Factors affecting functional prognosis in survivors of primary central nervous system germinal tumors

Surg Neurol 1994;41:9-15

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Factors Affecting Functional Prognosis in Survivors of Primary Central Nervous System Germinal Tumors Nobuo Ono, M.D., Tohru Kakegawa, M.D., Akira Zama, M.D., Masaru Nakamura, M.D., Hiroshi K. Inoue, M.D., Masaru Tamura, M.D., Tetsuo Wakao, M.D., Jiro Uki, M.D., Fumikazu Takeda, M.D., Hideyuki Kurihara, M.D., Tsuneo Shimizu, M.D., and Ichiro Handa, M.D. Department of Neurosurgery, Gunma University School.of Medicine, Gunma, and Yamanashi Central Hospital, Yamanashi, Saitama Cance~ Center, Saitama, Kanto Neurosurgical Hospital, Saitama, and National Takasaki Hospital, Gunma, Japan

Ono N, Kakegawa T, Zama A, Nakamura M, Inoue HK, Tamura M, Wakao T, Uki J, Takeda F, Kurihara H, Shimizu T, Handa I. Factors affecting functional prognosis in survivors of primary central nervous system germinal tumors. Surg Neurol 1994;41:9-15.

We evaluated 79 patients of whom 62 survived treatment for intracranial germinal tumors between 1964 and 1992. The survivors were assessed for their Karnofsky scores and intellectual and reproductive functions to verify factors associated with better prognosis. Thirty-one tumors were pineal, 17 were suprasellar, and ten were in the basal ganglia. These included 50 germinomas, five teratomas, and seven tumors of extra-embryonic origin producing afetoprotein or human chorionic gonadotropin. Although patients with germinoma or benign teratoma had better Kaplan-Meier survival rates than those with extra-embryonic origin tumors, the mean Karnofsky scores of the survivors did not differ significantly among the three histologic groups. On the other hand, although survival rates did not differ significantly among different tumor site groups, the mean Karnofsky score of the pineal group was higher than that of the suprasellar or basal ganglia group. Intellectual and reproductive functions were severely affected in the basal ganglia and suprasellar tumor groups, respectively. The Karnofsky score of survivors treated after 1977 was higher than for those treated before 1977. The score of patients who received less than 55 Gy irradiation was better than those who received more than 55 Gy. No patient who received less than 45 Gy developed a recurrence, suggesting that a lower dose may suffice for pure germinomas. Tumors of extra-embryonic origin, however, should be treated with combined chemotherapy to minimize subsequent irradiation. Factors affecting survivors' capabilities are discussed.

KEY WORDS: Chemotherapy; Germinal tumors; Irradiation; Karnofsky score; Tumor marker

The management and outcome of primary central nervous system (CNS) germinal tumors have been dramatically improved in the last 30 years by: (1) the introduction of high-resolution computed tomography (CT) and magnetic resonance imaging (MRI) [36]; (2) pretreatment and posttreatment measurement o f tumor markers in the serum and cerebrospinal fluid (CSF) [ 9 , 2 3 26,32]; (3) advances in microsurgical and stereotactic surgical techniques [8,21,25,29]; and (4) new chemotherapeutic agents [ 1,2,4,16,23 ]. Although the probability o f survival for patients with these tumors has increased, long-term side effects of treatment have subsequently become evident. These delayed manifestations include neurotoxicity, spinal deformities, growth impairment, reproductive dysfunction, mental retardation, and development of second malignancies [5,6, 11,12]. The quality of life achieved by survivors is now the focus o f considerable attention. H e r e we report our retrospective study o f social, intellectual, and reproductive functions of survivors o f germinal CNS tumors. T o determine a minimum effective treatment, the results were analyzed and factors affecting survivors' capabilities were determined. These parameters included the primary tumor site, age at diagnosis, year of diagnosis, histology, and treatment details including surgery, irradiation, and chemotherapy.

Clinical Materials Address reprint requests to: Nobuo Ono, M.D., Department of Neu-

rosurgery, Gunma University School of Medicine, 3-39-22 Showamachi, Maebashi, Gunma 371, Japan. Received March 12, 1993; accepted May 14, 1993. © 1994 by Elsevier Science Inc.

Seventy-nine patients with CNS germinal tumors were treated between 1964 and 1992 at G u n m a University School of Medicine and affiliated hospitals. At the time 0090-3019/94/$7.00

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Table 1. Survivor Characteristics According to Tumor Site

Table 2. Survivor Treatments According to Histology

Basal No of survivors Histology germinoma teratoma extra-embryonic Age at diagnosis median (years) standard deviation Sex (% male) Surgery craniotomy stereotactic transsphenoidal rate of surgery shunt procedure Radiotherapy cranial craniospinal mean dose (Gy) Chemotherapy

Pineal

Suprasellar

ganglia

Synchro

31

17

10

4

62

25 5 1

13 0 4

8 0 2

4 0 0

50 5 7

15.2 7.0 90

13.7 7.1 47

11.7 2.8 90

15 2.2 50

14.2 6.4 76

6 2 0 26% 22

11 0 1 71% 1

3 7 0 100% 2

2 0 0 50% 1

22 9 I 52% 26

13 14 50.4 3

7 10 47.5 4

4 6 56.9 1

1 3 47.0 0

25 33 50.5 8

Germinoma

Teratoma

Extraembryonic

Total

50 90.4

5 86

7 85.7

62 89.7

15.2 78

9 100

10.7 42.9

14.2 76

Total

Abbreviation: Synchro, synchronous of pineal and suprasellar tumors.

of this study 15 of these patients had died, two were lost to follow-up, and 62 were still alive. The survivors, including 47 males and 15 females aged 5 to 39 years (mean 14 years), were evaluated in detail for their quality of life. They now have an average age of 24 years at the mean follow-up time of 10 years. Thirty-one tumors were pineal (M: F -- 28 : 3), 17 were suprasellar (M : F = 8 : 9), ten were in the basal ganglia (M : F = 9:1), and four were synchronous in the pineal and suprasellar regions (M : F = 2 : 2) (Table 1). The most frequent initial symptoms were: headaches and vomiting in 27 (87%) and diplopia in 14 (45%) of 31 pineal tumor patients; diabetes insipidus in 14 (82 %) of 17 suprasellar and in three of four synchronous tumor; and hemiparesis in eight of ten basal ganglia tumor patients [25]. There were a total of 50 germinomas, five benign teratomas, and seven tumors of extra-embryonic origin producing cz-fetoprotein (AFP > 200 ng/mL) or human chorionic gonadotropin ( H C G > 1000 mIU/mL). Some mixed germinal tumors were diagnosed according to their main component. We used immunochemical methods to measure serum and cerebrospinal fluid (CSF) tumor markers, including AFP, H C G , carcinoembryonic antigen (CEA), and placental alkaline phosphatase (PLAP). The levels of tumor markers reflected the tumor type, and correlated well with the histologic diagnoses: yolk sac carcinoma produced AFP; choriocarcinoma, HCG; embryonal carcinoma, AFP and HCG; teratoma, CEA; and germinoma, PLAP, as revealed by immunohistochemistry [9,20,24-26].

No. of survivors Mean Karnofsky score Age (years) Sex (% male) Surgery total resection partial resection biopsy shunt procedure total Radiotherapy cranial craniospinal Chemotherapy

0 0 21 21 42

5 0 0 4 9

2 1 3 1 7

7 1 24 26 58

19 30 2

1 1 0

5 2 6

25 33 8

Germinal tumors were diagnosed in 11 cases without direct surgery by measuring serum and CSF tumor markers and by tumor response to radiochemotherapy. Histological diagnoses were surgically verified in 32 cases. Cytological study of the CSF was conclusive for germinoma in six cases. The other diagnoses of 13 pineal germinomas were based on characteristic clinical findings, neuroimages, and early responses to irradiation (20 Gy). Among these 13 tumors, markers were absent in six cases and were not measured in seven cases. These histologically unverified pineal tumors may have included highly radiosensitive pineocytomas or pineoblastomas. However, because of race and age distributions of pineal tumors in Japan[3,22], germinomas were much more likely and even one exception would not alter this report's content and conclusions. Treatments included surgery, irradiation, and chemotherapy. A total of 58 operations included 22 craniotomies, nine stereotactic biopsies, one transsphenoidal resection, and 26 shunt procedures. All benign teratomas were treated by total resection (Table 2). N o operative mortality was observed, however, morbidity was seen in an early case of a pineal teratoma. Two teratomas were treated initially by irradiation. Germinomas and extra-embryonic origin tumors were treated primarily by radiotherapy and radiochemotherapy, respectively. Twenty-five received cranial irradiation only, and 33 also received local and total craniospinal irradiation. The mean total doses were approximately 50 Gy to the primary tumor site, and 30 Gy to the whole brain. An additional 30 Gy to the spine was administered in 33 cases. The daily dose was 2 Gy. Thirteen patients received doses to their brain that were at least 10% lower (28-44 Gy, mean 39 Gy), mainly to reduce the side effects of irradiation, whereas 11 cases received doses that were at least 10% higher (>55 Gy), because recur-

Functional Prognosis in CNS Germinal Tumors

Surg Neurol 1994;41:9-15

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Figure 1. Left: Survival curves for the teratoma group (solid. line), germinoma group (dashed line), and extra-embryonic origin tumor group (dotted line). Log rank: p < .001. Right: Survival curves for the suprasellar group (solid line), basal ganglia group (dotted line), pineal group (dashed line), and synchronous group (dots and dashes). No difference is statistically significant.

rences or a positive AFP or H C G level was detected before chemotherapy was introduced. Eight patients, mainly those with tumors o f extra-embryonic origin, underwent c h e m o t h e r a p y - - s e v e n received a platinumbased regimen [23,35].

Method of Outcomes A s s e s s m e n t The outcomes studied were evaluated primarily on our review o f their medical records. Follow-up by telephone interview was attempted for every patient lost to routine follow-up. From the time of diagnosis, survival curves were estimated using the K a p l a n - M e i e r method [14], and survival differences among groups were assessed using the log rank or generalized Wilcoxon test. The quality o f life was graded according to the Karnofsky Performance Scale score in patients who survived for more than 1 year [ 15]. To assess their intelligence quotient (IQ), survivors aged 16 years or less were assessed for verbal and performance abilities according to the Revised Wechsler Intelligence Scale for Children [17], and those older than 16 years were assessed according to the Wechsler Adult Intelligence Scale [34]. Survivors aged 15 years or older were also questioned regarding their libido, menstrual function, and secondary sex char-

0

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YEARS

acteristics to assess their reproductive functions. T o determine various prognostic indicators, the functional status of each patient was correlated with the primary tumor site, age at diagnosis, year of diagnosis, histology, surgery, irradiation course and dose, and chemotherapy. Statistical analyses were performed using the unpaired Wilcoxon test.

Results

Survival Curves K a p l a n - M e i e r life-table estimates are shown in Figure 1. Patients with germinoma or benign teratoma had better survival rates (log rank, p < 0.0001) than did those with tumors o f extra-embryonic origin as expected. However, survival distributions did not vary significantly according to any other parameter such as age, sex, tumor site, or treatment. N o germinoma recurred in a group of 13 patients who received a lower mean dose of 39 Gy irradiation to the brain.

Survivors' Karnofsky Scores The mean Karnofsky score o f survivors was 90.4 in the germinoma group, 86 in the benign teratoma group, and 85.7 in an extra-embryonic origin tumor group. These did not differ significantly, despite significant differences in the K a p l a n - M e i e r survival rates among different histologic groups. On the other hand, the mean Karnofsky score was 93.9 in the pineal tumor group, 87.6 in the suprasellar group, 80 in the basal ganglia group, and 90

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Table 3. Mean Karnofsky Scores According to Tumor Site Parameters Karnofsky score Age at diagnosis ~ = 11 years ~ = 12 years Sex male female Year of admission 1964-1977 1978-1992 Histology Germinoma Nongerminoma Radiotherapy cranial craniospinal Low-dose 45 Gy = 45 Gy High-dose = 55 Gy 55 Gy Chemotherapy yes no

(No)

Pineal

Suprasellar

Basal ganglia

Total

93.9

87.6

80

89.7

p value

(25) (37)

92.5 94.1

87.1 88

71.7 92.5

86 91.9

0.12

(47) (15)

92.9 100

83.8 91.1

77.8 100

88.3 93.3

0.19

(10) (52)

83.3 96

70 90

60 82.2

79 91.5

0.016

(50) (12)

94.8 88.3

87.7 87.5

81.3 75

90.4 85.8

0.15

(25) (33)

93.1 94.3

85.7 89

75 83.3

88 90.3

0.38

(13) (44)

91.4 94.5

90 86.9

(-) 80

90.7 89.5

0.42

(46) (11)

94.2 90

88.8 70

93.3 76.7

92 80.9

0.006

(8) (54)

100 92.9

93.3 86.4

60 81.3

91.3 89.3

0.34

in the synchronous t u m o r group. The pineal group score was significantly higher than in the suprasellar (p < 0.01) or basal ganglia (p ~ 0.001) groups. To determine prognostic factors, other than t u m o r site, for better functional status among groups, we defined eight distinguishing parameters: age at diagnosis ( ~ =- 11 years or older), sex, year of admission (before or after 1977), histology (germinoma or nongerminomatous tumor), extent o f irradiation (cranial or craniospihal), dose o f irradiation ( 1 0 % or m o r e below the standard, ~ 45 G y or ~ = 45 Gy), (10% or m o r e higher than the standard, ~ 55 G y or ~ - - 55 Gy), and additional c h e m o t h e r a p y (yes or no) (Table 3). T h e mean Karnofsky score of patients treated after 1977 was significantly higher than o f those treated before 1977 (p ~ 0.05). T h e score o f patients who received radiotherapy not exceeding 55 G y was significantly better than o f those who received m o r e than 55 Gy (p ~ 0.01). N o other significant difference in scores was noted among the different groups. T h e mean Karnofsky score did not exceed 80 in 15 survivors. For 12 o f those subjects the mean I Q score decreased to less than 7 0 - - s i x had a treatment delay, three sustained radiation injury, two experienced recurrence, and one sustained operative morbidity. Two suprasellar t u m o r patients lost their useful vision. Severe hemiparesis or mental retardation remained in five basal ganglia t u m o r patients. Overall, survivors of pineal tu-

mors maintained the best quality o f life with m i n i m u m residual symptoms.

Intellectual Function Approximately two-thirds o f survivors, especially pineal and suprasellar t u m o r patients, maintained a mean I Q of 85 (minus one standard deviation) (Table 4). On the other hand, no basal ganglia t u m o r patient retained a mean I Q of 85. Low intelligence was m o s t c o m m o n and profound in patients with basal ganglia tumors.

Reproductive Function Fifty-seven survivors (M : F = 44 : 13) aged m o r e than 15 years were asked regarding their reproductive functions. N o n e o f ten suprasellar t u m o r females menstruated reg-

Table 4. Intelligence Quotient (IQ) Among Survivors Tumor location

Normal IQ ~ = 85

Moderately decreased 65-84

Severely decreased < ~- 64

Pineal Suprasellar Basal ganglia Synchronous Total

23/31 (74%) 13/17 (76%) 0 3/3 (100%) 39/60 (65%)

4/31 (13%) 4/17 (24%) 5/9 (56%) 0 13/60 (22%)

4/31 (13%) 0 4/9 (44%) 0 8/60 (13%)

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Table 5. Reproductive Functions in Survivors Aged over 15 Years Female

Patient No.

Normal menstruation

Irregular menstruation

Hormonal therapy

Amenorrhea

Pineal and basal ganglia Suprasellar and synchronous

3 10

3 (100%) 0

0 2 (20%)

0 4

0 4

Male

Patient No.

Apparently normal

Hormonal therapy

No secondary sex characteristics

Low IQ

Pineal and basal ganglia Suprasellar and synchronous

35 9

30 (86%) 1 (11%)

0 4

1 ~3~) 4

4 (11%) 0

ularly, two irregularly, four menstruated with gonadal hormone therapy, and four were amenorrheic, whereas three female patients without a suprasellar tumor menstruated regularly (Table 5). O f nine suprasellar tumor males, only one had normal secondary sex characteristics without gonadal hormonal therapy as compared to 30 of 35 pineal and basal ganglia tumor males who had apparently normal reproductive function. Finally, 16 survivors aged greater than 28 years were asked questions regarding marriage and parenthood. Among these, there were ten (M: F = 9 : 1) pineal and five ( M : F -- 2 : 3) suprasellar tumors. One male with a basal ganglia tumor was too mentally retarded to get married. N o suprasellar tumor patient was able to have a child, because o f hypopituitarism, except for one suprasellar germinoma patient who had a child before disease onset. By contrast, five o f t e n pineal tumor patients were married and had a child, in spite of whole craniospinal irradiation therapy.

Long-term Survivors of Extra-embryonic Origin Tumors Four patients with tumors of extra-embryonic origin survived for more than 5 years after irradiation and chemotherapy. Their mean Karnofsky score is now 88. T h r e e of these were already described elsewhere [23,24,35]. Surprisingly, a 12-year-old suprasellar embryonal carcinoma patient menstruated without hormonal therapy 10 years after five courses of combined chemotherapy with cisplatin, vinblastine, and bleomycin followed by local irradiation.

Discussion Factors that influence survival and functional prognoses of CNS germinal tumors have been reported [6,12,18, 19,30]. In our series, histology was found to affect substantially the survival rate. However, histology did not affect the survivors' quality o f life, as reflected in their Karnofsky scores, or their intellectual and reproductive functions, partly because only seven patients survived

extra-embryonic origin tumors. In contrast, tumor site was a critical determinant of function, despite there being no significant difference in survival among different tumor site groups. Only the pineal tumor group achieved a mean Karnofsky score exceeding 9 0 - - t h e best outcome at the mean follow-up time of 10 years in our series. The score of survivors o f suprasellar tumors was significantly lower than that of subjects with pineal tumors. The suprasellar tumor group had a less favorable functional outcome because of visual disturbances and endocrinologic deficits [7,27]. However, the mortality during hospitalization resulting from suprasellar tumors was somewhat less than that from pineal tumors in our series, probably because surgical intervention for histologic verification was easier for suprasellar tumors in the pre-CT era. This difference was not significant, perhaps because the surgical verification rate (26%) for pineal tumors was much lower than that (50% to 100%) for tumors at other sites. In contrast, basal ganglia tumor patients had the lowest mean Karnofsky score o f 80 because o f hemiparesis and mental retardation. These subjects all had biopsies safely performed mainly through a stereotactic approach to verify that eight of ten tumors were germinomas. Although the pineal and suprasellar groups contained the same fraction ofgerminomas, the basal ganglia group received a significantly higher mean dose o f 57 Gy for unknown reasons. High-dose irradiation was associated with the sequelae of marked ipsilateral cerebral hemiatrophy evident on CT scans and MRI [10,28]. Low intelligence may signify transneuronal degeneration between the basal nucleus neurons and the cerebral cortex [10]. The mean Karnofsky score significantly differed between the group o f patients treated before 1977 and those treated after 1977 in our series. Profound intellectual deterioration and other dysfunctions often resulted from treatment delay before 1977. The development o f neuroimaging methods such as CT, MRI, the use of tumor markers, innovative operative techniques, and new radiochemotherapeutic regimens have allowed earlier, more precise diagnosis and better t r e a t m e n t - - r e sulting in improved quality of life. Age at diagnosis may also be an important prognostic

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Surg Neurol 1994;41:9-15

factor for function [6,17]. In our series, the average age o f patients who died o f extra-embryonic origin tumors was 18.3 years, which was significantly greater than the survivors' mean age o f 10:7 (p < 0.05). Whereas older patients tended to die o f extra-embryonic origin tumors, the mean Karnofsky score o f 86 in survivors aged less than 11 years at diagnosis was somewhat lower than the score o f 92 in the older group, partly because the younger group o f subjects included more basal ganglia tumors (mean onset age, 11.7 years) that are often associated with severe mental retardation. Those differences in outcome have not been consistently observed in other studies [17,18]. N o prospective study o f intelligence was performed prior to surgery and irradiation in our studies. Therefore, insufficient data were available to comment conclusively regarding therapy for delayed intellectual deterioration, which has been described especially in young children [5,6,11]. One survivor, a 12year-old suprasellar germinoma patient with a mean IQ o f 71, could attend college 9 years after 48 Gy local and 30 Gy total craniospinal irradiation, although he complained o f a m e m o r y disturbance associated with mild brain atrophy on CT scans. In treating this patient it was difficult to assess an optimum dose o f irradiation for a patient o f this age based on alterations in neuropsychologic function. The optimum radiation dose for germinomas remains controversial [30]. A dose o f 50 Gy is recommended for cerebral germinoma [33], and lower doses are recomm e n d e d in children [13]. Lower doses (30 to 40 Gy) or a smaller field o f irradiation may be sufficient, especially when combined with chemotherapy [4]. In our series, 13 patients received doses o f 28 to 44 Gy (mean 39 Gy) to minimize side effects. Although the mean Karnofsky score of this group was not significantly higher than that o f others receiving more than 45 Gy, no patient developed a recurrence between 3 and 28 years after therapy, suggesting that a lower dose is sufficient for pure germinomas. However, germinomas sometimes contain a teratoma component, which is often quite radioresistant. Even when a teratoma or other malignant component is suspected, a cranial radiation dose in excess o f 55 Gy should be avoided as long as long-term survival is expected with chemotherapy, because the Karnofsky score in survivors who received more than 55 Gy was worse in our series. If additional radiation becomes necessary, radiosurgery may decrease the risk o f radiation damage and prevent tumor recurrence. In the near future, radiosurgery, such as with a gamma knife, may become a component of multimodality [ 11]. The Karnofsky score o f survivors did not differ significantly between the brain-irradiated and craniospinally irradiated groups. Although whole craniospinal irradiation caused no apparent deleterious effect when

Ono et a!

the patient was over 12 years old, we found that patients less than 11 years old were unlikely to attain their mean height following irradiation [27]. Prophylactic spinal irradiation is o f value if recurrence can be prevented without increasing radiation-induced morbidity. Therefore, spinal irradiation is indicated only in cases with poor risk factors such as synchronous germinomas, positive CSF cytology, positive CSF tumor markers, ventricular enhancement on CT scans, evidence o f spinal metastases on MRI or extensive surgery. Otherwise, prophylactic spinal irradiation is not necessary, because a high germinoma extinction rate is made possible with a larger local irradiation field [30]. Germinal tumors should be divided into standard and p o o r risk groups through staging studies to determine whether additional spinal irradiation or chemotherapy would be optimal. Remote metastases, especially from extra-embryonic origin tumors, are associated with decreased survival rates and Karnofsky scores. In our series, extraneural metastases occurred in six (9.7 %) o f 62 surgical patients [1,31,35], but none o f 15 nonsurgical patients. Five o f those died of metastases and the remaining subject had a Karnofsky score of 70. Apparently, surgery was associated with metastasis, although this result conflicts with other series [8,19,29], in which a biopsy was recommended to clarify the exact histology and select the best treatment. However, pineal tumor patients who receive more aggressive surgery can be at greater risk for postoperative complications and hematogenous metastases that may influence the quality o f life [21]. It seems to be less harmful than direct surgical removal o f a pineal tumor to follow our strategy o f an initial 20 G y irradiation test dose to the tumor while measuring serum and CSF tumor markers according to neuroimaging and CSF cytologic studies and considering the race and age distribution o f pineal tumors in Japan [3,22]. T u m o r marker analysis, together with clinical and imging findings that may confirm the diagnosis, are sometimes histologically more conclusive than histologic analysis o f a small biopsy specimen from a pineal tumor because o f the heterogeneity of germinal tumors [ 2 3 - 2 6 , 3 2 ] . If a diagnosis can be made on the basis o f serum and CSF markers we try to avoid extensive surgery in germinoma patients, because o f possible hematogenous metastasis. This strategy seems optimal in survivors o f pineal germinomas. Because extra-embryonic origin tumors are not radiocurable, chemotherapy is the most promising approach. Effective chemotherapy may minimize the administered radiation dose and thus may minimize delayed neurotoxicity, particularly in children [4,5]. Although Karnofsky scores in our series did not differ significantly between a group who received chemotherapy and one who did not receive, chemotherapy is preferred to high-dose (more than 55 Gy) irradiation because more malignant

Functional Prognosis in CNS Germinal Tumors

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tumors exist in the extra-embryonic origin tumor group. However, more extensive clinical and biologic investigations and a long-term intervention program including prospective studies in primary CNS germinal tumor patients are essential to improve further treatments and functional prognoses.

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