Radiotherapy Dose Research Articles

Pattern of care and clinical outcome of patients with carcinoma endometrium and the impact of central histopathological review on management: A tertiary cancer centre experience.

Endometrial carcinoma (EC) is the third most common gynecological malignancy in India. Recent PORTEC-3 analysis emphasized the role of central histopathological review. We aimed to retrospectively analyze the demographic and histopathological characteristics of EC patients treated at our institute and assess the impact of the central histopathological review on management and also analyze clinical outcomes in this cohort of patients. Data of 75 EC patients treated at our center between 2013 and 2022 were retrieved from our departmental archives. Patients were analyzed for demographic details, histopathological findings, details of surgery and histopathology (HPE), results of a review of HPE, adjuvant treatment details, and clinical outcomes. All patients with HPE outside of our institute were reviewed at our center prior to initiation of treatment. In cases of discordance, patients were discussed in the multidisciplinary tumor board for the final treatment decisions. Patients were staged as per International Federation of Gynaecology and Obstetrics 2018. The median age was 57 years (range: 37-74 years). Twenty-seven patients with HPE reported from the outside center were reviewed at our institute and changes were observed in 26 patients (96.3%). HPE review changes were observed in terms of histological grade, histological type, myometrial invasion, and lymph node involvement in five (18.5%), three (11.1%), seven (25.9%), and three (42.8%), respectively. HPE review leads to changes in the management of 19/26 patients. Stage distribution was I: II: III in 48 (64%): 9 (13.3%): 18 (24%) patients, respectively. The median external beam radiotherapy dose was 50 Gray (range: 45-50.4 Gray at 1.8-2 Gray per fraction). The median brachytherapy dose for patients treated with brachytherapy alone was 7 Gray each for three sessions and in combination with EBRT was 6 Gray each in two sessions. At a median follow-up of 51 months (range: 6-116 months), seven (9.3%) patients developed distant metastasis, two (2.7%) patients had local plus distant metastasis, and two (2.7%) patients had local recurrence. The overall survival and disease-free survival rates at 3 years were 93.5% and 86.7%, respectively. EC patients treated at our center have excellent local control rates with a combination of external beam radiotherapy and brachytherapy. The central histopathological review may result in changes impacting patient management and should be routinely done prior to initiation of treatment in EC.

3D Unsupervised deep learning method for magnetic resonance imaging-to-computed tomography synthesis in prostate radiotherapy

Background and purposeMagnetic resonance imaging (MRI)-to-computed tomography (CT) synthesis is essential in MRI-only radiotherapy workflows, particularly through deep learning techniques known for their accuracy. However, current supervised methods are limited to specific center’s learnings and depend on registration precision. The aim of this study was to evaluate the accuracy of unsupervised and supervised approaches in the context of prostate MRI-to-CT generation for radiotherapy dose calculation. MethodsCT/MRI image pairs from 99 prostate cancer patients across three different centers were used. A comparison between supervised and unsupervised conditional Generative Adversarial Networks (cGAN) was conducted. Unsupervised training incorporates a style transfer method with. Content and Style Representation for Enhanced Perceptual synthesis (CREPs) loss. For dose evaluation, the photon prescription dose was 60 Gy delivered in volumetric modulated arc therapy (VMAT). Imaging endpoint for sCT evaluation was Mean Absolute Error (MAE). Dosimetric endpoints included absolute dose differences and gamma analysis between CT and sCT dose calculations. ResultsThe unsupervised paired network exhibited the highest accuracy for the body with a MAE at 33.6 HU, the highest MAE was 45.5 HU obtained with unsupervised unpaired learning. All architectures provided clinically acceptable results for dose calculation with gamma pass rates above 94 % (1 % 1 mm 10 %). ConclusionsThis study shows that multicenter data can produce accurate sCTs via unsupervised learning, eliminating CT-MRI registration. The sCTs not only matched HU values but also enabled precise dose calculations, suggesting their potential for wider use in MRI-only radiotherapy workflows.

Dosimetric Impact of Prescription Point Placement in Heterogeneous Medium for Conformal Radiotherapy Dose Calculation with Various Algorithms

Objective: The aim of the study is to compare the accuracy of dose calculation for different dose calculation algorithms with different prescription points (air, tissue, air–tissue interface in carcinoma lung patients and bone, tissue, and bone–tissue interface in carcinoma buccal Mucosa tumors). Materials and Methods: Forty-one patients with carcinoma lung and buccal mucosa were retrospectively selected for this study. A three-dimensional conformal radiotherapy reference plan was created using the prescription point in the tissue with Monte Carlo (MC) algorithms for both the groups of patients. The reference plan was modified by changing the prescription point and algorithms in the tissue, air, air–tissue interface for lung patients and tissue, bone, and bone–tissue interface for buccal mucosa patients. The dose received by the target volume and other organs at risk (OAR) structures was compared. To find out the statistical difference between different prescription points and algorithms, the statistical tests were performed with repeated measures ANOVA. Results: The target volume receiving 95% dose coverage in lung patients decreased to −3.08%, −5.75%, and −1.87% in the dose prescription point at the air–tissue interface with the dose calculation algorithms like MC, collapsed cone (CC), and pencil beam (PB), respectively, compared to that of the MC tissue. Spinal cord dose was increased in the CC and PB algorithms in all prescription points in patients with lung and buccal mucosa. OAR dose calculated by PB in all prescription points showed a significant deviation compared to MC tissue prescription point. Conclusion: This study will help demonstrate the accuracy of dose calculation for the different dose prescription points with the different treatment algorithms in radiotherapy treatment planning.

Response of various histological types of locally advanced rectal cancer to neoadjuvant multimodality therapy.

To determine the response of various histological types of locally advanced rectal cancer to neoadjuvant multimodality therapy. The non-randomised, quasi-experimental retrospective cohort study was conducted at the Combined Military Hospital, Rawalpindi, Pakistan, and comprised data of patients treated between January 1, 2020, to September 30, 2021. The data retrieved related to histologically proven and locally advanced rectal cancer patients aged 18-70 years receiving neoadjuvant chemoradiotherapy. Radiotherapy dose was 45 gray to pelvis with a boost to gross tumour of 5.4 gray in 3 fractions by using volumetric arc therapy concurrently with capecitabine 625mg/m² daily. A magnetic resonance imaging scan of pelvis with contrast was done at 5-10 weeks before surgery. Histological response to neoadjuvant treatment of various histological types was evaluated using the Rectal Cancer Regression Grade. Data was analysed using SPSS 22. Of the 182 patients evaluated, 108(59.34%) were included; 64(59.3%) males and 44(40.7%) females. The overall mean age was 45.4±5.2 years. Regression status was grade 1 in 24(22%) patients, grade 2 in 43(40%) and grade 3 in 41(38%) (p=0.074). There were 12(11.11%) patients with signet ring cell and 10(83.3%) showed pathological tumour regression. There were 17(15.74%) patients with mucinous variant, and 12(70.5%) had tumour regression. There were 79(73.15%) patients with adenocarcinoma, and 59(74.6%) of them showed tumour regression. . There was less tumour regression in mucinous and signet ring cell variants of adenocarcinoma. Modification and intensification of neoadjuvant therapy may be required in such histologies.

Impact of dose volume parameters and clinical characteristics on radiation-induced acute oral mucositis for head and neck cancer patients treated with carbon-ion radiotherapy dose volume outcome analysis.

To assess the predictive value of different dosimetric parameters for acute radiation oral mucositis (ROM) in head and neck cancer (HNCs) patients treated with carbon-ion radiotherapy (CIRT). 44patients with HNCs treated with CIRT were evaluated for acute ROM which was defined as severe when the score ≥3 (acute ROM was scored prospectively using the Radiation Therapy Oncology Group (RTOG) score system). Predictive dosimetric factors were identified by using univariate and multivariate analysis. Male gender, weight loss >5%, and total dose/fractions were related factors to severe ROM. In multivariate analysis, grade ≥3 ROM was significantly related to the Dmax, D10, D15, and D20 (P < 0.05, respectively). As the receiver operating characteristics (ROC) curve shows, the area under the curve (AUC) for D10 was 0.77 (p = 0.003), and the cutoff value was 51.06 Gy (RBE); The AUC for D15 was 0.75 (p = 0.006), and the cutoff value was 42.82 Gy (RBE); The AUC for D20 was 0.74 (p = 0.009), and the cutoff value was 30.45 Gy (RBE); The AUC for Dmax was 0.81 (p < 0.001), and the cutoff value was 69.33 Gy (RBE). Male gender, weight loss, and total dose/fractions were significantly association with ROM. Dmax, D10, D15 and D20 were identified as the most valuable predictor and we suggest aDmax limit of 69.33 Gy (RBE), D10 limit of 51.06 Gy (RBE), D15 limit of 42.82 Gy (RBE), and D20 limit of 30.45 Gy (RBE) and for oral mucosa.

High Rates of Organ Preservation in Rectal Cancer with Papillon Contact X-ray Radiotherapy: Results from a Swiss Cohort.

Rectal cancer typically necessitates a combination of radiotherapy (RT), chemotherapy, and surgery. The associated functional disorders and reduction in quality of life have led to an increasing interest in organ preservation strategies. Response strongly correlates with RT dose, but dose escalation with external beam remains limited even with modern external beam RT techniques because of toxicity of the surrounding tissues. This study reports on the use of Papillon, an endocavitary Radiotherapy device, in the treatment of rectal cancer. The device delivers low energy X-rays, allowing for safe dose escalation and better complete response rate. Between January 2015 and February 2024, 24 rectal cancer patients were treated with the addition of a boost delivered by Papillon to standard RT, with or without chemotherapy, in an upfront organ preservation strategy. After a median follow-up (FU) of 43 months, the organ preservation rate was 96% (23/24), and the local relapse rate was 8% (2/24). None of our patients developed grade 3 or more toxicities. Our results demonstrate that the addition of Papillon contact RT provides a high rate of local remission with sustained long-term organ preservation, offering a promising alternative to traditional surgical approaches in patients with rectal cancer.

Algorithms to identify radiotherapy intent in unresected non-metastatic non-small-cell lung cancer: an I-O Optimise analysis.

This study aimed to develop and evaluate the performance of algorithms for identifying radiotherapy (RT) treatment intent in real-world data from patients with non-metastatic non-small-cell lung cancer (NSCLC). Using data from IPO-Porto hospital (Portugal) and the REAL-Oncology database (England), three algorithms were developed based on available RT information (#1: RT duration, #2: RT duration and type, #3: RT dose) and tested versus reference datasets. Study results showed that all three algorithms had good overall accuracy (91-100%) for patients receiving RT plus systemic anticancer therapy (SACT) and algorithms #2 and #3 also had good accuracy (>99%) for patients receiving RT alone. These algorithms could help classify treatment intent in patients with NSCLC receiving RT with or without SACT in real-world settings where intent information is missing/incomplete.

The expanding role of radiation oncology across the prostate cancer continuum.

Radiotherapy is used in the treatment of prostate cancer in a variety of disease states with significant reliance on imaging to guide clinical decision-making and radiation delivery. In the definitive setting, the choice of radiotherapy treatment modality, dose, and fractionation for localized prostate cancer is determined by the patient's initial risk stratification and other clinical considerations. Radiation is also an option as salvage therapy in patients with locoregionally recurrent disease after prior definitive radiation or surgery. In recent years, the role of radiation has expanded for patients with metastatic disease, including prostate-directed radiotherapy in de novo low volume metastatic disease, metastasis-directed therapy for oligorecurrent disease, and palliative management of symptomatic metastases in the advanced setting. Here we review the expanding role of radiation in the treatment of prostate cancer in the definitive, locoregionally recurrent, and metastatic settings, as well as highlight the role of imaging in clinical reasoning, radiation planning, and treatment delivery.

Post-Excision Soft X-Ray Radiotherapy for Keloids: Experience in a Tertiary Referral Center

Introduction: Keloid is an abnormal proliferation of scar tissue that grows beyond the original margins of the injury. Even after complete resection, recurrences are common and pose a poorly understood challenge in dermatology. There is lack of large prospective clinical trials; thus, treatment recommendations are based on retrospective analyses and small cohort studies. Superficial radiotherapy is recommended in recurrent keloids; however, the successful treatment rates vary greatly. The aim of this study was to evaluate the keloid recurrence rate after post-excision soft X-ray radiotherapy and the associated factors. Methods: We reviewed retrospective data of all patients, treated with adjuvant post-excision soft X-ray radiotherapy with 12 Gy in 6 sessions at the tertiary referral center, Department of Dermatology, University Hospital Zurich, Switzerland, between 2005 and 2018. We analyzed individual keloids as separate cases. Successful treatment was defined as no sign of recurrence within 2 years. Results: Of the 200 identified patients, 90 met the inclusion criteria and were included in the final analysis. In 90 patients, 104 cases of treated keloids were analyzed. Keloids were mainly located on the trunk (49%) and were mostly caused by previous surgery (52.2%). 50% of the keloids did not relapse within 2 years after therapy. A significant factor leading to recurrence was the presence of previous therapy, with prior topical therapies, such as steroid injections or 5-fluorouracil, leading to most relapses. 69.2% of keloid cases who relapsed were pretreated. Soft X-ray radiotherapy was well tolerated, with posttreatment hyperpigmentation noted in 34% of patients, particularly in patients with non-Caucasian origin (61.3%). Conclusion: Treatment of refractory keloids is difficult. Post-excision radiotherapy is an established adjuvant treatment option; nevertheless, recurrence rates are high, especially in pretreated keloids. Prospective studies determining the exact dosage and fraction of post-excisional radiotherapy are needed to determine the optimal radiation parameters.

QOL-50. THE ROLE OF TUMOR SIZE IN COGNITIVE FUNCTIONING AMONG SURVIVORS TREATED FOR MEDULLOBLASTOMA

Abstract BACKGROUND Medical and treatment variables, including presence of post-operative cerebellar mutism syndrome (CMS), shunt placement, craniospinal radiation, and total radiotherapy (RT) dose, have been evaluated as potential risk factors for adverse cognitive effects among pediatric patients diagnosed and treated for medulloblastoma. Larger brain tumor size is associated with increased risk of medical complications, but cognitive risk of larger tumor size remains unknown. METHODS Cognitive scores were examined for 40 participants diagnosed and treated for medulloblastoma. The age-appropriate Wechsler Intelligence Scale was administered at the start of RT and up to 10 years post-RT (M=4.96, SD=3.78). A total of 162 evaluations were examined across participants. Linear mixed models examined change in Wechsler Index scores over time since RT based on tumor size, which was dichotomized at the median diameter (small ≤4.6cm versus large &amp;gt;4.6cm), covarying for maternal education, total RT dose, and presence of CMS. RESULTS Patients (72.5% male) were diagnosed with medulloblastoma and began RT at a mean age of 8.89 years. Groups did not differ on demographic or medical variables with the exception of presence/absence of CMS, with a higher proportion of patients diagnosed with CMS having large-size tumors (40%) versus small-size tumors (5%). Tumor size did not predict change in IQ, working memory, or processing speed performance over time since RT after accounting for covariates. CMS was associated with significant decline in processing speed (p&amp;lt;.001) and IQ over time (p&amp;lt;.05); RT dose was associated with significant working memory and IQ decline (both p&amp;lt;.05); and maternal education was associated with decline in processing speed, working memory, and IQ (all p&amp;lt;.05). CONCLUSIONS While tumor size may be associated with treatment intensity and other medical risk factors, CMS and RT dose significantly increase cognitive risk, independent of tumor size. Lower socioeconomic status also increases cognitive risk post-RT, which may illuminate pathways for prevention and intervention efforts.

GCT-28. THE IMPACT OF RESIDUAL TUMOR ON THE OUTCOMES OF CENTRAL NERVOUS SYSTEM GERMINOMA

Abstract BACKGROUND The inclusion of chemotherapy in the treatment backbone of central nervous system germinoma has helped reduce the field and dose of radiotherapy. Typically, patients wirh residual disease after chemotherapy are treated with higher doses of radiotherapy, which may not be necessary. Hence, we aimed to assess the impact of residual disease at different points during therapy on the outcomes of germinoma patients. METHODS We performed an extensive review of all germinoma patients diagnosed at Hospital Garrahan in Argentina over the last 20 years. We evaluated the chemotherapy response after 2 cycles and 4 cycles of chemotherapy and after radiotherapy. RESULTS Thirty nine germinoma were included (localized 34; disseminated 5). All patients were treated as per the SIOP-CNS-GCT-96 strategy. At the end of 2 cycles of chemotherapy, 21 patients achieved a complete response (CR), 10 had a partial response (PR), and 8 patients didn’t have MRI evaluation. At the end of 4 chemotherapy cycles, 10 additional patients achieved a CR, 7 still had a PR, while one patient didn’t have MRI evaluation. Only 3 patients had residual tumour after radiotherapy; one had a second-look surgery that didn’t show any evidence of viable tumour. None of the patients with residual tumour at the end of chemotherapy or radiotherapy relapsed with a median follow up of 6.3 years. CONCLUSION Residual tumor at the end of both chemotherapy and radiotherapy does not have an impact on the outcomes. Clinical trials in germinomas may need to investigate administering the same dose of radiotherapy for patients regardless of the presence of residual disease at the end of chemotherapy. Furthermore, patients with no residual disease at the end of two cycles of chemotherapy may benefit from moving directly to radiotherapy without the need to receive two additional cycles of chemotherapy.

GCT-14. TREATMENT APPROACH FOR METASTATIC INTRACRANIAL GERMINOMA: A MULTI-INSTITUTIONAL EXPERIENCE

Abstract BACKGROUND Germinoma is the most common CNS germ cell tumor in children. Treatment with 24Gy craniospinal irradiation (CSI) with boost to 40Gy alone results in excellent survival irrespective of disease stage. For localized germinoma, recent studies have demonstrated the efficacy of neoadjuvant chemotherapy in decreasing the field/dose of radiation therapy (RT) needed for cure. For metastatic germinoma however, the optimal RT approach when combined with chemotherapy is unclear. Herein, we present our experience in treating patients with metastatic germinoma. METHODS We performed a retrospective, IRB-approved study of patients with metastatic germinoma diagnosed between 2001-2023 at Boston Children’s Hospital, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Mass General Hospital. Clinical features, treatment plan, and outcomes were collected and analyzed using the Kaplan-Meier method and Fisher’s exact test. RESULTS Twenty-eight patients with metastatic germinoma were identified. Median age at diagnosis was 15.9 years (range:6.2-25.9). Metastasis was intracranial in 20, craniospinal in three and CSF-only in five patients. Six patients received CSI only. Twenty-two patients received neoadjuvant chemotherapy and CSI. Median number of chemotherapy cycles was 4 (range:3-6). Seventeen patients had complete response, four patients had partial response, and one patient had progressive disease with chemotherapy. All patients went on to receive CSI, with median dose of 21Gy (range:18-36Gy) with median IF boost to 36Gy (range:30-51.6Gy). Median duration of follow-up was 11 years (range:0.3-25.3). There were no recurrences or deaths within the cohort. Analysis of long-term outcomes data revealed no significant differences in frequency of endocrinopathies, CNS vasculopathies, or memory loss between the doses of RT. CONCLUSIONS Our data show that neoadjuvant chemotherapy followed by CSI is associated with excellent overall survival in patients with metastatic germinoma. Importantly, our experience suggests that in combination with neoadjuvant chemotherapy, 21Gy CSI may be sufficient as a curative dose in this patient population.

GCT-09. VENTRICULAR RELAPSES OF INTRACRANIAL GERM CELL TUMORS FOLLOWING FOCAL RADIOTHERAPY

Abstract BACKGROUND Non-germinomatous germ cell tumors (NGGCTs) require treatment involving combinations of chemotherapy, surgery, and radiotherapy. The radiotherapy field is typically focal in Europe and craniospinal in North America. Unlike germinomas, there are conflicting results for the effectiveness of ventricular field irradiation, and there is not enough data documenting the histology and tumor markers for tumors that relapse along the ventricles in patients who receive focal irradiation. METHODS We performed a literature review for English-language literature from 1998 to 2024 to to analyze the incidence, histopathology and tumor marker levels for NGGCT patients who initially received chemotherapy followed by focal radiotherapy and ended up having of ventricular relapses. RESULTS We identified 47 cases with relapsed NGGCT. However, only 8 cases were along the ventricles. Six of these were ventricular only, including two presumed germinomas based on tumor markers, three biopsy-proven germinomas, and only one case with bHCG levels exceeding ≥1000 IU/l. Two had combined relapses involving both the ventricular and spinal regions; one had pathology-proven germinoma but with elevated alpha-fetoprotein, and the other exhibited bHCG levels between 50 and 200 IU/l. CONCLUSION Ventricular relapses in NGGCT patients who receive focal radiotherapy should be investigated further. Whole ventricular radiotherapy may be required to prevent the relapse of germinoma elements. However, further information is essential before making any changes in the radiotherapy doses and fields.

QOL-24. TREATMENT- AND TIME-RELATED IMPACT ON LONG-TERM NEUROCOGNITIVE OUTCOMES IN ADULT SURVIVORS OF A PEDIATRIC BRAIN TUMOR

Abstract Treatment for pediatric brain tumors has been associated with the risk of developing long-term neurocognitive impairment. However, it is not well understood which neurocognitive profiles exist within this population. We investigated neurocognitive functioning (NF) in survivors in early adulthood and aimed to assess the impact of radiotherapy dose (RTD) and time since treatment (TxT) on NF. Forty-six survivors of pediatric brain tumors (mean age 23.99±4.71, mean age at diagnosis 9.29±4.54) performed an extensive neurocognitive test battery resulting in intelligence (n=5), memory (n=2), and language (n=3) scores. NF in long-term survivors was compared to sex-, age-, and education-matched controls, and between the different treatment strategies (surgery-only n=19, chemotherapy n=8, radiotherapy n=11, or chemo-radiotherapy n=8). Furthermore, relation between max-RTD (range 40.28 – 61.61 Gy) as well as TxT and NF was assessed. Three ANCOVA models were tested, and false discovery rate (FDR) was applied. For all scales and domain scores, survivors scored lower compared to controls. Scores were significant lower on full scale intelligence (pfdr&amp;lt; 0.001), verbal comprehension (pfdr&amp;lt; 0.001), working memory (pfdr= 0.003), perceptual reasoning (pfdr&amp;lt; 0.001), processing speed (pfdr&amp;lt; 0.001), spoken word comprehension (pfdr= 0.001), and semantic word generation (pfdr= 0.036) compared to controls. NF was not significantly different between the different treatments, nor did the association with max-RTD reach significance. TxT was associated with verbal comprehension and spoken word comprehension; albeit significance was not retained after FDR correction. In this study, the overall survivor cohort scored lower on multiple cognitive outcomes. More detailed analysis of various risk factors might further elucidate the different neurocognitive profiles for this population. Furthermore, more detailed analysis of RTD distributions and affected brain structures may provide greater insight on the impact of radiotherapy on NF.

GCT-01. CENTRAL NERVOUS SYSTEM GERM CELL TUMORS – GENERATING A CONSENSUS IN THEIR DIAGNOSIS AND MANAGEMENT

Abstract BACKGROUND Despite the excellent outcomes of central nervous system (CNS) germ cell tumors (GCTs), there still exists significant differences in how GCTs are diagnosed and managed in different parts of the world. Additionally, the long-term toxicities and morbidities of the current therapies, and their substantial negative impact on the social wellbeing of our patients should clearly indicate that the current achievements are not enough. Further, important molecular data have emerged over the past decade that we have not witnessed their translation into any of the ongoing clinical trials. METHODS A comprehensive review of all major CNS GCT clinical trials will be discussed, in addition to a detailed review of the several issues of debate. Moreover, the latest developments in molecular landscape of GCTs will be provided in order to identify the hurdles that affect their incorporation in GCT clinical trials. RESULTS Tumor marker cut-offs that differentiate between germinoma and non-germinomatous germ cell tumors are clearly different between the various groups around the world. Additionally, differences exist in the chemotherapy backbones, radiation therapy field and dose, and the appropriate regimens to treat some of the rarer GCTs. Furthermore, there is no clear guideline on how to treat patients who do not achieve complete response after chemotherapy. CONCLUSIONS Discussing the clear differences that exist in the diagnosis and management of CNS GCTs is a critical first step in generating a clear consensus between the North American, European, Asian, and Latin American groups, which will certainly guide future clinical trials, improve the outcomes as well as the long-term treatment effects for this group of patients.

EPID-04. CAUSES AND LONG-TERM COURSE OF OTOTOXICITY IN PEDIATRIC MEDULLOBLASTOMA AND EPENDYMOMA PATIENTS – CUMULATIVE PLATINUM AND COCHLEAR IRRADIATION DOSE MATTER

Abstract BACKGROUND Ototoxicity is a well-known side effect of treatment with platinum-containing chemotherapy and radiotherapy (RT). Nevertheless, precise dose-effect relationships are still lacking. METHODS Patients from the HIT2000 trial receiving first-line treatment for medulloblastoma (MB) or ependymoma (EPN) who were alive at last follow-up and had at least one audiogram prior to and after administration of chemotherapy with cisplatinum and radiotherapy were included into this study. Treatment details (incl. cochlear irradiation dose [CID]) and audiological outcome were analyzed. The ototoxicity was graded using the HIT scoring. RESULTS Courses of 101 patients were analyzed. Median audiology follow-up was 6 years [range: 1.0–18.1 years]. Ototoxicity grade ≥1 was documented for n=66 patients (65.4%). For n=27 this resulted in treatment modification. Univariable analyses revealed different proportions of ototoxicity (grade ≥1) regarding histology (CMB: 50/65, LCAMB: 3/3, DMB/MBEN: 8/12, EPN: 5/21; p&amp;lt;0.001), tumor location (supratentorial: 3/9, infratentorial: 63/92; p&amp;lt;0.001), metastatic status at diagnosis (M0: 46/77, M+: 20/24; p=0.003), radiation field (CSI: 59/75, local RT: 6/21, no RT: 1/5; p&amp;lt;0.001), CID (continuous variable, p=0.001) and cumulative cisplatinum dose (continuous variable, p&amp;lt;0.001). Certainly, disease specific parameters (histology/staging) were related to treatment intensity (cisplatinum/irradiation dose). Multivariable analyses confirmed the impact of cumulative cisplatinum dose (p=0.01) and CID (p=0.04). ROC-analyses allowed the definition of cut-offs for high risk of ototoxicity grade ≥1 (cisplatinum: 70mg/m2 BSA, CID: 37.5 Gy) and ototoxicity risk estimation, when applying doses above the respective cut-offs (cisplatinum dose increase by 1mg/m2 BSA results in 4% higher risk for ototoxicity grade ≥1; CID dose increase by 1 Gy results in 4.6% higher risk for ototoxicity grade ≥1). CONCLUSIONS Ototoxicity affects a majority of children receiving adjuvant treatment for MB and EPN. To avoid disabilities and negative effect on quality of live, dosage of cisplatinum and radiotherapy should be scrutinized and reduced whenever possible.

DIPG-41. CONVECTION ENHANCED DELIVERY-MEDIATED RADIOSENSITIZATION FOR DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. The only approved standard of care is radiation therapy (RT). Studies examining the role of other systemic agents have failed to demonstrate a survival benefit, partially due to tumor extension to areas of the brain where the blood-brain barrier (BBB) remains intact. As our laboratory has recently determined active NAD(P)H Quinone Dehydrogenase 1 (NQO1) expression in patient-derived DMG tumor samples, we sought to investigate NQO1 bioactivatable agent Napabucasin to augment reactive oxygen species (ROS) production and overcome radioresistance in DMG. Furthermore, we explore the safety and feasibility of convection-enhanced deliver (CED) to overcome limitations of the BBB. METHODS Using two DMG cell lines, we performed clonogenic survival assays with increasing doses of RT with and without Napabucasin. We then created subcutaneous xenograft mouse models, treating with (1) vehicle control, (2) Napabucasin, (3) 2 Gy of RT daily, or (4) combination treatment with RT and Napabucasin. Using a syngeneic orthotopic DMG mouse model, we implanted 7-day osmotic infusion pumps containing either vehicle control or 80uM Napabucasin. Mice then underwent a second randomization with or without daily RT for 5 days. RESULTS We identified a robust radiosensitizing effect with Napabucasin using in vitro clonogenic survival assays. In subcutaneous flank models, combination treatment led to a statistically significant smaller tumor volume post-treatment completion when compared to any monotherapy. In our syngeneic orthotopic DMG mouse model, RT after CED pump implantation in the brainstem did not lead to significant morbidity or mortality. Combination RT and CED of Napabucasin led to a significant survival benefit when compared to monotherapy. CONCLUSIONS In this study, we show Napabucasin as a promising radiosensitizer in DMG. Furthermore, this is the first preclinical study showing safety/efficacy of CED with concurrent RT in DMG.

DIPG-59. RADIATION-INDUCED DIPG IN A CHILD PREVIOUSLY IRRADIATED FOR CRANIOPHARYNGIOMA: CASE REPORT AND LITERATURE REVIEW

Abstract BACKGROUND Radiation-induced second malignancies occur in a subset of patients following cranial radiation therapy (RT). In Craniopharyngioma (CP), adjuvant RT is commonly recommended for residual tumor or recurrence, and radiation-induced malignant gliomas (RIMGs) are rarely reported. METHODS We report a case of radiation-induced diffuse intrinsic pontine glioma (DIPG) in pediatric Craniopharyngioma and conducted a review of previously reported cases. RESULTS A 14-year-old boy presented with complaints of headaches and vomiting for 1 month; difficulty in walking, and slurred speech for 1 week, with Lansky Performance Score (LPS) of 20. Eight years before this admission, he underwent surgical excision and 3D-conformal RT for Craniopharyngioma. His recent MRI brain was suggestive of DIPG and after a multidisciplinary discussion re-irradiation (30Gy in 10 fractions) was given. He has been alive for 5 months since diagnosis with improved symptoms and LPS (70). Including the index case, 19 cases of RIMGs in CP were identified. All except one were reported from high-income countries. Only 4 involved the pons/brainstem. The median age at CP diagnosis was 7.0 years (2.0-22.0 years), and with RIMG was 18 (6.8-41.0 years). Median latency period was 10.0 years (4.5-25.0 years). The female-to-male ratio was 1.8:1. The median previous RT dose was 54.8 Gy (49.3-60.1 Gy) with 37% cases treated with 3D conformal and 37% with conventional RT (not specified in 26%). Cerebral cortex (66.6%) was the most common site for the RIMG with temporal lobe predisposition. Chemotherapy was given in 56%, surgical excision in 50% and repeat RT in 31% cases with a median survival of 4 months (0-13 months). CONCLUSION We report the first case of radiation-induced DIPG in pediatric Craniopharyngioma in an LMIC. RIMG appears to be a rare occurrence in CP and doesn’t seem to be associated with the RT type. The overall prognosis is extremely poor.

GCT-25. THE IMPACT OF RESIDUAL DISEASE ON THE OUTCOMES OF CENTRAL NERVOUS SYSTEM GERMINOMAS – A MULTICENTER INSTITUTION EXPERIENCE

Abstract BACKGROUND Germinomas make up about two-thirds of central nervous system (CNS) germ cell tumors and are highly radio-sensitive with excellent survival rate of more than 90%. Current standard of care involves the combination of chemotherapy with reduced-dose radiotherapy. Typically, patients with residual disease receive a higher dose of radiotherapy. However, recent clinical trials showed that there were no differences in the outcomes between those who had complete response (CR) versus partial response (PR) to initial chemotherapy. Hence, we aimed to assess the outcomes of germinoma patients based on the responses to both chemotherapy and radiotherapy. METHODS A multicenter retrospective chart review of patients with germinoma from four large academic institutions was conducted. RESULTS Data from 41 germinoma patients treated between 2011 and 2022 were analyzed. Thirty-two patients had stable disease (SD)(2), PR(28), or CR(2) to chemotherapy. At the end of radiotherapy, 12 had CR, 5 had PR, and 13 had SD. All patients were alive at the time of review, with a median duration of survival from diagnosis of 78.85 months (range 3.90-278.67). One patient experienced radiographic progression following chemotherapy with SD noted following radiotherapy. CONCLUSION Relapses are extremely rare in patients who have residual disease at the end of therapy for germinoma. Future prospective clinical trials are needed to test the possibility of treating germinoma patients who have residual disease with a dose of radiotherapy comparable to that used in patients who achieve complete response.

GCT-17. EXPLORING NEW THRESHOLDS FOR BETA-HCG IN CENTRAL NERVOUS SYSTEM GERMINOMA

Abstract BACKGROUND Human chorionic gonadotropin (beta-HCG) levels in serum and cerebrospinal fluid (CSF) are critical in the management of patients with germinoma. The threshold for beta-HCG diagnosis is a topic of debate and differs in Europe, ≤50 IU/L, North America ≤100 IU/L, and ≤200 IU/L in Brazil/Japan. METHODS We conducted a meta-analysis of English-language publications (1990-2023) to assess how beta-HCG cut-off levels impact treatment outcomes. Standard descriptive statistics summarized all data. RESULTS Forty-nine patients with biopsied germinoma were identified. Eighteen had beta-HCG level of 50-100 IU/L (cohort 1), 21 had 100-200 IU/L (cohort 2), and 10 had &amp;gt;200 IU/L (cohort 3). In cohort 1, treatment with chemotherapy plus radiotherapy was administered to 9 patients. Eight of them received radiotherapy like germinoma treatment (≤30Gy), primarily employing whole ventricle irradiation (WVI). Nine patients received radiotherapy alone with total dose 30-59.6Gy. Fifteen patients in cohort 2 received chemotherapy plus radiotherapy. Eight of them received radiotherapy ≤30Gy for different fields [WVI – 4, whole brain (WB) – 3, cerebrospinal irradiation (CSI) – 1). In 7 patients the dose of radiotherapy exceeded 30Gy (local radiotherapy – 4, CSI – 3). Radiotherapy alone was used in 5 patients, chemotherapy alone – 1 patient. In cohort 3, radiotherapy only was primarily used. Six patients received CSI (50-54Gy), one – CSI+WB+local radiotherapy (12.8Gy+27.2Gy+50.6Gy). One patient received combined treatment and 2 patients received chemotherapy alone. Relapses occurred in each cohort. In cohort 1 – 2 metastatic relapses (1 after WVI 24Gy, 1 after radiotherapy &amp;gt;30Gy). Three children from cohort 2, who received chemotherapy plus radiotherapy were diagnosed with relapse (1 after WB 23.4Gy, 2 after radiotherapy &amp;gt;30Gy). In cohort 3 two metastatic relapses were diagnosed – only after chemotherapy. CONCLUSIONS Relapse rates across all beta-HCG level are similar. However, study groups are small and treatment regimens vary, warranting further investigation.