Intracranial Nongerminomatous Germ Cell Tumors Research Articles

Increased Human Chorionic Gonadotropin Level in a Nonsexually Active Young Female

BackgroundQuantitative and qualitative human chorionic gonadotropin (hCG) tests are obtained in the emergency department (ED) to determine if a female of child-bearing age is pregnant. A positive hCG result is commonly assumed to indicate an intrauterine or other form of pregnancy. However, elevated hCG levels can also result from various other conditions, such as ovarian tumors, pituitary tumors, and thyroid disorders. Intracranial germ cell tumors, rare central nervous system tumors capable of secreting hCG, primarily affect adolescent and young adult females. Case ReportA 16-year-old female student without significant past medical history presented to our ED with a complaint of intermittent bilateral frontal headache for two days. Last menstrual period started two days prior to presentation. The headache was associated with phonophobia, photophobia, nausea, and vomiting. Serum quantitative hCG was elevated. She denied history of sexual activity or sexual assault. Transabdominal ultrasound was negative for intrauterine pregnancy. Obstetrics and gynecology as well as pediatric oncology were consulted. Subsequent investigations, including brain imaging, revealed a 3.5 cm mass in the right caudate nucleus and corpus callosum. The patient was diagnosed with an intracranial nongerminomatous germ cell tumor, necessitating hospitalization and prompt initiation of chemotherapy. Why Should an Emergency Physician Be Aware of This?An elevated quantitative hCG is not always indicative of pregnancy, especially in a young patient without sexual history. In the case of a nonrevealing transabdominal ultrasound, obstetrics and gynecology should be consulted for discussion of further testing and imaging. Emergency physicians should include malignancy high on their differential since prompt initiation of chemotherapy, evaluation by surgical services, and family planning will be required.

GCT-26. INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMOR WITH MALIGNANT TRANSFORMATION TO EMBRYONAL RHABDOMYSARCOMA

Abstract BACKGROUND Non-germinomatous germ cell tumors (NGGCT) constitute 35%- 45% of intracranial germ cell tumors. Growing teratoma syndrome has been observed in patients with NGGCTs after starting chemotherapy. While growing teratomas are typically benign, this process can rarely involve malignant transformation and result in poor prognosis. We present the case of a patient with pineal NGGCT and growing teratoma syndrome with malignant transformation to embryonal rhabdomyosarcoma. CASE REPORT A 13-year-old male presented with headaches and vision changes. An MRI brain demonstrated a 26 x 25 x 19 mm (AP X TR X CC) mixed solid and cystic pineal mass with no evidence of metastatic disease. Due to elevated alpha fetoprotein levels in the serum and cerebrospinal fluid, he was diagnosed with intracranial NGGCT. Treatment was initiated with alternating cycles of Carboplatin/Etoposide and Ifosfamide/Etoposide. After 2 cycles of chemotherapy, a complete biochemical response was noted but MRI showed increased tumor size (presumed growing teratoma syndrome). The patient underwent complete tumor resection. Histology showed embryonal rhabdomyosarcoma as a somatic malignancy arising in a mature teratoma. Further molecular characterization revealed somatic NF1 and KRAS pathogenic mutations that are consistent with the primary diagnosis. Methylation profiling, however, did not exhibit a match with any known malignancies. Continued complete response was noted following two additional chemotherapy cycles. The patient is planned for six total chemotherapy cycles followed by high-dose craniospinal radiation with boost to the primary tumor. CONCLUSIONS Malignant transformation is a rare phenomenon in NGGCT. There is no standard of care for these patients. Further studies are needed to define ideal therapy for this patient population.

Intracranial non-germinomatous germ cell tumors in children and adolescents: how can the experience from an uppermiddle-income country contribute to the worldwide effort to improve outcomes?

Non-germinomatous germ cell tumors (NGGCT) accounts for one third of intracranial GCT. While the germinoma group have an excellent overall survival, the standard of practice for children with NGGCT is still under evaluation. Describe the results of the of the Brazilian consortium protocol. Since 2013, 15 patients with a diagnosis of NGGCT by histopathology and/or serum/cerebrospinal fluid (CSF) tumor markers, βHCG >200mlU/ml and/or positive alpha-fetoprotein were treated with neoadjuvant chemotherapy with carboplatin, cyclophosphamide and etoposide followed by ventricular radiotherapy (RTV) of 18Gy with boost (32Gy) to the primary site. Metastatic patients underwent craniospinal irradiation (CSI) and "slow responders" to the four initial cycles of CT, to autologous stem cell transplantation (ASCT) followed by CSI. Mean age, 13.1 years. Thirteen males. Primary sites: pineal (n=12), suprasellar (n=2) and bifocal (n=1). Four patients were metastatic at diagnosis. Eight patients had CSF and/or serum alpha-fetoprotein levels > 1,000ng/ml. Tumor responses after chemotherapy demonstrated complete in six cases and partial in seven, with "second-look" surgery being performed in five cases, and two patients presenting viable lesions being referred to ASCT. The main toxicity observed was hematological grades 3/4. Two patients with metastatic disease, one with Down Syndrome and AFP > 1,000ng/ml and the other with choriocarcinoma and pulmonary metastases, developed progressive disease resulting in death, as well as two other patients without evidence of disease, due to endocrinological disorders. Event-free and overall survival at 2 and 5 years were 80% and 72.7%, respectively, with a mean follow-up of 48 months (range, 7-107). Despite the small number of patients, in our series, treatment with six cycles of chemotherapy and RTV with focal boost for localized disease (n=11) and ACST for identified slow responders (n=2) seem to be effective strategies contributing to the overall effort to improve outcomes of this group of patients.

Treatment Course and Outcomes of Intracranial Teratomas in Pediatric Patients: A Retrospective 15-Year Case Series Study

Introduction: There is no standard treatment paradigm for intracranial teratomas, a rare subset of primary intracranial non-germinomatous germ cell tumors (NGGCT), which comprise less than 1% of pediatric brain tumors. This case series retrospectively analyzes treatment and outcomes of pediatric intracranial teratomas from a single institution. Methods: Authors reviewed a comprehensive pathology database at Stanford’s Lucile Packard Children’s Hospital for intracranial teratomas in pediatric patients treated from 2006 to 2021; their demographics, treatment, and clinical course were analyzed. Results: Among 14 patients, median follow-up time was 4.6 years and mean age at diagnosis was 10.5 years. Ten had elevated tumor markers and underwent chemotherapy as initial treatment for NGGCT. Ultimately, these patients all required surgery for progressive or residual disease. Two patients did not undergo radiation. After biopsy or resection, 8 patients had pure mature teratoma, five had mixed germ cell tumor with teratoma component, and one had immature teratoma. The patient with immature teratoma died during chemotherapy from septic shock. No patients experienced recurrence. Common sequelae were endocrine (42.8%) and eye movement (50.0%) abnormalities. Discussion/Conclusion: We highlight the variable treatment course and outcome for pediatric patients with intracranial teratomas. Elevated tumor markers at presentation, along with imaging findings, favor chemotherapy initiation for presumed NGGCT. Resection of residual tumor is recommended even if tumor markers return to normal. Prognosis remains excellent; no patients had recurrence with a median follow-up of 4.6 years.

Final report of the phase II NEXT/CNS-GCT-4 trial: GemPOx followed by marrow-ablative chemotherapy for recurrent intracranial germ cell tumors.

Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx). A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR. Treatment response was determined based on radiographic tumor assessments and tumor markers. A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease. GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy.

​Occult extracranial malignancy after complete remission of pineal mixed germ cell tumors: a rare case report and literature review

Background​Extracranial metastasis can occur in intracranial germ cell tumors (GCTs), but it is very rare. Recurrence or metastasis of non-germinomatous germ cell tumors (NGGCTs) is often accompanied by elevated tumor markers. ​Occult extracranial metastases or recurrences with negative markers are often difficult to detect in time, resulting in a very poor prognosis.Case presentationA 12-year-old boy was admitted to our institution with dizziness, headache, vomiting, and sleepiness. Magnetic resonance imaging (MRI) showed a pineal mass, accompanied by a significant increase in serum alpha-fetoprotein (AFP). The patient subsequently underwent total removal of the tumor. Pathology revealed that the tumor was a mixed GCT, consisting of mature teratoma, germinoma, and yolk sac tumor. Intracranial GCT achieved complete remission after intensive adjuvant chemotherapy and radiotherapy. Regular follow-up MRI revealed no recurrence of the intracranial tumor and continued monitoring of tumor markers revealed no abnormalities. ​Eight months later, the patient was readmitted due to progressive abdominal pain. Imaging and physical examination revealed abdominal occupation and lymphatic mass in the neck. He received salvage chemotherapy, anti-PD-1 immunotherapy, and palliative chemotherapy, but still developed multiple organ dysfunction syndromes (MODS) due to tumor progression and eventually died after one month.Conclusions​This profound case suggests that intracranial NGGCTs may develop occult extracranial malignancy, which can be very severe at the time of clinical symptoms and has an extremely poor prognosis. Therefore, in addition to tumor marker monitoring, regular follow-up with extracranial imaging may be warranted to detect extracranial tumors as early as possible, although perhaps not as frequently as with neuroimaging.

PD-L1 and PD-1 expression in pediatric central nervous system germ cell tumors

Central nervous system (CNS) germ cell tumors (GCTs) represent 2–3% of all primary CNS tumors. The majority are germinomas, which are radiosensitive and have an excellent prognosis. Contrarily, CNS non-germinomatous GCTs (NGGCTs) have less favorable prognosis and require more aggressive treatment. The expression of checkpoint/immune markers in CNS GCTs, particularly NGGCTs, is unknown. We previously reported a case of a patient whose intracranial NGGCT (predominantly choriocarcinoma) responded to immune checkpoint inhibition therapy. This case led us to evaluate our archive of intracranial GCTs for expression of PD-L1 and PD-1. With IRB approval, we searched the pathology archives at our institution for CNS GCTs. Demographic, radiologic, clinical, and histologic information was extracted from the medical records. Immunohistochemistry for lymphocytic markers (CD4, CD8, CD20), PD-1, and PD-L1 was performed. PD-L1 was considered positive if greater than 1% of tumor cells were positive and PD-1 was reported as a percentage of positive inflammatory cells. Fifty cases were identified, including 28 germinomas (mean age at diagnosis: 15.5 years; 17 males, 11 females), and 22 NGGCTs (mean age at diagnosis: 12.0 years, 21 males, 1 female). Germinomas were mostly suprasellar (17/28) and NGGCTs were predominantly pineal (17/22). Twenty-two germinomas (79%) were positive for PD-L1 expression, and 13 NGGCTs (57%) were positive for PD-L1. Cases of choriocarcinoma showed the most diffuse PD-L1 expression. PD-1 expression was seen in lymphocytes among 27/28 of the germinomas and 20/23 of the NGGCTs (ranging from 1–40% of lymphocytes). As expected, larger quantities of inflammatory cells were present in cases of germinoma. We demonstrate immune activity in CNS GCTs, and our results suggest that immune checkpoint inhibitors may be efficacious in the treatment of intracranial GCTs. Among NGGCTs, cases of choriocarcinoma showed the highest expression of PD-L1 in tumor cells, suggesting that this subtype may have the greatest benefit from checkpoint blockade.

Survival outcomes, hematologic complications and growth impairment after sequential chemoradiotherapy in intracranial NGGCTs: aretrospective study.

This study aimed to evaluate the clinical features, prognostic factors, and survival outcomes for patients with intracranial nongerminomatous germ cell tumors (NGGCTs), with aparticular focus on treatment toxicity for long-term survivors. Intracranial NGGCTs treated with platinum-based chemotherapy and craniospinal irradiation (CSI) in our institution were retrospectively analyzed. Hematological complications following sequential chemoradiotherapy as well as height and weight in childhood survivors were evaluated. Plasma growth hormone (GH) concentrations prior to and after radiotherapy were obtained for the comparisons. Atotal of 111 intracranial NGGCTs were included. The 3‑year overall survival (OS) and event-free survival (EFS) rates were 83.5% ± 3.9% and 71.0% ± 4.8%, respectively. Acombined treatment modality consisting of ≥ 4cycles of platinum-based chemotherapy and CSI was associated with an improved OS (P = 0.003) and EFS (P < 0.001). Thrombocytopenia of any grade occurred in 35.4% (34/96) of patients, and the threshold age for an increased risk of thrombocytopenia was 14 years (area under the curve AUC = 0.752, P < 0.0001) as derived from receiver operating characteristic (ROC) analysis. Growth impediment was found in 8of 56(14%) patients. The age for receiving radiotherapy was found to inversely correlate with height development, revealing acut-off age of 11.5 years for risking growth impairment (AUC = 0.806, P = 0.004). Consistently, asignificant decline in plasma growth hormone after radiotherapy was observed in patients ≤ 11.5 years (P < 0.01) but not patients > 11.5 years. (P > 0.05). Our study suggested that acombined treatment modality with at least four cycles of chemotherapy and CSI was safe and effective for patients with intracranial NGGCTs. Radiotherapy should be used with caution for patients < 11.5 years due to growth impairment.

GCT-27. CLINICAL FEATURES AND PROGNOSTIC FACTORS OF NONGERMINOMATOUS GERM CELL TUMORS IN 111 CONSECUTIVE PATIENTS IN A SINGLE INSTITUTION: IMPACT OF IRRADIATION AND CHEMOTHERAPY CYCLES ON SURVIVAL

BACKGROUNDLimited data is available in intracranial nongerminomatous germ cell tumors (NGGCTs) in Chinese population. Here we aimed to retrospectively assess the clinical-pathological and prognostic factors of NGGCTs in a single large institution in China.METHODSFrom June 2003 to December 2018, 111 consecutive NGGCTs were treated in Guangdong Sanjiu Brain Hospital, China.RESULTSThe median follow-up was 36.2 months (range, 1.2 to 131.2 months). Three-year EFS and OS for 111 NGGCTs patients were 78.5%±4.5% and 82.8%±4.0%, respectively. 98 patients received CSI plus boost yielded better survival than those who received reduced-volume radiotherapy or no radiotherapy (3y OS, 86.7% vs. 51.4%, p=0.007). Patients had at least four cycles of chemotherapy were strongly associated with improved 3-year OS, compared to those received less than 4 cycles (94.1% vs. 63.6%, p＜0.001). There was no significant difference in survival of patients stratified by age, surgery, hydrocephalus, as well as tumor diameter. Multivariate analysis identified chemotherapy cycles less than 4 was the only prognostic factor that conferring a worse OS (p=0.003). Patients both received CSI and at least 4 courses of chemotherapy were correlated with lower incidence of relapse (p=0.044).CONCLUSIONSMultimodal approach including CSI and enough courses of chemotherapy was effective and should be recommended for the treatment of newly diagnosed NGGCTs in Chinese population.

CTNI-62. CLINICAL FEATURES AND PROGNOSTIC FACTORS OF NONGERMINOMATOUS GERM CELL TUMORS IN 111 CONSECUTIVE PATIENTS IN A SINGLE INSTITUTION: IMPACT OF IRRADIATION AND CHEMOTHERAPY CYCLES ON SURVIVAL

Abstract BACKGROUND Limited data is available in intracranial nongerminomatous germ cell tumors (NGGCTs) in Chinese population. Here we aimed to retrospectively assess the clinical-pathological and prognostic factors of NGGCTs in a single large institution in China. METHODS From June 2003 to December 2018, 111 consecutive NGGCTs were treated in Guangdong Sanjiu Brain Hospital, China. RESULTS The median follow-up was 36.2 months (range, 1.2 to 131.2 months). Three-year EFS and OS for 111 NGGCTs patients were 78.5%±4.5% and 82.8%±4.0%, respectively. 98 patients received CSI plus boost yielded better survival than those who received reduced-volume radiotherapy or no radiotherapy (3y OS, 86.7% vs. 51.4%, p=0.007). Patients had at least four cycles of chemotherapy were strongly associated with improved 3-year OS, compared to those received less than 4 cycles (94.1% vs. 63.6%, p＜0.001). There was no significant difference in survival of patients stratified by age, surgery, hydrocephalus, as well as tumor diameter. Multivariate analysis identified chemotherapy cycles less than 4 was the only prognostic factor that conferring a worse OS (p=0.003). Patients both received CSI and at least 4 courses of chemotherapy were correlated with lower incidence of relapse (p=0.044). CONCLUSIONS Multimodal approach including CSI and enough courses of chemotherapy was effective and should be recommended for the treatment of newly diagnosed NGGCTs in Chinese population.

CTNI-60. NEOAJUVANT CHEMOTHERAPY FOLLOWED BY CRANIOSPINAL IRRADIATION FOR INTRACRANIAL NGGCTS: CLINICAL OUTCOMES AND AGE-STRATIFIED TOXICITIES IN A COHORT OF 111 PATIENTS

Abstract BACKGROUND Intracranial non-germinomatous germ cell tumors (NGGCTs) are rare tumors with limited studies available worldwide. Despite significantly improved survivals, there are still approximately 30% of patients experience relapse and require salvage treatment. This study aimed to access the clinical-pathological features and prognostic factors with specific interests to recurrence as well as adverse effects. METHODS From June 2005 and December 2018, 111 consecutive intracranial NGGCTs patients (87 localized stage and 24 metastatic stage) diagnosed based on histological confirmation, or alternatively by clinical presentation, radiological outcomes and elevated tumor markers were retrospectively analyzed. RESULTS After a median follow-up of 46.2 months, Three- and five- year OS were 83.5% ± 3.9% and 78.6% ± 5.1%, respectively. Three- and five- year EFS were 71.0% ± 4.8% and 64.7% ± 5.7%, respectively. Patients received craniospinal irradiation (CSI) integrated combined treatment yielded superior 3-year OS (P=0.007), EFS (P=0.002), and relapse rate (P=0.004) compared to those without CSI. A combination of minimum 4 cycles of induction chemotherapy and CSI integrated approach was the independent prognostic factor (P=0.007) conferring favorable 3-year OS and EFS of 93.9%±3.5% and 84.0%±5.4%, respectively. Poor prognosis of histological subtypes were particularly benefit from this treatment modality (P&amp;lt; 0.001). Age-thresholds for risking therapy-related thrombocytopenia and growth impairment by ROC analysis were 14 (AUC=0.752, P&amp;lt; 0.0001) and 11.5 (AUC=0.806, P&amp;lt; 0.01) yr., respectively. CONCLUSIONS Our study suggested that multimodal approach consisting of ≥4 cycles of induction chemotherapy and CSI plus focal boost with or without second-look surgery was recommended for NGGCTs. However, CSI should be used with caution when patients &amp;lt; 11.5-yr due to growth impairment. More precise risk stratifications are highly demanded for delivery of the most appropriate management in the future.

Proton Therapy for Intracranial Non-Germinomatous Germ Cell Tumors

Proton radiation therapy (RT) is the most conformal available RT modality. The survival and progression outcomes among patients with intracranial non-germinomatous germ cell tumors treated with proton RT have not been reported. Retrospective review of 38 patients with NGGCT treated between May 2005 and September 2016 at the Massachusetts General Hospital and Francis H. Burr Proton Center. A subset of 12 patients were enrolled in a prospective protocol. Patients with prior recurrences were excluded. Thirty-eight patients with a median age of 12 years (range 5-22) were identified. Twenty-eight (74%) were male, 10 (26%) were female. 31 (82%) were white. Twenty-one (55%) had hydrocephalus at diagnosis, and 12 (32%) required a shunt. 9 (24%) had evidence of metastatic disease at diagnosis (positive CSF cytology OR disseminated disease). Location of the primary tumor was suprasellar in 12 (32%), pineal in 15 (39%), and bifocal in 10 (26%) patients; one patient had a primary cerebellar tumor. Almost one-third underwent GTR (32% vs. 24% STR, 26% biopsy alone, 18% no surgery). All patients received induction chemotherapy (100%), the majority with 6 alternating cycles of carboplatin/etoposide & ifosfamide/etoposide. Ten patients (26%) had a second look surgery after chemotherapy. RT field was CSI in 26 (68%), WVRT in 11 (29%), and IF-only in 1 (3%). The median CSI dose was 27 Gy RBE (18-36). At a median follow-up of 4.1 years among 35 patients still alive, 5-year PFS was 80%, and 5-year OS was 88%. Of the 5 patients that recurred, 1 recurrence was local, 3 were distant (1 shunt related), and 1 patient had a failure by markers only. Proton RT is associated with excellent local control and overall survival in this large series of a very rare tumor (Table 1).Abstract 1028; Table 1Factors associated with progression-free survival in NGGCTNGGCT3-year PFSp-valueOverall85%Location*0.322Suprasellar100%Pineal77%Bifocal77%Gender0.144Male81%Female100%Disseminated disease at diagnosis0.295Yes100%No82%Field of RT0.187#WVRT81%CSI92%*Suprasellar vs. Pineal/Bifocal #WVRT vs. CSI; only one patient treated with IF-only who recurred at 21 months. Open table in a new tab

Early outcomes and patterns of failure following proton therapy for nonmetastatic intracranial nongerminomatous germ cell tumors.

Although dosimetric comparisons demonstrate the advantage of proton therapy (PT) over conventional radiotherapy for nongerminomatous germ cell tumors (NGGCT), clinical outcome data for this rare tumor are lacking. We sought to evaluate outcomes for children with NGGCT treated with PT. Between 2007 and 2016, 14 children (median age 11, range, 5-19 years) with nonmetastatic NGGCT were treated with PT after induction chemotherapy. Most (8/14) were mixed germ cell. Five of 14 patients had complete resection of their primary tumor before radiation. Off study, eight patients received 36Gy (RBE [relative biological effectiveness]) craniospinal irradiation (CSI). On study, two patients received 30.6Gy (RBE) whole-ventricle irradiation and four received focal radiation alone. All patients received a total dose of 54Gy (RBE) to the tumor/tumor bed. At a median follow-up of 2.8 years, all patients were alive with no local recurrences. Three-year progression-free survival was 86%. Both metastatic recurrences occurred in patients treated with focal radiation alone; one with an immature teratoma developed an isolated spinal recurrence 5 months after treatment. Another with a mixed germ cell tumor developed a multifocal ventricular and shunt tract recurrence 7 months after treatment. Serious toxicity was minimal, including cataracts and hormone deficiency, and limited to children who received CSI. Early outcomes in children treated for NGGCT suggest the high conformality of PT does not compromise disease control and yields low toxicity. This pattern of failure data adds to growing evidence suggesting chemotherapy followed by focal radiotherapy alone is inadequate in controlling localized NGGCT.

Optimal Radiotherapy Target Volumes in Intracranial Non-Germinomatous Germ Cell Tumors: Long-Term Institutional Experience with Chemotherapy, Surgery and Dose and Field Adapted Radiotherapy

Optimal Radiotherapy Target Volumes in Intracranial Non-Germinomatous Germ Cell Tumors: Long-Term Institutional Experience with Chemotherapy, Surgery and Dose and Field Adapted Radiotherapy

Optimal radiotherapy target volumes in intracranial nongerminomatous germ cell tumors: Long-term institutional experience with chemotherapy, surgery, and dose- and field-adapted radiotherapy.

To evaluate patterns of failure after multimodality treatment of nongerminomatous germ cell tumors (NGGCTs). We retrospectively reviewed records of 34 patients diagnosed with primary intracranial NGGCT between 1988 and 2014. Thirty-four patients received induction chemotherapy followed by radiation with or without surgery. Median follow-up was 11.1 years (0.8-23.3). Outcomes were significantly improved in these 34 patients (5-year overall survival [OS]: 88% versus 50%, P=0.0092), so analysis is restricted to that subset. Disease-free survival (DFS) was 67, 60, and 54% at 5, 10, and 15 years, respectively. Elevated cerebrospinal fluid-α-fetoprotein (CSF-AFP) at diagnosis was associated with poorer DFS (37 vs. 89% at 10 years; P=0.01). There was no statistically significant difference in OS, or DFS, or patterns of failure for limited radiotherapy volumes versus larger volumes; however, patients receiving initial local radiotherapy had 32% distant central nervous system (CNS) recurrence at 10 years compared to 0% for those receiving initial larger field irradiation (P=0.09). Fifteen patients recurred. All four patients who relapsed in the spine had received local radiotherapy and had elevated serum and CSF-AFP at baseline. All three patients with ventricular relapse received local radiation therapy. NGGCT patients continue to relapse beyond 5 years. Late ventricular relapse occurred even in patients without clear evidence of germinoma component. Elevated CSF-AFP at diagnosis is associated with poor DFS and risk for distant CNS relapse. Patients with residual radiographic disease after chemotherapy or residual malignant histologies after second-look surgery have inferior outcomes. Our data support consideration of treatment intensification for these patients.

Outcome of patients with intracranial non-germinomatous germ cell tumors-lessons from the SIOP-CNS-GCT-96 trial.

Following promising results to increase survival and reduce treatment burden in intracranial non-germinomatous germ cell tumors (NGGCTs), we conducted a European study using dose-intense chemotherapy followed by risk-adapted radiotherapy. All patients received 4 courses of cisplatin/etoposide/ifosfamide. Non-metastatic patients then received focal radiotherapy only (54 Gy); metastatic patients received 30 Gy craniospinal radiotherapy with 24 Gy boost to primary tumor and macroscopic metastatic sites. Patients with localized malignant NGGCT (n = 116) demonstrated 5-year progression-free survival (PFS) and overall survival (OS) of 0.72 ± 0.04 and 0.82 ± 0.04, respectively. Primary tumor sites were: 67 pineal, 35 suprasellar, 5 bifocal, 9 others. One patient died postsurgery in clinical remission; 3 patients progressed during treatment and 27 (23%) relapsed afterward. Fourteen were local, 6 combined, and 7 distant relapses (outside radiation field). Seventeen of the 27 relapsed patients died of disease. Patients with metastatic disease (n = 33) demonstrated 5-year PFS and OS of 0.68 ± 0.09 and 0.75 ± 0.08, respectively; 1 patient died following progression on treatment and 9 (27%) relapsed afterward (5 local, 1 combined, 3 distant). Only one metastatic patient with recurrence was salvaged. Multivariate analysis identified diagnostic alpha-fetoprotein level (serum and/or cerebrospinal fluid level >1000 ng/mL, 19/149 patients, of whom 11 relapsed; P < 0.0003) and residual disease following treatment, including after second-look surgery (n = 52/145 evaluable patients, 26 relapsed; P = 0.0002) as significant prognostic indicators in this cohort. In localized malignant NGGCT, craniospinal radiotherapy could be avoided without increased relapses outside the radiotherapy field. Chemotherapy and craniospinal radiotherapy remain the gold standard for metastatic disease.

Noncarboplatin-induced Sensorineural Hearing Loss in a Patient With an Intracranial Nongerminomatous Germ Cell Tumor

Treatment for intracranial germ cell tumors includes platinum-based chemotherapy and external beam radiation therapy, which are risk factors for hearing loss. In patients who experience significant sensorineural ototoxicity due to cochlear hair cell injury, dose reduction of chemotherapy may be necessary. This report describes an adolescent male, with excellent treatment response for an intracranial nongerminomatous germ cell tumor, who developed sensorineural hearing loss, which was central rather than cochlear in origin and unrelated to carboplatin. This patient highlights the need to carefully differentiate the type and etiology of sensorineural hearing loss in patients with brain tumors receiving ototoxic chemotherapy.

PTPS-12INTENSIVE CHEMOTHERAPY FOLLOWED BY REDUCED RADIATION DOSE FOR INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMORS

PTPS-12. INTENSIVE CHEMOTHERAPY FOLLOWED BY REDUCED RADIATION DOSE FOR INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMORS Teruyoshi Kageji1, Yoshifumi Mizobuchi1, Kohei Nakajima1, Shinji Nagahiro1, Hiroyoshi Watanabe2, Nami Inoue2, Kazumi Okamura2, and Shoji Kagami2; Department of Neurosurgery, School of Medicine, the University of Tokushima, Tokushima, Japan; Department of Pediatrics, School of Medicine, the University of Tokushima, Tokushima, Japan PURPOSE: It is well known that an intracranial non-germinomatous germ cell tumors (NGGCT), especially the patients who demonstrated high level of serum tumor marker has poor prognosis after standard treatment of chemotherapy and whole brain and spinal radiation. The radiation for childhood can be induce significant neurodevelopmental, neuroendocrine, somatic growth, cognitive impairments and secondary tumors. The objective of this study was to determine whether intensive chemotherapy followed by reduced radiation dose is effective in patients with poor prognosis group of intracranial NGGCT. PATIENTS AND METHODS: We have treated 15 patients (mean age 17 y.o.) with poor prognosis group of an intracranial 24 NGGCTs. The serum b-HCG ranged from 0 to 151052 mIU/ml and AFP ranged from 0 to 4120 ng/ml.The NAT(neo-adjuvant therapy),which isprecedingchemotherapy before surgery, was performed in 9 patients which presented with serum b-HCG of over 500 mIU/ml or AFP 500 ng/ml. As chemo-radiotherapy, the ICE regimen (ifosfamide, cisplatin, etoposide) and whole brain (30Gy) and spinal (24Gy) irradiation was used for 9 patients of poor prognosis group from 1998 to 2006. The intensive regimen (cisplatin, etoposide, cyclophosphamide, bleomycin, carboplatin) and reduced radiotherapy (whole ventricle radiation 30Gy) have been induced for 6 patients since 2007. RESULTS: Mean follow-up period is 76 months. In ICE regimen, five of nine (56%) died (CSF dissemination: 3, secondary GBM: 1, sepsis: 1). In intensive regimen, none died and had serious complications. The initial chemotherapy achieves complete remission in 33%. The 3-year, 5-year and 10-year survival rate of all patients was 68%, 68% and 51%, respectively. The 5-year survival rate of the ICE and intensive regimen was 50% and 100%, respectively. CONCLUSION: Intensive chemotherapy followed by reduced radiation dose and field for poor prognosis group of intracranial NGGCT was safe and expected favorable prognosis and reducing or avoiding late effects. Neuro-Oncology 17:v179–v185, 2015. doi:10.1093/neuonc/nov228.12 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

Treatment results and prognostic factors for intracranial nongerminomatous germ cell tumors: single institute experience.

This study aimed to evaluate the treatment of intracranial nongerminomatous germ cell tumors (NGGCT) and to identify the prognostic factors for survival. Thirty-nine patients with nondisseminated NGGCTs, excluding those with pure mature teratomas, were treated between January 1985 and December 2010. Twenty-four patients received gross total or partial removal, 11 had excision biopsies, and 4 had no surgery. Radiotherapy was given postoperatively or definitively with a median tumor bed dose of 54Gy (range 30-54) with or without craniospinal irradiation. All patients received ten cycles of adjuvant chemotherapy, vinblastine, bleomycin, etoposide, and cisplatin after radiotherapy, except for one with mixed anaplastic astrocytoma component who received oral temozolomide. Survival and prognostic factors were estimated by the Kaplan-Meier method and log-rank tests, respectively. After a median follow-up of 77.7months (range 14-336), the 6-year overall survival (OS) and progression-free survival (PFS) were 74.4 and 79.5%, respectively. Inferior PFS was associated with lesions in the suprasellar region (p = 0.017), poor pathological features (p = 0.048), and with poor image (p < 0.0001) and tumor marker (TM) response (p = 0.003) to irradiation. Decreased OS was associated with lesions in the suprasellar region (p = 0.026) and with poor image (p < 0.0001) and TM response (p = 0.027) to irradiation. Neither the extent of surgery nor the radiation field was found to significantly influence survival. By our multimodality approach, patients achieved comparable outcomes. Other than poor pathological features, patients with poor responses to radiotherapy are prone to early recurrence and inferior survival. These patients should be focused for more intensive adjuvant treatment.

Treatment Results and Prognostic Factors for Intracranial Non-germinomatous Germ Cell Tumors: Single Institute Experience

Treatment Results and Prognostic Factors for Intracranial Non-germinomatous Germ Cell Tumors: Single Institute Experience