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Improvement of Long-term Results with Neoadjuvant Chemotherapy and Radiotherapy for Central Nervous System Germinoma
Accepted Manuscript Improvement of Long-term Results with Neoadjuvant Chemotherapy and Radiotherapy for Central Nervous System Germinoma Shingo Takano, Tetsuya Yamamoto, Eiichi Ishikawa, Hiroyoshi Akutsu, Kei Nakai, Masahide Matsuda, Ai Muroi, Yasushi Shibata, Masashi Mizumoto, Koji Tsuboi, Akira Matsumura PII:
S1878-8750(15)00777-9
DOI:
10.1016/j.wneu.2015.06.029
Reference:
WNEU 2981
To appear in:
World Neurosurgery
Received Date: 12 May 2015 Revised Date:
13 June 2015
Accepted Date: 15 June 2015
Please cite this article as: Takano S, Yamamoto T, Ishikawa E, Akutsu H, Nakai K, Matsuda M, Muroi A, Shibata Y, Mizumoto M, Tsuboi K, Matsumura A, Improvement of Long-term Results with Neoadjuvant Chemotherapy and Radiotherapy for Central Nervous System Germinoma, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.06.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Improvement of Long-term Results with Neoadjuvant Chemotherapy and Radiotherapy for Central Nervous System Germinoma
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Shingo Takano1, Tetsuya Yamamoto1, Eiichi Ishikawa1, Hiroyoshi Akutsu1, Kei Nakai1, Masahide Matsuda1, Ai Muroi1, Yasushi Shibata1, Masashi Mizumoto2, Koji Tsuboi2, Akira Matsumura1
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Keywords Chemoradiotherapy, Germinoma, Neuroendoscopy
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Department of Neurosurgery, Faculty of Medicine and 2Proton Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
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Abbreviations: HCG: human chorionic gonadotropin KPS: Karnofsky performance status MRI: magnetic resonance imaging
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Corresponding author: Shingo Takano, MD, PhD 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan E-mail: [email protected] FAX: +81-29-853-3214 Tel: +81-29-853-3220
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Abstract OBJECTIVE: To evaluate the role of neoadjuvant chemotherapy and radiotherapy in the treatment of central nervous system germinomas in 38 patients who received definitive treatment and were followed-up >5 years between 1980–2009. METHODS: The median age at diagnosis and follow-up period were 16.5 years and 128.3 months, respectively. Treatment was irradiation alone or adjuvant platinum-based chemotherapy followed by reduced-dose local irradiation. Seven patients progressed at 12.9–133.9 months and 1 died of disease 89.3 months after therapy initiation. RESULTS: The treatment strategies were divided into three groups: Group A (1980– 1988, n=5): whole brain with local irradiation; Group B (1989–2002, n=16): chemotherapy with or without reduced irradiation dose; and Group C (2003–2009, n=17): neoadjuvant chemotherapy (3 courses) followed by 30.6-Gy whole ventricle irradiation for patients with localized complete response, and additional local boost of 19.8-Gy for others. There were 7 recurrent cases, all in Group B. The progression-free survival was significantly longer in Groups A and C vs. Group B (p<0.001). Decreased Karnofsky performance status was observed in 2 (40%), 6 (37.5%), and 0 cases in Groups A–C, respectively. The main reasons for the good results in Group C might be the neoadjuvant chemotherapy with whole ventricle radiotherapy and introduction of neuroendoscopy, especially for pineal lesions, resulting in a substantial reduction of time from the diagnosis to 1st treatment. CONCLUSIONS: Chemotherapy followed by whole ventricle radiotherapy, with or without local boost, and with use of neuroendoscopy results in good disease-control without late complications in germinoma patients.
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Keywords Chemoradiotherapy, Germinoma, Neuroendoscopy
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INTRODUCTION Germinomas are generally curable using only radiation therapy, with reported 10-year overall survival rates >90% (10, 18). The radiation dose and field are considered important to prevent recurrence and radiation injuries such as cognitive dysfunction. Therefore, several trials of chemotherapy regimens without radiation therapy have been performed; however, the long-term outcomes have indicated unacceptable rates of recurrence (3, 8, 9, 17). In contrast, chemotherapy combined with reduced-dose radiation therapy has produced promising results for the control of germinoma (2, 10), although progression was observed even with this combined therapy, with reported recurrence rates between 6.3–20.8% (2, 4, 6, 7, 11, 16, 19). The present study retrospectively analyzed the long-term outcomes of 38 consecutive patients to verify the optimal treatment strategy for patients with newly diagnosed central nervous system germinomas.
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MATERIALS and METHODS Patients Characteristics A retrospective review of medical records at our department from 1980 to 2009 identified 38 patients with central nervous system germinoma. Of these 38 patients, 29 (76.3%) were men and 9 were women, with an age range from 7 to 38 years (median, 16.5 years). The clinical diagnosis of germinoma was based on the typical age, magnetic resonance imaging (MRI), and serum and/or cerebrospinal fluid analysis of the levels of alpha-fetoprotein, human chorionic gonadotropin (HCG), and β-HCG. The histological diagnosis was established from specimens obtained by endoscopic biopsy procedures or resection via craniotomy or the transsphenoidal approach, according to the World Health Organization classification of tumors of the nervous system. A flexible fiberscope Neu-4L (Machida, Japan) and videoscope (VEF type V; Olympus, Tokyo) were used for neuroendoscopic biopsy and third ventriculostomy (14, 15). We explained the treatment strategies about the disease to all patients involved in this study and treated them. Germinoma Treatment Protocol Patients with pure germinomas and germinomas with syncytiotrophoblastic giant cells were classified with histology, serum markers, and typical MRI. The clinical diagnosis was based on a slightly elevated level of HCG (<50 IU/L) or β-HCG (<5 ng/ml), without elevated levels of alpha-fetoprotein. The patients were divided into three groups according to the period of treatment. The treatment protocol for patients with
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germinomas treated between 1980 and 1989 (Group A) consisted of 30.6 Gy to the whole brain, without histological verification, followed by additional radiation therapy of 19.8 Gy to the primary site. The treatment protocol between 1990 and 2003 (Group B) consisted of introduction of chemotherapy with reduced-field radiation using cisplatin (20 mg/m2) and etoposide (100 mg/m2) on days 1–5 (PE regimen in 11 cases); or bleomycin (20 mg/m2 on days 1, 7, and 14) and vincristine and cisplatin (20 mg/ m2 on days 1–5; PVB regimen in 3 cases); or Ifosfamide 900 mg/m2, cisplatin 20 mg/m2 and etoposide 60 mg/m2 on days 1-5: ICE regimen in 1 case); or none in 1 case. In this period, radiation therapy was omitted in two cases and delivered to the local (30.6 Gy) or extended local (24–30.6 Gy) field in others. The treatment protocol from 2003 until 2009 (Group C) consisted of 3 cycles of the PE regimen or carboplatin (150 mg/m2) and etoposide (150 mg/m2) on days 1–3 (CARE regimen) followed by reduced-dose field radiation therapy (whole ventricle [30.6 Gy] and local boast [19.8 Gy]), with residual enhancement at the completion of two cycles of chemotherapy. Patients with ventricular dissemination or basal ganglia germinoma received an additional 24 Gy to the whole brain. Patient and treatment characteristics in each group are demonstrated in Table 1.
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Follow-Up and Statistical Analysis Differences between the patients and treatment characteristics of each group were examined using the Fischer exact or Student’s t-test. The patients were usually followed-up every 6 months until 5 years after the initial treatment, and every 6–12 months thereafter. The progression-free and overall survival rates were defined as the time (months) to tumor progression or death from any cause and time (months) to death from any cause or the last follow-up, respectively. The progression-free and overall survival rates were calculated using the Kaplan-Meier method. The prognostic factors were evaluated using the log-rank test. RESULTS Long-Term Outcomes of Germinoma The treatment course and characteristics of all patients are demonstrated in Figure 1A and Table 2. Thirty-seven of the 38 patients remained alive during the follow-up period, which ranged from 60 to 384 months (median, 128.3 months). One patient in Group B died of progressive disseminated disease at 89.2 months (case 8). The treatment modalities used in this study were resection or biopsy in 32 patients and chemotherapy
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and radiation therapy in all 38 patients. Salvage surgery was not used in any patient. To determine the optimal treatment for germinoma, the 38 patients were divided into 3 groups as described in the Materials and Methods section (Group A: n=5, Group B: n=16, Group C: n=17). The 5-, 10-, 15-, and 20-year overall survival rates in all germinoma patients were 100%, 95.5%, 90.9%, and 75.0%, respectively (Table 2). There were no significant differences in the overall survival rates between the treatment modalities (Fig. 2A). Tumor recurrence developed in 7 patients during the follow-up period, all of whom belonged to Group B. The 5-, 10-, 15-, and 20-year progression-free survival rates were 92.1%, 73.9%, 50.0%, and 36.4%, respectively (Table 1), and all recurrences developed between 12.9 and 133.9 months (median, 63.5 months) after starting the initial therapy (Fig. 1A). The sites of recurrence were the extra-radiation field in 4 patients as dissemination (cases 8, 9, 15, 18) (Figs. 3–5), disseminated disease in 2 chemotherapy alone cases (cases 10, 11), and radiation in-field in 1 patient (case 18) (Fig. 6). There were statistically significant differences in the progression-free survival rates between the treatment modalities (p<0.001; log rank test, Fig. 2B).
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Late Complication Due to the Disease or Treatment As mentioned above, there were 7 cases of recurrence, all of which occurred in Group B. Six of these patients survived with additional treatment (radiation plus chemotherapy), whereas one patient died at 89.2 months due to progressive disease. Four of these patients showed reduced Karnofsky performance status (KPS) during the disease course, owing to mild cognitive dysfunction due to ventricular dissemination at 133.9 months (Fig. 6, case 17) followed by additional whole brain irradiation (KPS 70 at 188.7 months), bladder bowel disturbance and paraparesis due to spinal dissemination at 69.3 months (Fig. 4, case 15; KPS 70 at 202.7 months), paraparesis due to primary lesion (case 9; KPS 70 at 99.5 months), and dysarthria due to symptomatic brainstem cavernoma at 103.6 months (case 10; KPS 70 at 239.1 months). Independent of the disease recurrence, three additional patients showed reduced KPS, resulting from systemic complications of lung fibrosis (case 5, Group A; KPS 50 at 348.6 months), mild cognitive dysfunction due to disease or radiation treatment (case 4, Group A; KPS 70 at 291.2 months), and mild cognitive dysfunction due to postoperative hemorrhagic complication (case 21, Group B; KPS 70 at 144.8 months). There were 4 cases with co-incidental or radiation-induced intracranial disease, including a ruptured distal anterior communication artery aneurysm and suspected radiation-induced aneurysm at 93 months in Group B (case 20), which was successfully treated by aneurysmal neck clipping; moyamoya disease at the diagnosis of germinoma
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in Group C (case 33), which was successfully treated by superficial temporal artery-middle cerebral artery bypass; and two patients with asymptomatic cavernoma at 33.9 and 82.6 months in Group C (cases 30, 38). These 4 patients maintained a KPS of 100% at the last follow-up. At the last follow-up, 2 of 5 (40%), 6 of 16 (37.5%), and 0 of 17 (0%) patients in Groups A, B, and C, respectively had a KPS <70 (p<0.05, Fig 1B).
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Usefulness of the Neuroendoscopic Procedure for Germinoma The use of neuroendoscopy was introduced into our diagnosis and treatment strategies for germinomas in 2003 (Group C). The treatment of hydrocephalus associated with germinomas was dramatically different between the groups (Table 2). A ventriculoperitoneal shunt was required in 60% and 25% of cases in Groups A and B, respectively, but in none in Group C. By contrast, endoscopic third ventriculoscopy was required in 52.9% of patients in Group C. Histology was obtained in none of the 5 cases in Group A and in 14 of 16 cases in Group B, including by the transcranial approach in 11 and transsphenoidal approach in 3 cases. On the other hand, histology was obtained in all 17 cases in Group C. Nine of 10 pineal lesion tumors in Group C were obtained by neuroendoscopy without any complications. Neuroendoscopy can permit a precise histological diagnosis of intracranial germinomas and is safe and effective in the management of hydrocephalus associated with these tumors. Next, the time course of the treatment for pineal lesion tumors in each group (Group A: n=3, Group B: n=5, Group C: n=9) was evaluated. The time from diagnosis to the beginning of the first treatment (chemotherapy or radiotherapy) and the time from diagnosis to the end of the first treatment were calculated in each case (Figure 7). The mean times from diagnosis to the beginning of the first treatment were 0, 27.2±14.8, and 14.2±9.2 days in Groups A, B, and C respectively. Because cases in Group A were treated with radiotherapy before a histological diagnosis was made, the time from diagnosis to the beginning of the first treatment (radiotherapy) was 0 days in this group. The time was significantly shorter in Group C compared to in Group B (p<0.05). The mean times from the diagnosis to the end of the first treatment were 65.0±20.7, 111.6±26.4, and 86.8±11.7 days in Groups A, B, and C respectively. The time was significantly longer in Group B compared to in Groups A (p<0.01) and C (p<0.05), indicating that the neuroendoscopic procedure for pineal lesion germinomas resulted in reduced periods for the treatment start and for the entire treatment. Among 16 patients with group B, craniotomy was performed in 9 cases for removal or biopsy, transsphenoidal approach in 3 cases for biopsy, stereotactic biopsy in 2 cases
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and no surgical approach in 2 cases. There was no problem with surgical approach including wound healing, except for one case of postsurgical epidual hematoma as a complication. Among 17 patients with group C, neuroendoscopic biopsy was performed in 10 cases, stereotactic biopsy in 2 cases, craniotomy in 4 cases and transsphenoidal approach in 1 case. Neuroendoscopic procedure in this study is less-invasive compared to craniotomy and simultaneously treat hydrocephalus with biopsy. Time interval from the neuroendoscopic procedure to first chemotherapy is minimum 6 days (median 14.2 days, ranging 6 to 22 days). Time from diagnosis or operation to 1st treatment in all 7 recurrent cases in Group B; 40 days (median) was also longer than that of neuroendoscopic groups, 14.2 days (median).
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DISCUSSION Neoadjuvant Chemotherapy and Radiotherapy After the introduction of chemotherapy, chemotherapy-only regimens or chemotherapy followed by reduced-dosage radiation therapy to focal fields have been used to avoid the harmful effects of radiation therapy (2, 21). However, these strategies result in high rates of recurrence, especially in the ventricular wall outside the radiation field (5, 12, 17). In our study, recurrence was observed in 7 cases, all of which were in Group B. Two of these were initially treated with chemotherapy-only regimens and recurred at 12.9 and 64.3 months, while the other 4 cases recurred at the extra-radiation field at 33.6, 59.4, 67.7, and 69.3 months. The recurrences in Group B were not limited to one regimen: PE regimen in3 cases, PE regimen without radiation in 2 cases, PVB regimen in 1 case and CARE regimen in 1 case. On the other hand, we treated patients in Group C with chemotherapy followed by reduced-dosage radiation therapy covering at least the whole ventricle (13), and demonstrated the effectiveness of this protocol. Furthermore, 6 of the 7 recurrent cases in Group B were observed with disseminated disease. We applied local boost irradiation of 19.8 Gy following whole ventricle irradiation of 30.6 Gy when the primary lesion had not completely disappeared on MRI at the completion of two cycles of chemotherapy. Adjuvant whole ventricle irradiation with local boost and combined chemotherapy protocol has been previously demonstrated to result in good tumor control (8). Thus, one of the reasons for the favorable results in Group C in our study may be the use of local boost irradiation. In addition, adjuvant reduced-field radiation therapy not covering the whole ventricle may be associated with an increased risk of recurrence (5, 7), and radiation therapy to cover the whole ventricle is essential for long-term tumor control (4). Adjuvant whole ventricle irradiation combined with chemotherapy demonstrated recurrence in 0/17
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cases at a median follow-up of 103.0 months in our study and in 0/27 cases at a median follow-up of 52 months in a previous report (7). Follow up period in Group C was only 104.6 months in median ranging from 65.1 to 143.9 months. Late recurrence more than our follow up period (including 133.9 months of case 18 in our study) has been rarely reported (5). Therefore we need still longer follow up for our current neoadjuvant chemotherapy and radiotherapy in CNS germinoma. Using a reduced dose and field of irradiation at the initial treatment is another advantage for the treatment at recurrence. Among the 7 recurrent cases in our study, 5 cases were successfully treated with additional whole brain and spinal radiation and chemotherapy. Thus, reduced dose and field of radiation are warranted for further radiation treatment of a recurrence. The recurrence of one case, originating at the basal ganglia, was not controlled by additional treatment and the patients died of progressive disease. Because the appropriate target volume of radiation therapy in treating basal ganglia germinoma is difficult to define (20), recurrence may develop in the extraventricular regions, such as in the optic nerve (20) or paranasal cavity, as in our case, and whole brain radiation may hence be essential for patients with basal ganglia lesions. Finally, recent molecular genetic study can provide individually promising therapeutic strategies in each case focusing on the inhibition of KIT/RAS activation and AKT1/mTOR pathway for CNS germ cell tumors (22). Histologically not verified cases are included in this study (4 in Group A and 2 in Group B). Among them, only one case that was initially not irradiated had a recurrence. All cases were well controlled with the therapy for a long time. They are considered with non-aggressive germ cell tumor, probably germinoma. Therefore we consider they are useful in the comparisons in this study.
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Introduction of Neuroendoscopy One of the reasons for the favorable results in Group C in our study may be the introduction of neuroendoscopy for the diagnosis and treatment, especially for pineal lesions. These neuroendoscopic procedures resulted in significant reductions of the times from the diagnosis to the beginning of the 1st treatment and to the end of the 1st treatment compared to in Group B. Neuroendoscopic procedures can permit a precise histological diagnosis of intracranial germinomas and are safe and effective in the management of hydrocephalus associated with these tumors (19). We calculated the time from diagnosis or operation to 1st treatment in all 7 recurrent cases in Group B. The time (median 40 days ranging from 12 to 60 days) was also longer than that of neuroendoscopic groups 14.2 days. These results suggest one of the reasons for the
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favorable results in Group C may be the introduction of neuroendoscopy. Of note, all 7recurrent cases were observed in Group B, and 6 of these were disseminated disease. Accordingly, the risk of tumor dissemination due to the neuroendoscopic procedures appears to be minimal when appropriate and prompt chemotherapy and radiotherapy are provided postoperatively.
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Late Complications Neoadjuvant chemotherapy and radiotherapy in Group C resulted in maintained high KPS, without late complications, as compared to the radiation alone group (Group A) and Group B. Reduced-dose and volume radiation therapy without recurrence is an ideal treatment for curable tumors such as germinoma. The 17 patients treated with our most recent protocol (Group C) demonstrated no recurrence and high QOL (KPS (>80) during a median follow-up of 103 months. Interestingly, co-incidental diseases were observed in 4 cases in Group C, all of which were related to stroke (2 cavernomas, 1 moyamoya disease, 1 cerebral aneurysm). Fortunately, these patients maintained a high KPS with appropriate therapy and careful observation. Although central nervous system germinomas have favorable cure rates, close attention during the long-term follow-up, with assessment of stroke risk factors and subsequent malignancies was recommended in the recent Surveillance, Epidemiology, and End Results database analysis (1). In conclusion, chemotherapy followed by reduced-dose radiation therapy to the whole ventricle with or without local boost, and together with use of neuroendoscopy resulted in prompt diagnosis and decision-making, and good disease control without late complications, thereby maintaining high KPS for patients with germinomas.
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ACKNOWLEDGEMENTS This work was supported in part by Grants-in-Aid for Scientific Research (to S.T., No. 24390339) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by the Japanese Foundation for Research and Promotion of Endoscopy (to S.T.). Disclaimer The authors do not report any conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
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REFERENCES 1. Acharya S, DeWees T, Shinohara ET, Perkins SM: Long-term outcomes and late effects for childhood and young adulthood intracranial germinomas. Neuro Oncol. 17:741-746, 2015. 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 20:857–865, 2002.
3.
Balmaceda C, Heller G, Rosenblum M, Diez B, Villablanca JG, Kellie S, 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 14:2908–2915, 1996.
4.
Calaminus G, Kortmann R, Worch J, Nicholson JC, Alapetite C, Garre` ML, Patte C, Ricardi U, Saran F, Frappaz D: SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro-Oncology 15:788–796, 2013.
5.
Chen YW, Huang PI, Ho DMT, Hu YW, Chang KP, Chiou SH, Guo WY, Chang FC, Liang ML, Lee YY, Chen HH, Hsu TR, Lin SC, Wong TT, Yen SH: Change in treatment strategy for intracranial germinoma: long-term follow-up experience at a single institute. Cancer 118:2752-62, 2012.
6.
7.
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M AN U
SC
2.
Jensen AW, Issalaack NN, Buckner JC, Schomberg PJ, Wetmore CJ, Brown PD: Long-term follow up of dose-adapted and reduced-field radiotherapy with or without chemotherapy for central nervous system germinoma. Int. J. Radiation Oncology Biol. Phys., 77: 1449–1456, 2010. Kanamori M, Kumabe T, Saito R, Yamashita Y, Sonoda Y, Ariga H, Takai Y, Tominaga T: Optimal treatment strategy for intracranial germ cell tumors: a single institution analysis. J Neurosurg Pediatrics 4:506–514, 2009.
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Kawabata Y, Takahashi JA, Arakawa Y, Shirahata M, Hashimoto N: Long term outcomes in patients with intracranial germinomas: a single institution experience of irradiation with or without chemotherapy. J Neurooncol 88:161–167, 2008.
9.
Kellie SJ, Boyce H, Dunkel IJ, Diez B, Rosenblum M, Brualdi L, et al: Intensive cisplatin and cyclophosphamide-based chemotherapy without radiotherapy for intracranial germinomas: failure of a primary chemotherapy approach. Pediatr Blood Cancer 43:126–133, 2004.
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8.
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10. Kersh CR, Constable WC, Eisert DR, Spaulding CA, Hahn SS, Jenrette JM III, et al: Primary central nervous system germ cell tumors: effect of histologic confirmation on radiotherapy. Cancer 61:2148–2152, 1988. 11. Matsutani M: Combined chemotherapy and radiation therapy for CNS germ cell tumors. The Japanese experience. J Neurooncol 54:311–316, 2001.
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12. Nguyen QN, Chang EL, Allen PK, Maor MH, Ater JL, Mahajan A, et al: Focal and craniospinal irradiation for patients with germinoma and pattern of failure. Cancer 107:2228–2236, 2006.
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13. Osuka S, Tsuboi K, Takano S, Ishikawa E, Matsushita A, Tokuuye K, Akine Y, Matsumura A: Long-term outcome of patients with intracranial germinoma. J Neurooncol 83:71–79, 2007.
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14. Osuka S, Takano S, Enomoto T, Ishikawa E, Tsuboi K, Matsumura A: Endoscopic observation of pathophysiology of ventricular diverticulum Childs Nerv Syst 23:897–900, 2007. 15. Sato M, Nakai Y, Takigawa T, Takano S, Matsumura A: Endoscopic third ventriculostomy for obstructive hydrocephalus caused by a large upper basilar artery aneurysm after coil embolization. Neurol Med Chir (Tokyo). 52:832-834, 2012. 16. Schoenfeld A, Haas-Kogan DA, Molinaro A, Banerjee A, Nicolaides T, Tihan T, Bollen AW, Gupta N, Mueller S: Pure germinomas of the central nervous system: treatment strategies and outcomes. J Neurooncol 120:643–649, 2014.
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17. Shim KW, Kim TG, Suh CO, Cho JH, Yoo CJ, Choi JU, et al: Treatment failure in intracranial primary germinomas. Childs Nerv Syst 23:1155–1161, 2007.
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18. Shirato H, Nishio M, Sawamura Y, Myojin M, Kitahara T, Nishioka T, et al: Analysis of long-term treatment of intracranial germinoma. Int J Radiat Oncol Biol Phys 37:511–515, 1997.
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19. Shono T, Natori Y, Morioka T, Torisu R, Mizoguchi M, Nagata S, Suzuki SO, Iwaki T, Inamura T, Fukui M, Oka K, Sasaki T: Results of a long-term follow-up after neuroendoscopic biopsy procedure and third ventriculostomy in patients with intracranial germinomas. J Neurosurg. 107(3 Suppl):193-198, 2007. 20. Sonoda Y, Kumabe T, Sugiyama S, Kanamori M, Yamashita Y, Saito R, et al: Germ cell tumors in the basal ganglia: problems of early diagnosis and treatment. J Neurosurg Pediatr 2:118–124, 2008.
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21. Ueba T, Yamashita K, Fujisawa I, Nakao1 S, Ooyama K, Yorihuji T, Kato SF, Seto S, Kageyama N: Long-term follow-up of 5 patients with intracranial germinoma initially treated by chemotherapy alone. Acta Neurochir (Wien) 149: 897–902, 2007.
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22. Wang L, Yamaguchi S, Burstein MD, Terashima K, Chang K, Ng HK, Nakamura H, He Z, Doddapaneni H, Lewis L, Wang M, Suzuki T, Nishikawa R, Natsume A, Terasaka S, Dauser R, Whitechead W, Adekunle A, Sun J, Qiao Y, Marth G, Muzny DM, Gibbs RA, Leal SM, Wheeler DA, Lau CC: Novel somatic and germline mutations in intracranial germ cell tumours. Nature 511: 241-245, 2014.
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Figure Legends Figure 1 Treatment time course and Karnofsky performance status (KPS) during the follow-up. A: Treatment time courses of all patients. There were 7 recurrent cases, all of which occurred in Group B (red bars; cases 8, 9, 10, 11, 15, 17, 19) after 67.7, 59.4, 12.9, 64.3, 69.3, 133.9, and 33.6 months (median, 63.5 months). One of these patients died from the disease (case 8). The mean follow-up periods were 267.2, 167.0, and 104.6 months in Groups A, B and C, respectively. B: The patients’ KPS during the follow-up in each group. A KPS lower than 70 was observed in 2 of 5, 6 of 16, and 0 of 17 cases in Groups A, B, and C, respectively (p<0.05). PFS, progression-free survival.
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Figure 2 Kaplan-Meier curves of overall survival (A) and progression-free survival (B) in each group. The progression-free survival was significantly shorter in Group B compared to in Groups A and C (p<0.001). mo, months.
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Figure 3 T1-weighted gadolinium-enhanced magnetic resonance images of a recurrent case in Group B (Case 8). A: Complete response after chemoradiation (PE regimen plus 30.6-Gy whole ventricle irradiation, and 19.8-Gy local irradiation) therapy for a right basal ganglia germinoma. B, C: Sixty-eight months later, local and paranasal sinus recurrences were observed.
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Figure 4 T1-weighted gadolinium-enhanced (A, C, D, E, F) and T2-weighted (B) magnetic resonance imaging (MRI) of a recurrent case in Group B (Case 15). A, B: Pineal lesion germinoma with hydrocephalus on pretreatment MRI. C, D: Sixty-eight months after complete remission by chemotherapy (PE regimen) and radiation (extended local 30.6-Gy). Axial (Th12 level) and sagittal T1-weighted gadolinium-enhanced spine MRIs show the extra-radiation field recurrence as spinal dissemination. E, F: No evidence of disease was observed in the intracranial and spine views after 113 months. Figure 5 Recurrent case in Group B (Case 18)
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A: Pineal lesion germinoma on pretreatment magnetic resonance imaging, B: Complete remission after PE chemotherapy and 30.6-Gy extended local irradiation. C, E: Extra-radiation field recurrences at the left medial temporal lobe and left lateral paraventricle were observed 34 months after treatment, D, F: Radiation field and recurrence site.
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Figure 6 T1-weighted gadolinium-enhanced magnetic resonance imaging of a recurrent case in Group B (Case 17). A: Pretreatment, a multicentric lesion (pineal and paraventricular) was observed. B: Dissemination appeared 133 months after complete remission with chemoradiation (ICE regimen plus 24-Gy whole brain irradiation) therapy.
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Figure 7 Time courses for the pineal lesion germinomas in each group. A: Time between the diagnosis and start of the 1st treatment, B: Time between the diagnosis and end of the 1st treatment. Both times were significantly shorter in Group C compared to in Group B **p<0.01, *p<0.05.
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14.2±6.1 3/2
19.8±9.6 13/3
2 2 1 0 0 1 (20%) 1 (20%) 3 (60%) 0 (0%) 0 (0%) 0 (0%) 2 (40%)
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statistics
17.2±6.4 13/4
ns ns ns
7 4 3 1 1 14 (87.5%) 1 (6.3%) 4 (25.0%) 0 (0%) 15 (93.8%) 7 (43.8%) 6 (37.5%)
8 5 2 1 1 17 (100%) 1 (5.9%) 0 (0%) 9 (52.9%) 17 (100%) 0 (0%) 0 (0%)
267.2±109.5 167.0±63.9 104.6±22.8
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follow up mean±SD (mo)
group C n 17
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group B n 16
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age M/F location pineal neurohypophysial multiple basal ganglia other pathological diagnosis STGC (high HCG-beta) shunt ETV* chemotherapy recurrence present KPS =<70
group A n5
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Table 1 Germinoma patients and treatment characteristics
*ETV: endoscopic third ventriculostomy
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Highlights Neoadjuvant chemotherapy followed by reduced-dose radiation therapy to the whole ventricle with use of neuroendoscopy improved long term outcome for patients with germinomas.
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Conflict of Interest Statement: The authors have no conflicts of interest to declare.
S1878-8750(15)00777-9
DOI:
10.1016/j.wneu.2015.06.029
Reference:
WNEU 2981
To appear in:
World Neurosurgery
Received Date: 12 May 2015 Revised Date:
13 June 2015
Accepted Date: 15 June 2015
Please cite this article as: Takano S, Yamamoto T, Ishikawa E, Akutsu H, Nakai K, Matsuda M, Muroi A, Shibata Y, Mizumoto M, Tsuboi K, Matsumura A, Improvement of Long-term Results with Neoadjuvant Chemotherapy and Radiotherapy for Central Nervous System Germinoma, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.06.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Improvement of Long-term Results with Neoadjuvant Chemotherapy and Radiotherapy for Central Nervous System Germinoma
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Shingo Takano1, Tetsuya Yamamoto1, Eiichi Ishikawa1, Hiroyoshi Akutsu1, Kei Nakai1, Masahide Matsuda1, Ai Muroi1, Yasushi Shibata1, Masashi Mizumoto2, Koji Tsuboi2, Akira Matsumura1
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Keywords Chemoradiotherapy, Germinoma, Neuroendoscopy
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Department of Neurosurgery, Faculty of Medicine and 2Proton Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
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Abbreviations: HCG: human chorionic gonadotropin KPS: Karnofsky performance status MRI: magnetic resonance imaging
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Corresponding author: Shingo Takano, MD, PhD 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan E-mail: [email protected] FAX: +81-29-853-3214 Tel: +81-29-853-3220
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Abstract OBJECTIVE: To evaluate the role of neoadjuvant chemotherapy and radiotherapy in the treatment of central nervous system germinomas in 38 patients who received definitive treatment and were followed-up >5 years between 1980–2009. METHODS: The median age at diagnosis and follow-up period were 16.5 years and 128.3 months, respectively. Treatment was irradiation alone or adjuvant platinum-based chemotherapy followed by reduced-dose local irradiation. Seven patients progressed at 12.9–133.9 months and 1 died of disease 89.3 months after therapy initiation. RESULTS: The treatment strategies were divided into three groups: Group A (1980– 1988, n=5): whole brain with local irradiation; Group B (1989–2002, n=16): chemotherapy with or without reduced irradiation dose; and Group C (2003–2009, n=17): neoadjuvant chemotherapy (3 courses) followed by 30.6-Gy whole ventricle irradiation for patients with localized complete response, and additional local boost of 19.8-Gy for others. There were 7 recurrent cases, all in Group B. The progression-free survival was significantly longer in Groups A and C vs. Group B (p<0.001). Decreased Karnofsky performance status was observed in 2 (40%), 6 (37.5%), and 0 cases in Groups A–C, respectively. The main reasons for the good results in Group C might be the neoadjuvant chemotherapy with whole ventricle radiotherapy and introduction of neuroendoscopy, especially for pineal lesions, resulting in a substantial reduction of time from the diagnosis to 1st treatment. CONCLUSIONS: Chemotherapy followed by whole ventricle radiotherapy, with or without local boost, and with use of neuroendoscopy results in good disease-control without late complications in germinoma patients.
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Keywords Chemoradiotherapy, Germinoma, Neuroendoscopy
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INTRODUCTION Germinomas are generally curable using only radiation therapy, with reported 10-year overall survival rates >90% (10, 18). The radiation dose and field are considered important to prevent recurrence and radiation injuries such as cognitive dysfunction. Therefore, several trials of chemotherapy regimens without radiation therapy have been performed; however, the long-term outcomes have indicated unacceptable rates of recurrence (3, 8, 9, 17). In contrast, chemotherapy combined with reduced-dose radiation therapy has produced promising results for the control of germinoma (2, 10), although progression was observed even with this combined therapy, with reported recurrence rates between 6.3–20.8% (2, 4, 6, 7, 11, 16, 19). The present study retrospectively analyzed the long-term outcomes of 38 consecutive patients to verify the optimal treatment strategy for patients with newly diagnosed central nervous system germinomas.
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MATERIALS and METHODS Patients Characteristics A retrospective review of medical records at our department from 1980 to 2009 identified 38 patients with central nervous system germinoma. Of these 38 patients, 29 (76.3%) were men and 9 were women, with an age range from 7 to 38 years (median, 16.5 years). The clinical diagnosis of germinoma was based on the typical age, magnetic resonance imaging (MRI), and serum and/or cerebrospinal fluid analysis of the levels of alpha-fetoprotein, human chorionic gonadotropin (HCG), and β-HCG. The histological diagnosis was established from specimens obtained by endoscopic biopsy procedures or resection via craniotomy or the transsphenoidal approach, according to the World Health Organization classification of tumors of the nervous system. A flexible fiberscope Neu-4L (Machida, Japan) and videoscope (VEF type V; Olympus, Tokyo) were used for neuroendoscopic biopsy and third ventriculostomy (14, 15). We explained the treatment strategies about the disease to all patients involved in this study and treated them. Germinoma Treatment Protocol Patients with pure germinomas and germinomas with syncytiotrophoblastic giant cells were classified with histology, serum markers, and typical MRI. The clinical diagnosis was based on a slightly elevated level of HCG (<50 IU/L) or β-HCG (<5 ng/ml), without elevated levels of alpha-fetoprotein. The patients were divided into three groups according to the period of treatment. The treatment protocol for patients with
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germinomas treated between 1980 and 1989 (Group A) consisted of 30.6 Gy to the whole brain, without histological verification, followed by additional radiation therapy of 19.8 Gy to the primary site. The treatment protocol between 1990 and 2003 (Group B) consisted of introduction of chemotherapy with reduced-field radiation using cisplatin (20 mg/m2) and etoposide (100 mg/m2) on days 1–5 (PE regimen in 11 cases); or bleomycin (20 mg/m2 on days 1, 7, and 14) and vincristine and cisplatin (20 mg/ m2 on days 1–5; PVB regimen in 3 cases); or Ifosfamide 900 mg/m2, cisplatin 20 mg/m2 and etoposide 60 mg/m2 on days 1-5: ICE regimen in 1 case); or none in 1 case. In this period, radiation therapy was omitted in two cases and delivered to the local (30.6 Gy) or extended local (24–30.6 Gy) field in others. The treatment protocol from 2003 until 2009 (Group C) consisted of 3 cycles of the PE regimen or carboplatin (150 mg/m2) and etoposide (150 mg/m2) on days 1–3 (CARE regimen) followed by reduced-dose field radiation therapy (whole ventricle [30.6 Gy] and local boast [19.8 Gy]), with residual enhancement at the completion of two cycles of chemotherapy. Patients with ventricular dissemination or basal ganglia germinoma received an additional 24 Gy to the whole brain. Patient and treatment characteristics in each group are demonstrated in Table 1.
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Follow-Up and Statistical Analysis Differences between the patients and treatment characteristics of each group were examined using the Fischer exact or Student’s t-test. The patients were usually followed-up every 6 months until 5 years after the initial treatment, and every 6–12 months thereafter. The progression-free and overall survival rates were defined as the time (months) to tumor progression or death from any cause and time (months) to death from any cause or the last follow-up, respectively. The progression-free and overall survival rates were calculated using the Kaplan-Meier method. The prognostic factors were evaluated using the log-rank test. RESULTS Long-Term Outcomes of Germinoma The treatment course and characteristics of all patients are demonstrated in Figure 1A and Table 2. Thirty-seven of the 38 patients remained alive during the follow-up period, which ranged from 60 to 384 months (median, 128.3 months). One patient in Group B died of progressive disseminated disease at 89.2 months (case 8). The treatment modalities used in this study were resection or biopsy in 32 patients and chemotherapy
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and radiation therapy in all 38 patients. Salvage surgery was not used in any patient. To determine the optimal treatment for germinoma, the 38 patients were divided into 3 groups as described in the Materials and Methods section (Group A: n=5, Group B: n=16, Group C: n=17). The 5-, 10-, 15-, and 20-year overall survival rates in all germinoma patients were 100%, 95.5%, 90.9%, and 75.0%, respectively (Table 2). There were no significant differences in the overall survival rates between the treatment modalities (Fig. 2A). Tumor recurrence developed in 7 patients during the follow-up period, all of whom belonged to Group B. The 5-, 10-, 15-, and 20-year progression-free survival rates were 92.1%, 73.9%, 50.0%, and 36.4%, respectively (Table 1), and all recurrences developed between 12.9 and 133.9 months (median, 63.5 months) after starting the initial therapy (Fig. 1A). The sites of recurrence were the extra-radiation field in 4 patients as dissemination (cases 8, 9, 15, 18) (Figs. 3–5), disseminated disease in 2 chemotherapy alone cases (cases 10, 11), and radiation in-field in 1 patient (case 18) (Fig. 6). There were statistically significant differences in the progression-free survival rates between the treatment modalities (p<0.001; log rank test, Fig. 2B).
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Late Complication Due to the Disease or Treatment As mentioned above, there were 7 cases of recurrence, all of which occurred in Group B. Six of these patients survived with additional treatment (radiation plus chemotherapy), whereas one patient died at 89.2 months due to progressive disease. Four of these patients showed reduced Karnofsky performance status (KPS) during the disease course, owing to mild cognitive dysfunction due to ventricular dissemination at 133.9 months (Fig. 6, case 17) followed by additional whole brain irradiation (KPS 70 at 188.7 months), bladder bowel disturbance and paraparesis due to spinal dissemination at 69.3 months (Fig. 4, case 15; KPS 70 at 202.7 months), paraparesis due to primary lesion (case 9; KPS 70 at 99.5 months), and dysarthria due to symptomatic brainstem cavernoma at 103.6 months (case 10; KPS 70 at 239.1 months). Independent of the disease recurrence, three additional patients showed reduced KPS, resulting from systemic complications of lung fibrosis (case 5, Group A; KPS 50 at 348.6 months), mild cognitive dysfunction due to disease or radiation treatment (case 4, Group A; KPS 70 at 291.2 months), and mild cognitive dysfunction due to postoperative hemorrhagic complication (case 21, Group B; KPS 70 at 144.8 months). There were 4 cases with co-incidental or radiation-induced intracranial disease, including a ruptured distal anterior communication artery aneurysm and suspected radiation-induced aneurysm at 93 months in Group B (case 20), which was successfully treated by aneurysmal neck clipping; moyamoya disease at the diagnosis of germinoma
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in Group C (case 33), which was successfully treated by superficial temporal artery-middle cerebral artery bypass; and two patients with asymptomatic cavernoma at 33.9 and 82.6 months in Group C (cases 30, 38). These 4 patients maintained a KPS of 100% at the last follow-up. At the last follow-up, 2 of 5 (40%), 6 of 16 (37.5%), and 0 of 17 (0%) patients in Groups A, B, and C, respectively had a KPS <70 (p<0.05, Fig 1B).
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Usefulness of the Neuroendoscopic Procedure for Germinoma The use of neuroendoscopy was introduced into our diagnosis and treatment strategies for germinomas in 2003 (Group C). The treatment of hydrocephalus associated with germinomas was dramatically different between the groups (Table 2). A ventriculoperitoneal shunt was required in 60% and 25% of cases in Groups A and B, respectively, but in none in Group C. By contrast, endoscopic third ventriculoscopy was required in 52.9% of patients in Group C. Histology was obtained in none of the 5 cases in Group A and in 14 of 16 cases in Group B, including by the transcranial approach in 11 and transsphenoidal approach in 3 cases. On the other hand, histology was obtained in all 17 cases in Group C. Nine of 10 pineal lesion tumors in Group C were obtained by neuroendoscopy without any complications. Neuroendoscopy can permit a precise histological diagnosis of intracranial germinomas and is safe and effective in the management of hydrocephalus associated with these tumors. Next, the time course of the treatment for pineal lesion tumors in each group (Group A: n=3, Group B: n=5, Group C: n=9) was evaluated. The time from diagnosis to the beginning of the first treatment (chemotherapy or radiotherapy) and the time from diagnosis to the end of the first treatment were calculated in each case (Figure 7). The mean times from diagnosis to the beginning of the first treatment were 0, 27.2±14.8, and 14.2±9.2 days in Groups A, B, and C respectively. Because cases in Group A were treated with radiotherapy before a histological diagnosis was made, the time from diagnosis to the beginning of the first treatment (radiotherapy) was 0 days in this group. The time was significantly shorter in Group C compared to in Group B (p<0.05). The mean times from the diagnosis to the end of the first treatment were 65.0±20.7, 111.6±26.4, and 86.8±11.7 days in Groups A, B, and C respectively. The time was significantly longer in Group B compared to in Groups A (p<0.01) and C (p<0.05), indicating that the neuroendoscopic procedure for pineal lesion germinomas resulted in reduced periods for the treatment start and for the entire treatment. Among 16 patients with group B, craniotomy was performed in 9 cases for removal or biopsy, transsphenoidal approach in 3 cases for biopsy, stereotactic biopsy in 2 cases
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and no surgical approach in 2 cases. There was no problem with surgical approach including wound healing, except for one case of postsurgical epidual hematoma as a complication. Among 17 patients with group C, neuroendoscopic biopsy was performed in 10 cases, stereotactic biopsy in 2 cases, craniotomy in 4 cases and transsphenoidal approach in 1 case. Neuroendoscopic procedure in this study is less-invasive compared to craniotomy and simultaneously treat hydrocephalus with biopsy. Time interval from the neuroendoscopic procedure to first chemotherapy is minimum 6 days (median 14.2 days, ranging 6 to 22 days). Time from diagnosis or operation to 1st treatment in all 7 recurrent cases in Group B; 40 days (median) was also longer than that of neuroendoscopic groups, 14.2 days (median).
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DISCUSSION Neoadjuvant Chemotherapy and Radiotherapy After the introduction of chemotherapy, chemotherapy-only regimens or chemotherapy followed by reduced-dosage radiation therapy to focal fields have been used to avoid the harmful effects of radiation therapy (2, 21). However, these strategies result in high rates of recurrence, especially in the ventricular wall outside the radiation field (5, 12, 17). In our study, recurrence was observed in 7 cases, all of which were in Group B. Two of these were initially treated with chemotherapy-only regimens and recurred at 12.9 and 64.3 months, while the other 4 cases recurred at the extra-radiation field at 33.6, 59.4, 67.7, and 69.3 months. The recurrences in Group B were not limited to one regimen: PE regimen in3 cases, PE regimen without radiation in 2 cases, PVB regimen in 1 case and CARE regimen in 1 case. On the other hand, we treated patients in Group C with chemotherapy followed by reduced-dosage radiation therapy covering at least the whole ventricle (13), and demonstrated the effectiveness of this protocol. Furthermore, 6 of the 7 recurrent cases in Group B were observed with disseminated disease. We applied local boost irradiation of 19.8 Gy following whole ventricle irradiation of 30.6 Gy when the primary lesion had not completely disappeared on MRI at the completion of two cycles of chemotherapy. Adjuvant whole ventricle irradiation with local boost and combined chemotherapy protocol has been previously demonstrated to result in good tumor control (8). Thus, one of the reasons for the favorable results in Group C in our study may be the use of local boost irradiation. In addition, adjuvant reduced-field radiation therapy not covering the whole ventricle may be associated with an increased risk of recurrence (5, 7), and radiation therapy to cover the whole ventricle is essential for long-term tumor control (4). Adjuvant whole ventricle irradiation combined with chemotherapy demonstrated recurrence in 0/17
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cases at a median follow-up of 103.0 months in our study and in 0/27 cases at a median follow-up of 52 months in a previous report (7). Follow up period in Group C was only 104.6 months in median ranging from 65.1 to 143.9 months. Late recurrence more than our follow up period (including 133.9 months of case 18 in our study) has been rarely reported (5). Therefore we need still longer follow up for our current neoadjuvant chemotherapy and radiotherapy in CNS germinoma. Using a reduced dose and field of irradiation at the initial treatment is another advantage for the treatment at recurrence. Among the 7 recurrent cases in our study, 5 cases were successfully treated with additional whole brain and spinal radiation and chemotherapy. Thus, reduced dose and field of radiation are warranted for further radiation treatment of a recurrence. The recurrence of one case, originating at the basal ganglia, was not controlled by additional treatment and the patients died of progressive disease. Because the appropriate target volume of radiation therapy in treating basal ganglia germinoma is difficult to define (20), recurrence may develop in the extraventricular regions, such as in the optic nerve (20) or paranasal cavity, as in our case, and whole brain radiation may hence be essential for patients with basal ganglia lesions. Finally, recent molecular genetic study can provide individually promising therapeutic strategies in each case focusing on the inhibition of KIT/RAS activation and AKT1/mTOR pathway for CNS germ cell tumors (22). Histologically not verified cases are included in this study (4 in Group A and 2 in Group B). Among them, only one case that was initially not irradiated had a recurrence. All cases were well controlled with the therapy for a long time. They are considered with non-aggressive germ cell tumor, probably germinoma. Therefore we consider they are useful in the comparisons in this study.
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Introduction of Neuroendoscopy One of the reasons for the favorable results in Group C in our study may be the introduction of neuroendoscopy for the diagnosis and treatment, especially for pineal lesions. These neuroendoscopic procedures resulted in significant reductions of the times from the diagnosis to the beginning of the 1st treatment and to the end of the 1st treatment compared to in Group B. Neuroendoscopic procedures can permit a precise histological diagnosis of intracranial germinomas and are safe and effective in the management of hydrocephalus associated with these tumors (19). We calculated the time from diagnosis or operation to 1st treatment in all 7 recurrent cases in Group B. The time (median 40 days ranging from 12 to 60 days) was also longer than that of neuroendoscopic groups 14.2 days. These results suggest one of the reasons for the
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favorable results in Group C may be the introduction of neuroendoscopy. Of note, all 7recurrent cases were observed in Group B, and 6 of these were disseminated disease. Accordingly, the risk of tumor dissemination due to the neuroendoscopic procedures appears to be minimal when appropriate and prompt chemotherapy and radiotherapy are provided postoperatively.
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Late Complications Neoadjuvant chemotherapy and radiotherapy in Group C resulted in maintained high KPS, without late complications, as compared to the radiation alone group (Group A) and Group B. Reduced-dose and volume radiation therapy without recurrence is an ideal treatment for curable tumors such as germinoma. The 17 patients treated with our most recent protocol (Group C) demonstrated no recurrence and high QOL (KPS (>80) during a median follow-up of 103 months. Interestingly, co-incidental diseases were observed in 4 cases in Group C, all of which were related to stroke (2 cavernomas, 1 moyamoya disease, 1 cerebral aneurysm). Fortunately, these patients maintained a high KPS with appropriate therapy and careful observation. Although central nervous system germinomas have favorable cure rates, close attention during the long-term follow-up, with assessment of stroke risk factors and subsequent malignancies was recommended in the recent Surveillance, Epidemiology, and End Results database analysis (1). In conclusion, chemotherapy followed by reduced-dose radiation therapy to the whole ventricle with or without local boost, and together with use of neuroendoscopy resulted in prompt diagnosis and decision-making, and good disease control without late complications, thereby maintaining high KPS for patients with germinomas.
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ACKNOWLEDGEMENTS This work was supported in part by Grants-in-Aid for Scientific Research (to S.T., No. 24390339) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by the Japanese Foundation for Research and Promotion of Endoscopy (to S.T.). Disclaimer The authors do not report any conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
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REFERENCES 1. Acharya S, DeWees T, Shinohara ET, Perkins SM: Long-term outcomes and late effects for childhood and young adulthood intracranial germinomas. Neuro Oncol. 17:741-746, 2015. 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 20:857–865, 2002.
3.
Balmaceda C, Heller G, Rosenblum M, Diez B, Villablanca JG, Kellie S, 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 14:2908–2915, 1996.
4.
Calaminus G, Kortmann R, Worch J, Nicholson JC, Alapetite C, Garre` ML, Patte C, Ricardi U, Saran F, Frappaz D: SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro-Oncology 15:788–796, 2013.
5.
Chen YW, Huang PI, Ho DMT, Hu YW, Chang KP, Chiou SH, Guo WY, Chang FC, Liang ML, Lee YY, Chen HH, Hsu TR, Lin SC, Wong TT, Yen SH: Change in treatment strategy for intracranial germinoma: long-term follow-up experience at a single institute. Cancer 118:2752-62, 2012.
6.
7.
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2.
Jensen AW, Issalaack NN, Buckner JC, Schomberg PJ, Wetmore CJ, Brown PD: Long-term follow up of dose-adapted and reduced-field radiotherapy with or without chemotherapy for central nervous system germinoma. Int. J. Radiation Oncology Biol. Phys., 77: 1449–1456, 2010. Kanamori M, Kumabe T, Saito R, Yamashita Y, Sonoda Y, Ariga H, Takai Y, Tominaga T: Optimal treatment strategy for intracranial germ cell tumors: a single institution analysis. J Neurosurg Pediatrics 4:506–514, 2009.
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Kawabata Y, Takahashi JA, Arakawa Y, Shirahata M, Hashimoto N: Long term outcomes in patients with intracranial germinomas: a single institution experience of irradiation with or without chemotherapy. J Neurooncol 88:161–167, 2008.
9.
Kellie SJ, Boyce H, Dunkel IJ, Diez B, Rosenblum M, Brualdi L, et al: Intensive cisplatin and cyclophosphamide-based chemotherapy without radiotherapy for intracranial germinomas: failure of a primary chemotherapy approach. Pediatr Blood Cancer 43:126–133, 2004.
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8.
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10. Kersh CR, Constable WC, Eisert DR, Spaulding CA, Hahn SS, Jenrette JM III, et al: Primary central nervous system germ cell tumors: effect of histologic confirmation on radiotherapy. Cancer 61:2148–2152, 1988. 11. Matsutani M: Combined chemotherapy and radiation therapy for CNS germ cell tumors. The Japanese experience. J Neurooncol 54:311–316, 2001.
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12. Nguyen QN, Chang EL, Allen PK, Maor MH, Ater JL, Mahajan A, et al: Focal and craniospinal irradiation for patients with germinoma and pattern of failure. Cancer 107:2228–2236, 2006.
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13. Osuka S, Tsuboi K, Takano S, Ishikawa E, Matsushita A, Tokuuye K, Akine Y, Matsumura A: Long-term outcome of patients with intracranial germinoma. J Neurooncol 83:71–79, 2007.
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14. Osuka S, Takano S, Enomoto T, Ishikawa E, Tsuboi K, Matsumura A: Endoscopic observation of pathophysiology of ventricular diverticulum Childs Nerv Syst 23:897–900, 2007. 15. Sato M, Nakai Y, Takigawa T, Takano S, Matsumura A: Endoscopic third ventriculostomy for obstructive hydrocephalus caused by a large upper basilar artery aneurysm after coil embolization. Neurol Med Chir (Tokyo). 52:832-834, 2012. 16. Schoenfeld A, Haas-Kogan DA, Molinaro A, Banerjee A, Nicolaides T, Tihan T, Bollen AW, Gupta N, Mueller S: Pure germinomas of the central nervous system: treatment strategies and outcomes. J Neurooncol 120:643–649, 2014.
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17. Shim KW, Kim TG, Suh CO, Cho JH, Yoo CJ, Choi JU, et al: Treatment failure in intracranial primary germinomas. Childs Nerv Syst 23:1155–1161, 2007.
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18. Shirato H, Nishio M, Sawamura Y, Myojin M, Kitahara T, Nishioka T, et al: Analysis of long-term treatment of intracranial germinoma. Int J Radiat Oncol Biol Phys 37:511–515, 1997.
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19. Shono T, Natori Y, Morioka T, Torisu R, Mizoguchi M, Nagata S, Suzuki SO, Iwaki T, Inamura T, Fukui M, Oka K, Sasaki T: Results of a long-term follow-up after neuroendoscopic biopsy procedure and third ventriculostomy in patients with intracranial germinomas. J Neurosurg. 107(3 Suppl):193-198, 2007. 20. Sonoda Y, Kumabe T, Sugiyama S, Kanamori M, Yamashita Y, Saito R, et al: Germ cell tumors in the basal ganglia: problems of early diagnosis and treatment. J Neurosurg Pediatr 2:118–124, 2008.
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21. Ueba T, Yamashita K, Fujisawa I, Nakao1 S, Ooyama K, Yorihuji T, Kato SF, Seto S, Kageyama N: Long-term follow-up of 5 patients with intracranial germinoma initially treated by chemotherapy alone. Acta Neurochir (Wien) 149: 897–902, 2007.
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22. Wang L, Yamaguchi S, Burstein MD, Terashima K, Chang K, Ng HK, Nakamura H, He Z, Doddapaneni H, Lewis L, Wang M, Suzuki T, Nishikawa R, Natsume A, Terasaka S, Dauser R, Whitechead W, Adekunle A, Sun J, Qiao Y, Marth G, Muzny DM, Gibbs RA, Leal SM, Wheeler DA, Lau CC: Novel somatic and germline mutations in intracranial germ cell tumours. Nature 511: 241-245, 2014.
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Figure Legends Figure 1 Treatment time course and Karnofsky performance status (KPS) during the follow-up. A: Treatment time courses of all patients. There were 7 recurrent cases, all of which occurred in Group B (red bars; cases 8, 9, 10, 11, 15, 17, 19) after 67.7, 59.4, 12.9, 64.3, 69.3, 133.9, and 33.6 months (median, 63.5 months). One of these patients died from the disease (case 8). The mean follow-up periods were 267.2, 167.0, and 104.6 months in Groups A, B and C, respectively. B: The patients’ KPS during the follow-up in each group. A KPS lower than 70 was observed in 2 of 5, 6 of 16, and 0 of 17 cases in Groups A, B, and C, respectively (p<0.05). PFS, progression-free survival.
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Figure 2 Kaplan-Meier curves of overall survival (A) and progression-free survival (B) in each group. The progression-free survival was significantly shorter in Group B compared to in Groups A and C (p<0.001). mo, months.
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Figure 3 T1-weighted gadolinium-enhanced magnetic resonance images of a recurrent case in Group B (Case 8). A: Complete response after chemoradiation (PE regimen plus 30.6-Gy whole ventricle irradiation, and 19.8-Gy local irradiation) therapy for a right basal ganglia germinoma. B, C: Sixty-eight months later, local and paranasal sinus recurrences were observed.
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Figure 4 T1-weighted gadolinium-enhanced (A, C, D, E, F) and T2-weighted (B) magnetic resonance imaging (MRI) of a recurrent case in Group B (Case 15). A, B: Pineal lesion germinoma with hydrocephalus on pretreatment MRI. C, D: Sixty-eight months after complete remission by chemotherapy (PE regimen) and radiation (extended local 30.6-Gy). Axial (Th12 level) and sagittal T1-weighted gadolinium-enhanced spine MRIs show the extra-radiation field recurrence as spinal dissemination. E, F: No evidence of disease was observed in the intracranial and spine views after 113 months. Figure 5 Recurrent case in Group B (Case 18)
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A: Pineal lesion germinoma on pretreatment magnetic resonance imaging, B: Complete remission after PE chemotherapy and 30.6-Gy extended local irradiation. C, E: Extra-radiation field recurrences at the left medial temporal lobe and left lateral paraventricle were observed 34 months after treatment, D, F: Radiation field and recurrence site.
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Figure 6 T1-weighted gadolinium-enhanced magnetic resonance imaging of a recurrent case in Group B (Case 17). A: Pretreatment, a multicentric lesion (pineal and paraventricular) was observed. B: Dissemination appeared 133 months after complete remission with chemoradiation (ICE regimen plus 24-Gy whole brain irradiation) therapy.
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Figure 7 Time courses for the pineal lesion germinomas in each group. A: Time between the diagnosis and start of the 1st treatment, B: Time between the diagnosis and end of the 1st treatment. Both times were significantly shorter in Group C compared to in Group B **p<0.01, *p<0.05.
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14.2±6.1 3/2
19.8±9.6 13/3
2 2 1 0 0 1 (20%) 1 (20%) 3 (60%) 0 (0%) 0 (0%) 0 (0%) 2 (40%)
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statistics
17.2±6.4 13/4
ns ns ns
7 4 3 1 1 14 (87.5%) 1 (6.3%) 4 (25.0%) 0 (0%) 15 (93.8%) 7 (43.8%) 6 (37.5%)
8 5 2 1 1 17 (100%) 1 (5.9%) 0 (0%) 9 (52.9%) 17 (100%) 0 (0%) 0 (0%)
267.2±109.5 167.0±63.9 104.6±22.8
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group C n 17
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age M/F location pineal neurohypophysial multiple basal ganglia other pathological diagnosis STGC (high HCG-beta) shunt ETV* chemotherapy recurrence present KPS =<70
group A n5
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Table 1 Germinoma patients and treatment characteristics
*ETV: endoscopic third ventriculostomy
p<0.001 ns p<0.01 p<0.01 p<0.001 p<0.01 p<0.05 A vs B p<0.01 A vs C p<0.01 B vs C p<0.05
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PFS
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Table 2 Survival of germinomas OS
35/38 (92.1%)
38/38 (100%)
10y
17/23 (73.9%)
21/22 (95.5%)
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7/14 (50.0%)
10/11 (90.9%)
4/11 (36.4%)
3/4 (75.0%)
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20y
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5y
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Figure 1 A
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Figure 4 E Th12
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Figure 5 A
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Figure Recurrent case 1
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Figure7
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Highlights Neoadjuvant chemotherapy followed by reduced-dose radiation therapy to the whole ventricle with use of neuroendoscopy improved long term outcome for patients with germinomas.
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Conflict of Interest Statement: The authors have no conflicts of interest to declare.