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A Multimodal Approach Including Craniospinal Irradiation Improves the Treatment Outcome of High-risk Intracranial Nongerminomatous Germ Cell Tumors
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Central Nervous System Tumor
A Multimodal Approach Including Craniospinal Irradiation Improves the Treatment Outcome of High-risk Intracranial Nongerminomatous Germ Cell Tumors Jun Won Kim, M.D.,* Woo Chul Kim, M.D.,x Jae Ho Cho, M.D.,* Dong-Seok Kim, M.D.,y Kyu-Won Shim, M.D.,y Chul Joo Lyu, M.D.,z Sung Chul Won, M.D.,z and Chang-Ok Suh, M.D.* Departments of *Radiation Oncology, yNeurosurgery, and zPediatrics, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; and xDepartment of Radiation Oncology, Inha University College of Medicine, Incheon, Korea Received Sep 1, 2011, and in revised form Dec 8, 2011. Accepted for publication Dec 22, 2011
Summary Thirty-two nongerminomatous germ cell tumor patients received combined treatment including chemotherapy, radiation and surgery. Craniospinal irradiation (CSI) was given to 84% of the patients. Ten-year recurrence-free and overall survival rates were 77.6% and 74.6%, respectively. Treatment failed (7/18) only in the poor prognosis group in which cerebrospinal fluid failure was predominant. Multimodal approach was effective for treating nongerminomatous germ cell tumors, and CSI should be considered for poor prognostic histology.
Purpose: To evaluate whether a multimodal approach including craniospinal irradiation (CSI) improves treatment outcome in nongerminomatous germ cell tumor (NGGCT) patients. Methods and Materials: We reviewed the records of 32 patients with NGGCTs. Fourteen patients belonged to the intermediate prognosis group (immature teratoma, teratoma with malignant transformation, and mixed tumors mainly composed of germinoma or teratoma), and 18 patients belonged to the poor prognosis group (other highly malignant tumors). Patients with pure germinoma or mature teratoma were excluded from this study. Nineteen patients were treated with a combination of surgery, chemotherapy, and radiotherapy (RT); 9 patients received chemotherapy plus RT; 3 patients received surgery plus RT; and 1 patient received RT alone. Twenty-seven patients received CSI with a median of 36 Gy (range, 20e41 Gy) plus focal boost of 18e30.6 Gy, and 5 patients received whole-brain RT (WBRT) (20e36 Gy) or focal RT (50.4e54 Gy). The rate of total and subtotal resection was 71.9%. The median follow-up for surviving patients was 121 months. Results: Treatment failed in 7 patients. Three of the 5 patients who received focal RT or WBRT had local failure. Four cerebrospinal fluid (CSF) failures occurred after CSI. No failure occurred in the intermediate prognosis group. Ten-year recurrence-free survival (RFS) and overall survival (OS) for all patients were 77.6% and 74.6%, respectively. Ten-year RFS for the intermediate and poor prognosis groups were 100% and 61.1%, respectively (p Z 0.012). OS for the two groups were 85.1% and 66.7%, respectively (p Z 0.215). Tumor histology and CSI were significant prognostic factors for RFS, and CSI was significantly associated with OS. Conclusions: A multimodal approach was effective for treating NGGCTs. CSI should be considered for patients with poor prognostic histology. Ó 2012 Elsevier Inc. Keywords: Nongerminomatous germ cell tumor, Multimodal approach, Craniospinal irradiation
Reprint requests to: Chang-Ok Suh, M.D., Department of Radiation Oncology, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemoon-gu, Seoul, 120-752, Korea. Tel: 82-2-2228-8095; Fax: 82-2-312-9033; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 84, No. 3, pp. 625e631, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.12.077
Presented at the 2011 Pediatric Radiation Oncology Society (PROS) Congress, Venice, Italy. Conflicts of interest: none.
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Introduction The incidence of primary intracranial germ cell tumors (GCTs) among children with brain tumors is higher in Japan, Korea, and Taiwan (10%e14%) than in North America or Europe (3%e4%) (1). The full spectrum of tumor histology for intracranial GCTs includes pure germinomas (60%e70% of intracranial GCTs), malignant germ cell tumors (embryonal carcinomas, yolk sac tumors, and choriocarcinomas; collectively 15%e20%), and teratomas (benign, immature, and malignant types, 15%e20%) (2, 3). Pure germinomas are highly radiosensitive, with disease-free survival rates of 90% or higher (4, 5). The remaining GCTs are conventionally classified as nongerminomatous GCTs (NGGCTs), and these tumors respond poorly to radiation and are associated with secretion of a-fetoprotein (AFP) and/or b-HCG (6). NGGCTs are, however, a heterogeneous group of tumors with histology-dependent tumor characteristics. Matsutani et al. divided intracranial GCTs into three prognosis groups (5). The good prognosis group consists of pure germinoma and mature teratoma; the intermediate prognosis group consists of immature teratoma, teratoma with malignant transformation, and mixed tumors mainly composed of germinoma or teratoma; and the poor prognosis group consists of choriocarcinoma, yolk sac tumors, embryonal carcinoma, and mixed tumors mainly composed of malignant germ cell tumors. The prognosis of a NGGCT is thought to be subtype-specific, and different subtypes require different treatment guidelines (7, 8). A combined-modality approach, including radiotherapy (RT), chemotherapy, and potential surgical resection, is recommended for NGGCTs (2, 5, 8, 9). However, there is no clear consensus on the treatment of NGGCTs. Treatment results have been less than satisfactory, especially for poor prognostic subtypes because these tumors tend to recur locally as well as disseminate (2, 9, 10). RT is an important component of multimodal treatment. However, appropriate primary tumor dose and RT volume (local, whole ventricle, whole brain, or craniospinal) have not been clearly defined (2, 11). In the current study, we attempted to establish the role of radiotherapy in multimodal treatment, including craniospinal irradiation (CSI) for NGGCT patients.
Methods and Materials Patient characteristics We searched the database registry of the Radiation Oncology Department at Yonsei Cancer Center and identified 32 patients who received radiotherapy as part of combination treatment for intracranial NGGCTs between 1982 and 2006. The median age of the patients was 14 years (range, 4e28 years). Twenty-nine patients were male and 3 were female. The most frequent tumor location was pineal (62.5%), followed by suprasellar (15.6%) and thalamic or basal ganglia (12.5%). A pathologic diagnosis was made in 23 patients, and 9 patients were diagnosed based on elevated tumor markers and NGGCT-compatible magnetic resonance imaging (MRI) findings. According to the World Health Organization classification system (12), 4 patients had immature teratomas, 2 patients had teratomas with malignant transformation, 1 patient had embryonal carcinoma, 4 patients had yolk sac tumors, 3 patients had choriocarcinomas, and the remaining 18 patients had mixed germ
International Journal of Radiation Oncology Biology Physics cell tumors. Patients who were diagnosed with pure germinoma or mature teratoma were excluded from the study (Table 1). Cerebrospinal fluid (CSF) cytology was examined in 26 patients, and 2 patients had positive results. However, spinal MRI showed that none of the patients had apparent spinal metastasis at initial diagnosis. Serum AFP and serum human chorionic gonadotropin (HCG) were measured before treatment in 31 of 32 patients. Tumor markers were elevated in 28 of 32 patients (serum AFP range, 13.2e9105 mIU/mL; serum HCG range, 14.8e5874 IU/mL). Nine patients had AFP elevation without HCG elevation, and 11 patients had HCG elevation alone. Both AFP and HCG were elevated in 8 patients. Patients were divided into two groups according to Matsutani classification of intracranial GCTs (5). Fourteen patients belonged to the intermediate prognosis group, and 18 patients to the poor prognosis group.
Treatments Patients who presented with NGGCT-compatible MRI findings and tumor marker elevation were treated with chemotherapy followed by radiation. When NGGCT was suspected on MRI without tumor marker elevation, biopsy or trial RT was performed. If the tumor responded well to 20e30 Gy of trial RT, it was regarded as a pure germinoma. These cases were not included in this study. The patients who responded poorly to trial RT underwent surgical intervention to confirm pathology. Surgical removal was attempted if feasible when residual tumor was apparent in the imaging studies after chemotherapy and/or RT. Nineteen patients (59.4%) were treated with a combination of surgical resection, chemotherapy, and RT; 9 patients (28.1%) received chemotherapy plus RT; 3 patients (9.4%) received surgical resection plus RT; and 1 patient (3.1%) received RT alone. Surgery was performed in 25 patients (78.1%). Fourteen patients (43.8%) received gross total resection, 9 patients (28.1%) underwent subtotal resection, biopsy was performed in 2 patients (6.3%), and no surgery was attempted in the remaining seven patients (21.9%). The rate of maximal resection (total þ subtotal) was 71.9%. Radiation was delivered with a cobalt 60 radiotherapy unit or 4e6 MV in daily fractions of 1.5e1.8 Gy, 5 days per week. Twenty-seven patients were treated with CSI of a median of 36 Gy (range, 20e41 Gy) plus focal boost of 18e30.6 Gy, 2 patients received whole-brain RT (WBRT) (20e36 Gy), and 3 patients received focal RT (50.4e54 Gy) without spinal irradiation. The median dose to the primary tumor site was 54 Gy (range, 20e60.6 Gy). Twenty-eight patients (75%) received cisplatin/carboplatin-based systemic chemotherapy in a total of 1e7 courses before and/or after radiotherapy. Nine patients received a combined regimen of cisplatin, etoposide, and bleomycin, 6 patients received cisplatin and etoposide, 5 patients received a combination of carboplatin, etoposide, and ifosfamide, and 8 patients received alternating courses of cisplatin/etoposide and vincristine/cyclophosphamide. One patient, who received one cycle of cisplatin and etoposide, discontinued chemotherapy because of elevated liver enzymes.
Statistical analysis The Kaplan-Meier method was used to calculate the rates of recurrence-free survival (RFS) and overall survival (OS) from the day of diagnosis. Differences between the two prognosis groups
Volume 84 Number 3 2012 Table 1
Nongerminomatous germ cell tumors
Patient characteristics
Characteristics Age 0e9 10e19 20e29 30 Sex Male Female Tumor location Pineal Suprasellar Thalamus or BG Multifocal Diagnostic modality Histologic Clinical Tumor subtype Immature teratoma TMT Embryonal carcinoma Yolk sac tumor Choriocarcinoma MGT MME Treatment OP þ CT þ RT CT þ RT OP þ RT RT alone
No. of patients (%)
627
100% and 61.1%, respectively (p Z 0.012). Ten-year OS for the two groups were 85.1% and 66.7%, respectively (p Z 0.215).
Patterns of recurrence 7 (21.9) 21 (65.6) 4 (12.5) 0 29 (90.6) 3 (9.4) 20 5 4 3
(62.5) (15.6) (12.5) (9.4)
23 (71.9) 9 (28.1) 4 2 1 4 3 8 10
(12.5) (6.3) (3.1) (12.5) (9.4) (25.0) (31.2)
19 9 3 1
(59.4) (28.1) (9.4) (3.1)
Abbreviations: BG Z basal ganglia; CT Z chemotherapy; MGT Z mixed tumor mainly of germinoma or teratoma; MME Z mixed tumor mainly of malignant elements; OP Z operation; RT Z radiotherapy; TMT Z teratoma with malignant transformation.
were estimated using the logerank test. p values less than 0.05 were considered statistically significant.
Results Survival and prognostic factors At the time of analysis, 8 of 32 patients (25%) died 4e79 months (median, 12 months) after diagnosis. The median follow-up of the 24 surviving patients was 121 months (range, 60e312 months). Ten-year RFS and OS for all patients were 77.6% and 74.6%, respectively. The results of univariate analyses of clinical variables are presented in Table 2. Intermediate prognosis group (p Z 0.012) and CSI (p Z 0.008) were significantly associated with increased RFS, and total radiation dose higher than 54 Gy (p Z 0.094) and administration of chemotherapy (p Z 0.065) showed a trend toward increased RFS. CSI was the only significant prognostic factor (p Z 0.022) for OS, and prognosis group (p Z 0.215), total tumor resection (p Z 0.162), and chemotherapy (p Z 0.114) showed a trend toward improved OS. Age, gender, tumor size, and tumor location were not strongly associated with survival. Figs. a and b show survival curves according to prognosis groups. Ten-year RFS for the intermediate and poor prognostic groups were
Table 3 shows the patterns of failure and outcomes of salvage treatment in 7 patients who experienced recurrence. The interval between initial diagnosis and time of recurrence varied from 1 to 33 months. In the intermediate prognosis group (n Z 14), 13 patients received CSI, and 12 patients received chemotherapy as part of the combined treatment. No failure was reported from the intermediate prognosis group. All 7 of the patients diagnosed with recurrence were from the poor prognosis group. In the poor prognosis group (n Z 18), 14 patients received CSI and treatment failed in 4, which were all CSF failures. Failure was noted in 3 of the remaining 4 patients who did not receive CSI, and all 3 were local failures. With respect to chemotherapy, which was given to 16 patients in the poor prognosis group, two local and three CSF failures occurred. The 2 patients who did not receive chemotherapy also experienced treatment failure, one locally and the other in CSF. Six of the 7 patients in whom treatment failed died from progression of recurrent disease. Treatment failed locally (in-field) in a 28-year-old female with mixed tumor of malignant elements (MME), 13 months after subtotal resection, chemotherapy, and focal RT of 50.4 Gy. She died of progressive disease in spite of salvage chemotherapy. A 13-year-old male with MME received subtotal resection, chemotherapy, and local RT of 23.4 Gy. He showed disease progression in a 1-month post-treatment evaluation and died of disease 3 months later. A 16-year-old male with MME, who received trial RT of 20 Gy to whole brain and total resection, failed locally 33 months after treatment. He was salvaged with surgical resection and is still alive and free of disease. Four patients were diagnosed with CSF failures 2e12 months later despite receiving CSI as a part of the initial treatment. Recurrence in CSF and sacral bone was noted in a 14-year-old male with choriocarcinoma, after combined treatment of trial RT, total resection, chemotherapy, and RT. He died of progressive disease despite salvage surgery and chemotherapy. A 19-year-old male with MME experienced CSF recurrence after chemotherapy, subtotal resection, and RT. He received no salvage treatment and died of progressive disease. The other 2 patients, a 6-year-old male with yolk sac tumor and a 13-year-old male with embryonal carcinoma, both had CSF recurrence after RT and chemotherapy. Both received no salvage treatment and died of progressive disease.
Toxicity A 24-year-old male with teratoma with malignant transformation was treated with WBRT of 18 Gy plus focal RT of 18 Gy followed by subtotal resection. He died of ventriculoperitoneal shunt-related sepsis at 3 months from the treatment. A 14-yearold male had been diagnosed with mixed germinoma and teratoma at the pineal region, and received total resection, chemotherapy, and focal RT 30.6 Gy plus CSI 30 Gy. At 57 months from initial radiotherapy, a cerebellar tumor developed and biopsy of the tumor confirmed anaplastic astrocytoma. He died of progressive disease 13 months after diagnosis of secondary malignancy despite salvage treatment including local RT of 50.4 Gy and concurrent temozolomide. These 2 patients showed no recurrence in follow-up images until time of death and were not counted as events of recurrence in RFS analysis.
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Table 2
Univariate analysis for patient survival 10-year RFS
Clinical variables Age <15 15 Gender Male Female Prognosis group Intermediate Poor Tumor size <4 cm 4 cm Tumor location Pineal Suprasellar Other Total resection Yes No RT dose <55 Gy 55 Gy CSI Yes No Chemo Yes No
10-year OS
Patient no.
%
95% CI
p value
%
95% CI
p value
20 12
80.0 72.7
63e97 46e99
0.797
74.7 75.0
55e94 51e100
0.969
29 3
78.8 66.7
64e94 13e100
0.708
75.3 66.7
59e91 13e120
0.823
14 18
100 61.1
e 39e84
0.012
85.1 66.7
66e104 45e88
0.215
22 10
76.2 80.0
58e94 71e109
0.948
72.4 80.0
54e91 55e105
0.783
20 5 7
79.2 60.0 85.7
61e97 17e100 60e100
0.579
74.7 60.0 85.7
55e94 17e103 60e112
0.623
14 18
85.7 71.1
67e100 50e92
0.289
85.7 66.7
67e104 45e88
0.162
24 8
69.8 100
51e88 e
0.094
70.8 87.5
53e89 65e110
0.309
27 5
85.2 26.7
72e99 0e71
0.008
80.9 40.0
66e96 2e83
0.022
28 4
82.1 37.5
68e96 19e94
0.065
78.0 50.0
62e94 1e99
0.114
Abbreviations: chemo Z chemotherapy; CSI Z craniospinal irradiation; OS Z overall survival; RFS Z recurrence-free survival; RT Z radiotherapy.
(a)
100%
100
third patient also had a tumor in the pineal region and received CSI of 40.5 Gy plus a focal boost of 14.4 Gy at age 6.
Discussion Intracranial NGGCTs are a heterogeneous group of tumors, and numerous studies have reported different recurrent patterns and survival among different subtypes (2, 5, 8, 10, 13, 14). The most
(b)
100
Survival Rate (%)
Endocrinologic work-up data were available for 26 of 32 patients. Ten patients (38%) had endocrine abnormalities at diagnosis, whereas 3 patients, who did not have endocrine dysfunction at diagnosis, developed hormone insufficiency after treatment. These patients were treated with hormone replacement during the follow-up period. Among the 3 patients with de novo endocrine dysfunction, 2 patients had tumors in the pineal region and had received CSI 30 Gy plus a focal boost of 30.6 Gy. They were 14 and 8 years old at the time of radiation treatment. The
80
Survival Rate (%)
85.1% 80 61.1%
60 Intermediate Poor
40 Log rank test p = 0.012
20 0
0
24
48
72
96
120
Recurrence-free Survival (months)
66.7% 60
Intermediate Poor
40
Log rank test p = 0.215
20 0
0
24
48
72
96
120
Overall Survival (months)
Fig. (a) Comparison of recurrence-free survival curves over 10 years according to prognosis groups. (b) Comparison of overall survival curves over 10 years according to prognosis groups.
Volume 84 Number 3 2012 Table 3 Age/sex
Nongerminomatous germ cell tumors
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Clinical characteristics and treatment outcome of recurrent cases Dx
Location
Treatment
RT dose
Recur site
Recur time
Salvage tx
Status
28/F 13/M 16/M 14/M
MME MME MME CC
S P & BG P P
SubT-CT-RT SubT-CT-RT tRT-total tCT-total-CT-RT
Focal 50.4 Focal 23.4 WB 20 CSI 30.6 þ focal 23.4
13 mo 1 mo 33 mo 12 mo
YST EC MME
P S P
tRT-RT tRT-CT-RT CT-subT-RT
tRT 18 þ CSI 36 tRT 19.8 þ CSI 34.5 focal 18 þ CSI 36
NR to CT None CR to OP PD to OP and CT None None None
DOD at 18 mo DOD at 4 mo NED at 243 mo DOD at 18 mo
6/M 13/M 19/M
Suprasellar P and BG Cbll Sacrum and CSF CSF CSF CSF
2 mo 9 mo 12 mo
DOD at 7 mo DOD at 9 mo DOD at 14 mo
Abbreviations: BG Z basal ganglia; Cbll Z cerebellum; CC Z choriocarcinoma; CSF Z cerebrospinal fluid; CR Z complete remission; CSI Z craniospinal irradiation; DOD Z died of disease; Dx Z diagnosis; EC Z embryonal carcinoma; MME Z mixed tumor composed of malignant elements; NED Z no evident disease; NR Z no response; OP Z operation; P Z pineal; PD Z progressive disease; S Z suprasellar; SubT Z subtotal resection; tCT Z trial chemotherapy; tRT Z trial radiotherapy; Tx Z treatment; WB Z whole brain radiotherapy; YST Z yolk sac tumor.
virulent are yolk sac tumors, embryonal carcinomas, choriocarcinomas, and mixed lesions in which these subtypes are prominently represented. Less virulent are immature teratomas and mixed tumors dominated by teratoma or germinoma and containing high-grade nongerminomatous components in relatively limited amounts, and these tumors occupy an intermediate position in terms of malignant potential (10, 14, 15). The current study is meaningful in that patients in the good prognosis group (pure germinoma and mature teratoma) were excluded and that survival still differed between the intermediate and poor prognosis groups. Although tissue confirmation is the gold standard for diagnosis of NGGCTs, biopsy and/or tumor resection often carry the risk of surgical complications, especially for these deep-seated tumors. Because intracranial germ cell tumors are often of mixed histologic composition, stereotactic biopsy with an inadequate amount of tissue samples may not provide accurate diagnosis. The initial level of tumor markers can assist diagnosis when CT or MRI findings suggest NGGCT. AFP is elevated in embryonal carcinoma, endodermal sinus tumor, or malignant teratoma. Any detectable elevation of AFP (generally, serum >5e10 ng/dL; CSF >2e5 ng/dL) should be diagnostic of a NGGCT. The cutoff level of b-HGC elevation for the diagnosis of NGGCT is controversial because b-HGC may be elevated up to 70e100 IU in pure germinomas and up to 100e200 IU in germinomas with syncytiotrophoblastic giant cells. Currently, any clear elevation of AFP or marked elevation of b-HCG typically more than 100e200 IU may be considered diagnostic of NGGCT without histologic confirmation (6). In the current study, 1 patient who received 19.8 Gy of trial RT and 3 patients who received three cycles of chemotherapy underwent surgical resection, and histologic assessment revealed mature teratoma. The final diagnoses of these tumors were mixed germ cell tumors based on the initial elevation of tumor markers. Initial evaluation with whole spine MRI and CSF cytology is important in detecting spinal dissemination of disease and determining the appropriate volume of radiation treatment. In the current study, 2 patients, 1 with embryonal carcinoma and 1 with mixed tumor of malignant element, were initially positive on CSF cytology but negative on whole-spine MRI. Both patients received combined treatment including CSI, and the patient with embryonal carcinoma experienced CSF failure 2 months after treatment and died of progressive disease. Previous studies reported disappointing treatment outcomes for the poor prognosis group with 5-year survival ranging from 8% to
44% (Table 4). In the current study, 10-year RFS and OS for the poor prognosis group were 61% and 67%, respectively, and the survival was significantly higher compared with that of other NGGCT studies. The majority of NGGCT patients who were treated at our institution had received combined-modality therapy. Fifty-nine percent of the patients were treated with RT, chemotherapy, and surgery and 28% were treated with RT plus chemotherapy. Radiation is an important component of multimodality therapy for NGGCTs (11, 16). Because local progression is the primary pattern of recurrence even after combined modality therapy, a high RT dose is required for the primary tumor site (17). A median dose of 54 Gy was delivered to the primary tumor site in the current study. Three patients had local failure, with 2 of the 3 patients having received only 20 Gy and 23.4 Gy to the primary tumor site. In other NGGCT studies, the most frequent median dose to the primary tumor site was 50 Gy (range, 43e54 Gy) (5, 7, 8, 10, 14). Another possible reason for the improved survival in the current study was that most patient received CSI. On univariate analysis, CSI was strongly associated with improved RFS and OS. Other studies also support the role of CSI in preventing spinal recurrence. In a multi-institutional study by Aoyama et al. (7), spinal canal recurrence was observed in 37.8% (3/8) of patients in the poor prognosis group who were not treated with CSI. None of the 5 patients in the same group who received CSI experienced spinal recurrence. Matsutani et al. (5) also reported a 21.7% (5/23) rate of spinal recurrence in patients in the poor prognosis group treated primarily by WBRT without spinal irradiation. In the current study, the main mode of treatment failure was CSF failure, and 4 patients in the poor prognosis group showed CSF recurrence even after CSI. One of these 4 patients had positive CSF cytology but negative MRI findings. Occult CSF spread may have occurred in the other 3 patients, although it was not detected by CSF cytology or spinal MRI. A CSI dose of 30e36 Gy may not have been adequate in patients with CSF dissemination. The benefit of surgical resection for NGGCT is controversial. Some studies have shown a trend toward improved control with more aggressive resection for malignant histiotypes (5, 9). In Europe and North America, delayed surgery for persistent disease after chemotherapy is preferred (18). In Japan, more aggressive resection is advocated for therapeutic and prognostic implications (5, 10). The rates of maximal resection (gross total þ subtotal) from previous reports ranged from 41% to 88% (5, 7e9, 14). However, these studies included patients in the good prognostic
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Table 4
Estimates of patient survival from selected radiotherapy series Survival by prognosis group
Study Matsutani (5) 1963e1994 Sawamura (10) 1970e1995 Aoyama (7) 1971e1994 Ogawa (14) 1981e2001 Kim (present) 1982e2006
Treatment (%) OP þ CT þ RT (14.2) OP þ RT (77.6) OP þ CT (5.2) OP (100) RT (94.6) CT (32.4) OP (100) RT (92) CT (54) OP þ CT þ RT (63) OP þ RT (37) OP þ CT þ RT (59.4) CT þ RT (28.1) OP þ RT (9.4)
Patient number
Survival
Good (n Z 66) Intermediate (n Z 45) Poor (n Z 23) Good (n Z 66) Intermediate (n Z 30) Poor (n Z 15) Good (n Z 5) Intermediate (n Z 6) Poor (n Z 13) Good (n Z 3) Intermediate (n Z 24) Poor (n Z 14) Intermediate (n Z 14) Poor (n Z 18)
5-y OS 95%; 10-y OS 93% 5-y OS 74%; 10-y OS 65% 5-y OS 18%; 10-y OS n/a 5-y OS 96%; 10-y OS 91% 5-y OS 74%; 10-y OS 64% 5-y OS 38%; 10-y OS 25% 5-y RFS 100% 5-y RFS 63% 5-y RFS 44% 5-y OS 100% 5-y OS 68% 5-y OS 8% 10-y RFS 100%; OS 85% 10-y RFS 61%; OS 67%
Abbreviations: CT Z chemotherapy; n/a Z not available; OP Z operation; OS Z overall survival; RFS Z recurrence-free survival; RT Z radiotherapy.
subtypes and did not report surgical resection rates stratified by prognosis group. The current study included only intermediateand poor-prognosis group patients, and the maximal resection rate of 69% is relatively high compared with resection rates in other studies. Reduced tumor burden through surgical resection may have been another contributing factor to the improved survival in this study. Studies reporting functional outcome or quality of life among long-term survivors of intracranial germinoma who were treated with CSI of 25.6e36 Gy and a total tumor dose of 50.4 Gy in childhood and adolescence have shown remarkable preservation of functional status (19, 20). In the current study, de novo development of pituitary dysfunction after CSI and focal boost was relatively low. Only 3 patients developed hormone insufficiency after combined treatment, and they were 14, 8, and 6 years old at the time of treatment. A major limitation of the current study is that the patients had not been routinely followed with neurocognitive evaluation. Higher radiation dose to tumor and wider coverage of normal tissue from CSI may increase incidence of late complications such as secondary malignancies, hormone insufficiency, and deterioration of neurocognitive function among survivors. Further studies should evaluate the effect of radiation dose and field size on the incidence and degree of neurologic sequelae. This was a single institution study with a relatively large number of patients with high-risk NGGCTs. A multimodal approach was effective in treating NGGCTs, and CSI should be considered, especially for patients with a poor prognostic histology. A total radiation dose of 54 Gy or higher to the primary tumor site and maximum tumor resection may improve local control.
References 1. Lee D, Suh Y. Histologically confirmed intracranial germ cell tumors; an analysis of 62 patients in a single institute. Virchows Archiv 2010; 457:347e357.
2. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: Natural history and pathogenesis. J Neurosurg 1985;63: 155e167. 3. Ho DM, Liu HC. Primary intracranial germ cell tumor. Pathologic study of 51 patients. Cancer 1992;70:1577e1584. 4. Cho J, Choi J, Kim D, et al. Low-dose craniospinal irradiation as a definitive treatment for intracranial germinoma. Radiother Oncol 2009;91:75e79. 5. Matsutani M, Sano K, Takakura K, et al. Primary intracranial germ cell tumors: A clinical analysis of 153 histologically verified cases. J Neurosurg 1997;86:446e455. 6. Kun L, MacDonald S, Tarbell N. Supratentorial brain tumors. In: Halperin E, Constine L, Tarbell N, et al., editors. Pediatric Radiation Oncology. ed. 5. Philadelphia: Lippincott Williams & Wilkins; 2011. p. 26e52. 7. Aoyama H, Shirato H, Yoshida H, et al. Retrospective multiinstitutional study of radiotherapy for intracranial nongerminomatous germ cell tumors. Radiother Oncol 1998;49:55e59. 8. Schild SE, Haddock MG, Scheithauer BW, et al. Nongerminomatous germ cell tumors of the brain. Int J Radiat Oncol Biol Phys 1996;36: 557e563. 9. Robertson PL, DaRosso RC, Allen JC. Improved prognosis of intracranial non-germinoma germ cell tumors with multimodality therapy. J Neuro-oncol 1997;32:71e80. 10. Sawamura Y, Ikeda J, Shirato H, et al. Germ cell tumours of the central nervous system: Treatment consideration based on 111 cases and their long-term clinical outcomes. Eur J Cancer 1998;34: 104e110. 11. Haas Kogan DA, Missett BT, Wara WM, et al. Radiation therapy for intracranial germ cell tumors. Int J Radiat Oncol Biol Phys 2003;56: 511e518. 12. World Health Organization. Classification of tumours. Pathology and genetics of tumours of the central nervous system. Lyon, France: IARC Press; 2000. 13. Aoyama H, Shirato H, Ikeda J, et al. Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors. J Clin Oncol 2002;20:857e865. 14. Ogawa K, Toita T, Nakamura K, et al. Treatment and prognosis of patients with intracranial nongerminomatous malignant germ cell tumors: A multiinstitutional retrospective analysis of 41 patients. Cancer 2003;98:369e376.
Volume 84 Number 3 2012 15. Matsutani M. Combined chemotherapy and radiation therapy for CNS germ cell tumorsdthe Japanese experience. J Neuro-oncolo 2001;54: 311e316. 16. Allen JC. Controversies in the management of intracranial germ cell tumors. Neurol Clin 1991;9:441e452. 17. Aoyama H. Radiation therapy for intracranial germ cell tumors. Prog Neurol Surg 2009;23:10. 18. Calaminus G, Bamberg M, Harms D, et al. AFP/beta-HCG secreting CNS germ cell tumors: long-term outcome with respect to initial
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symptoms and primary tumor resection. Results of the cooperative trial MAKEI 89. Neuropediatrics 2005;36:71e77. 19. Sutton LN, Radcliffe J, Goldwein JW, et al. Quality of life of adult survivors of germinomas treated with craniospinal irradiation. Neurosurgery 1999;45:1292e1297. discussion 1297. 20. Merchant TE, Sherwood SH, Mulhern RK, et al. CNS germinoma: Disease control and long-term functional outcome for 12 children treated with craniospinal irradiation. Int J Radiat Oncol Biol Phys 2000;46:1171e1176.
Radiation Oncology biology
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Clinical Investigation: Central Nervous System Tumor
A Multimodal Approach Including Craniospinal Irradiation Improves the Treatment Outcome of High-risk Intracranial Nongerminomatous Germ Cell Tumors Jun Won Kim, M.D.,* Woo Chul Kim, M.D.,x Jae Ho Cho, M.D.,* Dong-Seok Kim, M.D.,y Kyu-Won Shim, M.D.,y Chul Joo Lyu, M.D.,z Sung Chul Won, M.D.,z and Chang-Ok Suh, M.D.* Departments of *Radiation Oncology, yNeurosurgery, and zPediatrics, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; and xDepartment of Radiation Oncology, Inha University College of Medicine, Incheon, Korea Received Sep 1, 2011, and in revised form Dec 8, 2011. Accepted for publication Dec 22, 2011
Summary Thirty-two nongerminomatous germ cell tumor patients received combined treatment including chemotherapy, radiation and surgery. Craniospinal irradiation (CSI) was given to 84% of the patients. Ten-year recurrence-free and overall survival rates were 77.6% and 74.6%, respectively. Treatment failed (7/18) only in the poor prognosis group in which cerebrospinal fluid failure was predominant. Multimodal approach was effective for treating nongerminomatous germ cell tumors, and CSI should be considered for poor prognostic histology.
Purpose: To evaluate whether a multimodal approach including craniospinal irradiation (CSI) improves treatment outcome in nongerminomatous germ cell tumor (NGGCT) patients. Methods and Materials: We reviewed the records of 32 patients with NGGCTs. Fourteen patients belonged to the intermediate prognosis group (immature teratoma, teratoma with malignant transformation, and mixed tumors mainly composed of germinoma or teratoma), and 18 patients belonged to the poor prognosis group (other highly malignant tumors). Patients with pure germinoma or mature teratoma were excluded from this study. Nineteen patients were treated with a combination of surgery, chemotherapy, and radiotherapy (RT); 9 patients received chemotherapy plus RT; 3 patients received surgery plus RT; and 1 patient received RT alone. Twenty-seven patients received CSI with a median of 36 Gy (range, 20e41 Gy) plus focal boost of 18e30.6 Gy, and 5 patients received whole-brain RT (WBRT) (20e36 Gy) or focal RT (50.4e54 Gy). The rate of total and subtotal resection was 71.9%. The median follow-up for surviving patients was 121 months. Results: Treatment failed in 7 patients. Three of the 5 patients who received focal RT or WBRT had local failure. Four cerebrospinal fluid (CSF) failures occurred after CSI. No failure occurred in the intermediate prognosis group. Ten-year recurrence-free survival (RFS) and overall survival (OS) for all patients were 77.6% and 74.6%, respectively. Ten-year RFS for the intermediate and poor prognosis groups were 100% and 61.1%, respectively (p Z 0.012). OS for the two groups were 85.1% and 66.7%, respectively (p Z 0.215). Tumor histology and CSI were significant prognostic factors for RFS, and CSI was significantly associated with OS. Conclusions: A multimodal approach was effective for treating NGGCTs. CSI should be considered for patients with poor prognostic histology. Ó 2012 Elsevier Inc. Keywords: Nongerminomatous germ cell tumor, Multimodal approach, Craniospinal irradiation
Reprint requests to: Chang-Ok Suh, M.D., Department of Radiation Oncology, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemoon-gu, Seoul, 120-752, Korea. Tel: 82-2-2228-8095; Fax: 82-2-312-9033; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 84, No. 3, pp. 625e631, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.12.077
Presented at the 2011 Pediatric Radiation Oncology Society (PROS) Congress, Venice, Italy. Conflicts of interest: none.
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Introduction The incidence of primary intracranial germ cell tumors (GCTs) among children with brain tumors is higher in Japan, Korea, and Taiwan (10%e14%) than in North America or Europe (3%e4%) (1). The full spectrum of tumor histology for intracranial GCTs includes pure germinomas (60%e70% of intracranial GCTs), malignant germ cell tumors (embryonal carcinomas, yolk sac tumors, and choriocarcinomas; collectively 15%e20%), and teratomas (benign, immature, and malignant types, 15%e20%) (2, 3). Pure germinomas are highly radiosensitive, with disease-free survival rates of 90% or higher (4, 5). The remaining GCTs are conventionally classified as nongerminomatous GCTs (NGGCTs), and these tumors respond poorly to radiation and are associated with secretion of a-fetoprotein (AFP) and/or b-HCG (6). NGGCTs are, however, a heterogeneous group of tumors with histology-dependent tumor characteristics. Matsutani et al. divided intracranial GCTs into three prognosis groups (5). The good prognosis group consists of pure germinoma and mature teratoma; the intermediate prognosis group consists of immature teratoma, teratoma with malignant transformation, and mixed tumors mainly composed of germinoma or teratoma; and the poor prognosis group consists of choriocarcinoma, yolk sac tumors, embryonal carcinoma, and mixed tumors mainly composed of malignant germ cell tumors. The prognosis of a NGGCT is thought to be subtype-specific, and different subtypes require different treatment guidelines (7, 8). A combined-modality approach, including radiotherapy (RT), chemotherapy, and potential surgical resection, is recommended for NGGCTs (2, 5, 8, 9). However, there is no clear consensus on the treatment of NGGCTs. Treatment results have been less than satisfactory, especially for poor prognostic subtypes because these tumors tend to recur locally as well as disseminate (2, 9, 10). RT is an important component of multimodal treatment. However, appropriate primary tumor dose and RT volume (local, whole ventricle, whole brain, or craniospinal) have not been clearly defined (2, 11). In the current study, we attempted to establish the role of radiotherapy in multimodal treatment, including craniospinal irradiation (CSI) for NGGCT patients.
Methods and Materials Patient characteristics We searched the database registry of the Radiation Oncology Department at Yonsei Cancer Center and identified 32 patients who received radiotherapy as part of combination treatment for intracranial NGGCTs between 1982 and 2006. The median age of the patients was 14 years (range, 4e28 years). Twenty-nine patients were male and 3 were female. The most frequent tumor location was pineal (62.5%), followed by suprasellar (15.6%) and thalamic or basal ganglia (12.5%). A pathologic diagnosis was made in 23 patients, and 9 patients were diagnosed based on elevated tumor markers and NGGCT-compatible magnetic resonance imaging (MRI) findings. According to the World Health Organization classification system (12), 4 patients had immature teratomas, 2 patients had teratomas with malignant transformation, 1 patient had embryonal carcinoma, 4 patients had yolk sac tumors, 3 patients had choriocarcinomas, and the remaining 18 patients had mixed germ
International Journal of Radiation Oncology Biology Physics cell tumors. Patients who were diagnosed with pure germinoma or mature teratoma were excluded from the study (Table 1). Cerebrospinal fluid (CSF) cytology was examined in 26 patients, and 2 patients had positive results. However, spinal MRI showed that none of the patients had apparent spinal metastasis at initial diagnosis. Serum AFP and serum human chorionic gonadotropin (HCG) were measured before treatment in 31 of 32 patients. Tumor markers were elevated in 28 of 32 patients (serum AFP range, 13.2e9105 mIU/mL; serum HCG range, 14.8e5874 IU/mL). Nine patients had AFP elevation without HCG elevation, and 11 patients had HCG elevation alone. Both AFP and HCG were elevated in 8 patients. Patients were divided into two groups according to Matsutani classification of intracranial GCTs (5). Fourteen patients belonged to the intermediate prognosis group, and 18 patients to the poor prognosis group.
Treatments Patients who presented with NGGCT-compatible MRI findings and tumor marker elevation were treated with chemotherapy followed by radiation. When NGGCT was suspected on MRI without tumor marker elevation, biopsy or trial RT was performed. If the tumor responded well to 20e30 Gy of trial RT, it was regarded as a pure germinoma. These cases were not included in this study. The patients who responded poorly to trial RT underwent surgical intervention to confirm pathology. Surgical removal was attempted if feasible when residual tumor was apparent in the imaging studies after chemotherapy and/or RT. Nineteen patients (59.4%) were treated with a combination of surgical resection, chemotherapy, and RT; 9 patients (28.1%) received chemotherapy plus RT; 3 patients (9.4%) received surgical resection plus RT; and 1 patient (3.1%) received RT alone. Surgery was performed in 25 patients (78.1%). Fourteen patients (43.8%) received gross total resection, 9 patients (28.1%) underwent subtotal resection, biopsy was performed in 2 patients (6.3%), and no surgery was attempted in the remaining seven patients (21.9%). The rate of maximal resection (total þ subtotal) was 71.9%. Radiation was delivered with a cobalt 60 radiotherapy unit or 4e6 MV in daily fractions of 1.5e1.8 Gy, 5 days per week. Twenty-seven patients were treated with CSI of a median of 36 Gy (range, 20e41 Gy) plus focal boost of 18e30.6 Gy, 2 patients received whole-brain RT (WBRT) (20e36 Gy), and 3 patients received focal RT (50.4e54 Gy) without spinal irradiation. The median dose to the primary tumor site was 54 Gy (range, 20e60.6 Gy). Twenty-eight patients (75%) received cisplatin/carboplatin-based systemic chemotherapy in a total of 1e7 courses before and/or after radiotherapy. Nine patients received a combined regimen of cisplatin, etoposide, and bleomycin, 6 patients received cisplatin and etoposide, 5 patients received a combination of carboplatin, etoposide, and ifosfamide, and 8 patients received alternating courses of cisplatin/etoposide and vincristine/cyclophosphamide. One patient, who received one cycle of cisplatin and etoposide, discontinued chemotherapy because of elevated liver enzymes.
Statistical analysis The Kaplan-Meier method was used to calculate the rates of recurrence-free survival (RFS) and overall survival (OS) from the day of diagnosis. Differences between the two prognosis groups
Volume 84 Number 3 2012 Table 1
Nongerminomatous germ cell tumors
Patient characteristics
Characteristics Age 0e9 10e19 20e29 30 Sex Male Female Tumor location Pineal Suprasellar Thalamus or BG Multifocal Diagnostic modality Histologic Clinical Tumor subtype Immature teratoma TMT Embryonal carcinoma Yolk sac tumor Choriocarcinoma MGT MME Treatment OP þ CT þ RT CT þ RT OP þ RT RT alone
No. of patients (%)
627
100% and 61.1%, respectively (p Z 0.012). Ten-year OS for the two groups were 85.1% and 66.7%, respectively (p Z 0.215).
Patterns of recurrence 7 (21.9) 21 (65.6) 4 (12.5) 0 29 (90.6) 3 (9.4) 20 5 4 3
(62.5) (15.6) (12.5) (9.4)
23 (71.9) 9 (28.1) 4 2 1 4 3 8 10
(12.5) (6.3) (3.1) (12.5) (9.4) (25.0) (31.2)
19 9 3 1
(59.4) (28.1) (9.4) (3.1)
Abbreviations: BG Z basal ganglia; CT Z chemotherapy; MGT Z mixed tumor mainly of germinoma or teratoma; MME Z mixed tumor mainly of malignant elements; OP Z operation; RT Z radiotherapy; TMT Z teratoma with malignant transformation.
were estimated using the logerank test. p values less than 0.05 were considered statistically significant.
Results Survival and prognostic factors At the time of analysis, 8 of 32 patients (25%) died 4e79 months (median, 12 months) after diagnosis. The median follow-up of the 24 surviving patients was 121 months (range, 60e312 months). Ten-year RFS and OS for all patients were 77.6% and 74.6%, respectively. The results of univariate analyses of clinical variables are presented in Table 2. Intermediate prognosis group (p Z 0.012) and CSI (p Z 0.008) were significantly associated with increased RFS, and total radiation dose higher than 54 Gy (p Z 0.094) and administration of chemotherapy (p Z 0.065) showed a trend toward increased RFS. CSI was the only significant prognostic factor (p Z 0.022) for OS, and prognosis group (p Z 0.215), total tumor resection (p Z 0.162), and chemotherapy (p Z 0.114) showed a trend toward improved OS. Age, gender, tumor size, and tumor location were not strongly associated with survival. Figs. a and b show survival curves according to prognosis groups. Ten-year RFS for the intermediate and poor prognostic groups were
Table 3 shows the patterns of failure and outcomes of salvage treatment in 7 patients who experienced recurrence. The interval between initial diagnosis and time of recurrence varied from 1 to 33 months. In the intermediate prognosis group (n Z 14), 13 patients received CSI, and 12 patients received chemotherapy as part of the combined treatment. No failure was reported from the intermediate prognosis group. All 7 of the patients diagnosed with recurrence were from the poor prognosis group. In the poor prognosis group (n Z 18), 14 patients received CSI and treatment failed in 4, which were all CSF failures. Failure was noted in 3 of the remaining 4 patients who did not receive CSI, and all 3 were local failures. With respect to chemotherapy, which was given to 16 patients in the poor prognosis group, two local and three CSF failures occurred. The 2 patients who did not receive chemotherapy also experienced treatment failure, one locally and the other in CSF. Six of the 7 patients in whom treatment failed died from progression of recurrent disease. Treatment failed locally (in-field) in a 28-year-old female with mixed tumor of malignant elements (MME), 13 months after subtotal resection, chemotherapy, and focal RT of 50.4 Gy. She died of progressive disease in spite of salvage chemotherapy. A 13-year-old male with MME received subtotal resection, chemotherapy, and local RT of 23.4 Gy. He showed disease progression in a 1-month post-treatment evaluation and died of disease 3 months later. A 16-year-old male with MME, who received trial RT of 20 Gy to whole brain and total resection, failed locally 33 months after treatment. He was salvaged with surgical resection and is still alive and free of disease. Four patients were diagnosed with CSF failures 2e12 months later despite receiving CSI as a part of the initial treatment. Recurrence in CSF and sacral bone was noted in a 14-year-old male with choriocarcinoma, after combined treatment of trial RT, total resection, chemotherapy, and RT. He died of progressive disease despite salvage surgery and chemotherapy. A 19-year-old male with MME experienced CSF recurrence after chemotherapy, subtotal resection, and RT. He received no salvage treatment and died of progressive disease. The other 2 patients, a 6-year-old male with yolk sac tumor and a 13-year-old male with embryonal carcinoma, both had CSF recurrence after RT and chemotherapy. Both received no salvage treatment and died of progressive disease.
Toxicity A 24-year-old male with teratoma with malignant transformation was treated with WBRT of 18 Gy plus focal RT of 18 Gy followed by subtotal resection. He died of ventriculoperitoneal shunt-related sepsis at 3 months from the treatment. A 14-yearold male had been diagnosed with mixed germinoma and teratoma at the pineal region, and received total resection, chemotherapy, and focal RT 30.6 Gy plus CSI 30 Gy. At 57 months from initial radiotherapy, a cerebellar tumor developed and biopsy of the tumor confirmed anaplastic astrocytoma. He died of progressive disease 13 months after diagnosis of secondary malignancy despite salvage treatment including local RT of 50.4 Gy and concurrent temozolomide. These 2 patients showed no recurrence in follow-up images until time of death and were not counted as events of recurrence in RFS analysis.
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Table 2
Univariate analysis for patient survival 10-year RFS
Clinical variables Age <15 15 Gender Male Female Prognosis group Intermediate Poor Tumor size <4 cm 4 cm Tumor location Pineal Suprasellar Other Total resection Yes No RT dose <55 Gy 55 Gy CSI Yes No Chemo Yes No
10-year OS
Patient no.
%
95% CI
p value
%
95% CI
p value
20 12
80.0 72.7
63e97 46e99
0.797
74.7 75.0
55e94 51e100
0.969
29 3
78.8 66.7
64e94 13e100
0.708
75.3 66.7
59e91 13e120
0.823
14 18
100 61.1
e 39e84
0.012
85.1 66.7
66e104 45e88
0.215
22 10
76.2 80.0
58e94 71e109
0.948
72.4 80.0
54e91 55e105
0.783
20 5 7
79.2 60.0 85.7
61e97 17e100 60e100
0.579
74.7 60.0 85.7
55e94 17e103 60e112
0.623
14 18
85.7 71.1
67e100 50e92
0.289
85.7 66.7
67e104 45e88
0.162
24 8
69.8 100
51e88 e
0.094
70.8 87.5
53e89 65e110
0.309
27 5
85.2 26.7
72e99 0e71
0.008
80.9 40.0
66e96 2e83
0.022
28 4
82.1 37.5
68e96 19e94
0.065
78.0 50.0
62e94 1e99
0.114
Abbreviations: chemo Z chemotherapy; CSI Z craniospinal irradiation; OS Z overall survival; RFS Z recurrence-free survival; RT Z radiotherapy.
(a)
100%
100
third patient also had a tumor in the pineal region and received CSI of 40.5 Gy plus a focal boost of 14.4 Gy at age 6.
Discussion Intracranial NGGCTs are a heterogeneous group of tumors, and numerous studies have reported different recurrent patterns and survival among different subtypes (2, 5, 8, 10, 13, 14). The most
(b)
100
Survival Rate (%)
Endocrinologic work-up data were available for 26 of 32 patients. Ten patients (38%) had endocrine abnormalities at diagnosis, whereas 3 patients, who did not have endocrine dysfunction at diagnosis, developed hormone insufficiency after treatment. These patients were treated with hormone replacement during the follow-up period. Among the 3 patients with de novo endocrine dysfunction, 2 patients had tumors in the pineal region and had received CSI 30 Gy plus a focal boost of 30.6 Gy. They were 14 and 8 years old at the time of radiation treatment. The
80
Survival Rate (%)
85.1% 80 61.1%
60 Intermediate Poor
40 Log rank test p = 0.012
20 0
0
24
48
72
96
120
Recurrence-free Survival (months)
66.7% 60
Intermediate Poor
40
Log rank test p = 0.215
20 0
0
24
48
72
96
120
Overall Survival (months)
Fig. (a) Comparison of recurrence-free survival curves over 10 years according to prognosis groups. (b) Comparison of overall survival curves over 10 years according to prognosis groups.
Volume 84 Number 3 2012 Table 3 Age/sex
Nongerminomatous germ cell tumors
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Clinical characteristics and treatment outcome of recurrent cases Dx
Location
Treatment
RT dose
Recur site
Recur time
Salvage tx
Status
28/F 13/M 16/M 14/M
MME MME MME CC
S P & BG P P
SubT-CT-RT SubT-CT-RT tRT-total tCT-total-CT-RT
Focal 50.4 Focal 23.4 WB 20 CSI 30.6 þ focal 23.4
13 mo 1 mo 33 mo 12 mo
YST EC MME
P S P
tRT-RT tRT-CT-RT CT-subT-RT
tRT 18 þ CSI 36 tRT 19.8 þ CSI 34.5 focal 18 þ CSI 36
NR to CT None CR to OP PD to OP and CT None None None
DOD at 18 mo DOD at 4 mo NED at 243 mo DOD at 18 mo
6/M 13/M 19/M
Suprasellar P and BG Cbll Sacrum and CSF CSF CSF CSF
2 mo 9 mo 12 mo
DOD at 7 mo DOD at 9 mo DOD at 14 mo
Abbreviations: BG Z basal ganglia; Cbll Z cerebellum; CC Z choriocarcinoma; CSF Z cerebrospinal fluid; CR Z complete remission; CSI Z craniospinal irradiation; DOD Z died of disease; Dx Z diagnosis; EC Z embryonal carcinoma; MME Z mixed tumor composed of malignant elements; NED Z no evident disease; NR Z no response; OP Z operation; P Z pineal; PD Z progressive disease; S Z suprasellar; SubT Z subtotal resection; tCT Z trial chemotherapy; tRT Z trial radiotherapy; Tx Z treatment; WB Z whole brain radiotherapy; YST Z yolk sac tumor.
virulent are yolk sac tumors, embryonal carcinomas, choriocarcinomas, and mixed lesions in which these subtypes are prominently represented. Less virulent are immature teratomas and mixed tumors dominated by teratoma or germinoma and containing high-grade nongerminomatous components in relatively limited amounts, and these tumors occupy an intermediate position in terms of malignant potential (10, 14, 15). The current study is meaningful in that patients in the good prognosis group (pure germinoma and mature teratoma) were excluded and that survival still differed between the intermediate and poor prognosis groups. Although tissue confirmation is the gold standard for diagnosis of NGGCTs, biopsy and/or tumor resection often carry the risk of surgical complications, especially for these deep-seated tumors. Because intracranial germ cell tumors are often of mixed histologic composition, stereotactic biopsy with an inadequate amount of tissue samples may not provide accurate diagnosis. The initial level of tumor markers can assist diagnosis when CT or MRI findings suggest NGGCT. AFP is elevated in embryonal carcinoma, endodermal sinus tumor, or malignant teratoma. Any detectable elevation of AFP (generally, serum >5e10 ng/dL; CSF >2e5 ng/dL) should be diagnostic of a NGGCT. The cutoff level of b-HGC elevation for the diagnosis of NGGCT is controversial because b-HGC may be elevated up to 70e100 IU in pure germinomas and up to 100e200 IU in germinomas with syncytiotrophoblastic giant cells. Currently, any clear elevation of AFP or marked elevation of b-HCG typically more than 100e200 IU may be considered diagnostic of NGGCT without histologic confirmation (6). In the current study, 1 patient who received 19.8 Gy of trial RT and 3 patients who received three cycles of chemotherapy underwent surgical resection, and histologic assessment revealed mature teratoma. The final diagnoses of these tumors were mixed germ cell tumors based on the initial elevation of tumor markers. Initial evaluation with whole spine MRI and CSF cytology is important in detecting spinal dissemination of disease and determining the appropriate volume of radiation treatment. In the current study, 2 patients, 1 with embryonal carcinoma and 1 with mixed tumor of malignant element, were initially positive on CSF cytology but negative on whole-spine MRI. Both patients received combined treatment including CSI, and the patient with embryonal carcinoma experienced CSF failure 2 months after treatment and died of progressive disease. Previous studies reported disappointing treatment outcomes for the poor prognosis group with 5-year survival ranging from 8% to
44% (Table 4). In the current study, 10-year RFS and OS for the poor prognosis group were 61% and 67%, respectively, and the survival was significantly higher compared with that of other NGGCT studies. The majority of NGGCT patients who were treated at our institution had received combined-modality therapy. Fifty-nine percent of the patients were treated with RT, chemotherapy, and surgery and 28% were treated with RT plus chemotherapy. Radiation is an important component of multimodality therapy for NGGCTs (11, 16). Because local progression is the primary pattern of recurrence even after combined modality therapy, a high RT dose is required for the primary tumor site (17). A median dose of 54 Gy was delivered to the primary tumor site in the current study. Three patients had local failure, with 2 of the 3 patients having received only 20 Gy and 23.4 Gy to the primary tumor site. In other NGGCT studies, the most frequent median dose to the primary tumor site was 50 Gy (range, 43e54 Gy) (5, 7, 8, 10, 14). Another possible reason for the improved survival in the current study was that most patient received CSI. On univariate analysis, CSI was strongly associated with improved RFS and OS. Other studies also support the role of CSI in preventing spinal recurrence. In a multi-institutional study by Aoyama et al. (7), spinal canal recurrence was observed in 37.8% (3/8) of patients in the poor prognosis group who were not treated with CSI. None of the 5 patients in the same group who received CSI experienced spinal recurrence. Matsutani et al. (5) also reported a 21.7% (5/23) rate of spinal recurrence in patients in the poor prognosis group treated primarily by WBRT without spinal irradiation. In the current study, the main mode of treatment failure was CSF failure, and 4 patients in the poor prognosis group showed CSF recurrence even after CSI. One of these 4 patients had positive CSF cytology but negative MRI findings. Occult CSF spread may have occurred in the other 3 patients, although it was not detected by CSF cytology or spinal MRI. A CSI dose of 30e36 Gy may not have been adequate in patients with CSF dissemination. The benefit of surgical resection for NGGCT is controversial. Some studies have shown a trend toward improved control with more aggressive resection for malignant histiotypes (5, 9). In Europe and North America, delayed surgery for persistent disease after chemotherapy is preferred (18). In Japan, more aggressive resection is advocated for therapeutic and prognostic implications (5, 10). The rates of maximal resection (gross total þ subtotal) from previous reports ranged from 41% to 88% (5, 7e9, 14). However, these studies included patients in the good prognostic
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Table 4
Estimates of patient survival from selected radiotherapy series Survival by prognosis group
Study Matsutani (5) 1963e1994 Sawamura (10) 1970e1995 Aoyama (7) 1971e1994 Ogawa (14) 1981e2001 Kim (present) 1982e2006
Treatment (%) OP þ CT þ RT (14.2) OP þ RT (77.6) OP þ CT (5.2) OP (100) RT (94.6) CT (32.4) OP (100) RT (92) CT (54) OP þ CT þ RT (63) OP þ RT (37) OP þ CT þ RT (59.4) CT þ RT (28.1) OP þ RT (9.4)
Patient number
Survival
Good (n Z 66) Intermediate (n Z 45) Poor (n Z 23) Good (n Z 66) Intermediate (n Z 30) Poor (n Z 15) Good (n Z 5) Intermediate (n Z 6) Poor (n Z 13) Good (n Z 3) Intermediate (n Z 24) Poor (n Z 14) Intermediate (n Z 14) Poor (n Z 18)
5-y OS 95%; 10-y OS 93% 5-y OS 74%; 10-y OS 65% 5-y OS 18%; 10-y OS n/a 5-y OS 96%; 10-y OS 91% 5-y OS 74%; 10-y OS 64% 5-y OS 38%; 10-y OS 25% 5-y RFS 100% 5-y RFS 63% 5-y RFS 44% 5-y OS 100% 5-y OS 68% 5-y OS 8% 10-y RFS 100%; OS 85% 10-y RFS 61%; OS 67%
Abbreviations: CT Z chemotherapy; n/a Z not available; OP Z operation; OS Z overall survival; RFS Z recurrence-free survival; RT Z radiotherapy.
subtypes and did not report surgical resection rates stratified by prognosis group. The current study included only intermediateand poor-prognosis group patients, and the maximal resection rate of 69% is relatively high compared with resection rates in other studies. Reduced tumor burden through surgical resection may have been another contributing factor to the improved survival in this study. Studies reporting functional outcome or quality of life among long-term survivors of intracranial germinoma who were treated with CSI of 25.6e36 Gy and a total tumor dose of 50.4 Gy in childhood and adolescence have shown remarkable preservation of functional status (19, 20). In the current study, de novo development of pituitary dysfunction after CSI and focal boost was relatively low. Only 3 patients developed hormone insufficiency after combined treatment, and they were 14, 8, and 6 years old at the time of treatment. A major limitation of the current study is that the patients had not been routinely followed with neurocognitive evaluation. Higher radiation dose to tumor and wider coverage of normal tissue from CSI may increase incidence of late complications such as secondary malignancies, hormone insufficiency, and deterioration of neurocognitive function among survivors. Further studies should evaluate the effect of radiation dose and field size on the incidence and degree of neurologic sequelae. This was a single institution study with a relatively large number of patients with high-risk NGGCTs. A multimodal approach was effective in treating NGGCTs, and CSI should be considered, especially for patients with a poor prognostic histology. A total radiation dose of 54 Gy or higher to the primary tumor site and maximum tumor resection may improve local control.
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2. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: Natural history and pathogenesis. J Neurosurg 1985;63: 155e167. 3. Ho DM, Liu HC. Primary intracranial germ cell tumor. Pathologic study of 51 patients. Cancer 1992;70:1577e1584. 4. Cho J, Choi J, Kim D, et al. Low-dose craniospinal irradiation as a definitive treatment for intracranial germinoma. Radiother Oncol 2009;91:75e79. 5. Matsutani M, Sano K, Takakura K, et al. Primary intracranial germ cell tumors: A clinical analysis of 153 histologically verified cases. J Neurosurg 1997;86:446e455. 6. Kun L, MacDonald S, Tarbell N. Supratentorial brain tumors. In: Halperin E, Constine L, Tarbell N, et al., editors. Pediatric Radiation Oncology. ed. 5. Philadelphia: Lippincott Williams & Wilkins; 2011. p. 26e52. 7. Aoyama H, Shirato H, Yoshida H, et al. Retrospective multiinstitutional study of radiotherapy for intracranial nongerminomatous germ cell tumors. Radiother Oncol 1998;49:55e59. 8. Schild SE, Haddock MG, Scheithauer BW, et al. Nongerminomatous germ cell tumors of the brain. Int J Radiat Oncol Biol Phys 1996;36: 557e563. 9. Robertson PL, DaRosso RC, Allen JC. Improved prognosis of intracranial non-germinoma germ cell tumors with multimodality therapy. J Neuro-oncol 1997;32:71e80. 10. Sawamura Y, Ikeda J, Shirato H, et al. Germ cell tumours of the central nervous system: Treatment consideration based on 111 cases and their long-term clinical outcomes. Eur J Cancer 1998;34: 104e110. 11. Haas Kogan DA, Missett BT, Wara WM, et al. Radiation therapy for intracranial germ cell tumors. Int J Radiat Oncol Biol Phys 2003;56: 511e518. 12. World Health Organization. Classification of tumours. Pathology and genetics of tumours of the central nervous system. Lyon, France: IARC Press; 2000. 13. Aoyama H, Shirato H, Ikeda J, et al. Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors. J Clin Oncol 2002;20:857e865. 14. Ogawa K, Toita T, Nakamura K, et al. Treatment and prognosis of patients with intracranial nongerminomatous malignant germ cell tumors: A multiinstitutional retrospective analysis of 41 patients. Cancer 2003;98:369e376.
Volume 84 Number 3 2012 15. Matsutani M. Combined chemotherapy and radiation therapy for CNS germ cell tumorsdthe Japanese experience. J Neuro-oncolo 2001;54: 311e316. 16. Allen JC. Controversies in the management of intracranial germ cell tumors. Neurol Clin 1991;9:441e452. 17. Aoyama H. Radiation therapy for intracranial germ cell tumors. Prog Neurol Surg 2009;23:10. 18. Calaminus G, Bamberg M, Harms D, et al. AFP/beta-HCG secreting CNS germ cell tumors: long-term outcome with respect to initial
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symptoms and primary tumor resection. Results of the cooperative trial MAKEI 89. Neuropediatrics 2005;36:71e77. 19. Sutton LN, Radcliffe J, Goldwein JW, et al. Quality of life of adult survivors of germinomas treated with craniospinal irradiation. Neurosurgery 1999;45:1292e1297. discussion 1297. 20. Merchant TE, Sherwood SH, Mulhern RK, et al. CNS germinoma: Disease control and long-term functional outcome for 12 children treated with craniospinal irradiation. Int J Radiat Oncol Biol Phys 2000;46:1171e1176.