Curr Oncol Rep (2014) 16:393 DOI 10.1007/s11912-014-0393-1
PEDIATRIC ONCOLOGY (S EPELMAN, SECTION EDITOR)
Advances in the Management of Central Nervous System Germ Cell Tumors Nathan E. Millard & Ira J. Dunkel
Published online: 17 May 2014 # Springer Science+Business Media New York 2014
Abstract Intracranial germ cell tumors represent a relatively small portion of pediatric central nervous system tumors, with a reported incidence ranging from 3.6% in North America to 15.3% in parts of Asia. They are known to arise in midline locations, most frequently the pineal gland and suprasellar regions, and affect males twice to three times more frequently than females, especially in the case of pineal-region tumors. The median age of diagnosis is 10–12 years. The treatment of intracranial germ cells tumors is complicated by their relative rarity, histologic heterogeneity, and a lack of widespread consensus on their optimal management. Despite these challenges, important progress continues to be made, with a move toward multicenter and international collaborative efforts that offer potential for clinical advancements. This review focuses on recent developments in the management of intracranial germ cell tumors, including updates in diagnosis, surveillance, biology, treatment, and outcomes. Keywords Intracranial germ cell tumor . Germinoma . Nongerminomatous germ cell tumor . Pediatrics
Introduction The WHO classification system divides intracranial germ cell tumors into germinomas and nongerminomatous germ cell tumors (NGGCTs). The latter category comprises a number of tumor subtypes, including choriocarcinoma, embryonal
carcinoma, mature and immature teratoma, yolk sac tumor/ endodermal sinus tumor, and mixed germ cell tumor. Germinomas represent approximately two-thirds of intracranial germ cell tumors while NGGCTs comprise the remaining third [1–3]. In Japan, central nervous system (CNS) germ cell tumors are often classified on the basis of prognosis, with pure germinoma and mature teratoma representing the “good prognosis” group. The “poor prognosis” group includes yolk sac tumor, choriocarcinoma, and embryonal carcinoma, as well as mixed tumors composed mostly of these three histologic subtypes. The remaining CNS germ cell tumor subtypes fall into the “intermediate prognosis” group [4]. Management of these rare tumors has been the subject of debate, and standards of care are constantly evolving in an effort to minimize the known sequelae of treatment, specifically the long-term effects of radiation therapy. The rarity of these tumors has continued to impede progress in their management, and international cooperation has been advocated in an effort to counter this. For example, an international CNS germ cell tumor symposium convened for the third time in 2013 in order to provide a forum for discussion of the similarities and differences between treatment strategies in various parts of the world, with 117 delegates from 25 countries representing the various disciplines involved in the care of these patients [5•]. To provide an appropriate background for the management updates described herein, the historical treatment and current therapies for germinomas and NGGCTs will be briefly reviewed.
This article is part of the Topical Collection on Pediatric Oncology N. E. Millard : I. J. Dunkel (*) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA e-mail: [email protected]
Germinoma
N. E. Millard e-mail: [email protected]
Germinomas are considered to be very radiosensitive tumors. Patients with localized germinoma who are treated with
Treatment of Localized Germinoma
393, Page 2 of 7
radiation therapy alone have long-term progression-free survival rates that exceed 90% [6]. Historically, these tumors were treated with 36-Gy craniospinal irradiation with a boost to the primary tumor site for a total of 50–54 Gy. Owing to the incidence of clinically significant radiation-induced late effects, including endocrinopathies, second malignancies, and neurocognitive impairment, recent studies have evaluated reduced-volume or reduced-dose radiation therapy. Investigations demonstrating the low incidence of spinal relapse in patients for whom spinal irradiation was eliminated suggested that radiation therapy can be limited to whole brain or whole ventricle with a boost to the primary tumor site without increasing the risk of spinal relapse [7]. The addition of neoadjuvant chemotherapy has been attempted in an effort to reduce the dose and/or volume of radiation [8]. Although multiple regimens have been shown to be effective, many experts advocate the use of carboplatin and etoposide owing to comparable efficacy and reduction in the number of complications suffered by patients with diabetes insipidus when compared with patients treated with ifosfamide and cisplatin-containing regimens. Despite the known chemosensitivity of germinomas, chemotherapy without irradiation is associated with significantly inferior outcomes and is not recommended as a treatment strategy [9]. Similarly, neoadjuvant chemotherapy followed by involvedfield radiation therapy without whole-brain or whole-ventricle irradiation was found to result in an unacceptably high rate of relapse within the ventricles outside the radiation field. At present, the standard of care therefore includes 21–24Gy whole-ventricle irradiation with a boost to the primary tumor site for a total of 40–45 Gy. The current Children’s Oncology Group study ACNS1123 is designed to evaluate the efficacy of further reduction of the radiation therapy dose to 18 Gy whole-ventricle irradiation with a boost of 12 Gy to the primary tumor site in patients with localized germinoma and a complete response to chemotherapy. The extent of surgical resection for pure germinoma has also been a matter of debate. As neurosurgical techniques evolve, the morbidity of resection continues to decrease. An analysis of pooled data from the first, second, and third International Central Nervous System Germ Cell Tumor Study groups by Souweidane et al. [10] found better outcomes in patients who had less than 1.5 cm2 of residual disease, suggesting that more aggressive resection may provide some benefit. In addition, they noted that a more aggressive resection could increase diagnostic accuracy, as many tumors thought to be pure germinomas may contain nongerminomatous elements due to sampling error, leading to undertreatment and inferior outcome. Until these hypotheses are supported in future studies, gross total resection is not considered the standard of care.
Curr Oncol Rep (2014) 16:393
Treatment of Disseminated Germinoma The standard of care for disseminated germinoma as defined by the presence of multiple CNS lesions on diagnostic MRI and/or cerebrospinal fluid (CSF) cytology findings positive for tumor cells remains craniospinal irradiation. Again, research efforts have focused on reducing radiation therapy dosing without compromising disease-related outcomes. Historically, 36 Gy of craniospinal irradiation was administered with a boost to the primary lesion(s) to 50 Gy. The German MAKEI 89 trial supported the reduction in craniospinal irradiation to 30 Gy with a boost to 45 Gy [6]. Most recently, the SIOP CNS GCT 96 trial [11••] demonstrated 98% event-free and overall survival with a craniospinal irradiation dose of 24 Gy with a boost to 40 Gy, as discussed in more detail later. Treatment of Relapsed Germinoma In relapsed germinoma patients who received reduced-dose radiation therapy for their initial disease, salvage therapy with additional irradiation may be successful with or without chemotherapy. Craniospinal irradiation is considered the standard of care for patients who received only chemotherapy as part of their initial treatment. For those patients with relapsed disease to whom craniospinal radiation was administered for upfront control, myeloablative chemotherapy with autologous hematopoietic cell rescue is often considered [12]. Nongerminomatous Germ Cell Tumors In comparison with germinomas, NGGCTs are much less radiosensitive. Treatment regimens using irradiation without chemotherapy have historically resulted in 5-year overall survival rates of only 20-40% [2, 3]. Radiation therapy remains an important component of treatment strategies for NGGCTs, however, as patients treated with chemotherapy alone have been observed to experience recurrent disease in approximately 50% of cases. The addition of neoadjuvant chemotherapy to radiation therapy has significantly improved survival in patients with NGGCT to the range of 60-70%, and is currently considered the standard of care, although as in patients with germinoma, recent clinical trials have evaluated the effectiveness of reducing patients’ exposure to radiation by stratifying patients by risk of disease progression. Chemotherapy generally is administered for four to six cycles and frequently comprises carboplatin or cisplatin in conjunction with etoposide, and in some cases cyclophosphamide or ifosfamide. Craniospinal irradiation is subsequently given at a dose of 30–36 Gy with a boost to the primary tumor site for a total of 54–60 Gy. The presence of a residual mass after chemotherapy and radiation therapy has been associated with disease recurrence
Curr Oncol Rep (2014) 16:393
in several studies, and some groups advocate second-look surgery intended to remove residual tumor that has not responded to other therapeutic modalities as there is a possibility that this represents previously undetected teratoma that requires surgical excision [10]. Updates in Diagnosis and Surveillance A review by Sethi et al. [13] of 70 patients treated at the Massachusetts General Hospital found that patients with intracranial germ cell tumors often experienced a delay in the time from symptom onset to diagnosis by MRI, with “delay” defined as a period of 6 months or longer. More than half (54%) of patients in their cohort had a duration of symptoms prior to diagnostic MRI that was greater than 6 months. Although they did not find any statistically significant differences between progression-free survival in patients who experienced a delay in diagnosis and those who did not, they did find that patients with delayed diagnosis were more likely to have disseminated disease at the time the diagnosis was made. Disseminated disease was defined as the presence of tumor cells in the CSF or noncontiguous disease in more than one location, with the important exclusion of patients with bifocal suprasellar/pineal disease. Sethi et al. drew attention to the fact that the standard of care for patients with disseminated disease is craniospinal irradiation rather than involved-field or wholeventricle irradiation, the result of which is an increased risk of radiation-related late effects. The reasons for delay in diagnosis were multifactorial in their analysis, but were thought to be most related to the subtle nature of symptoms with a relatively slow onset, particularly in the case of suprasellar tumors. They noted that pineal-region tumors were more likely to present with signs of increased intracranial pressure due to blockage of CSF flow and resultant hydrocephalus, leading more rapidly to diagnosis with a median time to diagnosis of 1 month in their study. In contrast, suprasellar tumors may present with slowly progressive endocrinopathies with inconclusive or nondiagnostic findings on initial MRI, leading to a significantly prolonged median time to diagnosis of 16.8 months. Their article highlights the difficulties in diagnosis of intracranial germ cell tumors as well as the potential consequences of disease dissemination related to delayed diagnosis. So-called bifocal germ cell tumors with lesions in both the pineal region and the suprasellar region occur in approximately 5–10% of cases of intracranial germ cell tumor at diagnosis. Historically, there has been some debate regarding whether these tumors represent localized tumors, best treated with reduced-volume radiation therapy (with or without chemotherapy), or disseminated disease requiring craniospinal irradiation. Current recommendations are to treat bifocal tumors as independent synchronous primary tumors rather than metastatic disease [14, 15]. Phi et al. [16] reviewed 181 intracranial germ cell tumor patients treated at Seoul National
Page 3 of 7, 393
University Hospital between 1998 and 2010, of whom 23 (12.8%) had bifocal disease at diagnosis. Although bifocal disease has historically been viewed as specific to and even pathognomonic of germinoma, Phi et al. discovered that five of 23 patients (21.7%) with bifocal disease in their series were diagnosed with mixed germ cell tumor by CSF or serum markers. They also reported that their patients with bifocal disease were five times more likely (p
PEDIATRIC ONCOLOGY (S EPELMAN, SECTION EDITOR)
Advances in the Management of Central Nervous System Germ Cell Tumors Nathan E. Millard & Ira J. Dunkel
Published online: 17 May 2014 # Springer Science+Business Media New York 2014
Abstract Intracranial germ cell tumors represent a relatively small portion of pediatric central nervous system tumors, with a reported incidence ranging from 3.6% in North America to 15.3% in parts of Asia. They are known to arise in midline locations, most frequently the pineal gland and suprasellar regions, and affect males twice to three times more frequently than females, especially in the case of pineal-region tumors. The median age of diagnosis is 10–12 years. The treatment of intracranial germ cells tumors is complicated by their relative rarity, histologic heterogeneity, and a lack of widespread consensus on their optimal management. Despite these challenges, important progress continues to be made, with a move toward multicenter and international collaborative efforts that offer potential for clinical advancements. This review focuses on recent developments in the management of intracranial germ cell tumors, including updates in diagnosis, surveillance, biology, treatment, and outcomes. Keywords Intracranial germ cell tumor . Germinoma . Nongerminomatous germ cell tumor . Pediatrics
Introduction The WHO classification system divides intracranial germ cell tumors into germinomas and nongerminomatous germ cell tumors (NGGCTs). The latter category comprises a number of tumor subtypes, including choriocarcinoma, embryonal
carcinoma, mature and immature teratoma, yolk sac tumor/ endodermal sinus tumor, and mixed germ cell tumor. Germinomas represent approximately two-thirds of intracranial germ cell tumors while NGGCTs comprise the remaining third [1–3]. In Japan, central nervous system (CNS) germ cell tumors are often classified on the basis of prognosis, with pure germinoma and mature teratoma representing the “good prognosis” group. The “poor prognosis” group includes yolk sac tumor, choriocarcinoma, and embryonal carcinoma, as well as mixed tumors composed mostly of these three histologic subtypes. The remaining CNS germ cell tumor subtypes fall into the “intermediate prognosis” group [4]. Management of these rare tumors has been the subject of debate, and standards of care are constantly evolving in an effort to minimize the known sequelae of treatment, specifically the long-term effects of radiation therapy. The rarity of these tumors has continued to impede progress in their management, and international cooperation has been advocated in an effort to counter this. For example, an international CNS germ cell tumor symposium convened for the third time in 2013 in order to provide a forum for discussion of the similarities and differences between treatment strategies in various parts of the world, with 117 delegates from 25 countries representing the various disciplines involved in the care of these patients [5•]. To provide an appropriate background for the management updates described herein, the historical treatment and current therapies for germinomas and NGGCTs will be briefly reviewed.
This article is part of the Topical Collection on Pediatric Oncology N. E. Millard : I. J. Dunkel (*) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA e-mail: [email protected]
Germinoma
N. E. Millard e-mail: [email protected]
Germinomas are considered to be very radiosensitive tumors. Patients with localized germinoma who are treated with
Treatment of Localized Germinoma
393, Page 2 of 7
radiation therapy alone have long-term progression-free survival rates that exceed 90% [6]. Historically, these tumors were treated with 36-Gy craniospinal irradiation with a boost to the primary tumor site for a total of 50–54 Gy. Owing to the incidence of clinically significant radiation-induced late effects, including endocrinopathies, second malignancies, and neurocognitive impairment, recent studies have evaluated reduced-volume or reduced-dose radiation therapy. Investigations demonstrating the low incidence of spinal relapse in patients for whom spinal irradiation was eliminated suggested that radiation therapy can be limited to whole brain or whole ventricle with a boost to the primary tumor site without increasing the risk of spinal relapse [7]. The addition of neoadjuvant chemotherapy has been attempted in an effort to reduce the dose and/or volume of radiation [8]. Although multiple regimens have been shown to be effective, many experts advocate the use of carboplatin and etoposide owing to comparable efficacy and reduction in the number of complications suffered by patients with diabetes insipidus when compared with patients treated with ifosfamide and cisplatin-containing regimens. Despite the known chemosensitivity of germinomas, chemotherapy without irradiation is associated with significantly inferior outcomes and is not recommended as a treatment strategy [9]. Similarly, neoadjuvant chemotherapy followed by involvedfield radiation therapy without whole-brain or whole-ventricle irradiation was found to result in an unacceptably high rate of relapse within the ventricles outside the radiation field. At present, the standard of care therefore includes 21–24Gy whole-ventricle irradiation with a boost to the primary tumor site for a total of 40–45 Gy. The current Children’s Oncology Group study ACNS1123 is designed to evaluate the efficacy of further reduction of the radiation therapy dose to 18 Gy whole-ventricle irradiation with a boost of 12 Gy to the primary tumor site in patients with localized germinoma and a complete response to chemotherapy. The extent of surgical resection for pure germinoma has also been a matter of debate. As neurosurgical techniques evolve, the morbidity of resection continues to decrease. An analysis of pooled data from the first, second, and third International Central Nervous System Germ Cell Tumor Study groups by Souweidane et al. [10] found better outcomes in patients who had less than 1.5 cm2 of residual disease, suggesting that more aggressive resection may provide some benefit. In addition, they noted that a more aggressive resection could increase diagnostic accuracy, as many tumors thought to be pure germinomas may contain nongerminomatous elements due to sampling error, leading to undertreatment and inferior outcome. Until these hypotheses are supported in future studies, gross total resection is not considered the standard of care.
Curr Oncol Rep (2014) 16:393
Treatment of Disseminated Germinoma The standard of care for disseminated germinoma as defined by the presence of multiple CNS lesions on diagnostic MRI and/or cerebrospinal fluid (CSF) cytology findings positive for tumor cells remains craniospinal irradiation. Again, research efforts have focused on reducing radiation therapy dosing without compromising disease-related outcomes. Historically, 36 Gy of craniospinal irradiation was administered with a boost to the primary lesion(s) to 50 Gy. The German MAKEI 89 trial supported the reduction in craniospinal irradiation to 30 Gy with a boost to 45 Gy [6]. Most recently, the SIOP CNS GCT 96 trial [11••] demonstrated 98% event-free and overall survival with a craniospinal irradiation dose of 24 Gy with a boost to 40 Gy, as discussed in more detail later. Treatment of Relapsed Germinoma In relapsed germinoma patients who received reduced-dose radiation therapy for their initial disease, salvage therapy with additional irradiation may be successful with or without chemotherapy. Craniospinal irradiation is considered the standard of care for patients who received only chemotherapy as part of their initial treatment. For those patients with relapsed disease to whom craniospinal radiation was administered for upfront control, myeloablative chemotherapy with autologous hematopoietic cell rescue is often considered [12]. Nongerminomatous Germ Cell Tumors In comparison with germinomas, NGGCTs are much less radiosensitive. Treatment regimens using irradiation without chemotherapy have historically resulted in 5-year overall survival rates of only 20-40% [2, 3]. Radiation therapy remains an important component of treatment strategies for NGGCTs, however, as patients treated with chemotherapy alone have been observed to experience recurrent disease in approximately 50% of cases. The addition of neoadjuvant chemotherapy to radiation therapy has significantly improved survival in patients with NGGCT to the range of 60-70%, and is currently considered the standard of care, although as in patients with germinoma, recent clinical trials have evaluated the effectiveness of reducing patients’ exposure to radiation by stratifying patients by risk of disease progression. Chemotherapy generally is administered for four to six cycles and frequently comprises carboplatin or cisplatin in conjunction with etoposide, and in some cases cyclophosphamide or ifosfamide. Craniospinal irradiation is subsequently given at a dose of 30–36 Gy with a boost to the primary tumor site for a total of 54–60 Gy. The presence of a residual mass after chemotherapy and radiation therapy has been associated with disease recurrence
Curr Oncol Rep (2014) 16:393
in several studies, and some groups advocate second-look surgery intended to remove residual tumor that has not responded to other therapeutic modalities as there is a possibility that this represents previously undetected teratoma that requires surgical excision [10]. Updates in Diagnosis and Surveillance A review by Sethi et al. [13] of 70 patients treated at the Massachusetts General Hospital found that patients with intracranial germ cell tumors often experienced a delay in the time from symptom onset to diagnosis by MRI, with “delay” defined as a period of 6 months or longer. More than half (54%) of patients in their cohort had a duration of symptoms prior to diagnostic MRI that was greater than 6 months. Although they did not find any statistically significant differences between progression-free survival in patients who experienced a delay in diagnosis and those who did not, they did find that patients with delayed diagnosis were more likely to have disseminated disease at the time the diagnosis was made. Disseminated disease was defined as the presence of tumor cells in the CSF or noncontiguous disease in more than one location, with the important exclusion of patients with bifocal suprasellar/pineal disease. Sethi et al. drew attention to the fact that the standard of care for patients with disseminated disease is craniospinal irradiation rather than involved-field or wholeventricle irradiation, the result of which is an increased risk of radiation-related late effects. The reasons for delay in diagnosis were multifactorial in their analysis, but were thought to be most related to the subtle nature of symptoms with a relatively slow onset, particularly in the case of suprasellar tumors. They noted that pineal-region tumors were more likely to present with signs of increased intracranial pressure due to blockage of CSF flow and resultant hydrocephalus, leading more rapidly to diagnosis with a median time to diagnosis of 1 month in their study. In contrast, suprasellar tumors may present with slowly progressive endocrinopathies with inconclusive or nondiagnostic findings on initial MRI, leading to a significantly prolonged median time to diagnosis of 16.8 months. Their article highlights the difficulties in diagnosis of intracranial germ cell tumors as well as the potential consequences of disease dissemination related to delayed diagnosis. So-called bifocal germ cell tumors with lesions in both the pineal region and the suprasellar region occur in approximately 5–10% of cases of intracranial germ cell tumor at diagnosis. Historically, there has been some debate regarding whether these tumors represent localized tumors, best treated with reduced-volume radiation therapy (with or without chemotherapy), or disseminated disease requiring craniospinal irradiation. Current recommendations are to treat bifocal tumors as independent synchronous primary tumors rather than metastatic disease [14, 15]. Phi et al. [16] reviewed 181 intracranial germ cell tumor patients treated at Seoul National
Page 3 of 7, 393
University Hospital between 1998 and 2010, of whom 23 (12.8%) had bifocal disease at diagnosis. Although bifocal disease has historically been viewed as specific to and even pathognomonic of germinoma, Phi et al. discovered that five of 23 patients (21.7%) with bifocal disease in their series were diagnosed with mixed germ cell tumor by CSF or serum markers. They also reported that their patients with bifocal disease were five times more likely (p
