Whole-ventricular Irradiation Research Articles

Unraveling the impact of upfront chemotherapy and proton beam therapy on treatment outcome and follow-up in central nervous system germ cell tumors: a single center experience.

Germ cell tumors (GCT) account for a minority of central nervous system (CNS) malignancies, highly prevalent in adolescents and young adults. Despite their aggressive biological behavior, prognosis is excellent in most cases with risk stratified treatment, consisting in a combination of chemotherapy and radiotherapy. Whole ventricular irradiation (WVI) and craniospinal irradiation, the treatment of choice for localized and metastatic disease, pose significant risk of collateral effects, therefore proton beam radiation (PBT) has been recently proposed for its steep dose fallout. We report our experience in a consecutive series of 17 patients treated for CNS GCT at our Institution from 2015 to 2021. Most frequent lesion location were sellar/suprasellar (35%) and bifocal germinoma (35%), followed by pineal (18%) and thalamic (12%). Two patients (12%), had evidence of disseminated disease at the time of diagnosis. At the latest follow-up all but one patient showed complete response to treatment. The only relapse was successfully rescued by additional chemotherapy and PBT. PBT was well tolerated in all cases. No visual, neurological or endocrinological worsening was documented during and after treatment. Neuropsychological evaluation demonstrated preservation of cognitive performance after PBT treatment. Our data, albeit preliminary, strongly support the favourable therapeutic profile of PBT for the treatment of CNS germ cell tumors.

Outcomes Following Proton Therapy for Non-Metastatic Central Nervous System Germinoma in Children and Adolescents

Radiation is a key component in the treatment of central nervous system pure germinoma (PG) in children and adolescents. Compared to photons, proton therapy (PT) improves normal tissue sparing and potentially reduces adverse effects, but there are sparse data on long-term patient outcomes. Herein, we present the largest reported single institution experience utilizing PT for the management of PG. We performed an IRB-approved retrospective review of a prospective database containing 35 patients with non-metastatic PG treated with PT between July 2007 and September 2021. The median age at treatment was 13 years. All patients had > 6 months of follow up. Two patients were diagnosed based on cerebral spinal fluid B-HCG levels and the remaining 33 patients through histopathology. Eleven patients had bifocal or multifocal intracranial disease. Most patients (n = 31, 88.6%) received induction chemotherapy with carboplatin + etoposide (n = 25, 80.6%) with all demonstrating a radiographic response to neoadjuvant therapy. Twenty-nine were treated with whole ventricular irradiation (WVI) with an involved field (IF) boost, 2 with craniospinal irradiation + WVI + IF, 2 with IF, 1 with CSI + IF, and 1 with whole brain + IF. Among this subgroup, the most common total dose was 30 GyRBE (n = 18, 51.4%). Of the 4 patients that did not receive chemotherapy, 3 received WVI + IF and 1 was treated with CSI + WVI + IF. The total dose in the patients not receiving chemotherapy was 45 GyRBE. Twenty-nine patients were treated with double scattered PT (DS) and 6 patients with pencil beam scanning PT (PBS). We utilized the cumulative incidence method to estimate local control (LC), freedom from distant metastases (FFDM), freedom from progression (FFP), and overall survival (OS). Treatment related toxicity was assessed according to the CTCAEv5. Median follow up was 6.2 years (Range: 0.9-15.2 years). The 10-year KM estimates for LC, FFDM, FFP, and OS were 100%, 100%, 100%, and 97% respectively. One patient developed acute lymphocytic leukemia 8 months after treatment and died. The sole ³ grade 3 radiation-related toxicity was a cavernoma with hemorrhage 3.6 years post treatment requiring surgical resection. The most common adverse events were hearing impairment requiring hearing aids (n = 3), hypersomnia requiring medication (n = 3), and new onset endocrinopathy (n = 1). Of the 22 evaluable patients ³18 years old at last follow up, 7 were high school graduates/in college, 8 college graduates, and 5 others gainfully employed. The use of proton therapy in the multi-modality approach to non-metastatic PG does not compromise local control. Although serious side effects are rare and treatment has minimal impact on survivors' early educational/career trajectory, the 100% cure rate supports further investigation into selective radiation dose and volume de-escalation.

RADT-42. EFFECTS OF RADIOTHERAPY FOR CNS NEOPLASMS IN PEOPLE WITH MULTIPLE SCLEROSIS

Abstract INTRODUCTION Patients with multiple sclerosis (MS) may be at higher risk of brain tumors (Khalil 2012, London 2020, etc.). However, MS patients have been reported to have adverse effects from radiotherapy, a mainstay of CNS treatment. In the last ten years, radiation techniques have improved. We submit a case report of an MS patient with demyelinating CNS lesions shortly after radiation therapy for an astrocytoma and review the literature. Case description: A 40-year-old woman with a history of MS treated with Siponimod underwent resection of a right frontotemporal grade 2 astrocytoma, IDH mutant. She received adjuvant proton radiotherapy (54 Gy(RBE) over 30 fractions) followed by temozolomide chemotherapy. She tolerated radiotherapy well and only experienced grade 1 dermatitis, fatigue, and hair loss within the field of treatment. 1-month post radiation MRI was stable. 4 months post radiation there was an asymptomatic new typical demyelinating lesion on FLAIR without T1 or contrast changes. This was outside the high dose radiation field (i.e. received ~30 Gy(RBE)). Her Siponimod had been held for concerns of interactions with radiation or chemotherapy. DISCUSSION Cases have been reported of people with MS experiencing adverse effects from radiotherapy. Murphy, et al., reported a 30-year-old woman with MS experiencing an attack of demyelination 2 months after radiotherapy (50 Gy over 25 fractions), and Borges, et al. presents a 28-year-old patient who experienced radiotherapy-induced inflammatory demyelination after receiving whole-ventricular irradiation (24 Gy over 15 fractions). Miller, et al., reported 6 patients without exacerbations of MS but had developed grade 4 neurotoxicity in a median of 1 year; most of those patients were treated with older radiation techniques, however. Radiotherapy effects in people with MS is a topic that should be revisited in the era of more conformal RT techniques, effective MS therapies, and cancer treatment including immunotherapy.

RADT-36. MANAGEMENT OF PATIENTS WITH METASTATIC CENTRAL NERVOUS SYSTEM (CNS) GERMINOMA; A LITERATURE REVIEW

Abstract BACKGROUND No consensus exists on the optimal irradiation volume/dose for patients with metastatic CNS germinoma. We reviewed the literature for a potential association between different treatment modalities and survival. METHODS We searched PubMed for studies on patients with primary metastatic CNS germinoma including detailed survival outcome data. We used the Kaplan-Meier method to estimate event-free survival (EFS) rates and log-rank test for comparison among treatment modalities. RESULTS We identified 124 patients from 38 studies published between 1990 and 2021. The median age of presentation was 15 years (range: 1.5–47 years). Treatment modalities included: chemotherapy only (n = 5), radiotherapy only (n = 31), and radio-chemotherapy (n = 88). Radiotherapy modalities included: craniospinal irradiation (CSI) (n = 69), whole-brain irradiation (WBI) (n = 19), whole ventricular irradiation (WVI) (n=16), focal and spine irradiation (n = 5), focal irradiation only (n = 9), and not specified (n = 1). The median focal irradiation dose was 36.6 Gy (range:19.5-59.8 Gy). The median doses for CSI, WBI, and WVI were 24 Gy (range: 10.8-49 Gy). Eighteen patients relapsed, 111 were alive without disease, 2 were alive with disease, and 12 died of disease. The median follow-up time was 5 years in survivors. Four patients who received only chemotherapy relapsed. Five-year EFS rates were similar in patients who received chemo-radiotherapy and radiotherapy alone (89%, 95%CI 81-97%, vs 88%, 95%CI 74-100%, p = 0.6). Patients who were treated with CSI had a longer 5-year EFS compared to patients treated with other modalities (92%, 95%CI 84-100% vs 80%, 95%CI 64-94% p = 0.03). EFS was similar in patients treated with CSI whether they received ≥ 24 Gy or less. CONCLUSION CSI is required to achieve prolonged relapse-free survival (RFS). CSI dose of < 24 Gy may be sufficient to achieve sustained RFS. Future trials are needed to evaluate the potential role of neoadjuvant chemotherapy in reducing the dose/volume of irradiation in patients with metastatic CNS germinoma.

Photon vs. Proton Whole Ventricular Radiotherapy for Non-Germinomatous Germ Cell Tumors

<h3>Purpose/Objective(s)</h3> The hypothesis is that dose to normal CNS structures is lower for children treated with proton therapy, as compared to photon therapy for children receiving whole ventricular radiotherapy (WVRT) for non-germinomatous germ cell tumors (NGGCT). We present data from patients enrolled in stratum 1 of the Children's Oncology Group study ACNS1123. <h3>Materials/Methods</h3> Dosimetric data for NGGCT patients on ACNS1123 who received 30.6 Gy WVRT were compared in a post-hoc analysis. Target segmentation was standardized using a contouring atlas as per the study protocol. The PTV was created by creating a 3-5mm geometric expansion from the CTV. Doses to cranial organs-at-risk (OARs) were compared between proton and photon treatments. Clinically relevant dose-volume parameters that were compared included mean dose and dose to 40% of the OAR volume (D40). A subgroup analysis of patients treated with 3 mm PTV margins was performed. Dosimetric comparisons between proton and photons plans were conducted using two-sided Wilcoxon's rank sum test for continuous variables. <h3>Results</h3> Fifty-eight patients had WVRT dosimetry available and were included; 13 (22%) received proton treatment and 45 (78%) received photon treatment. Median age was 10 years old (range 0-21). Mean and D40 doses to the supratentorial brain, cerebellum (see Table), and bilateral temporal, parietal and frontal lobes were statistically significantly lower amongst proton-treated patients compared to photon-treated patients. In a subgroup analysis of patients uniformly treated with a 3 mm planning target volume, patients who received proton therapy continued to have statistically significantly lower doses to brain OARs. <h3>Conclusion</h3> Children treated with proton therapy for WVRT had lower doses to normal brain structures when compared to those treated with photon therapy. Future work will help elucidate whether this dosimetric advantage of proton therapy translates to a reduction in toxicities for these patients.

GCT-11. 24 Gy whole ventricular radiotherapy alone is sufficient for disease control in localised germinoma in CR after initial chemotherapy – final of the SIOP CNS GCT II study

SIOP CNS GCT II aimed to establish if 24 Gy Whole Ventricular Radiotherapy (WVRT) in localised germinoma is sufficient for tumour control. After central review of radiological response after ‘CarboPEI’ chemotherapy, patients in complete remission (CR) were consolidated with 24 Gy WVRT. Between 2/2012 and 7/2018, 194 patients from 8 European countries with histologically-confirmed fully-staged localised germinoma were registered, of whom 167 were protocol pts. CR after chemotherapy was achieved in 65 patients, Of the 102 patients not in CR after chemotherapy 91 had partial remission (PR), 8 stable disease (SD), 3 progressive disease (PD). All 65 patients in CR received 24 Gy WVRT alone; two of these relapsed, both locally, 7 and 12 months after diagnosis. Of the 102 non-CR patients after chemotherapy, 91 with PR and 8 with SD received 24 Gy WVRT and 16 Gy boost, of which five relapsed (four local, one distant) 2 -7 years from diagnosis. One additional patient who remained in CR died of infection in CR, 4 years after Dx. In three patients with PD all received 24 Gy ventricular irradiation with varying tumour boosts. 16-30 Gy, no relapses occurred. Median follow-up of the whole group was 4,2 years. 4- years event-free survival (EFS) for patients in CR treated with WVRT only (n=65) was 97% (standard error 2%). 4-years EFS for patients with non-CR ( WVRT 24 Gy and 16 Gy to 30 Gy tumour boost) (n=102) was 95% (standard error 2%). Localised germinoma in CR after chemotherapy had an excellent outcome with 24 Gy WVRT alone. 24 Gy WVRT is therefore considered the standard consolidation treatment in this group and should be used as the standard for further treatment studies in localised germinoma evaluating the recent international consensus on radiological response criteria ( Lancet Oncology accepted).

GCT-05. Multi-institutional analysis of treatment modalities in metastatic germinoma in children

Abstract BACKGROUND: Primary intracranial germ cell tumors (GCTs) are rare heterogeneous tumors, with germinoma accounting for two-thirds of cases. Neoadjuvant chemotherapy with response-based reduced radiotherapy dose and field has become the standard management of localized CNS germinomas, however, treatment of primary metastatic disease has remained controversial. Furthermore, there is limited published research on the use of neoadjuvant chemotherapy in primary metastatic germinoma. METHODS: We performed a retrospective multi-institutional data collection and analysis of patients diagnosed with metastatic germinoma since 2000 to assess the overall survival (OS) and event-free survival (EFS) of the different treatment modalities administered. RESULTS: We identified 78 patients with germinoma, in two tertiary care centers, of which nine patients (11.5%; eight males) had metastatic disease. The median age at presentation was 13.3 years. All patients had a biopsy at presentation confirming the diagnosis. Three patients had positive CSF cytology (M1). Six patients received craniospinal irradiation (CSI) with boost to primary and metastatic sites, of which five patients received total CSI dose of 24 Gy, while the dose was unknown for one patient. One patient required one cycle of chemotherapy prior to CSI due to worsening visual changes, which subsequently resolved. One patient received two cycles followed by whole ventricular irradiation (WVI) of 23.4 Gy with a boost to the primary bed. One patient received WVI without neoadjuvant chemotherapy. One patient developed anoxic brain injury and only received chemotherapy. He died of recurrent progressive disease 15 months post-diagnosis. The median follow-up time was 77.5 months (range 15-130.5 months), with an OS of 88.9%. Further multi-institutional data collection and analysis is underway and will be presented at the meeting. CONCLUSION: We anticipate our results may elucidate the role of neoadjuvant chemotherapy in the treatment of metastatic germinoma, and whether when combined with lower CSI doses did not compromise EFS/OS.

Photon versus proton whole ventricular radiotherapy for non-germinomatous germ cell tumors: A report from the Children's Oncology Group.

To determine if proton therapy reduces doses to cranial organs at risk (OARs) as compared to photon therapy in children with non-germinomatous germ cell tumors (NGGCT) receiving whole ventricular radiotherapy (WVRT). Dosimetric data for patients with NGGCT prospectively enrolled in stratum 1 of the Children's Oncology Group study ACNS1123 who received 30.6Gy WVRT were compared. Target segmentation was standardized using a contouring atlas. Doses to cranial OARs were compared between proton and photon treatments. Clinically relevant dose-volume parameters that were analyzed included mean dose and dose to 40% of the OAR volume (D40). Mean and D40 doses to the supratentorial brain, cerebellum, and bilateral temporal, parietal, and frontal lobes were statistically significantly lower amongst proton-treated patients, as compared to photon-treated patients. In a subgroup analysis of patients uniformly treated with a 3-mm planning target volume, patients who received proton therapy continued to have statistically significantly lower doses to brain OARs. Children treated with proton therapy for WVRT had lower doses to normal brain structures, when compared to those treated with photon therapy. Proton therapy should be considered for patients receiving WVRT for NGGCT.

Advances in Molecular Profiling and Developing Clinical Trials of CNS Germ Cell Tumors: Present and Future Directions.

The last decade has seen significant improvements in the management and understanding of the pathogenesis of CNS germ cell tumors (GCTs) by studies on genomic and epigenomic analyses, and published results of clinical trials. This review highlights the new findings to stay up-to-date on the knowledge and better inform the future directions. CNS GCTs are characterized by either MAPK or PI3K pathway mutations. Germinoma has a striking global hypo-methylation, analogous to its hypothesized cell-of-origin; primordial germ cell. Micro RNA cluster mir-371-373 and mir-302/367 are characteristic of GCTs, which have potential for liquid biopsy. Clinical trials have revealed whole-ventricular irradiation for germinoma and local radiotherapy for localized non-germinomatous GCTs seem to be sufficient for tumor control. Advancements in basic, translational, and clinical studies are improving our understanding of this rare disease. Further studies are needed, especially in the field of radiomics, liquid biopsy, genomic structural variants, and treatment stratification, to better structure the future management scheme.

The Efficacy of Maximal Tumor Resection Combined With Whole Ventricle Radiotherapy in Patients With Glioblastoma Involving the Ventricle

Patients with glioblastoma (GBM) that involve the ventricle are at higher risk of ventricle opening during surgery and potential ventricular tumor spread. We evaluated the role of whole ventricular radiotherapy (WVRT) during postoperative temozolomide-based chemoradiotherapy.A retrospective review of 382 patients with GBM who received surgical resection followed by temozolomide-based chemoradiotherapy between 2005 to 2019 at a single institution was conducted. Propensity score matching was performed to compensate the difference in characteristics between patients that did (WVRT(+); n = 59) or did not (WVRT(-); n = 323) receive WVRT. Local, outfield, intraventricular, and leptomeningeal failure rates were compared.All WVRT(+) patients had tumor ventricle involvement and ventricle opening during surgery. In the propensity matched cohort, WVRT(+) group exhibited a significantly lower 2-year intraventricular failure rate compared to the WVRT(-) group (2.1% vs. 11.8%; P = 0.045), but no difference in other treatment outcomes. Recursive partitioning analysis stratified patients at higher risk of intraventricular failure (tumor ventricle involvement, MGMT unmethylation, and ventricle opening) with a 2-year rate of 14.2%. WVRT reduced intraventricular failure rates only in high-risk patients (0% vs. 14.2%; P = 0.054) or those with MGMT-unmethylated GBM in the matched cohort (0% vs. 17.3%; P = 0.036). WVRT did not cause a significant decline in performance status but caused a decrease in post-treatment absolute lymphocyte count, although it was recovered to a similar level with that of the WVRT(-) group.WVRT reduced intraventricular failure rates in patients with tumor ventricle involvement and ventricle opening during surgery. Our results merit further prospective evaluation of WVRT in GBM.K. Kim: None. J. Yoo: None. S. Kang: None. J. Chang: None. H. Yoon: None. C. Suh: None.

Efficacy of Whole-Ventricular Radiotherapy in Patients Undergoing Maximal Tumor Resection for Glioblastomas Involving the Ventricle.

Background and PurposePatients with glioblastoma (GBM) involving the ventricles are at high risk of ventricle opening during surgery and potential ventricular tumor spread. We evaluated the effectiveness of whole-ventricular radiotherapy (WVRT) in reducing intraventricular seeding in patients with GBM and identified patients who could benefit from this approach.Methods and MaterialsWe retrospectively reviewed the data of 382 patients with GBM who underwent surgical resection and temozolomide-based chemoradiotherapy. Propensity score matching was performed to compensate for imbalances in characteristics between patients who did [WVRT (+); n=59] and did not [WVRT (–); n=323] receive WVRT. Local, outfield, intraventricular, and leptomeningeal failure rates were compared.ResultsAll patients in the WVRT (+) group had tumor ventricular involvement and ventricle opening during surgery. In the matched cohort, the WVRT (+) group exhibited a significantly lower 2-year intraventricular failure rate than the WVRT (–) group (2.1% vs. 11.8%; P=0.045), with no difference in other outcomes. Recursive partitioning analysis stratified the patients in the WVRT (–) group at higher intraventricular failure risk (2-year survival, 14.2%) due to tumor ventricular involvement, MGMT unmethylation, and ventricle opening. WVRT reduced the intraventricular failure rate only in high-risk patients (0% vs. 14.2%; P=0.054) or those with MGMT-unmethylated GBM in the matched cohort (0% vs. 17.3%; P=0.036).ConclusionsWVRT reduced the intraventricular failure rate in patients with tumor ventricular involvement and ventricle opening during surgery. The MGMT-methylation status may further stratify patients who could benefit from WVRT. Further prospective evaluation of WVRT in GBM is warranted.

Intracranial germ cells tumour: a single institution experience in Argentina.

Intracranial germ cell tumor (iGCT) represents a rare and heterogeneous group, with variable incidence and diverse treatment strategies. Although multiagent chemotherapy with reduced radiotherapy strategy has been applied by several cooperative groups in North America and Western Europe, there is a paucity of data to understand if this combined regimen is suitable in low-middle income countries (LMIC). We evaluate the outcome in a cohort of iGCT treated by SIOP-CNS-GCT-96 strategy at hospital J.P Garrahan in Argentina over the last 20years. Radiation field and dose included focal radiotherapy (FRT) before 2009 or focal radiotherapy plus whole ventricular radiotherapy (WVRT) after 2009 for localized germinoma and FRT or FRT plus WVRT or CSI for non germinomatous germ cell tumors (NGGCT) RESULTS: Sixty iGCT were identified; 39 germinoma and 21 NGGCT. Median follow-up was 6.57years (range 0.13-20.5). 5-year PFS and OS were 83.5% (95% CI [165.53-223.2]) and 88.7% (95% CI [169.84-223.2]) for the germinoma group, while for the NGGCT group were 75% (95% CI [133.27-219.96]) and 64.2% (95% CI [107.38-201.81]) respectively. The localized germinoma group showed poor results between 2000 and 2009 with 5-year PFS and OS of 69 and 75% respectively, and an excellent outcome between 2010 and 2019 with a 5-years PFS and OS of 92.8 and 100%. A univariable analysis identified this difference in survival as related to the field of radiotherapy, specifically whole ventricular radiotherapy. FRT increased the risk of recurrence in localized germinoma, involving not only ventricular relapses; but spinal cord and disseminated disease as well. There were no relapses of localized NGGCT after FRT and FRT plus WVRT. Herein we demonstrate that intensive chemotherapy followed by FRT plus WVRT for germinoma is a feasible and effective strategy, warranting further study in the developing world.

GCT-76. 24Gy WHOLE VENTRICULAR RADIOTHERAPY ALONE IS SUFFICIENT FOR DISEASE CONTROL IN LOCALISED GERMINOMA IN CR AFTER INITIAL CHEMOTHERAPY – EARLY RESULTS OF THE SIOP CNS GCT II STUDY

SIOP CNS GCT II aimed to establish if 24Gy Whole Ventricular Radiotherapy (WVRT) in localised germinoma is sufficient for tumour control. After central review of radiological response after ‘CarboPEI’ chemotherapy, patients in complete remission (CR) were consolidated with 24Gy WVRT. Between 2/2012 and 7/2018, 182 patients from 8 European countries with histologically-confirmed fully-staged localised germinoma were registered. 70 patients were in CR after chemotherapy, 98 in partial remission (PR), seven had stable disease, two progressive disease, and in five no response data were documented. Of the 70 patients in CR, 58 received 24Gy WVRT alone; two of these relapsed, one local and one disseminated, two and six years after diagnosis. Of the 98 patients in PR after chemotherapy, 86 received 24Gy WVRT and 16Gy boost, of which five relapsed (three local, two distant) 12–24 months from diagnosis. Twelve patients in each of the CR/PR groups received non-protocol or undocumented radiotherapy fields/doses. Median follow-up was 3.7 years. Event-free survival (EFS) for patients in CR and with WVRT only (n=58) was 98% at 4 years. 4-years EFS of patients with PR and WVRT 24Gy and 16Gy tumor boost (n=86) was 95%. Localised germinoma in CR after chemotherapy had an excellent outcome with 24Gy WVRT alone; 24GY WVRT can therefore be considered standard consolidation treatment in this group. International consensus on radiological response criteria is of utmost importance to avoid over- and undertreatment of such patients and to pave the way for further treatment reduction in this group of patients.

GCT-41. RESPONSE-BASED RADIATION THERAPY IN PATIENTS WITH NEWLY DIAGNOSED CENTRAL NERVOUS SYSTEM LOCALIZED GERMINOMA: A CHILDREN’S ONCOLOGY GROUP (COG) PROSPECTIVE PHASE 2 CLINICAL TRIAL

BACKGROUNDThe objective of stratum 2 of COG ACNS1123 was to evaluate children and young adults (3–21 years) with localized central nervous system (CNS) germinoma and investigate whether simplified pre-irradiation chemotherapy followed by response based dose-reduced whole ventricular irradiation (WVI) would maintain a high progression-free survival (PFS) while reducing long term treatment burden.METHODSPre-irradiation chemotherapy consisted of 4 cycles of carboplatin and etoposide every 21 days followed by response-based irradiation (XRT). Patients with a complete response (CR) to pre-XRT chemotherapy received 18Gy WVI + 12Gy boost to the tumor bed. Patients with partial response (PR) but less than 1.5 cm residual proceeded to 24Gy WVI + 12Gy boost. All patients were also enrolled on COG ALTE07C1 to prospectively evaluate and longitudinally model the cognitive, social and behavioral functioning.RESULTSDuring a total accrual time of 45.5 months from 05/2012 to 06/2018, 137 eligible patients were enrolled. Median age was 14.09 years (4.95–21.46), 73% were male, and 45.26% had elevated βhCG in serum and/or cerebrospinal fluid. Twenty-nine patients (21.17%) did not have tissue biopsy. Eleven patients underwent second-look surgery; 7 had mature teratoma and 4 had non-viable tumor. Eighty-one patients (59.13%) had a CR. There were 4 relapses in patients receiving 18Gy WVI + boost, but no deaths. No unexpected treatment-related events were observed. The estimated 3-year PFS was 94.4 ±2.7% among 74 evaluable subjects.CONCLUSIONThis study shows promise in XRT reduction for patients with localized CNS germinoma and CR. Long-term survival outcomes and ALTE07C1 data are being evaluated.

GCT-67. CENTRAL NERVOUS SYSTEM GERMINOMA IN TWO CAUCASIAN AMERICAN SIBLINGS WITH AUTISM SPECTRUM DISORDER

BACKGROUNDCentral nervous system germ cell tumors (CNS-GCT) account for approximately 5% of all pediatric brain tumors. These tumors are pathologically heterogeneous, but have recurrent somatic mutations in KIT and rare germline variants in a Japanese cohort. Chromosomal abnormalities, specifically Klinefelter Syndrome, are associated with increased tumor development and familial cases have been reported, but no germline tumor syndromes are known. We describe a pair of siblings, both with autism spectrum disorder (ASD) that developed CNS-GCT, which previously has not been described outside of Japan. CASES: We report two siblings with ASD who developed CNS germinomas within two months of each other. The older brother, with basal ganglia and hypothalamic tumors, underwent surgical resection followed by treatment per ACNS0232 with chemotherapy and whole-ventricular irradiation (WVI). The younger sibling, with a midbrain tumor, also received ACNS0232, but due to poor response required additional chemotherapy and WVI. Both siblings are without evidence of disease 7 years after end of therapy. Genetic testing, including chromosomal microarray, karyotyping, and whole genome sequencing did not elucidate any variant identified as causative at that time.CONCLUSIONSCNS-GCT are rare tumors, diverse in both histopathologic diagnosis and clinical outcomes. Currently there are known somatic alterations and germline chromosomal disorders associated with increased tumor development, but no known inheritable causes. Despite this, familial CNS-GCT have been reported in patients of Japanese descent. The description of two Caucasian American siblings with ASD and CNS-GCT is novel, refuting that familial CNS-GCT are limited to the Japanese population.

GCT-08. PROTON BEAM RADIOTHERAPY FOR PEDIATRIC AND YOUNG-ADULT PATIENTS WITH INTRACRANIAL GERM CELL TUMOR

BACKGROUNDTo reduce treatment-related adverse events in pediatric and young-adult patients with brain tumors, proton beam radiotherapy (PBT) has recently been performed instead of conventional X-ray radiotherapy. However, whether PBT is as effective as X-ray radiotherapy has not been sufficiently investigated, especially in patients receiving whole-ventricular irradiation.METHODSWe report a retrospective observation of 15 patients with intracranial germ cell tumors (GCT), who received PBT at our institution from April 2014 to September 2019. We evaluated their clinical course, short-term adverse events, and prognosis. RESULTS/CONCLUSIONFifteen patients (9 males and 6 females; median age 13 years) who received PBT following induction chemotherapy were analyzed. Nine patients received 23.4–27.0 GyE of whole-ventricular irradiation due to GCT in the pituitary gland, pineal body, or hypothalamic area. Three patients received 23.4 GyE of whole-brain irradiation: one of them had boost irradiation for basal ganglia. Three patients received 30.6 GyE of craniospinal irradiation (CSI). Six of the 15 patients experienced nausea (grade 2, according to the CTCAE version 4.0). Four patients, including two who received CSI, showed myelosuppression: decrease in white blood cell count, lymphocyte cell count, and neutrophil count (grade 3). No other severe short-term adverse events of >grade 2 was observed in any of the patients. At a median follow-up of 21 months (2‐62 months) after irradiation. all patients are alive without recurrence. Our results may be encouraging and further investigations with a larger scale is warranted.

GCT-20. EVALUATION OF NEURORADIOLOGICAL RESPONSE TO INDUCTION CHEMOTHERAPY FOR PATIENTS WITH LOCALISED GERMINOMA IN THE SIOP CNS GCT II TRIAL

INTRODUCTIONThe SIOP-CNS-GCT-96 trial demonstrated excellent survival for patients with germinoma. Localised patients received either craniospinal irradiation (CSI) 24Gy plus tumour-bed-boost 16 Gy or 2xcarboPEI chemotherapy (carboplatin/etoposide alternating with etoposide/ifosfamide) and focal-radiotherapy 40 Gy. Following trial closure, whole-ventricular-irradiation (WVI) was delivered with focal-radiotherapy to avoid ventricular relapse. Accordingly, current research priorities focus on reducing treatment burden and long-term neurocognitive sequelae.METHODSSIOP-CNS-GCT-II employed national central radiological review to assess whether dropping the 16Gy boost was safe for localized germinoma in complete-remission (CR) following 2xcarboPEI: i.e. no disease on clinical/marker/radiological assessment. Any abnormal thickening/enhancement after chemotherapy was to be classified as partial-remission (PR). Patients with less than CR after chemotherapy received a boost.RESULTSShortly before trial closure (2018), it was noted that national CR rates were discrepant across the largest recruiting countries. For German patients, CR rates were ~80%, compared with ~30–40% for UK and France. A formal neuroradiology review was therefore convened. A total of 59 cases were randomly selected (UK, n=32; France, n=14 and Germany, n=13), including those deemed to be in CR and PR. Cases included those with disease at pituitary, pineal and bifocal sites. Both diagnostic scan and scan after induction chemotherapy were used for assessment. Detailed analysis is ongoing and will be presented.CONCLUSIONResidual changes at both pituitary and pineal sites of uncertain significance may remain after chemotherapy. This process should facilitate consensus to define the best response criteria allowing treatment reduction for CNS germinoma for future clinical trials.

Secreting Germ Cell Tumors of the Central Nervous System: A Long-Term Follow-up Experience

Simple SummaryNongerminomatous germ cell tumors of the central nervous system are rare tumours. Differently from germinomas, they have a severe prognosis above all when presenting with high alfafetoprotein levels. We report the results of a combined chemo- and radiotherapy approach in 28 patients affected by this disease with craniospinal irradiation and a boost tailored on the response to pre-radiant chemotherapy. Metastatic patients and high-risk disease are discussed as well. The 5 years overall survival and event-free survival were both 81% while at 10 years they were 81% and 76% respectively. Our series, even if small, concerns nongerminomatous germ cell tumors only (whereas in some papers they are mixed with pure germinomas), furthermore our patients had a very long follow-up (over 11 years) with encouraging survival data for localized and metastatic disease. Improving survival while trying to contain/avoid the long-term sequelae of chemotherapy and radiotherapy are the main goals of future studies.Introduction: Due to the rarity of nongerminomatous germ cell tumors (NGGCT) with non-standard treatment as yet, we report retrospectively our 30 year experience with chemotherapy followed by craniospinal irradiation (CSI), plus a boost of whole ventricular irradiation (WVI)/tumor bed (TB), tailored to pre-radiation chemotherapy response. Methods: Between 1988 and 2016, 28 patients received four cycles of PEB (cisplatin/etoposide/bleomycin), then CSI, and two further PEB cycles. Between 1988 and1994, CSI was 25.5 Gy for patients in complete remission (CR), 30 Gy if in partial remission (PR) or metastatic, with a boost to TB up to 45–54 Gy. In the period of 1995–2010, the boost included WVI and any extra-ventricular tumor sites up to 45 Gy. After 2010, CSI was reduced to 25.5 Gy for all non-metastatic patients, and a boost was given only to TB up to 40.5/45.5 Gy, depending on patients’ CR/PR status. After 2003, patients with alfafetoprotein (αFP) > 1000 ng/mL received intensified treatment, also including autologous stem cell transplantation. Results: Among 28 patients (23 males; median age 12 years, 6 metastatic), 25 responded to PEB, and three progressed (PD) after one to four cycles; 26 received radiotherapy obtaining 13 CR, 7 PR and 5 stable disease (SD), 1 PD; 6 (21%) died (5 for disease, 1 for pneumonia while in CR). Five-year overall survival (OS) and progression-free survival (PFS) were both 81%; 10 year OS and PFS 81% and 76%, respectively (median follow-up 11 years). Conclusions: Survival for children with NGGCT, independently from disease extent, was encouraging. Further studies should elucidate which patients could benefit from reduced volume and dose irradiation.

Carboplatin-based regimen in pediatric intracranial germ-cell tumors (IC-GCTs): effectiveness and ototoxicity.

Induction chemotherapy with carboplatin followed by radiotherapy has been used for many years for treating intracranial germ-cell tumors (IC-GCTs) in Thailand. The objective of this study was to assess treatment outcomes, focusing on survival and ototoxicity. The outcomes of all patients with IC-GCT treated at Ramathibodi Hospital and the Prasat Neurological Institute between 2000 and 2017 were reviewed and analyzed, including all patient characteristics and treatment modalities. Five-year overall survival (OS) and event-free survival (EFS) were analyzed using the Kaplan-Meier method, and factors affecting survival were compared using the log-rank test. Fifty-three patients age 1-14 years (median, 11 years) were included in this study. The median follow-up time was 63 months. The 5-year EFS and OS rates were 94.3% and 96.2% for all patients, respectively. No statistical difference in OS or EFS was observed between the data of recipients in the carboplatin-based and historical cisplatin-based therapies in our institutes. Concerning radiotherapy, omission of radiotherapy or focal irradiation results in worse long-term survival outcomes, but reduction in dose of radiotherapy to less than 40 Gy did not cause any negative impact on survival rates. Furthermore, carboplatin was associated with lower rates of hearing loss than cisplatin (5.7% vs 87.5%). Induction chemotherapy with carboplatin-based regimens was associated with excellent survival rates and low ototoxicity in patients with IC-GCT. Radiotherapy should be given to all patients with a minimal volume equivalent to whole-ventricular radiotherapy, during which doses of lower than 40 Gy can be effectively used.

The relationship between ventricular volume and whole‐brain irradiation dose in central nervous system germ cell tumors

Advanced irradiation techniques, including intensity-modulated radiation therapy (IMRT), aim to limit irradiation to adjoining tissues by conforming beams to a well-defined volume. In intracranial germinomas, whole-ventricular IMRT decreases the volume of irradiation to surrounding parenchyma. This study examined the relationship between ventricular volume and radiation dose to surrounding tissue. We retrospectively reviewed age, sex, ventricular and brain volume, ventricular dose, and volume of brain that received 12Gy (V12) for patients diagnosed with germ cell tumors at our institution treated with whole-ventricular IMRT between 2002 and 2016. Variables were assessed for correlation and statistical significance. Forty-seven patients were analyzed. The median whole-ventricular irradiation dose was 24Gy with a median boost dose of 30Gy. The median ventricular volume was 234.3 cm3 , and median brain volume was 1408 cm3 . There was no significant difference between mean ventricular volume of suprasellar versus pineal tumors (P=.95). The median V12 of the brain, including the ventricles, was 58.9%. The strongest correlation was between ventricular volume and V12, with an r2 (coefficient of determination) of .47 (P<.001). Multiple regression analysis indicated that total boost dose and boost planning target volume significantly predicted V12 (P<.001). Although whole-ventricular IMRT limited irradiation to surrounding tissue in our cohort, a significant percentage of the brain received at least 12Gy. This study suggests that there is a positive correlation between ventricular volume and the volume of brain parenchyma receiving at least 12Gy with an important contribution from the boost phase of treatment.