Improved Outcome of Central Nervous System Germ Cell Tumors: Implications for the Role of Risk-adapted Intensive Chemotherapy
01 Mar 2010-Journal of Korean Medical Science (Korean Academy of Medical Sciences)-Vol. 25, Iss: 3, pp 458-465
TL;DR: It is suggested that risk-adapted intensive chemotherapy may improve the outcome of patients with malignant CNS-GCTs and should be considered as a first line treatment according to the clinical requirements.
Abstract: To determine the impact of treatment protocols on the outcome of central nervous system germ cell tumors (CNS-GCTs), we reviewed the medical records of 53 patients who received front-line chemotherapy from September 1997 to September 2006. Pure germinoma, normal alpha-fetoprotein level and beta-human chorionic gonadotropin level <50 mIU/mL were regarded as low-risk features and the others as high-risk. Patients from different time periods were divided into 3 groups according to the chemotherapy protocols. Group 1 (n=19) received 4 cycles of chemotherapy comprising cisplatin, etoposide and bleomycin. Group 2 (n=16) and group 3 (n=18) received 4 cycles of chemotherapy with cisplatin, etoposide, cyclophosphamide and vincristine in the former and with carboplatin, etoposide, cyclophosphamide and bleomycin in the latter. In group 2 and group 3, high-risk patients received double doses of cisplatin, carboplatin and cyclophosphamide. Radiotherapy was given after chemotherapy according to the clinical requirements. The event-free survivals of groups 1, 2, and 3 were 67.0%, 93.8%, and 100%, respectively (group 1 vs. 2, P=0.06; group 2 vs. 3, P=0.29; group 1 vs. 3, P=0.02). Our data suggest that risk-adapted intensive chemotherapy may improve the outcome of patients with malignant CNS-GCTs.
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TL;DR: Neo-adjuvant CTX for localized germinomas seems to be unnecessary as a method to reduce radiation dose in the RT protocol, however, the effective control of multifocal or disseminated germinoma can be achieved by neo- adjuvantCTX followed by response-adapted reduced dose RT.
Abstract: This prospective randomized clinical study will address the efficacy of radiation (RT)-alone and combined with pre-RT chemotherapy (CTX) treatments and propose the novel standard treatment strategy for intracranial primary pure germinoma. Between 2005 and 2008, there were 54 patients diagnosed with intracranial primary pure germinomas in a single institute. Twenty-eight patients were enrolled. The mean age of the patients was 16.2 years (range 6–31 years). There were 19 men and 9 women (men/women ratio = 2.1:1). There were 21 patients with solitary tumors and 7 with multiple tumors. These patients were randomized as RT-only treatment group (11 solitary and 3 multiple tumors) and combined (10 solitary and 4 multiple tumors, neo-adjuvant CTX followed by response-adapted RT) treatment group. The follow-up period for RT only group has a median of 58 months (mean 58.2 months, range 41–82 months), and for combine therapy group, the median was 68.5 months (mean 67.8 months, range 41–88 months). All 14 patients in the RT-only group showed complete response (CR) and no recurrence. Eleven patients in the combined group had CR and three patients had partial response after neo-adjuvant CTX. All patients responded to RT as CR without recurrence. At the time of analysis, all 28 patients were alive without evidence of disease. Neo-adjuvant CTX for localized germinomas seems to be unnecessary as a method to reduce radiation dose in our RT protocol. However, the effective control of multifocal or disseminated germinoma can be achieved by neo-adjuvant CTX followed by response-adapted reduced dose RT.
17 citations
TL;DR: Navigational tracking improved the accuracy of the neuroendoscopic approach and minimized brain trauma in pediatric patients without hydrocephalus, and the absence of ventriculomegaly in patients with brain tumor may not serve as a contraindication to neuro endoscopic tumor biopsy.
Abstract: Intraventricular endoscopic procedures to resect or biopsy peri- or intraventricular tumors may have not been used in patients with small ventricles due to the presumed difficulties with ventricular cannulation and the perceived risk of morbidity. The purpose of this study is to review the feasibility and safety of neuroendoscopic procedures in the biopsy of pediatric brain tumors with a small ventricle. Between January 2006 and January 2013, 72 children were identified with brain tumors confirmed by transventricular endoscopic biopsy. Patients were divided into non-hydrocephalus and hydrocephalus groups, and the ratio of the two groups was 20:52. In 20 pediatric brain tumors with small ventricle, the targeted lesion was successfully approached under the guidance of neuronavigation. Navigational tracking was especially helpful in entering small ventricles and in approaching the third ventricle through the narrow foramen of Monro. The histopathologic diagnosis was established in all 20 patients: nine germinomas, three mixed germ cell tumors, two pilomyxoid astrocytomas, and two pilocytic astrocytomas. The tumor biopsy sites were the suprasellar area (n = 10), pineal area (n = 4), lateral ventricular wall (n = 4), and mammillary body (n = 1). There were no major morbidities related to the endoscopic procedure. Neuroendoscopic biopsy or resection of peri- or intraventricular tumors in pediatric patients without hydrocephalus is feasible. Navigation-guided neuroendoscopic procedures improved the accuracy of the neuroendoscopic approach and minimized brain trauma. The absence of ventriculomegaly in patients with brain tumor may not serve as a contraindication to neuroendoscopic tumor biopsy.
16 citations
TL;DR: Germinoma must be considered in patients with insipidus diabetes with a sellar mass with thickening of pituitary stalk; and ectopic germinomamust be suspected in patientsWith slowly progressive hemiparesis with cerebral hemiatrophy, even with a rare condition, colocalization of midline and off-midline germinomas must be suspected.
Abstract: Germinomas are malignant intracranial germ tumors, usually found in suprasellar regions. Less than 10% are localized in off-middle structures, and synchronous involvement of both structures has only exceptionally been published. A case of an 18-year-old male patient with progressive right-sided hemiparesis and panhypopituitarism was reviewed. Brain MRI showed a solid mass involving pituitary and hypothalamus with thickening of pituitary stalk, high intensity lesions on T2-weighted imaging in left internal capsule, caudate nucleus, globus pallidus, and mild atrophy of the left internal capsule and cerebral peduncle. Nonadenomatous lesions were considered in the differential diagnosis. Alfa-fetoprotein (AFP) levels were negative in both serum and cerebrospinal fluid (CSF), while β-human chorionic gonadotrophin (β-HCG) levels were slightly increased in CSF. A transsphenoidal biopsy identified a germinoma. Four cycles of chemotherapy with bleomicine, etoposide, and cysplatin were given, followed by radiotherapy, but patients died due to a recidiva. Conclusion. Germinoma must be considered in patients with insipidus diabetes with a sellar mass with thickening of pituitary stalk; and ectopic germinoma must be suspected in patients with slowly progressive hemiparesis with cerebral hemiatrophy. Even with a rare condition, colocalization of midline and off-midline germinoma must be suspected in the presence of these typical signs of both localizations.
16 citations
Cites background from "Improved Outcome of Central Nervous..."
...However, biopsy-proven germinomas can have nongerminomatous elements among the unbiopsied sites and nonsecreting tumors can also have nongerminomatous components with a less favorable prognosis [14]....
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...The optimal management strategy for CNSGCTs remains unsettled due to a lack of prospective trials, mainly due to the infrequency of these tumors [14]....
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TL;DR: The current carboplatin-based chemotherapy protocol is safe and effective for the treatment of pediatric patients with IC-GCTs and it is concluded that no lethal hematological complications were associated with this treatment.
Abstract: Purpose
Cisplatin-based chemotherapy has been commonly used for the treatment of intracranial germ cell tumors (IC-GCTs). However, this treatment exhibits some adverse effects such as renal problems and hearing difficulty. Carboplatin-based chemotherapy was administered to pediatric patients with IC-GCTs from August 2004 at the Samsung Medical Center. In this study, we assessed the responses and adverse effects of carboplatin-based chemotherapy in pediatric IC-GCTs patients according to the risk group, and compared the results with those of the previous cisplatin-based chemotherapy.
4 citations
01 Jan 2015
TL;DR: Stereotactic radiosurgery (SRS) has advantages over other therapeutic modalities in certain settings and has a role in the management of pediatric brain tumors, however, that role is limited by the propensity of pediatric neural tumors to disseminate along cerebrospinal fluid pathways or to infiltrate surrounding brain.
Abstract: Pediatric brain tumors encompass a heterogeneous group of diseases. For many tumors, such as low-grade glioma and standard-risk medulloblastoma, the long-term survival rate is high. Clinical investigation for these diseases in recent decades has focused on addressing late effects of therapy, in particular the neurocognitive effects of cranial radiation. Chemotherapy has been used effectively in many settings to delay radiation, to reduce radiation dose and volume, or to replace cranial irradiation entirely. For other tumors, diffuse intrinsic pontine glioma most notoriously, prognosis remains abysmal and currently available treatments are primarily palliative. Stereotactic radiosurgery (SRS) has advantages over other therapeutic modalities in certain settings and has a role in the management pediatric brain tumors. That role is limited, however, by the propensity of pediatric neural tumors to disseminate along cerebrospinal fluid (CSF) pathways or to infiltrate surrounding brain.
1 citations
References
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TL;DR: Germinomas are highly curable with RT alone and lower doses of RT to the craniospinal axis without chemotherapy appear to produce equally effective DFS and OS as do higher doses ofRT or combination chemotherapy and RT.
Abstract: Purpose: To determine the optimal dose and treatment outcome of patients treated with radiation for intracranial germinoma. Methods and Materials: Between 1975 and 1995, 40 patients with the diagnosis of intracranial germinoma were treated with radiation (RT) to the central nervous system. All patients received whole-brain (WB) RT (median dose: 32.4 Gy, range: 15-44.37 Gy) and a boost to the tumor volume (median total tumor volume dose: 52 Gy, range: 45-59.5 Gy). Thirty patients received RT to the spine (median dose: 26 Gy, range: 18.75-37.5 Gy). Four patients were treated with cisplatin-based chemotherapy and WB RT with a boost to the tumor volume (dose range: 51-54 Gy). A low-dose RT only group was defined as <25.5 Gy to the WB (9 patients); <50 Gy to the primary site (14 patients); and <22 Gy to the spine (9 patients) Seventeen tumors were biopsy-proven germinoma, and 17 patients presented with multiple midline germinomas (MMG). Among 26 patients who had tumor markers measured, 27% had elevation of (3-human chorionic gonadotropin and by definition, no patient had an elevation of AFP. Twenty-four percent of 26 patients who had spine imaging or cerebral spinal fluid cytology had evidence of tumor seeding at diagnosis. The male to female ratio was 1.9:1. Median age at diagnosis was 14 years for male patients and 9.5 years for female patients (p = 0.02), (overall age ranges: 0.5-31 years). Median follow-up was 62 months ( range: 3-226 months). Late effects of 29 patients with follow-up of a20 months and adequate documentation in their medical records were analyzed. Results: The 5-year actuarial rate of disease-free survival (DFS) and overall survival (OS) for biopsy-proven germinomas and presumed germinomas was 97%. No patient died of germinoma. There were no local failures regardless of the dose of RT, elevation of HCG tumor marker, or CSF dissemination at presentation. At presentation 22 patients had evidence of at least one endocrine abnormality. At follow-up there were no new patients diagnosed with an endocrine abnormality; however, 13 out of 22 patients had an increase in the number of endocrine deficiencies requiring hormone replacement. At presentation, 14 patients showed evidence of growth retardation. At follow-up there were no new cases of growth failure in the remaining patients. Conclusions: Germinomas are highly curable with RT alone. Lower doses of RT to the craniospinal axis without chemotherapy appear to produce equally effective DFS and OS as do higher doses of RT or combination chemotherapy and RT. Craniospinal RT may be indicated for patients with MMG or patients with evidence of spinal seeding. Long-term effects of growth retardation, and other endocrine deficiencies appear to be correlated with disease at presentation rather than solely with treatment.
107 citations
"Improved Outcome of Central Nervous..." refers methods in this paper
...In the past, radiation therapy was used as a single modality for the treatment of CNS-GCTs (4-12)....
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TL;DR: The endocrinologic presentation, tumor marker status, and early response to radiation measured on computed tomography are useful means for selecting patients for radiation therapy.
Abstract: Radiation therapy (XRT) was used in the treatment of 25 patients with tumors of the pineal and suprasellar locations. A tissue diagnosis was obtained before XRT in 5 patients, and 20 were irradiated without histologic verification. The overall survival rate is 80% (76% with no evidence of disease [NED]). Megavoltage XRT was delivered to the entire neuraxis in 22 patients, and 86% (19/22) are alive from 4 to 88 months (median, 30 months) after treatment. In two of three patients treated only to local fields, tumor recurred in the spine; both are dead of disease. Biopsy-proven germinomas and multiple midline tumors responded favorably to XRT, whereas solitary pineal tumors and teratomas with marker positivity (human chorionic gonadotropin, alpha-fetoprotein) did not respond as well. The endocrinologic presentation, tumor marker status, and early response to radiation measured on computed tomography are useful means for selecting patients for radiation therapy.
106 citations
"Improved Outcome of Central Nervous..." refers background or methods in this paper
...(5) suggested that nongerminomatous or secreting tumors were relatively resistant to radiotherapy....
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...In the past, radiation therapy was used as a single modality for the treatment of CNS-GCTs (4-12)....
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TL;DR: Antitumor activity against intracranial malignant teratoma by combination chemotherapy with cisplatin and etoposide with a synergistic cytotoxic effect was achieved by use of both agents in combination.
Abstract: ✓ Antitumor activity against intracranial malignant teratoma by combination chemotherapy with cisplatin and etoposide was evaluated in experimental and clinical studies. A human teratoma cell line (Tera 2) was exposed in vitro to cisplatin and/or etoposide, after which cell growth inhibition and alterations of deoxyribonucleic acid (DNA) histograms were observed. The results indicated that a synergistic cytotoxic effect was achieved by use of both agents in combination. Four cases of recurrent intracranial germ-cell tumor (three malignant teratomas and one germinoma) were treated with cisplatin and etoposide. With this combinationtherapy, regression of the tumor was observed in all four cases (three complete and one partial), for a total response rate of 100%. During a follow-up period of 9 to 22 months, no recurrence or progression has been noted in three of these cases.
100 citations
"Improved Outcome of Central Nervous..." refers background in this paper
...In the 1980s, investigators began to report the effectiveness of systemic chemotherapy especially for nongerminomatous CNS-GCTs (13-15)....
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TL;DR: This Phase II study was designed to determine response to chemotherapy and survival after response‐based radiation (RT) in children with CNS germ cell tumors.
Abstract: Background
This Phase II study was designed to determine response to chemotherapy and survival after response-based radiation (RT) in children with CNS germ cell tumors.
Procedure
Children with germinomas and normal markers received cisplatin 100 mg/m2 + etoposide, alternating with vincristine + cyclophosphamide (CPM) 2 g/m2/d, for four cycles. Children with nongerminomatous tumors or with abnormal markers received doubled doses of cisplatin and CPM. For germinoma patients in complete response (CR), RT was decreased from 50.4 to 30.6 Gy. High-risk patients received neuraxis RT: 50.4 Gy local + 30.6 Gy neuraxis in CR; 54 Gy local + 36 Gy if less than CR.
Results
Of 12 germinoma patients, 4 had cerebrospinal fluid (CSF) human chorionic gonadotropin (HCG) 6.9–21 mIU/ml. Of 14 nongerminomatous patients, HCG in serum or CSF was >50 mIU/ml in 9, α-fetoprotein (AFP) abnormal in 9. Four germinoma patients attained CR, six PR, one SD, one not evaluable after resection. Two nongerminomatous patients had CR, three PR, three SD, one PD, four not evaluable after resection; one inadequately treated patient had progressive disease (PD). Both PD patients died; one SD patient died during a seizure. Eleven germinoma patients are PF at median 66 months; one patient in CR refused RT, had PD at 10 months, received RT, and was PF at 56 months. Eleven of 14 nongerminomatous patients were PF at median 58 months.
Conclusion
Response (germinoma, 91%; nongerminomatous, 55%) and survival are encouraging after this regimen plus response-based RT. Pediatr Blood Cancer 2007;48:285–291. © 2006 Wiley-Liss, Inc.
96 citations
Additional excerpts
...According to the Children’s Oncology Group report in 2007 on the efficacy of pre-radiation chemotherapy with response-based radiation therapy in children with CNS-GCTs, although the number of patients was small (n=26), 3-yr OS was 100% for germinomas and 79% for nongerminomatous GCTs (23)....
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TL;DR: The relative roles of surgical resection, radiotherapy, and chemotherapy in the management of patients with intracranial nongerminomatous malignant germ cell tumors have been controversial.
Abstract: 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, 14-194 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 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.
87 citations
"Improved Outcome of Central Nervous..." refers background in this paper
...(22) reported a higher 5-yr survival rate in chemotherapy group than that in non-chemotherapy group (84% vs....
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...(22), the median radiation dose was 50 Gy to the primary site and 30 Gy to the whole brain and whole spine, which is also higher than that used in our patients....
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