Event-free Survival Research Articles

GCT-12. OUTCOMES OF INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMOURS (NGGCT) TREATED AT A SINGLE UK PROTON CENTRE ACCORDING TO UK CHILDREN’S CANCER AND LEUKAEMIA GROUP (CCLG) GUIDANCE, INCLUDING EARLY IMPROVED OUTCOMES USING WHOLE VENTRICULAR RADIOTHERAPY (WVRT) FOR LOCALISED DISEASE

Abstract BACKGROUND After SIOP-CNS-GCT-II closed in 2018, the CCLG recommended, with caveats, following standard trial arms: 4 Cisplatin-Etoposide-Ifosfamide (PEI) cycles, then focal radiotherapy (FRT) (54Gy/30fractions) to primary site(s) for localised NGGCT and craniospinal-irradiation (CSI) (30Gy/20fr) + boosts (24Gy/15fr cranial, 20.8Gy/13fr spinal) for metastatic disease. Since 04/2021, the CCLG formally recommended adding WVRT (24Gy/15fr) for localised NGGCT, and considering 2x standard, 2x high-dose PEI for high-risk (HR) cases (diagnostic AFP>1000ng/ml). METHODS Retrospective review of all CNS-NGGCT patients referred 12/2018-06/2023. We collected patient, tumour and treatment factors, acute toxicities (CTCAE grade≥3), and event-free survival (EFS) from radiotherapy until 09/2023. RESULTS Twenty-four patients (21M:3F) included, 14 localised (4xHR), 10 (including 2 incompletely staged) treated as metastatic (3xHR). Median age 11 years, median follow-up 16 months (m). Primary sites: 13 pineal, 5 pituitary/suprasellar, 6 bifocal. Patients were treated according to CCLG guidance. One received FRT without WVRT. One incompletely staged bifocal standard-risk (SR) NGGCT after partial response to PEI had surgery, local+metastatic progression, then second-line chemotherapy before CSI. All seven HR patients received intensified chemotherapy. Nine had post-chemotherapy surgery for residual, two showing necrosis/inflammation, three mature teratoma, two mixed viable GCT. Three relapses (1/17 SR, 2/7 HR) made early EFS 0.875. Of 13 localised patients receiving WVRT, 2 progressed. One bifocal SR patient developed spinal metastases at 5.0m and died despite chemotherapy+spinal irradiation. One unifocal HR patient developed posterior parafalcine metastasis at 3.9m, received GemPOx (Gemcitabine-Paclitaxel-Oxaliplatin), surgery, high dose Carboplatin-Etoposide-Thiotepa with stem-cell rescue, and photon CSI and remains disease-free at 13.2m. One metastatic HR patient progressed at 0.9m and died at 3.0m despite chemotherapy. Acute toxicities were grade 3 lymphopenia in two CSI patients. CONCLUSIONS Despite short follow-up, initial EFS is excellent in SR disease. No localised WRVT-receiving NGGCT patient progressed within the ventricular volume, suggesting benefit of low-dose WVRT.

MDB-56. CLINICAL OUTCOME AND SURVIVAL OF INFANT MEDULLOBLASTOMA PATIENTS: THE BAMBINO GESÙ CHILDREN’S HOSPITAL EXPERIENCE

Abstract Young children diagnosed with medulloblastoma (MB) pose a significant challenge due to the high susceptibility of the developing brain to neurotoxic agents such as craniospinal irradiation (CSI). Different innovative strategies were developed with the aim to enhance outcomes while either delaying or avoiding CSI. We describe a case series of patients affected by infant MB treated according to the Italian Infants High Risk recommendation. Retrospective data from 42 children with MB younger than 5 years of age at diagnosis treated between 2007 and 2023 at Bambino Gesù Children Hospital were recorded. Demographic, clinical, surgical, radiological, molecular, and histopathological data were collected. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method. Seventeen patients were excluded for first-line radiotherapy. Conclusively, 25 patients (13 male, 12 female) with a median age of 25.3 months at diagnosis were eligible for the analysis. Eleven patients had metastatic disease at diagnosis. Histotype: 13/25 classic, 6/25 desmoplastic nodular (DNMB), 4/25 extensive nodularity (MBEN) and 2/25 large cell/anaplastic. DNA methylation profile: SHH-subgroup: 12/25, group 3: 8/25 and group 4: 5/25. MYC amplification was detected in 3 cases. In five cases a cancer predisposition syndrome was found. The median duration of follow-up was 48 months. EFS at 12, 24 and 60 months was 80% (95%CI: 58.4-91.1), 72% (95%CI: 50.1-85.5), and 68% (95%CI: 46.1-82.5), respectively. OS at 12, 24 and 60 months was 80% (95%CI: 67.3-96), 80% (95%CI: 58.4-91.1) and 68% (95%CI: 46.1-82.5) respectively. Significant better survival was found for MBEN/DNMB histotype, with no significant difference between molecular subgroups. We reported high EFS and OS in a population of infant MB treated according Italian Infants High Risk recommendation. Our patients presented an average intelligence quotient in the normal range at a median follow-up of 4 years from diagnosis and no long-term toxicity after treatment.

GCT-07. CONTRIBUTORS TO DELAYED TREATMENT OF NON-GERMINOMATOUS GERM CELL TUMORS IN CHINA: A TERTIARY-CENTER REVIEW

Abstract BACKGROUND Non-Germinomatous Germ Cell Tumors (NGGCT) are rare malignancies with potential for treatment delays. This study aims to identify risk factors and systemic challenges contributing to delayed management of NGGCT in China. METHODS We reviewed the clinical features and referral pattern of 56 consecutively diagnosed NGGCT patients at Shanghai Children’s Medical Center (SCMC) from 9/2018-2/2023. Patients were diagnosed by pathology (n=42), or by elevated markers alone (n=14, AFP>10ng/ml, and/or β-HCG>50mIU/ml). Patients were treated per COG ACNS0122. Delay of treatment was defined as chemotherapy initiated more than 6 months after symptom onset. RESULTS Forty-three males and 13 females were included. Median age at diagnosis was 9.17year (4month-16year). Primary tumor locations included the pineal region (n=31), sellar region (n=19), basal ganglia (n=5), and posterior fossa (n=1). Presenting symptoms included features of increased intracranial pressure (ICP, n=29), endocrine symptoms (n=21), blurred vision or squint (n=7), and hemiplegia (n=4). Delayed treatment occurred in 16 cases (29%), and was more likely in patients with non-pineal region primary (Chi-square p=0.003), and absence of symptoms pertaining to increased ICP (Chi-square p<0.001). Reasons for delay included lack of parental recognition on symptoms (n=7), misdiagnosis (n=3), and inappropriate/incomplete workup (n=6). As a national referral center, patients commuted a median of 483 km (range: 12-2943km) to SCMC (median 2 hospitals (1,5) before SCMC), including 10 patients with obvious hydrocephalus travelling before any CSF diversion procedure. Three-year Event-Free Survival (EFS) was 76.9% and Overall Survival was 86.0%. There was a trend to inferior outcome in patients with delay in treatment (3y EFS 69.6%) compared with those without (3year EFS 80.6%, p=0.112). CONCLUSIONS Delay in treatment is common for children with NGGCT managed at a tertiary referral center in China. Improving public awareness, training for primary-care clinicians, and establishing a national referral network are potential strategies to enhancing the outcome.

Taxane combined with lobaplatin or anthracycline for neoadjuvant chemotherapy of triple-negative breast cancer: a randomized, controlled, phase II study

BackgroundPrevious studies have shown that the addition of platinum to neoadjuvant chemotherapy (NAC) improved outcomes for patients with triple-negative breast cancer (TNBC). However, no studies have assessed the efficacy and safety of the combination of taxane and lobaplatin. In this study, we conducted a randomized controlled phase II clinical study to compare the efficacy and safety of taxane combined with lobaplatin or anthracycline.MethodsWe randomly allocated patients with stage I–III TNBC into Arm A and Arm B. Arm A received six cycles of taxane combined with lobaplatin (TL). Arm B received six cycles of taxane combined with anthracycline and cyclophosphamide (TEC) or eight cycles of anthracycline combined with cyclophosphamide and sequential use of taxane (EC-T). Both Arms underwent surgery after NAC. The primary endpoint was the pathologic complete response (pCR). Secondary endpoints were event-free survival (EFS), overall survival (OS), and safety.ResultsA total of 103 patients (51 in Arm A and 52 in Arm B) were assessed. The pCR rate of Arm A was significantly higher than that of Arm B (41.2% vs. 21.2%, P = 0.028). Patients with positive lymph nodes and low neutrophil-to-lymphocyte ratio (NLR) benefited significantly more from Arm A than those with negative lymph nodes and high NLR (Pinteraction = 0.001, Pinteraction = 0.012, respectively). There was no significant difference in EFS (P = 0.895) or OS (P = 0.633) between the two arms. The prevalence of grade-3/4 anemia was higher in Arm A (P = 0.015), and the prevalence of grade-3/4 neutropenia was higher in Arm B (P = 0.044).ConclusionsNeoadjuvant taxane plus lobaplatin has shown better efficacy than taxane plus anthracycline, and both regimens have similar toxicity profiles. This trial may provide a reference for a better combination strategy of immunotherapy in NAC for TNBC in the future.

LGG-15. DEEP LEARNING ENABLES LONGITUDINAL RISK PREDICTION FOR PEDIATRIC LOW-GRADE GLIOMAS AFTER SURGERY

Abstract BACKGROUND Disease progression is challenging to predict following surgery for pediatric low-grade glioma (pLGG), and early progression indicators on MRI surveillance imaging would help guide management. Longitudinal surveillance imaging data may capture subtle temporal tumor changes and patterns that could inform recurrence risk but are difficult to synthesize clinically. We applied deep, self-supervised learning to longitudinal surveillance MRI to predict short-interval event-free-survival (EFS) risk from time-of-scan. METHODS We retrospectively collected data from 278 patients (2,174 scans) who underwent surgical resection for pLGG at Dana-Farber Cancer Institute/Boston Children’s Hospital (DFCI/BCH) from 1990-2022. A deep-learning model was pretrained with T2-FLAIR sequences to determine the chronological scan order for each patient (temporal pretraining). The model was fine-tuned to predict 1-year EFS from point-of-scan using a subset of scans from DFCI/BCH and then validated on a hold-out dataset (511 scans, 67 patients). Separately, the model was fine-tuned on an external dataset from the Children’s Brain Tumor Network (CBTN) and validated on a hold-out set (204 scans, 61 patients). Results were compared to a model trained without temporal pretraining. RESULTS Median follow-up and interval between scans were 73 and 6.3 months for DFCI/BCH and 20 and 5.8 months for CBTN. Temporal pretraining improved performance for 1-year EFS, for DFCI/BCH (AUC: 0.83 [0.71-0.90] vs. 0.78 [0.62-0.91]; F1-score: 0.80 vs. 0.67), and CBTN hold-out sets (AUC: 0.75 [0.58-0.90] vs. 0.53 [0.35-0.70], p=0.01; F1-score: 0.65 vs. 0.55). Increasing the number of longitudinal scans available to the model incrementally improved performance up to 7 scans/patient for DFCI/BCH and 10 scans/patient for CBTN. CONCLUSIONS Deep-learning with temporal pretraining improves the predictive analysis of tumor growth patterns in postoperative pLGG surveillance MRI, enabling accurate short-interval EFS prediction. This model could help inform patients and clinicians regarding surveillance regimen and initiation of adjuvant therapy.

GCT-05. UPDATED REPORT ON TREATMENT MODALITIES IN METASTATIC GERMINOMA IN CHILDREN: A MULTI-INSTITUTIONAL ANALYSIS

Abstract BACKGROUND Primary intracranial germ cell tumors (GCTs) are rare heterogeneous tumors; germinoma accounts for two-thirds of cases. While neoadjuvant chemotherapy followed by response-based reduced radiotherapy dose and field is the established approach for managing localized CNS germinomas, controversy persists regarding the treatment of primary metastatic disease. Additionally, limited research exists on the utilization of neoadjuvant chemotherapy in primary metastatic germinoma. METHODS A retrospective multi-institutional analysis was conducted to assess overall survival (OS) and event-free survival (EFS) among patients diagnosed with metastatic germinoma who were treated with various modalities. RESULTS We identified 88 patients, including 63 males and 25 females. The median age at presentation was 13.5 years. All patients, who had undergone both brain and spine MRIs, had their diagnoses confirmed through a biopsy, positive CSF cytology, and/or positive CSF tumor markers at presentation. Primary Tumor location was pineal (n=37), suprasellar (n=27), bifocal (n=14) and others (n=9). Eight patients underwent subtotal resection. Craniospinal irradiation (CSI; 21-24 Gy) was administered to 71 patients (81%), while eight patients (9%) received whole ventricular irradiation (WVI; 23.4-30 Gy). Whole brain radiation was given to four patients (5%; 24 Gy), and two patients (2%) had unknown fields. Boosts to primary and/or metastatic sites were administered in all but seven patients. Notably, thirty patients (34%) received CSI without neoadjuvant chemotherapy. At the end of therapy, 69 patients had complete response, 10 partial response and the response was unknown in six. Three patients did not receive irradiation, all died of disease progression. The median follow-up was 64 months (range 6-159 months), yielding an OS of 96.6%. Ongoing multi-institutional data collection and analysis will be presented at the meeting. CONCLUSION Our study is one of the largest studies to date in metastatic germinoma and may provide insight into the role of neoadjuvant chemotherapy with lower CSI doses.

MDB-14. TREATMENT AND OUTCOMES OF MEDULLOBLASTOMA: FIRST REPORT FROM ARMENIA

Abstract BACKGROUND Medulloblastoma accounts for approximately 20% of all primary CNS tumors. Although advanced diagnostic tools and risk-adjusted treatment regimens produce a more than 70% five-year overall survival in HICs the data from LMICs is scarce. This study analyzed the outcome of children with medulloblastoma treated in Armenia. METHODS Demographic and treatment data was collected from medical records of pediatric and young adult patients (≤ 25 years) treated in four major centers in Armenia from 1995-2023. Event-free survival and overall survival were estimated using Kaplan-Meier method. RESULTS During the study period 41 patients with medulloblastoma were registered (20.7% of primary CNS tumors), male-to-female ratio 1.73:1. The median age at diagnosis was 8 years (range: 0.83-25 years). Most common presenting symptoms were nausea and vomiting (82.5%), headache (75%) and ataxia (50%). Metastatic status was evaluated (spinal MRI and CSF cytology) in 48.8% of patients (25% M+ disease). Risk assessment was available for 30 patients (12 standard-risk and 18 high-risk). All patients underwent surgery, gross-total or near-total resection was achieved in 53.7% of cases. Radiation therapy and chemotherapy given to 63.4% and 58.5% of cases, respectively. Of 8 infants included in this study 4 were treated with chemotherapy only, 3 died without further treatment. Median time from surgery to RT/chemotherapy was 6 weeks. Five-year EFS and OS were estimated 58.3% (95% CI 37.5-71%) and 62.5% (95% CI 43.75-77.1%), respectively. Patients with GTR/NTR had a higher OS than patients with STR (83.3% vs 33.3%, p=0.005). No statistically significant difference in EFS/OS was detected based on risk group, metastatic status, or completion of the protocol. CONCLUSIONS OS was lower than expected in this study. Accurate risk assessment and risk-stratified treatment were often lacking during the study period. Compliance to the standardized treatment protocols and multidisciplinary care are needed for improving outcomes of medulloblastoma.

GCT-13. OUTCOMES OF INTRACRANIAL GERMINOMA TREATED AT A SINGLE UK PROTON CENTRE ACCORDING TO UK CHILDREN’S CANCER AND LEUKAEMIA GROUP (CCLG) GUIDELINES

Abstract BACKGROUND After SIOP-CNS-GCT II closed in 2018, the CCLG recommended, with caveats, following the standard trial arms: 4 cycles of chemotherapy (Etoposide-Carboplatin alternating with Etoposide-Ifosfamide) followed by whole ventricular radiotherapy (WVRT) (24Gy/15fractions) and boost (16Gy/10fr) to the primary site(s) for localised germinoma and craniospinal irradiation (CSI) (24Gy/15fr) followed by boost (16Gy/10fr) to primary and metastatic sites for metastatic disease. Since 04/2021, the CCLG formally recommended omitting the boost for localised unifocal germinoma in complete radiological response after chemotherapy. From autumn 2022, we also omitted boosts to completely responded primary sites for localised bifocal germinoma. METHODS Retrospective reviewed of all patients referred to our proton centre 12/2018–06/2023. We collected patient, tumour and treatment factors, acute toxicities (CTCAE grade≥3), and event-free survival(EFS) from radiotherapy until 09/2023. RESULTS Forty-two patients (36M:6F) were included, 23 localised and 19 (including 3 incompletely staged) treated as metastatic. Primary sites: 21 pineal, 8 pituitary/suprasellar, 10 bifocal and 3 atypical (optic nerve, periventricular, thalamic). Diagnosis was by histopathology in 40 and bifocal disease with negative CSF and serum markers in 2. Median age was 15 years (IQR 13-16), median follow-up 13 months (IQR 6-15). Patients were treated according to CCLG guidance, apart from three patients with metastatic pure germinoma, of whom one received 2 cycles Cisplatin-Etoposide, and two received 5 and 3 cycles of Vinblastine before CSI, and one patient with metastatic germinoma plus teratoma who received 2 cycles of Cisplatin-Etoposide and non-germinoma radiotherapy doses (30Gy/20fr CSI, 24Gy/15fr cranial boosts). No patient had subsequent surgery. All remained progression free at last follow-up. Eight patients developed acute grade 3 toxicities: 3 vomiting (2 CSI, 1 WVRT), and 5 lymphopenia (all CSI). CONCLUSIONS Disease control was excellent, with no relapses to date. Proton therapy was well tolerated with low rates of acute high grade toxicities.

Neoadjuvant PD-(L)1 blockade plus platinum-based chemotherapy for potentially resectable oncogene-positive non-small cell lung cancer

BackgroundWhether programmed cell death-1/ligand-1 (PD-1/PD-L1) blockade-based neoadjuvant treatment may benefit locally advanced oncogene-mutant non–small cell lung cancer (NSCLC) patients remains controversial. This retrospective study was designed to observe the efficacy and safety of neoadjuvant PD-1/PD-L1 blockade plus chemotherapy versus chemotherapy and corresponding tyrosine kinase inhibitors (TKIs) in patients with resectable oncogene-positive NSCLC.MethodsPatients with potential resectable NSCLC harbouring oncogene alterations who had received neoadjuvant treatment were retrospectively recruited, and an oncogene-negative cohort of patients who received neoadjuvant PD-(L)1 blockade-based neoadjuvant treatment was reviewed for comparison during the same period. The primary aim was to observe the treatment efficacy and event-free survival (EFS) of these agents. Safety profile, molecular target, and immunologic factor data, including PD-L1 expression and tumour mutational burden (TMB), were also obtained.ResultsA total of 46 patients were recruited. Thirty-one of them harboured oncogene alterations, including EGFR, KRAS, ERBB2, ROS1, MET, RET, ALK, and FGFR3 alterations. Among the oncogene-positive patients, 18 patients received neoadjuvant PD-(L)1 blockade immunotherapy plus chemotherapy (oncogene-positive IO group), 13 patients were treated with neoadjuvant chemotherapy and/or corresponding TKIs or TKIs alone (oncogene-positive chemo/TKIs group), and the other 15 patients were oncogene negative and received neoadjuvant PD-(L)1 blockade plus chemotherapy (oncogene-negative IO group). The pathological complete response (pCR) and major pathological response (MPR) rates were 22.2% (4 of 18) and 44.4% (8 of 18) in the oncogene-positive IO group, 0% (P = 0.120) and 23.1% (3 of 13) (P = 0.276) in the oncogene-positive chemo/TKIs group, and 46.7% (7 of 15) (P = 0.163) and 80.0% (12 of 15) (P = 0.072) in the oncogene-negative IO group, respectively. By the last follow-up, the median EFS time had not reached in the oncogene-positive IO group, and was 29.5 months in the oncogene-positive chemo/TKIs group and 38.4 months in the oncogene-negative IO group.ConclusionCompared with chemotherapy/TKIs treatment, neoadjuvant treatment with PD-(L)1 blockade plus platinum-based chemotherapy was associated with higher pCR/MPR rates in patients with partially resectable oncogene-mutant NSCLC, while the pCR/MPR rates were lower than their oncogene-negative counterparts treated with PD-(L)1 blockade-based treatment. Specifically, oncogene alteration types and other predictors of response to immunotherapy should be taken into account in clinical practice.

LMIC-15. OUTCOMES OF PEDIATRIC MEDULLOBLASTOMA IN LOW- AND MIDDLE-INCOME COUNTRIES: A REPORT OF 330 PATIENTS FROM 8 COUNTRIES

Abstract BACKGROUND AND AIMS Reports from low-and middle-income countries (LMICs) indicate lower survival in medulloblastoma (MB), though these studies are mainly from single institutions. This multi-institutional, retrospective study aimed to analyze the outcomes for MB in 9 centers in 8 LMICs. METHODS Patients <18 years old with newly diagnosed MB, treated from January 2014 to December 2018 in Egypt, El Salvador, Malaysia, Mexico, Pakistan, Peru, Philippines, and Uruguay were included. Data on demographics, clinical presentation, treatment and biological characteristics were collected. Factors associated with patient outcomes were analyzed. RESULTS The study included 330 patients with a median age of 7.7 years. Of these, 49 patients (15%) were <3 years old and 212 (64%) were male. Eighty-eight patients (26%) had experienced symptoms for >3 months at diagnosis. Gross total resection was achieved in 153 (47%) patients. Sixty-three patients (19%) experienced post-operative infections. Eighty-four patients (24%) had metastatic disease at diagnosis. The histologic subtype was not specified in 98 cases (30%), and 25 patients (7%) had molecular subgroups identified. Radiotherapy was administered to 216 patients (64%). The median number of chemotherapy cycles was 8 (range 0-14). There were 64 patients (19%) who abandoned treatment, and 24 patients (7%) died due to treatment-related toxicity. The 5-year event-free survival (EFS) was 44±4%, while the 5-year overall survival was 58±4%. The 5-year EFS for patients <3 years was 42±9%, while 44±4% for older patients (p=0.49). The 5-year EFS for patients with metastasis was 38±7%, while it was 46±4% for patients without metastasis (p=0.13). CONCLUSIONS This large, multinational cohort of MB in LMICs describes poor outcomes, which may be attributed to delays in care, high abandonment rate, surgical complications, treatment-related mortality and a low fraction of patients receiving radiotherapy. Interventions to build care capacity can be prioritized based on these data.

RADT-05. MATURE OUTCOMES OF A PHASE II PROSPECTIVE STUDY OF PROTON RADIOTHERAPY FOR LOCALIZED BRAIN TUMORS

Abstract BACKGROUND Proton radiotherapy (PRT) is a highly targeted form of radiation that spares more normal brain tissue compared to modern photon radiotherapy. Therefore, we expect the late effect profile in children treated with PRT with curable brain tumors should be improved. METHODS Between 2010-2022, 100 patients were enrolled, treated with PRT, and then followed for disease control, hearing, neurocognitive and endocrine outcomes. Late effects of the tumor and treatment delivered were graded using CTCAE v4.0. RESULTS Median age at PRT was 8.0 years (1.1-20.8) and median follow up was 8.7 years (0.3-12.7). Tumor types included 40 (40%) ependymomas, 19 (19%) low grade gliomas (LGG), 21 (21%) craniopharyngiomas, and 20 (20%) other histologies. 26% of patients were treated with chemotherapy in addition to PRT. The location of PRT was 38 (38%) infratentorial, 56 (56%) supratentorial, and 6 (6%) both. The median radiation dose was 52.2 GyRBE (48.6-59.4). 8-year event-free survival (EFS) and overall survival (OS) was 71.7% and 86.2% for all patients. 8-year EFS and OS was 59.9% and 82.4% for ependymomas, 78.2% and 94.7% for LGG, 80.0% and 87.7% for craniopharyngiomas and 79.1% and 84.7% for all other tumor types. 19% of patients had new grade 3+ toxicities that were at least possibly related to radiotherapy. Baseline full-scale intelligence quotient (FSIQ) was 98.0 and follow-up FSIQ was 101.8 (p=0.14). 43% of patients had new endocrine deficiencies after radiation. 8 patients suffered new high-grade hearing loss after PRT. Dosimetry on critical brain structures was collected and correlated with late effects. More details will be presented at the conference. CONCLUSION PRT remains an effective treatment for children with curable brain tumors. While late effects of the tumor and treatment are still present, the overall burden of late effects is lower than other reports.

GCT-16. LONG-TERM OUTCOMES AND COMPLICATION MANAGEMENT IN CNS GERM CELL TUMORS: INSIGHTS FROM A PHASE II HISTOPATHOLOGY-STRATIFIED TREATMENT TRIAL

Abstract BACKGROUND This detailed examination merges outcomes from a Phase II clinical trial targeting central nervous system (CNS) germ cell tumors (GCTs) conducted between 1995 and 2003. It evaluates the impact of histopathologically driven treatment modalities on survival, recurrence, and post-treatment life and social outcomes, aiming to delineate the long-term effects of such stratified treatment approaches. METHODS The cohort comprised 228 patients, stratified into three groups based on histology: germinoma (n=161), intermediate prognosis (n=38), and poor prognosis (n=28), each receiving customized chemotherapy and radiation treatments. With a median follow-up duration of 222 months, this longitudinal study scrutinized survival rates, recurrence patterns, and a spectrum of socio-economic and health-related outcomes. RESULTS For the germinoma group, the 10- and 20-year event-free survival (EFS) rates stood impressively at 82% and 73%, respectively, with overall survival (OS) rates reaching 97% and 92%. The intermediate prognosis group witnessed 10- and 20-year EFS rates of 76% and 66%, and OS rates of 87% and 70%. The poor prognosis group recorded EFS rates of 49% at both intervals, with OS diminishing to 61% and 53%. Notably, germinomas localized in the basal ganglia exhibited high relapse rates absent initial whole-brain radiation, yet were effectively managed upon subsequent interventions. The comprehensive follow-up illuminated striking disparities in socio-economic achievements: higher educational attainments, more stable employment, and improved health outcomes were predominantly observed among patients without recurrence. Non-recurrent germinoma patients, in particular, showcased enhanced educational and employment status, vividly illustrating the profound impact of disease progression and treatment on life quality. CONCLUSIONS The findings highlight the critical importance of customized initial treatments for improving survival and life quality in CNS GCT patients, stressing the need for detailed long-term follow-up to address relapses and complications effectively. The study advocates for personalized care that balances treatment intensity to optimize long-term outcomes, enhancing post-treatment care.

LMIC-16. PRE-IRRADIATION CHEMOTHERAPY AND DELAYED RADIATION THERAPY IN INFANTS AND YOUNG CHILDREN WITH WITH CENTRAL NERVOUS SYSTEM EMBRYONAL TUMOURS

Abstract BACKGROUND Established strategies for infants and young children(IYC) with embryonal tumours of the central nervous system(CNSET) - autologous stem-cell rescue(ASCT) and intraventricular chemotherapy(IVCT) – are not universally available. We report the outcomes of IYC with CNSET treated using the strategy of surgery, pre-irradiation chemotherapy and delayed radiation. METHODS Children <3years diagnosed with CNSET- medulloblastoma(MB), atypical teratoid/rhabdoid tumour(ATRT), embryonal tumour with multilayered rosettes(ETMR), CNS primitive neuroectodermal tumours(PNET)- and pineoblastoma(PB),underwent standard evaluation and staging, maximal safe excision, pre-irradiation chemotherapy(cyclophosphamide, etoposide and carboplatin;CEJ) upto 36months of age and either ris-adapted craniospinal with boost or focal irradiation. We performed a retrospective intention-to-treat outcome analysis. RESULTS Of 117children <3years with CNSET treated January2011- December2022, 72 were treated with this strategy.The median age was 25months (range6-35), 49males,histology medulloblastoma-42(58%), ATRT-9(12.5%), PNET-8(11.1%), ETMR-8(11.1%) and PB-5(6.8%); 23(32%) metastatic.The median chemotherapy cycles were 6(range 1-15). 36 children went on to receive RT; CSI in 33 (20standard-dose,13reduced-dose) and focal in 3. At last follow-up, 27children are in remission, 43 have relapsed/progressed (9 received salvage treatment) and 2 died due to chemotherapy toxicity. The 3-year and 5-year event-free-survival(EFS) are 35% and 3-year and 5-year overall-survival(OS) are 41.8% and 40.2%. The 3-year EFS/OS for MB are 51.1%/ 62.8%,PNET 25%/25%,ATRT 11.1%/11.1%,ETMR 12.5%/12.5% and PB 0%. Only metastasis was prognostic in medulloblastoma (HR 2;95% CI 0.86-4.6 for EFS and HR 1.7;95% CI 0.67-4.5 for OS); age, molecular group and histology were not prognostic. Long-term follow-up (n=17) documented >grade2 late effects in all (endocrine-16, neurocognitive-8, vision-3, hearing -8 and neurological-10). CONCLUSION The use of moderate-intensity pre-irradiation chemotherapy is feasible and effective in infants and young children with CNSETs. Despite inferior outcomes compared to ASCT or IVCT,this strategy could be used in resource-limited settings.

PATH-02. THE IMPACT OF EVOLVING DIAGNOSTIC METHODOLOGY ON THE CLASSIFICATION AND OUTCOME OF CENTRAL NERVOUS SYSTEM TUMOURS IN CHILDHOOD: A RETROSPECTIVE COHORT STUDY

Abstract BACKGROUND Central nervous system tumours are the second most common childhood tumours and the largest cause of childhood cancer death in Australia. Tumours arise from many cell types within the developing and mature CNS, leading to a wide spectrum of clinical behaviour despite overlapping histological appearances. Emerging molecular testing methods allow more precise determination of cell lineage as well as genetic and epigenetic changes driving tumour development. Particularly since 2016, molecular findings have been incorporated into international classification schema, potentially impacting the frequency of individual diagnoses and their observed prognosis. METHODS We performed a retrospective cohort study including patients with newly diagnosed CNS tumours at Royal Children’s Hospital, Melbourne between 2011 and 2020 (total 473). The first and last 100 eligible patients in the data set were reviewed for diagnosis, survival and recorded use of molecular testing. Reviewed patients were assigned to one of two cohorts, Cohort 1 2011-2013 (pre-2016 WHO revision) or Cohort 2 2018-2020 (post-2016 WHO revision). RESULTS The frequency of diagnoses on biopsy rather than imaging alone was stable (81% Cohort 1 vs 83% Cohort 2). Molecular testing utilization increased markedly over time (10 molecular investigations in Cohort 1 vs 348 in Cohort 2). The incidence of astrocytic and oligodendroglial diagnoses was stable. The incidence of embryonal and neuronal/ mixed glial neuronal diagnoses increased in Cohort 2, and the incidence of ependymal diagnoses decreased (p=0.0122). There were no event free or overall survival differences between the whole of Cohorts 1 and 2, with numbers of individual diagnoses too small for meaningful comparisons over time. CONCLUSIONS Access to molecular testing has impacted on the pattern of reported diagnoses of central nervous system tumours in children. Although outcomes have not changed, it is hoped that over time, improved molecular understanding will lead to more effective therapy selection.

LMIC-13. ENCOURAGING EXPERIENCE OF CONCURRENT CARBOPLATIN DURING CRANIOSPINAL IRRADIATION USING IMAGE GUIDED INTENSITY MODULATED PROTON BEAM (IMPT) IN HIGH-RISK EMBRYONAL TUMORS: FIRST REPORT FROM A LOW MIDDLE-INCOME COUNTRY

Abstract BACKGROUND Concurrent carboplatin during craniospinal irradiation (CSI) using photon radiotherapy in High risk (HR) embryonal tumors has been shown to improve the event free survival in select subgroup of patients. Experience of using concurrent carboplatin during CSI using proton therapy is limited. METHOD A retrospective audit was done in Children <18 years from January 2018 to December 2023 diagnosed with HR embryonal tumors who received image guided pencil beam intensity modulated proton beam therapy-based CSI (35Gy/21#) along with concurrent carboplatin 35mg/m2 at least for 15 fractions. The patient demographics, pathological diagnosis, treatment related toxicities and date of follow-up were recorded in predesigned proforma using electronic medical record. RESULTS Twenty children with HR embryonal tumors with median age at diagnosis 5 years (Range: 1-15 years) with M: F ratio of 3:1 were included in the study. Fifteen (75%) of the patients had HR medulloblastoma defined by spinal metastases or HR molecular subtype of which 5 patients had group 3 medulloblastoma (3- leptomeningeal disease at baseline, 2- MYC amplification) while rest had embryonal tumors (3-NOS, 1-Pinealoblastoma and 1-ETMR). Carboplatin was well tolerated, however 12 (60%) patients developed neutropenia requiring daily G-CSF for an average of 5 days. Average time to complete radiotherapy was 45 days with median interruption of 4 days (Range 1-7). Radiotherapy induced toxicities included Grade 3 skin toxicity in 6 (30%) and grade 2 weight loss in 3 (15%). At a median follow up of 14 months (Range: 4-58), the PFS was 80% in the whole cohort while in the Group 3 Medulloblastoma the PFS was only 20% which was statistically significant(p=0.004). CONCLUSIONS Carboplatin along with proton CSI is well tolerated in children with HR embryonal tumors without significant adversities. Experience is encouraging especially in non-group 3 medulloblastoma patients in our cohort of children with HR embryonal tumors.

Patterns of recurrence after radiotherapy for high-risk neuroblastoma: Implications for radiation dose and field

BackgroundPrognosis for patients with high-risk neuroblastoma (HR-NBL) is guarded despite aggressive therapy, and few studies have characterized outcomes after radiotherapy in relation to radiation treatment fields. MethodsMulti-institutional retrospective cohort of 293 patients with HR-NBL who received autologous stem cell transplant (ASCT) and EBRT between 1997–2021. LRR was defined as recurrence at the primary site or within one nodal echelon beyond disease present at diagnosis. Follow-up was defined from the end of EBRT. Event-free survival (EFS) and OS were analyzed by Kaplan-Meier method. Cumulative incidence of locoregional progression (CILP) was analyzed using competing risks of distant-only relapse and death with Gray’s test. ResultsMedian follow-up was 7.0 years (range: 0.01–22.4). Five-year CILP, EFS, and OS were 11.9 %, 65.2 %, and 77.5 %, respectively. Of the 31 patients with LRR and imaging review, 15 (48.4 %) had in-field recurrences (>12 Gy), 6 (19.4 %) had marginal failures (≤12 Gy), and 10 (32.3 %) had both in-field and marginal recurrences. No patients receiving total body irradiation (12 Gy) experienced marginal-only failures (p = 0.069). On multivariable analyses, MYCN amplification had higher risk of LRR (HR: 2.42, 95 % CI: 1.06–5.50, p = 0.035) and post-consolidation isotretinoin and anti-GD2 antibody therapy (HR: 0.42, 95 % CI: 0.19–0.94, p = 0.035) had lower risk of LRR. ConclusionsDespite EBRT, LRR remains a contributor to treatment failure in HR-NBL with approximately half of LRRs including a component of marginal failure. Future prospective studies are needed to explore whether radiation fields and doses should be defined based on molecular features such as MYCN amplification, and/or response to chemotherapy.

Importance of Adequate Surgical Local Control in Fusion-Negative Para-Testicular Rhabdomyosarcoma: Data From the Cooperative Weichteilsarkom Studiengruppe Trials (CWS-96 and CWS-2002P) and the European Soft Tissue Sarcoma Registry (SoTiSaR)

BackgroundThis study aimed to assess the impact that the quality of primary and subsequent surgeries has on the survival of patients with para-testicular rhabdomyosarcoma (PTRMS).MethodsPatients with localized (IRS I–III) and metastatic (IRS IV) PTRMS were enrolled in the two Cooperative Weichteilsarkom Studiengruppe (CWS) trials (CWS-96, CWS-2002P) and the Soft Tissue Sarcoma Registry (SoTiSaR).ResultsAmong 196 patients (median age, 8.4 years), 106 (54.1%) had primary complete resection. Image-defined lymph node (LN) disease was detected in 21 (11.5%) patients in the localized cohort and 12 (92.3%) patients in the metastatic cohort. The 5-year event-free survival (EFS) and overall survival (OS) were respectively 87.3% and 94.0% for the patients with localized PTRMS and 46.2% and 42.2% for the patients with metastatic PTRMS. Protocol violations during the primary surgery (PV-PS) were observed in 70 (42%) of the IRS I–III patients. This resulted in higher rates of R1/R2 resections (n = 53 [76%] vs n = 20 [21%]; p < 0.001) with a need for pretreatment re-excision (PRE) (n = 50 [83%] vs n = 10 [17%]; p < 0.001) compared with the patients undergoing correct primary surgery. Protocol violations during PRE occurred for 13 (20%) patients. Although PV-PS did not influence the 5-year EFS or OS in the localized PTRMS cohort, the unadjusted log-rank test showed that R status after PRE is a prognostic factor for 5-year OS (R1 vs R0 [81.8% vs 97.6%]; p = 0.02).ConclusionsThe quality of surgical local control in PTRMS is unsatisfactory. Emphasis should be placed on evaluating the resection status after PRE in further clinical trials.

CO170 Real-World Survival Outcomes in Patients with Intermediate-to-High-Risk Non-Muscle Invasive Bladder Cancer Utilizing Medicare Claims Data: Estimating Event Free Survival and Evaluating Its Prediction of Overall Survival

CO170 Real-World Survival Outcomes in Patients with Intermediate-to-High-Risk Non-Muscle Invasive Bladder Cancer Utilizing Medicare Claims Data: Estimating Event Free Survival and Evaluating Its Prediction of Overall Survival

Azacitidine as epigenetic priming for chemotherapy is safe and well-tolerated in infants with newly diagnosed KMT2A-rearranged acute lymphoblastic leukemia: Children's Oncology Group trial AALL15P1.

Infants less than 1 year old diagnosed with KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL) are at high risk of remission failure, relapse, and death due to leukemia, despite intensive therapies. Infant KMT2A-r ALL blasts are characterized by DNA hypermethylation. Epigenetic priming with DNA methyltransferase inhibitors increases the cytotoxicity of chemotherapy in preclinical studies. The Children's Oncology Group trial AALL15P1 tested the safety and tolerability of five days of azacitidine immediately prior to the start of chemotherapy on day six, in four post-induction chemotherapy courses for infants with newly diagnosed KMT2A-r ALL. The treatment was welltolerated, with only two of 31 evaluable patients (6.5%) experiencing dose-limiting toxicity. Whole genome bisulfite sequencing of peripheral blood mononuclear cells (PBMCs) demonstrated decreased DNA methylation in 87% of samples tested following five days of azacitidine. Event-free survival was similar to prior studies of newly diagnosed infant ALL. Azacitidine is safe and results in decreased DNA methylation of PBMCs in infants with KMT2A-r ALL, but the incorporation of azacitidine to enhance cytotoxicity did not impact survival. Clinicaltrials.gov identifier: NCT02828358.

Acute promyelocytic leukemia in children cancer hospital Egypt

BackgroundPediatric acute promyelocytic leukemia (APL) accounts for 5 to 15% of all myelocytic leukemia. A retrospective analysis of pediatric patients diagnosed and treated with APL was conducted at CCHE from July 2012 to the end of December 2019, to report the prevalence, clinical characteristics, results, and risk factors associated with induction failure and early death.ResultSixty-two patients were reported, with an age greater than ten, an initial poor coagulation profile, and a total leukocyte count (TLC) greater than 30 103/mm3 influencing 5-year overall (OS) and event-free survival (EFS), as well as a high promyelocyte count affecting 5-year EFS. Patients received a regimen based on the COG AAML0631 protocol. High-risk patients with an initial TLC > 10 × 103/mm3 and an initial promyelocytic count of 30% or more with a substantial P-value are prognostic markers for early death during induction. In females, wild FLT3 increases the risk of differentiation syndrome (DS). Receiving steroids with all-trans retinoic acid (ATRA) induction may reduce the occurrence of DS. Relapse alters the outcome. In the current study, 45 patients are alive in complete remission, with a 5-year OS of 72.5% and a 5-year EFS of 69.4%, respectively.ConclusionPediatric APL outcomes are influenced by age above 10, an initial poor coagulation profile, and a promyelocyte count of more than 10%. An initial leukocyte count of more than 10 × 103/mm and an initial promyelocytic count of more than 30% increase the risk of early death. Receiving steroids with ATRA may reduce the occurrence of DS.