. R. Postirradiation cerebellar glioma. J. Neurosurg. 63:300-303; 1985. Reiring, E. H.; Roer, W. H. Meningioma following radiadium therapy. J. Neurosurg. 29: 192-194; 1967. Rimm I. J.; Li, F. C.; Tarbell, N. J.; Winston, K. R.; Sallan, S. E. Brain tumors after cranial irradiation for childhood acute lymphoblastic leukemia. Cancer 59: 1506- 1508; 1987. Robinson, R. G. A second brain tumour and irradiation. J. Neurol. Neurosurg. Phys. 4 1: 1005- 10 12; 1978. Schoenberg, B. S.; Christine, B. W.; Whisnant, J. P. The descriptive epidemiology of primary intracranial neoplasms: the Connecticut experience. Am. J. Epidemiol. 104:499510; 1976. Schrantz, J. L.; Araoz, C. A. Radiation induced meningeal fibrosarcoma. Arch. Path. 93:26-3 1; 1972. Schultz, R. J.; Albert, R. E. III. Dose to organs of the head and neck from the X-ray treatment of tineu cupitis. Arch. Environ. Health 17:935-950; 1986. Soffer, D.; Pittaluga, S.; Feiner, M.; Beller, A. J. Intracranial meningiomas following low-dose irradiation to the head. J. Neurosurg. 59: 1048-1053; 1983. Song, R. L.; Donaldson, S. S.; Yorke, C. H. Malignant astrocytoma following radiotherapy of a crainopharyngioma. J. Neurosurg. 48:622-627; 1978. Tanaka, J.; Garcia, J. H.; Netsky, M. G.; Williams, J. P. Late appearance of meningioma at the site of partially removed oligodendroglioma. J. Neurosurg. 43:80-85; 1975.
February 1990, Volume 18,Number 2 65. Terry, R. D.; Hyams, V. J.; Davidoff, L. M. Combined nonmetastasizing fibrosarcoma and chromophobe tumor of the pituitary. Cancer l2:79 l-798; 1959. 66. Tubenstein, A. B.; Shalit, M. N.; Cohen, M. L.; Zandbank, U.; Reishenthal, E. Radiation induced cerebral meningioma: a recognizable entity. J. Neurosurg. 6 1:966-97 1; 1984. 67. Tucker, M. A.; Coleman, C. N.; Cox, R. S.; Varghese, A. and Rosenberg, S. A. Risk of second cancers after treatment for Hodgkin’s disease. NEJM 3 18:76-8 1; 1988. 68. van Wagenen, G. Vital statistics from a breeding colony. J. Med. Primatol. 1:2-20; 1972. 69. Waga, S.; Handa, H. Radiation induced meningioma with review of literature. Surg. Neurol. 5:2 15-2 19; 1976. 70. Wakisaka, S.; Kemper, T. L.; Nakagaki, H.; O’Neill, R. R. Brain tumors induced by radiation in Rhesus monkeys. Fukoka Acta Med. 73~585; 1982. 71. Waltz, T. A.; Brownell, B. Sarcoma: A possible late result of effective radiation therapy for pituitary adenoma. J. Neurosurg. 24:90 l-907; 1966. following irradiation. Cancer 38: 72. Watts, C. Meningioma 1939-1940; 1976. 73. Winston, K. R.; Sotrel, A,; Schnitt, S. J. Meningeal melanocytoma. J. Neurosurg. 66:50-57; 1987. 74. Yochmowitz, M. G.; Wood, D. H.; Salmon, Y. L. Delayed effects of proton irradiation in Macaca mulatta. II. Mortality (15 year report). USAFASM-TR-83-2; 1983. 75. Zochodne, D. W.; Cairncross, J. G.; Acre, F. P.; MacDonald, J. C. F.; Blume, W. T.; Girvin, J. P.; Kaufmann, J. C. E. Can. J. Neural. Sci. 11:475-478; 1984.
18, pp. 399-406 copyright
0364%3016/90 $3.00 + .OO 0 1990 Pel-gamon press PIG
0 Brief Communication CNS TlJMOR INDUCTION BY RADIOTHERAPY: A REPORT OF FOUIR NEW CASES AND ESTIMATE OF DOSE REQUIRED LILLIAN W. CAVIN, M.D.,‘,2 GLENN V. DALRYMPLE, M.D.,~Y~,~ E. LYNN MCGUIRE, ANN W. MANERS, M.D.2,3 AND JOHN R. BROADWATER, M.D.*,2,3 ‘Nuclear University
M.S.,‘>*
Medicine Service, John L. McClellan Veterans Administration Hospital, Little Rock, AR; ‘Radiology Department, the of Arkansas for Medical Sciences, Little Rock, AR; and ‘Central Arkansas Radiation Therapy Institute, Little Rock, AR We have analyzed 60 cases of intra-axial brain tumors associated with antecedent radiation therapy. These include four new cases. The patients had originally received radiation therapy for three reasons: (a) cranial irradiation for acute lymphoblastic leukemia (ALL), (b) definitive treatment of CNS neoplasia, and (c) treatment of benign disease (mostly cutaneous infections). The number of cases reported during the past decade has greatly increased as compared to previous years. Forty-six of the 60 intra-axial tumors have been reported since 1978. The relative risk of induction of an intra-axial brain tumor by radiation therapy is estimated to be more than 100, as compared to individuals who have not had head irradiation. CNS Neoplasms,
Radiation, Tumor-induction,
Radiation therapy, Radiation risk.
cases. This represents some 85% of the total cases reported in the literature. The present report adds four new cases of radiation induced intra-axial tumors.
INTRODUCTION For many years, radiation has been known to induce malignancy. Since the mid 1950’s, some 260 reports of induction of CNS tumors (both intra-axial and extra-axial) by radiation therapy have been published. Of these, 205 were extra-axial (1, 3-6, S-12, 16, 19, 20, 23, 24, 26-30, 32, 37, 38, 43, 45, 47, 49-52, 56, 60, 62, 64, 65, 66, 69, 71-73) and 55 intra-axial(2, 7, 13-15, 17, 18, 21, 22, 25, 31, 33-36, 39-42, 44, 46,48, 53-55, 57-59, 61, 63, 67, 68,70,74,75). Most of tlhe extra-axial tumors were benign meningiomas induced by “soft” X rays used to epilate the scalp of patients with Tineu capatis (1,45). The current report concerns the problem of induction of intra-axial tumors. While the numbers of reported intra-axial tumors are smaller, the significance of the radiation induced intraaxial tumor is much greater. More than 60% of the intraaxial tumors were highly malignant glioblastoma multiforme. The number of reports of radiation induced CNS tumors-especially the intra-axial tumors-is increasing. As late as 1978 Bachman and Ostrow stated that “There are no previous reports of glioblastoma occurring following central nervous system irradiation” (6). While not entirely correct, this does point out that the induction of intraaxial brain tumors was not perceived to be a problem of great importance. Since .l978, there have been 46 reported
METHODS
AND MATERIALS
Patients We have located 60 cases of radiation induced intraaxial tumors-55 are from the world literature, four are the new cases from our institution which are reported here, and one case remains unpublished. From the information provided in the literature, correspondence with the authors of 32 cases, and our own cases, we have enough information for basic statistical evaluation in 42 patients. We do not have enough information on the remaining 18 cases to use these for statistical evaluation. Dosimetry We have combined information from the published reports (where available) together with that gained through correspondence to estimate the brain doses from irradiation. Only two published cases contained actual graphical representations of the original isodose curves (63, 75). Additional data from the original authors was used for the dose reconstruction in 14 cases (4, 13,22, 35,40,44, 53,54,57,58,63). Isodose distributions for our four cases were constructed with a computer. Accepted
* Deceased 11 November 1988. Reprint requests to: Glenn V. Dalrymple, M.D., John L. McClellan Memorial Vetemns Hospital, Slot 115LR, 4300 West Markham, Little Rock, AF: 72205. 399
for publication
9 August
1989.
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For 18 patients information is available from the original reports for Nominal Standard Dose (NSD) calculation and correlation with the anatomic location of the tumor. Nine of these patients were treated for acute lymphoblastic leukemia (ALL) and nine were treated for CNS neoplasia. Fifteen additional ALL patients were given 2400 cGy (we assume this was given as 12 fractions over 16 days) for NSD estimation (2,22,33,42,57). NSD is also estimated for an additional eight patients treated for CNS neoplasia, with estimates based on information in the original reports. Criteria for radiation induction The criteria for considering a neoplasm to be radiation induced were proposed by Cahan et al. (1 l), and later modified by Schrantz and Araoz (60). Briefly restated, the criteria are: 1. The tumor should appear in the irradiated area. 2. The tumor was not present prior to irradiation. 3. A latent period must elapse between irradiation and the appearance of the tumor. 4. The existence of the radiation induced tumor must be histologically proven. A fifth criterion could be applied to virtually all of the cases in our series in which definitive radiation therapy was used to treat a CNS neoplasm. Namely, the radiation induced tumor should be of a different histologic type than the lesion originally treated. Total dose and NSD For 46 cases (42 from the literature and our 4) we have stated the radiation dose in cGy and as the Nominal Standard Dose. For this the Ellis expression was used (2 1). NSD = [D] [N]-“.24 [T]-‘.” where D = dose in cGy for total treatment, N = number of fractions of therapy, T = time over which radiation was given (days). The NSD is given in units of RETS (radiation equivalent therapeutic). The use of NSD allows for comparison of a wide variety of treatment plans with different fractionations and treatment times. We appreciate that the NSD has not enjoyed widespread acceptance in clinical radiation therapy. For comparison of multiple treatment studies, in our view, it has value. Statistical evaluation We have divided the 60 patients into three groups based on the reason for initial irradiation: (a) patients with ALL who received CNS irradiation either prophylactically (251 26) or for CNS leukemia (l/26) (b) patients irradiated for primary CNS neoplasia (including pituitary tumors, medulloblastoma, astrocytoma, meningioma) (c) patients irradiated for benign disease (Tinea capitis, hemangiomas).
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Factors for our analysis are (a) age at irradiation (b) time from irradiation to induced tumor(c) total dose (cGy) (d) NSD (RETS) and (e) the histology of the induced tumor. All three data sets contained missing elements. The situation was improved as a consequence of personal contact with the authors of the published reports. This yielded information for a re-estimation of the isodose distribution to the patient’s brain. Where dose estimates were contained within the published reports, no change from the original value was found. Student’s “t” test was used to compare means of responses. Because of the known problem with multiple comparisons using t tests, the significance levels were appropriately adjusted by the Bonferroni correction (25). Estimate of relative risk of tumor induction for patients with ALL BEIR III defines relative risk (RR) as the ratio of the risk among the exposed to that obtained in the absence of exposure (48). For the patients with ALL (they have had head irradiation), RR is computed as the number of tumors per patient year for patients with ALL divided by the number of tumors per patient year for non-irradiated individuals. The spontaneous incidence of glioblastoma for non-irradiated individuals has been reported to be 5/100,000 patient years for individuals O-l 5 years of age (59). Arkansas ALL cases The charts of all 70 patients treated with cranial irradiation for acute lymphoblastic leukemia were reviewed. In general, the patients were seen at the Arkansas Childrens’ Hospital. All were treated at the Central Arkansas Radiation Therapy Institute (CARTI) in Little Rock, Arkansas. Age at irradiation, date of irradiation, and followup were recorded. This information was then used to calculate the total number of person-years. From 1976 to July 1, 1988, 70 patients, representing 3 10 person-years, have received cranial irradiation for ALL. Case reports Case 1. A 17-month old black male, was diagnosed with ALL August 1977 and placed on chemotherapy (methotrexate, prednisone, vincristine, and intrathecal methotrexate). He went into immediate remission. He developed signs of CNS leukemia and was treated with 2400 cGy (12 fractions, 16 days, 974 RETS; 4 MeV X rays). Whole head irradiation was used (see Fig. 1 for isodose distribution). Except for behavioral problems, he remained in remission and chemotherapy was stopped in October of 198 1. In September 1986 he developed clinical and radiographic evidence of a brain tumor. CT scan showed a mass on the left (see Fig. 1). Brain biopsy revealed glioblastoma multiforme plus recurrence of ALL. He died in September 1987; no autopsy was performed. The time from irradiation to tumor diagnosis was 8 years 11 months.
CNS tumor induction 0 L. W. GAVINef al.
401
Fig. 1. Isodose curve (left) and CT scan (right) showing dose of 2000 to 2400 cGy at site of later tumor development (glioblastoma). This child received cranial irradiation for ALL. Case 2. A white female age 3 years 9 months, was diagnosed with ALL in February 1980. Chemotherapy was begun, and prophylactic cranial irradiation of 2400 cGy ( 12 fractions, 16 days, 97,4 RETS; 4 MeV X rays) in March 1980. She went into remission, and remained on chemotherapy, including intrathecal methotrexate, until March 1983. She did relatively well but experienced some difficulty in schoolwork with learning disabilities in math, spelling, and reading, although I.Q. was reported as normal. In August 1987 she developed clinical signs of a brain tumor, and CT scan showed a left fronto-parietal enhancing mass which on craniotomy w,as found to be a glioblastoma. The elapsed time from initial therapy to the induced tumor was 7 years 5 months. The patient remains alive with disease at the time of this communication. Case 3. A 5-year old black male, had a left temporal lobe astrocytoma (grade 2) resected January 1975. Postoperative radiation consisted of 5200 cGy to the left temporal region (26 fractions, 36 days, 1450 RETS; 6oCo teletherapy). He did well for over 112years post treatment. He then developed clinical and radiological signs of a new brain tumor in the left cerebral hemisphere. In March 1987, a glioblastoma multiforme was incompletely resected from the left temporal lobe. Tlhe location of the tumor is shown by an MRI scan (March 1987). Note the location of the tumor as compared with the isodose contours of the initial radiation therapy (Fig. 2). The time from initial radiation therapy to diagnosis of glioblastoma multiforme was 12 years 9 months. The patient remains alive at the time of this communication. Case 4. A 24-year ol’d white female, had incomplete resection of a basophilic adenoma of the pituitary in
March 1977. Postoperatively she received 4500 cGy (25 fractions, 35 days, 6 MeV X rays). The NSD was 1405 RETS. She did well until 1986, when she developed signs of a space occupying intracranial mass. CT scan (Fig. 3) showed a left frontal mass which was partially removed July 1986. Histopathology revealed a glioblastoma multiforme. There was no evidence of recurrence of the pituitary tumor. Note the relationship of the region of initial radiation therapy and the location of the glioblastoma (Fig. 3). The time from radiation therapy to diagnosis of glioblastoma was 9 years 2 months. The patient died April 1987. RESULTS The results for the ALL patients are summarized in the first row of Table 1. A total of 26 cases of radiation induced CNS tumors have been found. This number represents 16 glioblastomas (62%), 8 astrocytomas, 1 neuroectodermal tumor, and 1 ependymoma. The average age at irradiation is 5.0 years and corresponds to the natural history of ALL. Average time to induction of tumor is 7.5 years, with a range from 4.6 to 11 years. The average total dose is 2389 cGy. Average NSD is 952 RETS. The results for the patients irradiated for primary CNS neoplasms are also shown in Table 1. Twenty-four patients comprise this group. Of these, glioblastomas were found in 2 1 (87%). Two astrocytomas and one ependymoma were also found. Average age at irradiation was 18.3 years. This value was higher than that for ALL, as would be expected. Average time to tumor induction was 11.Oyears with a range of 1 year to 26 years, and average total dose was 4544 cGy. Average NSD was also greater than that for ALL patients- 1384 RETS.
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Fig. 2. Isodose curve (left) and MRI scan (right) with left temporal lobe glioblastoma demonstrated area on isodose curve. This patient had been irradiated for an astrocytoma 12 years earlier.
Ten patients form the smallest category, that of patients irradiated for benign disease. In this group one glioblastoma and three astrocytomas were found. In addition, six tumors described only as “malignant brain tumors” occurred in patients originally irradiated for Tinea capitis. No further pathologic information could be obtained for these six cases. Information on the 10 cases in this group is insufficient to estimate NSD. The average age at irradiation was 9.8 years with an average time from irradiation to induced tumor of 9.9 years. The average total dose was 3 13 cGy.
by cross-hatched
A major difficulty in computing risk estimates concerns the actual number of patients who have been irradiated. We have two incidences of patients with ALL who have received head irradiation and who have developed glioblastoma multiforme. Both of these patients were natives of Arkansas and were treated at the Central Arkansas Radiation Therapy Institute (CARTI). Since opening in 1976, 70 patients have received brain irradiation for ALL at CARTI. Through June 1988, they represent 3 10 personyears. Of these 19 are alive without recurrence, 30 died of leukemia, 1 died with glioblastoma multiforme and 1
Fig. 3. Isodose curve (left) and CT scan (right) in a patient previously irradiated for pituitary adenoma. The large enhancing mass on the CT scan was a glioblastoma. Note that dose at the tumor site ranged from 3000-4500 cGy.
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403
is currently still alive with GM (current report), 2 died of other causes, 1 is alive with disease, and 16 are unknown. (We assume that these patients are alive and well, for purpose of estimating relative risk.) For 3 10 person-years, we anticipate .016 cases. Since two cases have been observed, the relative risk is 125. Table 2 contains the experience of several investigators. The reported relative risk ranges from 20 to 226. Our estimate of 125 falls within this range. DISCUSSION
Animal experimental data A small body of animal experimental data exists, which has a bearing upon the problem of radiation induced CNS tumors in patients. In the early 1960’s, Dalrymple et af. irradiated large numbers of Rhesus monkeys with protons (18). The proton energies ranged from 32 to 2300 MeV. The energies were chosen to simulate the space radiation proton spectrum. The number of glioblastomas (9 animals) observed in the colony of 55 MeV proton survivors (a total of 78 monkeys) is almost 3-fold greater than the total number of other radiation induced tumors (4 monkeys) seen in this group (37, 74). Of the survivors of 800 cGy (surface dose), 33% died of glioblastoma. Later re-evaluation of the dosimetry indicated focal areas of the brain to have received doses as high as 2000 cGy (18). No other cases of glioblastoma have been seen at any other proton energy, after x-irradiation, or in the non-irradiated controls. Since Rhesus monkeys are known to have a very low rate of spontaneous malignancy (68), the very high incidence of glioblastoma after 55 MeV proton irradiation is remarkable. Two other instances of radiation induced glioblastoma in Rhesus monkeys are known (34, 70). The findings of radiation induced glioblastomas in these three groups raised the question whether this phenomenon could occur in humans. Patients with ALL Prophylactic cranial irradiation in patients with ALL has been used extensively since the early 1970’s (31). The combination of chemotherapy (including intrathecal methotrexate) plus radiation greatly reduces the probability of CNS recurrence of ALL. While ALL patients are treated with relatively low radiation doses (approximately 2400 cGy, 975 RETS), they receive total cranial irradiation. The distribution of the radiation induced tumors is also different from the higher dose, definitive therapy group. Of the 26 ALL cases, 24 had radiation induced gliomas (16 glioblastomas, 8 astrocytomas). Average interval from radiation to tumor in this group was 6-8 years, shorter than that of the primary CNS neoplasia group. Some oncologists have reduced prophylactic cranial irradiation in this group, not necessarily from fear of brain tumor induction, but because of possible neurological damage (Albo V, oral personal communication April
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Table 2. Risk of development
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of malignant brain tumors after radiation therauv for ALL
Author
Total dose GY
NSD (RETS)
Number of subjects
Number of tumors observed
Personyears
Number of tumors expected
RR*
Rimm (57) Fontana (22) Albo (2, 17) Cavin (present report)
2400 2400 2400 2400
974 974 974 974
92 37 468 70
1 3 9 2
2500 3800 4700 310
.06 .03 .04 .016
20 100 226 125
* Relative risk = observed cases/expected cases.
1988). Intellectual impairment, post head irradiation, prompted Freeman et al. to explore alternative forms of CNS prophylaxis (46). Both of our reported ALL patients had learning disabilities after irradiation and chemotherapy. Table 2 indicates an increased relative risk of tumor induction by head irradiation. The exact cause of this observed increase is not known, although many authors have implicated a variety of possibilities ranging from altered immune status to interaction of radiotherapy and intrathecal chemotherapy (22). Each of these explanations is possible, but problems arise when looking for common denominators. An interesting aspect is that in a series of 1507 patients with Hodgkin’s disease, no brain tumors were found (67). The key to the development of brain tumors thus seems to be head irradiation. Other tumors were found in the soft tissues, especially in the irradiated areas (67).
Patients with CNS neoplasia Patients irradiated for primary CNS neoplasia were treated with a different radiotherapy program than patients with ALL. For the former group, a relatively small volume of brain receives a high radiation dosage. This is illustrated in Figure 2, where the total dose of 5200 cGy is centered on the tumor bed. While it may be argued that this was the site of a previous astrocytoma and the second tumor might represent malignant degeneration, this rationale assumes a quiescent astrocytoma for a period
of almost 12 years. While this seems unlikely, such a possibility cannot be entirely excluded. No such argument can be espoused in case #4, however, in which a glioblastoma occurred in the radiation field following therapy for pituitary adenoma. Other such cases have been reported where a tumor of glial origin has followed radiotherapy for another tumor type after many years (7, 15, 35, 41, 53, 54, 63). Relative risk cannot be estimated for this group. Unlike patients irradiated for ALL, we do not know how many patients were irradiated but have not shown evidence of a second tumor. Patients with benign disease The patients treated for Tinea capitis and other benign conditions show a very different pattern of radiation induced tumors. These patients, in general, received the lowest radiation doses. Several dose estimates have been published, based upon reconstruction of the actual irradiation conditions. For our purposes, we will assume the total brain dose to be less than 200 cGy. We realize that some parts of the cranial vault, meninges, etc. could have received considerably higher doses, depending upon a number of factors (61). Most of the induced tumors in this group were meningiomas, but a few intra-axial tumors have been reported. One of these cases is a glioblastoma. Risk estimates for tumors following irradiation are not available, except in the cases of radiation induced meningiomas.
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