Treatment and Prognosis of Patients with Intracranial Nongerminomatous Malignant Germ Cell Tumors

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1 369 Treatment and Prognosis of Patients with Intracranial Nongerminomatous Malignant Germ Cell Tumors A Multiinstitutional Retrospective Analysis of 41 Patients Kazuhiko Ogawa, M.D. 1 Takafumi Toita, M.D. 1 Katsumasa Nakamura, M.D. 2 Takashi Uno, M.D. 3 Hiroshi Onishi, M.D. 4 Jun Itami, M.D. 5 Naoto Shikama, M.D. 6 Naokatsu Saeki, M.D. 7 Yoshihiko Yoshii, M.D. 8 Sadayuki Murayama, M.D. 1 1 Department of Radiology, University of the Ryukyus, Okinawa, Japan. 2 Department of Radiology, Kyushu University, Fukuoka, Japan. 3 Department of Radiology, Chiba University, Chiba, Japan. 4 Department of Radiology, Yamanashi Medical College, Yamanashi, Japan. 5 Department of Radiology, International Medical Center of Japan, Tokyo, Japan. 6 Department of Radiology, Shinshu University, Nagano, Japan. 7 Department of Neurosurgery, Chiba University, Chiba, Japan. 8 Department of Neurosurgery, University of the Ryukyus, Okinawa, Japan. Address for reprints: Kazuhiko Ogawa, M.D., Department of Radiology, University of the Ryukyus School of Medicine, 207 Uehara, Nishihara-cho, Okinawa, , Japan; Fax: (011) ; kogawa@med.u-ryukyu.ac.jp Received December 30, 2002; revision received March 20, 2003; accepted April 2, BACKGROUND. The relative roles of surgical resection, radiotherapy, and chemotherapy in the management of patients with intracranial nongerminomatous malignant germ cell tumors have been controversial. The authors retrospectively investigated the results of different treatment regimens in patients with these tumors. METHODS. The records of 41 patients who were treated between 1981 and 2001 were reviewed. They were grouped into patients with a good prognosis (n 3), an intermediate prognosis (n 24), and a poor prognosis (n 14) based on the histology of their tumors. Fifteen patients (37%) underwent surgical resection and received radiotherapy, and 26 patients (63%) also received chemotherapy. The median follow-up of 18 patients who remained alive was 61 months (range, months). RESULTS. The 5-year actuarial overall survival rates for patients in the good prognosis, intermediate prognosis, and poor prognosis groups were 100%, 68%, and 8%, respectively. In the analysis, histology alone had a statistically significant impact on overall survival (P ). All 3 patients in the good prognosis group were treated successfully with surgical resection and radiotherapy. In the intermediate prognosis group, the 5-year actuarial overall survival rate was 44% for patients who underwent surgical resection and received radiotherapy (n 9) and 84% for patients who also received chemotherapy (n 15; P 0.01). Patients in the poor prognosis group who underwent surgical resection and received radiotherapy (n 3) or who underwent incomplete resection and received both radiotherapy and chemotherapy (n 8) all died of disease, whereas 2 of 3 patients who underwent macroscopic total resection and received both radiotherapy and chemotherapy survived free of disease. CONCLUSIONS. The treatment of patients with intracranial nongerminomatous malignant germ cell tumors should be based on tumor histology. For patients who had a good prognosis (mature teratoma with germinoma), surgical resection and radiotherapy were sufficient; however, for patients in the intermediate prognosis group, multimodal treatment, including surgical resection, radiotherapy, and chemotherapy, was effective. Conversely, for patients in the poor prognosis group, more intensive multimodal treatment, including macroscopic total resection, may improve the survival rate. Cancer 2003;98: American Cancer Society. KEYWORDS: brain neoplasms, germ cell tumor, germinomas, nongerminomatous, surgery, radiation therapy, chemotherapy. Primary intracranial germ cell tumors are uncommon malignancies in the central nervous system, making up less than 1% of all intracranial neoplasms. 1 3 They have a peak incidence in the second 2003 American Cancer Society DOI /cncr.11495

2 370 CANCER July 15, 2003 / Volume 98 / Number 2 TABLE 1 Characteristics of Intracranial Nongerminomatous Malignant Germ Cell Tumors in 41 Patients Histology No. of patients Patient age (yrs) Tumor location Median Range P S T or B P S M Teratoma Immature Malignant transformation Embryonal carcinoma Yolk sac tumor Choriocarcinoma Mixed tumor Mainly germinoma or teratoma a Mainly malignant elements Total P: pineal area; S: suprasellar area; T or B: thalamus or basal ganglia; M: multifocal areas. a Of these 14 patients, 3 had mature teratoma with germinoma. and third decade of life and usually arise in midline locations, predominantly in the pineal or suprasellar regions of the brain. Like their gonadal counterparts, they are histologically diverse, comprising several (mostly malignant) variants. Of the intracranial germ cell tumors, germinoma is the most common and is cured the most readily by radiotherapy, with 5-year disease free survival rates approaching 90% in modern series. 4 7 In contrast, intracranial nongerminomatous germ cell tumors are rare lesions and are distinguished as a separate entity because of their relatively poor response to radiotherapy. 1,2,8 Using the World Health Organization (WHO) classification system, 9 these tumors were classified into four basic types (teratomas, yolk sac tumors, choriocarcinomas, and embryonal carcinomas) or were classified as mixed tumors (mixed germ cell tumor) if they were made up of two or more components. Teratomas were divided into three subtypes according to the degree of differentiation of the tumor cells: mature teratomas, immature teratomas, and teratoma with malignant transformation. The poor treatment results in patients with these tumors, except mature teratoma, have been attributed to a high recurrence rate after surgical resection and conventional radiotherapy. The use of chemotherapy for the treatment of patients with nongerminomatous germ cell tumors has been suggested, because it has been effective in the treatment of patients with testicular nongerminomatous germ cell tumors, although there has been no clear consensus regarding the optimal management of chemotherapy for these tumors. 4,10 Nongerminomatous germ cell tumors often are regarded as a single category because of their rarity; however, different patterns of recurrence and survival have been reported among different subtypes Therefore, the relative roles of surgical resection, radiotherapy, and chemotherapy in the management of patients with such lesions have remained controversial. 7 In the current study, we reviewed a retrospective, multiinstitutional series of 41 patients with histologically proven nongerminomatous malignant germ cell tumors and investigated the optimal management for patients with each histologic subtype of this rare disease. MATERIALS AND METHODS Patient Characteristics A retrospective review of medical records from 1980 to 2001 identified 41 patients with documented, histologically confirmed intracranial nongerminomatous malignant germ cell tumors who were treated with radiotherapy with or without chemotherapy in the Departments of Radiology at the University of the Ryukyus Hospital, Kyushu University Hospital, Chiba University Hospital, Yamanashi Medical College Hospital, Shinshu University Hospital, and International Medical Center of Japan. The patients ranged in age from 5 years to 52 years (median, 14 years). Thirty-six patients were male, and 5 patients were female. According to the WHO classification system, 9 5 patients had immature teratomas, 8 patients had teratomas with malignant transformation, 4 patients had embryonal carcinoma, 1 patient had a yolk sac tumor, 2 patients had choriocarcinoma, and the remaining 21 patients had mixed germ cell tumors with various components (Tables 1, 2). Eight of 41 patients had immature teratomas or immature teratomas/mainly

3 Nongerminomatous Germ Cell Tumors/Ogawa et al. 371 TABLE 2 Histologic Components of Mixed Tumors in 21 Patients Histology No. of patients Germinoma or teratoma Main component Germinoma teratoma a 6 6 b Germinoma embryonal carcinoma Germinoma yolk sac tumor Germinoma choriocarcinoma Germinoma teratoma a yolk sac tumor Teratoma a embryonal carcinoma Teratoma a yolk sac tumor Teratoma a choriocarcinoma Teratoma a yolk sac tumor choriocarcinoma Total Malignant germ cell tumor a Immature teratoma components were found in 9 of 16 patients with teratoma components. b Of these six patients, three had mature teratoma with germinoma. TABLE 3 Therapeutic Classification of Intracranial Germ Cell Tumors a Good prognosis group Germinoma, pure Mature teratoma Intermediate prognosis group Germinoma with syncytiotrophoblastic giant cells Immature teratoma Teratoma with malignant transformation Mixed tumors mainly composed of germinoma or teratoma Poor prognosis group Choriocarcinoma Yolk sac tumor Embryonal carcinoma Mixed tumors mainly composed of choriocarcinoma, yolk sac tumor, or embryonal carcinoma a Classification proposed by 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: mixed tumors (median age, 12.5 years; range, 9 34 years). According to the histologic grading system of Gonzalez-Crussi, 14 2 immature teratomas were Grade 2 lesions (immature tissues made up between 10% and 50% of the sampled tumor cut surface), and the remaining 6 immature teratomas were Grade 3 lesions ( 50% of the surface examined was composed of incompletely differentiated tissues of uncertain metastatic potential). Cerebrospinal fluid cytology was examined in 18 patients before treatment, and 1 patient was identified as having tumor cells in the cerebrospinal fluid. No patients were considered to have apparent spinal metastases at the time of initial diagnosis. Levels of the tumor markers serum -fetoprotein (AFP) and serum human chorionic gonadotropin (HCG), with or without serum -HCG, were measured prior to therapy in 35 of 41 patients. Markers were elevated in 25 of 35 patients (serum HCG: range, miu (International Units)/mL; serum -HCG: range, miu/ml; serum AFP: range, miu/ml). HCG alone was elevated in 10 patients, AFP alone was elevated in 9 patients, and both AFP and HCG were elevated in 6 patients. All 41 patients were diagnosed initially using computed tomography (CT) scans of the brain or, more recently, a combination of CT and magnetic resonance imaging (MRI) scans of the brain. We divided the patients into three groups according to the histologic components of their tumors, as proposed by Matsutani et al. 4 Table 3 shows the tumor types that fell into the different prognostic classifications. In the current study, we assumed that mature teratoma with germinoma implied a good prognosis. According to this classification system, there were 3 patients in the good prognosis group, 24 patients in the intermediate prognosis group, and 14 patients in the poor prognosis group. Treatments Fifteen patients (37%) underwent surgical resection and received radiotherapy, and the remaining 26 patients underwent surgical resection and received both radiotherapy and chemotherapy. Fifteen patients underwent macroscopic total resection, 21 patients underwent subtotal resection, and the remaining 5 patients underwent biopsy only. Radiotherapy was administered with a 60 Co teletherapy unit or with a 4-MV, 6 MV, or 10 MV linear accelerator; daily fractions of Grays (Gy) 5 days per week were used most often. Nine patients received localized field radiotherapy, and 3 patients received whole-ventricle radiotherapy. Two patients received whole-brain radiotherapy (WBRT), and 19 patients received WBRT followed by a local boost: The remaining 8 patients received craniospinal irradiation with a local boost. The total dose to the primary site ranged from 10 Gy to 60 Gy (median, 50 Gy). Whole-brain doses ranged from 19.5 Gy to 35.2 Gy (median, 30 Gy), and whole-ventricle doses ranged from 18 Gy to 24 Gy (median, 24 Gy). The doses to the whole spine ranged from 19.5 Gy and 35.2 Gy (median, 30 Gy). Twenty-seven patients (66%) received systemic chemotherapy with a total of 3 6 courses (median, 4 courses) before and/or after radiotherapy. All patients received cisplatin or carboplatin in combination with other agents. The most commonly used regimen was a

4 372 CANCER July 15, 2003 / Volume 98 / Number 2 TABLE 4 Recurrence Patterns Histology Total no. of patients Site of first recurrence (%) Intracranial Spinal Good prognosis group 3 0 (0) 0 Intermediate prognosis group 24 9 (38) 2 (8) Poor prognosis group 14 9 (64) 3 (21) Total (44) 5 (12) combination of cisplatin and etoposide (PE; 16 patients), and the next most common was a combination of carboplatin and etoposide (CARB-VP; 6 patients). The remaining five patients received cisplatin, vinblastine, and bleomycin (PVB) combination therapy. Cycles usually were repeated every 3 4 weeks. PE therapy consisted of cisplatin (20 mg/m 2 ) and etoposide (60 mg/m 2 ) for 5 consecutive days (Days 1 5). 15 In the CARB-VP therapy, carboplatin (450 mg/m 2 ) was given on Day 1 and etoposide (150 mg/m 2 ) was given for 3 consecutive days (Days 1 3). 16 The PVB regimen consisted of cisplatin (20 mg/m 2 ) for 5 consecutive days (Days 1 5), vinblastine (4 6 mg/m 2 ) on Days 1 and 8, and bleomycin (10 15 mg/m 2 ) on Days 1, 8, and Statistical Analysis The median follow-up for the 18 living patients was 61 months (range, months), and no patient was lost to follow-up. Overall survival and intracranial control rates were calculated actuarially according to the Kaplan Meier method 18 and were measured from the day of surgery. Differences between groups were estimated using the log rank test. 19 A probability level of 0.05 was chosen for statistical significance. Statistical analysis was performed with the SPSS software package (Version 6.1; SPSS Inc., Chicago, IL). RESULTS Recurrence Patterns The incidence and site of first recurrence in the different prognosis groups are indicated in Table 4. There were no recurrences in any of the three patients in the good prognosis group. Eleven of 24 patients (46%) in the intermediate prognosis group and 12 of 14 patients (86%) in the poor prognosis group developed recurrent disease. The tumors most commonly recurred intracranially. Among 24 patients in the intermediate prognosis group, the 5-year intracranial control rate was 83% for patients who underwent surgical resection and received both radiotherapy and chemotherapy (median total radiation dose, 50 Gy; range, Gy) but only 36% for patients who underwent surgical resection and received radiotherapy, but not chemotherapy (median total radiation dose, 50 Gy; range, Gy). Among 14 patients in the poor prognosis group, the 5-year intracranial control rate was 18% for patients who underwent surgical resection and received both radiotherapy and chemotherapy (median total radiation dose, 50 Gy; range, Gy); whereas all patients who underwent surgical resection and received radiotherapy but not chemotherapy (median total radiation dose, 50 Gy; range, Gy) experienced intracranial recurrence. Spinal recurrence was observed in two patients in the intermediate prognosis group (teratoma with malignant transformation and mixed tumor of teratoma with malignant transformation and yolk sac tumor) and in three patients in the poor prognosis group (yolk sac tumor, embryonal carcinoma, and mixed tumor of embryonal carcinoma with mature teratoma). Of the 33 patients who did not receive prophylactic spinal irradiation, 5 patients (15%) developed spinal recurrences; whereas 8 patients who received spinal irradiation experienced no spinal recurrences (2 patients in the good prognosis group, 4 patients in the intermediate prognosis group, and 2 patients in the poor prognosis group). Survival Twenty-three of 41 patients (56%) died during the period of the current analysis. The 5-year and 10-year actuarial overall survival rates for all patients were 50% and 34%, respectively. The 5-year actuarial overall survival rate was 100% for patients in the good prognosis group, 68% for patients in the intermediate prognosis group, and 8% for patients in the poor prognosis group (Fig. 1). In a univariate analysis, histology alone had a statistically significant impact on overall survival (P ). No significant differences in survival were seen with respect to other factors (Table 5). Treatment Modality and Survival According to Histology To determine the optimal management for patients with each type of tumor histology, treatment modality and survival were analyzed for each group according to histology. In the good prognosis group, 3 patients underwent surgical resection (macroscopic total resection in 2 patients and subtotal resection in 1 patient) and WBRT or craniospinal radiotherapy with a local boost (total dose, Gy to the primary tumor site). Those three patients did not receive chemother-

5 Nongerminomatous Germ Cell Tumors/Ogawa et al. 373 TABLE 5 Univariate Analysis of Various Potential Prognostic Factors for Survival in Patients with Nongerminomatous Malignant Germ Cell Tumors Variable No. of patients 5 yr OS rate (%) P value FIGURE 1. Actuarial overall survival rates, according to histologic diagnosis, in patients with intracranial nongerminomatous malignant germ cell tumors. apy during the initial treatment, and they remained alive and free of disease at the end of the study period. Among 24 patients in the intermediate prognosis group, there was no significant difference in survival (P 0.54) between patients who were treated with a primary total dose 50 Gy (5-year survival rate, 65%) and patients who were treated with a primary total dose 50 Gy (5-year survival rate, 63%). There also was no significant difference in survival (P 0.11) between patients who underwent macroscopic total resection (5-year survival rate, 78%) and patients who underwent partial resection or biopsy (5-year survival rate, 53%). Conversely, the 5-year actuarial overall survival rates in patients who received chemotherapy and patients who did not receive chemotherapy were 84% and 44%, respectively (Fig. 2). There was a statistically significant difference in the overall survival rate between the 2 groups (P 0.01). Among 14 patients in the poor prognosis group, 3 patients who underwent surgical resection and received radiotherapy, and 8 patients who underwent incomplete resection (partial resection or biopsy) and received both radiotherapy and chemotherapy died of disease. In contrast, 2 of 3 patients who underwent macroscopic total resection and received both radiotherapy and chemotherapy survived free of disease (follow-up: 62 months for 1 patient with embryonal carcinoma and 14 months for 1 patient with a mixed tumor comprised of choriocarcinoma with germinoma. DISCUSSION In the current study, histology alone had a significant impact on survival for patients with intracranial nongerminomatous malignant germ cell tumors. Several reports also have indicated that histology is the most important prognostic factor for patients with these Age (yrs) Gender Male Female KPS (%) Histology a Good prognosis Intermediate prognosis Poor prognosis Tumor size (cm) No. of tumors Single Multiple Macroscopic total resection Yes No Total dose of RT (Gy) Spinal RT Yes 8 67 No Use of chemotherapy Yes No OS: overall survival; KPS: Karnofsky performance status; RT: radiotherapy; Gy: grays. a Good prognosis: mature teratoma with germinoma; Intermediate prognosis: immature teratoma, teratoma with malingnant transformation, or mixed tumors mainly composed of teratoma or germinoma; poor prognosis: choriocarcinoma; yolk sac tumor, embryonal carcinoma, or mixed tumors mainly composed of these tumor types. tumors and that treatment recommendations should be based on the assessment of the histologic type. 1,3,4,13,15,20 25 In patients with a good prognosis, excellent results have been obtained by treating mature teratoma with surgical resection and by treating germinoma with radiotherapy. 4,26,27 Aoyama et al. indicated that the 5-year survival rate was 100% for 5 patients with mature teratoma with or without germinoma. 27 In the current study, favorable results also were observed in three patients who had mature teratoma with germinoma (good prognosis group) who underwent surgical resection and received radiotherapy. These results indicate that surgical resection and radiotherapy are sufficient to control mature teratoma with germinoma.

6 374 CANCER July 15, 2003 / Volume 98 / Number 2 FIGURE 2. Actuarial overall survival rates, according to the administration of chemotherapy, in patients with intracranial nongerminomatous malignant germ cell tumors in the intermediate prognosis group. In the current study, patients in the intermediate prognosis group had a 5-year survival rate of 68%, which is comparable to the 60 70% rate reported previously. 4,23,26 Several recent reports have suggested that chemotherapy may improve the overall duration and rate of survival when used in conjunction with radiotherapy as a part of the initial treatment, 22,28 and cisplatin/carboplatin-based chemotherapy has been proven effective for the treatment of patients with intracranial germ cell tumors as well as gonadal germ cell tumors. 8,11,22,29 32 Matsutani et al. reported that the 5-year survival rates for patients with an intermediate prognosis were 62% for patients who did not received additional chemotherapy and 92.9% for patients who received additional chemotherapy (P 0.049). 33 In the current study, the 5-year overall survival rates for patients in the intermediate prognosis group were 84% for patients who underwent surgical resection and received both radiotherapy and additional chemotherapy and 44% for patients who did not receive additional chemotherapy. There was a statistically significant difference in overall survival rates between the 2 groups (P 0.01). Several other authors have reported that combined surgical resection and radiotherapy, together with chemotherapy, leads to favorable outcomes. 25,32 Although the optimal management of radiotherapy remains unclear for patients with tumors in the intermediate prognosis group, several authors have recommended a total dose 50 Gy to the primary tumor site for these patients. 2,24,25,27,34 In the current study, among the 15 patients who underwent surgical resection and received both radiotherapy and chemotherapy, the 5-year intracranial control rate was 83%, with a median total dose of 50 Gy. A total dose of 50 Gy appears to be appropriate for patients with an intermediate prognosis when they undergo surgical resection and receive both radiotherapy and chemotherapy. Several authors have advocated the use of prophylactic spinal irradiation in the treatment of patients with nongerminomatous germ cell tumors. 4,13,27,30 Schild et al. showed that patients who had a component of teratoma with malignant transformation had a significantly increased risk of spinal failure compared with patients who had other nongerminomatous germ cell tumors. 13 Matsutani et al. observed a 21.7% rate (5 of 23 patients) of spinal recurrence in patients with a poor prognosis who were treated primarily by WBRT without prophylactic spinal irradiation. 4 In the current study, 5 of 33 patients (15%; 2 patients in the intermediate prognosis group and 3 patients in the poor prognosis group) who did not receive prophylactic spinal irradiation experienced spinal recurrence, whereas 8 patients who received prophylactic spinal irradiation had no spinal recurrence. Six of those eight patients had tumors that indicated an intermediate or poor prognosis. These results suggest that prophylactic spinal irradiation may prevent spinal recurrence in patients who have an intermediate or poor prognosis. Although chemotherapy regimens consisting of cisplatin or carboplatin combinations were effective in patients in the intermediate prognosis group, they have not been effective in patients with tumors that indicate a poor prognosis. 16,33 Even with multimodal treatments that include surgical resection, radiotherapy, and chemotherapy, patients with an initially poor prognosis do not fare well. In the current study, the 5-year actuarial survival rate of patients in the poor prognosis group was only 8%, and all 8 patients who underwent incomplete resection and received both radiotherapy and chemotherapy died of their disease. In contrast, 2 of 3 patients who underwent macroscopic total resection and received both radiotherapy and chemotherapy survived free of disease at a followup of 14 months and 62 months, respectively. Several reports also have suggested that macroscopic total resection may have a role in the management of patients with these tumors. 4,13,32,35 37 Schild et al. indicated that patients who underwent subtotal resections or biopsies had significantly poorer survival rates compared with patients who underwent complete resection of their tumors. 13 The 3-year survival rate was 0% for patients who underwent biopsy alone and 32% for patients who underwent subtotal resection, compared with 73% for patients who underwent macroscopic total resection (P ). Ushio et al. indicated that adjuvant therapy, consisting of combination chemotherapy with cisplatin and etoposide and concurrent radiotherapy, followed by macroscopic total tumor resection, was highly effective in

7 Nongerminomatous Germ Cell Tumors/Ogawa et al. 375 the treatment of five patients with yolk sac tumors, embryonal carcinoma, or mixed germ cell tumors containing yolk sac tumor components. 38 All 5 of these patients survived free of disease for months (average survival, 88 months). Recent technologic advances in surgery and perioperative care have greatly improved the safety of a surgical approach to the treatment of patients with pineal or suprasellar tumors and have made a more radical resection feasible for many patients. 3,36,39 More intensive multimodal treatment, such as combined macroscopic total resection, radiotherapy, and chemotherapy, may improve the survival rate for patients with a poor prognosis. Further prospective studies with greater numbers of patients will be necessary to validate this treatment modality. REFERENCES 1. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg. 1985; 63: Kersh CR, Constable WC, Eisert DR, et al. Primary central nervous system germ cell tumors. Effect of histologic confirmation on radiotherapy. Cancer. 1988;61: Hoffman HJ, Otsubo H, Hendrick EB, et al. Intracranial germ-cell tumors in children. J Neurosurg. 1991;74: 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: Shirato H, Nishio M, Sawamura Y, et al. Analysis of longterm treatment of intracranial germinoma. Int J Radiat Oncol Biol Phys. 1997;37: Linstadt D, Wara WM, Edwards MS, Hudgins RJ, Sheline GE. Radiotherapy of primary intracranial germinomas: the case against routine craniospinal irradiation. Int J Radiat Oncol Biol Phys. 1998;15: Packer RJ, Cohen RH, Cooney K. Intracranial germ cell tumors. Oncologist. 2000;5: Patel SR, Buckner JC, Smithson WA, Scheithauer BW, Groover RV. Cisplatin-based chemotherapy in primary central nervous system germ cell tumors. J Neurooncol. 1992; 12: World Health Organization. Classification of tumours. Pathology and genetics of tumours of the central nervous system. Lyon: IARC Press, Brandes AA, Pasetto LM, Monfardini S. The treatment of cranial germ cell tumours. Cancer Treat Rev. 2000;26: Balmaceda C, Heller G, Rosenblum M, et al. Chemotherapy without irradiation a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. The First International Central Nervous System Germ Cell Tumor Study. J Clin Oncol. 1996;14: Edwards MS, Hudgins RJ, Wilson CB, Levin VA, Wara WM. Pineal region tumors in children. J Neurosurg. 1988;68: Schild SE, Haddock MG, Scheithauer BW, et al. Nongerminomatous germ cell tumors of the brain. Int J Radiat Oncol Biol Phys. 1996;36: Gonzalez-Crussi F. Extragonadal teratomas. Atlas of tumor pathology. Second series, fascicle 18. Washington, DC: Armed Forces Institute of Pathology, Yoshida J, Sugita K, Kobayashi T, et al. Prognosis of intracranial germ cell tumours: effectiveness of chemotherapy with cisplatin and etoposide (CDDP and VP-16). Acta Neurochir (Wien). 1993;120: Matsutani M, Sano K, Takakura K, Fujimaki T, Nakamura O. Combined treatment with chemotherapy and radiation therapy for intracranial germ cell tumors. Childs Nerv Syst. 1998;14: Matsukado Y, Abe H, Tanaka R, et al. [Cisplatin, vinblastine and bleomycin (PVB) combination chemotherapy in the treatment of intracranial malignant germ cell tumors a preliminary report of a Phase II study the Japanese Intracranial Germ Cell Tumor Study Group]. Gan No Rinsho. 1986;32: Japanese. 18. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53: Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;50: Dearnaley DP, A Hern RP, Whittaker S, Bloom HJ. Pineal and CNS germ cell tumors: Royal Marsden Hospital experience Int J Radiat Oncol Biol Phys. 1990;18: Fuller BG, Kapp DS, Cox R. Radiation therapy of pineal region tumors: 25 new cases and a review of 208 previously reported cases. Int J Radiat Oncol Biol Phys. 1994;28: Aoyama H, Shirato H, Ikeda J, Fujieda K, Miyasaka K, Sawamura Y. Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors. J Clin Oncol. 2002;20: Sawamura Y, Ikeda J, Shirato H, Tada M, Abe H. 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: Wolden SL, Wara WM, Larson DA, Prados MD, Edwards MB, Sneed PK. Radiation therapy for primary intracranial germcell tumors. Int J Radiat Oncol Biol Phys. 1995;32: Schild SE, Scheithauer BW, Haddock MG, et al. Histologically confirmed pineal tumors and other germ cell tumors of the brain. Cancer. 1996;78: Sano K. So-called intracranial germ cell tumours: are they really of germ cell origin? Br J Neurosurg. 1995;9: Aoyama H, Shirato H, Yoshida H, et al. Retrospective multiinstitutional study of radiotherapy for intracranial non-germinomatous germ cell tumors. Radiother Oncol. 1998;49: Jaing TH, Wang HS, Hung IJ, et al. Intracranial germ cell tumors: a retrospective study of 44 children. Pediatr Neurol. 2002;26: Beyer J, Kingreen D, Krause M, et al. Long term survival of patients with recurrent or refractory germ cell tumors after high dose chemotherapy. Cancer. 1997;79: Buckner JC, Peethambaram PP, Smithson WA, et al. Phase II trial of chemotherapy followed by reduced-dose radiation for CNS germ cell tumors. J Clin Oncol. 1999;17: Allen JC, Kim JH, Packer RJ. Neoadjuvant chemotherapy for newly-diagnosed germ-cell tumors of the central nervous system. J Neurosurg. 1987;67: Robertson PL, DaRosso RC, Allen JC. Improved prognosis of intracranial non-germinoma germ cell tumors with multimodality therapy. J Neurooncol. 1997;32:71 80.

8 376 CANCER July 15, 2003 / Volume 98 / Number Matsutani M. Combined chemotherapy and radiation therapy for CNS germ cell tumors the Japanese experience. J Neurooncol. 2001;54: Baranzelli MC, Patte C, Bouffet E, et al. An attempt to treat pediatric intracranial FP and HCG secreting germ cell tumors with chemotherapy alone. SFOP experience with 18 cases. J Neurooncol. 1998;37: Weiner HL, Finlay JL. Surgery in the management of primary intracranial germ cell tumors. Childs Nerv Syst. 1999;15: Nam DH, Cho BK, Shin HJ, Ahn HS, Kim IH, Wang KC. Treatment of intracranial nongerminomatous malignant germ cell tumor in children: the role of each treatment modality. Childs Nerv Syst. 1999;15: Herrmann HD, Westphal M, Winkler K, Laas RW, Schulte FJ. Treatment of nongerminomatous germ-cell tumors of the pineal region. Neurosurgery. 1994;34: Ushio Y, Kochi M, Kuratsu JI, Itoyama Y, Marubayashi T. Preliminary observations for a new treatment in children with primary intracranial yolk sac tumor or embryonal carcinoma. J Neurosurg. 1999;90: Allen JC. Controversies in the management of intracranial germ cell tumors. Neurol Clin. 1991;9: