Craniospinal Irradiation Research Articles

Automated contouring, treatment planning, and quality assurance for VMAT craniospinal irradiation (VMAT-CSI)

PurposeCreate a comprehensive automated solution for pediatric and adult VMAT-CSI including contouring, planning, and plan check to reduce planning time and improve plan quality.MethodsSeventy-seven previously treated CSI patients (age, 2-67 years) were used for creation of an auto-contouring model to segment 25 organs at risk (OARs). The auto-contoured OARs were evaluated using the Dice Similarity Coefficient (DSC), 95% Hausdorff Distance (HD95), and a qualitative ranking by one physician and one physicist (scale: 1-acceptable, 2-minor edits, 3-major edits). The auto-planning script was developed using the Varian Eclipse Scripting API and tested with 20 patients previously treated with either low-dose VMAT-CSI (12 Gy) or high-dose VMAT-CSI (36 Gy + 18 Gy boost). Clinically relevant metrics, planning time, and blinded physician review were used to evaluate significance of differences between the auto and manual plans. Finally, the plan preparation for treatment and plan check processes were automated to improve efficiency and safety of VMAT-CSI.ResultsThe auto-contours achieved an average DSC of 0.71 ± 0.15, HD95 of 4.81 ± 4.68, and reviewers’ ranking of 1.22 ± 0.39, indicating close to “acceptable-as-is” contours. Compared to the manual CSI plans, the auto-plans for both dose regimens achieved statistically significant reductions in body V50% and Dmean for parotids, submandibular, and thyroid glands. The variance in the dosimetric parameters decreased for the auto-plans as compared to the manual plans indicating better plan consistency. From the blinded review, the auto-plans were marked as equivalent or superior to the manual-plans 88.3% of the time. The required time for the auto-contouring and planning was consistently between 1-2 hours compared to an estimated 5-6 hours for manual contouring and planning.ConclusionsReductions in contouring and planning time without sacrificing plan quality were obtained using the developed auto-planning process. The auto-planning scripts and documentation will be made freely available to other institutions and clinics.

Proton Craniospinal Irradiation for Treatment of Leptomeningeal Metastasis in Patients with Solid Malignancy: The MD Anderson Cancer Center Experience (S27.006)

Proton Craniospinal Irradiation for Treatment of Leptomeningeal Metastasis in Patients with Solid Malignancy: The MD Anderson Cancer Center Experience (S27.006)

Helical tomotherapy craniospinal irradiation in primary brain tumours: Toxicities and outcomes in a peadiatric and adult population

ObjectiveAs craniospinal irradiation (CSI) is delivered more frequently by helical tomotherapy (HT) with few reports about late effects, we analysed all patients treated in our centre over an 11-year period. Methods and materialsOur study included all patients that underwent CSI by HT, between September 2009 and January 2020, in the Department of Radiation Oncology of the Toulouse Cancer Institute. Acute radiotherapy toxicities were reported and medium- to long-term outcomes analysed. ResultsAmong the 79 patients included, 70.9 % were younger than 18 years at diagnosis, the median age was 13 (range: 1–52) at the time of radiation therapy, 67.1 % of patients had medulloblastoma. Half of them (49.4 %) had a metastatic disease at diagnosis. The median dose of CSI was 36 Gy (range, 18–36). Seventy-seven patients received a radiation boost to the original location of the primary tumour (97.5 %), 32 patients also received a boost to their metastatic sites (40.5 %). Median follow-up was 55.5 months (95 %CI = [41.2; 71.8]). The 3-year event-free survival rate was 66.3 % (95 %CI = [54.2; 75.9]). Most patients presented with acute haematological toxicities during CSI (85.9 %), predominantly severe thrombocytopenia (39.7 %). Among the 64 patients assessed for medium- and long-term outcomes, 52 survived and 47 were alive and disease-free at the latest follow-up visit on record. There were 3.8 % secondary tumours: two meningiomas and one diffuse intrinsic pontine glioma. Adult and paediatric patients respectively presented with secondary cataract (4.3 % vs 22.0 %), persistent hearing disorders (26.1 % vs 29.3 %), pulmonary or cardiac late effects (4.3 % vs 2.4 %), hormonal pituitary gland deficiencies (30.0 % vs 56.8 %) and psycho-cognitive disorders (56.5 % vs 53.7 %). ConclusionCSI dispensed by HT, did not result in any additional acute or late toxicities when compared to 3D-CSI. There was no increase in the secondary tumour rate compared to that reported in the literature

Abstract 4889: Integrative multi-omic analysis reveals novel prognostic biological entities in pediatric medulloblastoma

Abstract Medulloblastoma is a cerebellar tumor for which relapses are associated with poor survival rates of less than 5%. Molecular heterogeneity and dose-limiting toxicities that occur with standard of care approaches, which include surgical resection, craniospinal irradiation, and chemotherapy, complicate the treatment of both primary and recurrent medulloblastoma due to adverse long-term sequela. While the integration of molecular analyses into the histopathology of pediatric medulloblastomas has changed the way these diseases are diagnosed, classified, and treated, there remains an unmet need to further understand the underpinnings of the disease to improve clinical outcomes and minimize neuronal, cognitive, and hormonal toxicities that occur with standard-of-care therapies. We therefore aimed to investigate novel subgroups of pediatric medulloblastoma as a basis for further defining biological properties and targets for the disease through multi-omic characterization. We derived single-nucleotide variant, copy number variant, expression, alternative splicing, and methylation array data from pediatric medulloblastomas profiled as part of the Children’s Brain Tumor Network (CBTN) and the Open Pediatric Cancer (OpenPedCan) projects. Using non-negative matrix factorization across the five datasets derived from genomic, transcriptomic, and epigenomic profiling, we identified 14 clusters found to be prognostically significant by Kaplan-Meier analysis of overall survival (p < 0.0001). Our model further subdivided sonic hedgehog (SHH) and Group 3/4 tumors, but not Wnt-driven tumors, suggesting that the latter forms a homogeneous molecular subgroup. Among our subgroups, we recapitulated the four classically defined medulloblastoma subtypes known to be associated with mutations in KDM6A, KMT2C, CTNNB1, PTCH1, TP53, KBTBD4, MYC, and MYCN. Cascading biological relationships across the copy number, methylation, and expression domains were observed among novel subgroups, potentially driving migratory, immuno-regulatory, GPCR-related, growth factor-related, and histone methylation biological programs. A comparison of subgroup expression profiles to transcriptional signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) program identified canonical oncogenic pathways unique to each subgroup as potentially targetable, including, but not limited to, MAPK, VEGFA, inflammatory, fatty acid metabolic, and PI3K/AKT signaling. Our work uncovers novel biological entities in pediatric medulloblastoma potentially driven by higher order mechanisms across the genome, transcriptome, and epigenome, with the possibility of informing novel precision medicine approaches for the disease. Citation Format: Komal Rathi, Varun Kesherwani, Ammar S. Naqvi, Yuankun Zhu, Alex Sickler, Xiaoyan Huang, Bo Zhang, Brian Rood, Adam C. Resnick, Adam A. Kraya. Integrative multi-omic analysis reveals novel prognostic biological entities in pediatric medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4889.

Abstract 5111: Rational synergistic radiosensitization strategies for group 3 medulloblastoma

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is comprised of 4 groups, termed Wnt, Shh, Group 3 and Group 4, each characterized by distinct molecular and clinical profiles. MYC-amplified Group 3 MB is associated imminent fatal metastatic relapse following standard treatment approaches, which currently include surgery, craniospinal irradiation and chemotherapy, highlighting an urgent need for identification of therapeutic vulnerabilities for these tumours. As such, using 4 novel patient-derived models of Group 3 MB that faithfully recapitulate the molecular and histological tumor characteristics, we characterised response to radiation of Group 3 MB in vitro to show that these tumors do not possess intrinsic radiation resistance. Furthermore, cumulative radiation experiments do not increase bulk radiation resistance in MB cells, highlighting the contribution of dynamic cell states to radiation response. In contrast, exposure to radiation leads to changes in cell clonogenic capacity as measured by limited dilution assays. Furthermore, RNA-seq data uncovered altered transcriptomic programs in response to cumulative radiation treatment. In particular, we observe differential regulation of genes encoding potassium ion channels and their regulators as well as genes encoding ECM and cell adhesion proteins. As part of our goal to evaluate the current multimodal treatment strategy of MB, we also show that a set of standard chemotherapeutic agents (etoposide, thiotepa and lomustine) currently used in the clinic do not produce a potent response at optimal doses in vitro, potentially accounting for abysmal survival outcomes seen in chemotherapy treated MB patients. As such, we conducted a screen of 144 FDA approved cancer drugs and identified therapeutics that selectively target Group 3 MB cells in contrast to normal tissue controls (foetal neural stem cells) in the low nanomolar dose range. In particular, topoisomerase inhibitor topotecan produces a potent response specific to MYC-amplified Group 3 MB, and sensitizes 2 patient-derived MB models to gamma irradiation. Altogether, our data characterizes Group 3 MB molecular and cellular responses to current treatment modalities and provides rationale for new clinical strategies to sensitize patients to radiation that will potentially allow to reduce the required radiation doses to treat these aggressive tumors, reduce the incidence of radiation treatment-related morbidity as well as improve cure rates. Citation Format: Julija Povilaikaite, Kaitlin Stitz, Nikhita Austin, Vijay Ramaswamy. Rational synergistic radiosensitization strategies for group 3 medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5111.

Dosimetry and efficiency comparison of knowledge-based and manual planning using volumetric modulated arc therapy for craniospinal irradiation.

Craniospinal irradiation (CSI) poses a challenge to treatment planning due to the large target, field junction, and multiple organs at risk (OARs) involved. The aim of this study was to evaluate the performance of knowledge-based planning (KBP) in CSI by comparing original manual plans (MP), KBP RapidPlan initial plans (RPI), and KBP RapidPlan final plans (RPF), which received further re-optimization to meet the dose constraints. Dose distributions in the target were evaluated in terms of coverage, mean dose, conformity index (CI), and homogeneity index (HI). The dosimetric results of OARs, planning time, and monitor unit (MU) were evaluated. All MP and RPF plans met the plan goals, and 89.36% of RPI plans met the plan goals. The Wilcoxon tests showed comparable target coverage, CI, and HI for the MP and RPF groups; however, worst plan quality was demonstrated in the RPI plans than in MP and RPF. For the OARs, RPF and RPI groups had better dosimetric results than the MP group (P < 0.05 for optic nerves, eyes, parotid glands, and heart). The planning time was significantly reduced by the KBP from an average of 677.80 min in MP to 227.66 min (P < 0.05) and 307.76 min (P < 0.05) in RPI, and RPF, respectively. MU was not significantly different between these three groups. The KBP can significantly reduce planning time in CSI. Manual re-optimization after the initial KBP is recommended to enhance the plan quality.

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

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

Bifocal germ cell tumor of pineal germinoma and neurohypophyseal embryonal carcinoma: illustrative case.

Bifocal germ cell tumors, with primarily identical tissue composition, occur concurrently in the neurohypophyseal and pineal regions. A 16-year-old male patient exhibited increased intracranial pressure symptoms, with concurrent tumors in the pineal and neurohypophyseal regions, causing obstructive hydrocephalus. His serum human chorionic gonadotropin level was elevated, measuring 506.6 mIU/mL. Upon gross endoscopic examination, the pineal tumor appeared white, whereas the neurohypophyseal tumor appeared red and hemorrhagic. Because of the limited sample size of the latter, a frozen section biopsy was feasible only for the pineal lesion, which indicated the presence of a germinoma. Subsequently, carboplatin and etoposide were administered, resulting in the reduction of the pineal tumor, but no effect was observed in the neurohypophyseal tumor. Histopathological analysis confirmed the pineal lesion as a germinoma, whereas the neurohypophyseal lesion was an embryonal carcinoma. Thus, the treatment was altered to ifosfamide, carboplatin, and etoposide (ICE), leading to a response in both tumors. The patient underwent three additional cycles of ICE therapy and high-dose chemotherapy, followed by whole craniospinal irradiation, achieving complete remission. Although most bifocal germ cell tumors share the same histological tissue, occasional differences may arise, necessitating separate biopsies for accurate assessment.

Abstract PR-011: The role of tumor microenvironment in metastasis and relapses of medulloblastoma using immunocompetent mouse models

Abstract Medulloblastoma (MB) is an embryonal malignant tumor that arises in the cerebellum of infants, children, and adolescents. Despite highly aggressive therapies, including surgery, radiation, and chemotherapy, metastasis remains the primary cause of death in these patients. The tumor microenvironment (TME) has an important role in metastasis and relapse in several cancer types, but it’s role in high-risk MBs (metastatic and relapse) has been understudied. Here, we investigated the process of relapse in an immunocompetent Shh MB mouse model based on somatic mutagenesis induced by Sleeping Beauty (SB)-mediated transposition on a genetically engineered strain carrying a loss-of-function Patched 1 gene (Ptch1) mutation. Lack of one functional copy of the Ptch1 gene predisposes this strain to develop MB. Somatic mutations induced by the transposon increase penetrance of tumor formation in the triple mutant mice carrying the SB transposon system and the Ptch1 mutation. We used this model to study the mechanisms of chemoresistance to cisplatin and cyclophosphamide, that constitute the backbone of the high-dose chemotherapy used to treat patients under the age of 3, who cannot receive craniospinal irradiation. By treating the SB mouse model with surgery followed by high-dose fractionated chemotherapy, we developed a model of MB chemoresistance which is relevant to the infant SHH-MB patient population. While chemotherapy improved mouse survival, only a small number of animals were cured, mirroring the outcome seen in infant patients with Shh MB. Deep sequencing and mapping of transposon-gDNA junctions, along with gene-centric common insertion site analysis (gCIS), revealed that Trp53 transposon insertions are found exclusively at relapse. In the metastatic compartment we observed convergence of gCISes on genes coding for epigenetic regulators, among them a prominent enrichment was found for PRC2 complex genes. RNA-seq analysis on the transcriptome of primary and recurrent tumors indicated that a majority of the differentially expressed genes are associated with inflammatory responses, IL6, and TNF-α/NF-κB signaling. Immunohistochemistry to visualize the expression levels of inflammatory markers: IL-6, CCL2, and F4-80 and spatial targeted multiplexed assays (Geomx) confirmed the increase of immune cells at progression. ChIP-qPCR on cytokine loci revealed binding of PRC2 and deposition of PRC2 mediated repressive histone mark H3K27me3 on the promoter of CCL2 highlighting LOF mutations in PRC2 components as potential epigenetic mechanisms for immune recruitment at progression. Inhibition of immune activation through pharmacological strategies might be a possible therapeutic option for infant SHH-MB. Citation Format: Niusha Khazaei, Ana Castillo Orozco, Wajih Jawhar, Geoffroy Danieau, Kiran Narta, Michael Taylor, Sorana Morrissy, Ana Stuecklin, Livia Garzia. The role of tumor microenvironment in metastasis and relapses of medulloblastoma using immunocompetent mouse models [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-011.

Pathologic Features of Brain Hemorrhage After Radiation Treatment: Case Series with Somatic Mutation Analysis

Radiation treatment for diseases of the brain can result in hemorrhagic adverse radiation effects. The underlying pathologic substrate of brain bleeding after irradiation has not been elucidated, nor potential associations with induced somatic mutations. We retrospectively reviewed our department's pathology database over 5 years and identified 5 biopsy specimens (4 patients) for hemorrhagic lesions after brain irradiation. Tissues with active malignancy were excluded. Samples were characterized using H&E, Perl's Prussian Blue, and Masson's Trichrome; immunostaining for B-cells (anti-CD20), T-cells (anti-CD3), endothelium (anti-CD31), macrophages (anti-CD163), α-smooth muscle actin, and TUNEL. DNA analysis was done by two panels of next-generation sequencing for somatic mutations associated with known cerebrovascular anomalies. One lesion involved hemorrhagic expansion among multifocal microbleeds that had developed after craniospinal irradiation for distant medulloblastoma treatment. Three bleeds arose in the bed of focally irradiated arteriovenous malformations (AVM) after confirmed obliteration. A fifth specimen involved the radiation field distinct from an irradiated AVM bed. From these, 2 patterns of hemorrhagic vascular pathology were identified: encapsulated hematomas and cavernous-like malformations. All lesions included telangiectasias with dysmorphic endothelium, consistent with primordial cavernous malformations with an associated inflammatory response. DNA analysis demonstrated genetic variants in PIK3CA and/or PTEN genes but excluded mutations in CCM genes. Despite pathologic heterogeneity, brain bleeding after irradiation is uniformly associated with primordial cavernous-like telangiectasias and disruption of genes implicated in dysangiogenesis but not genes implicated as causative of cerebral cavernous malformations. This may implicate a novel signaling axis as an area for future study.

Phantosmia during proton radiation and differences in frequency of phantosmia rates based on proton craniospinal irradiation technique for pediatric brain tumor patients.

Unusual olfactory perception, often referred to as "phantosmia" or "cacosmia" has been reported during brain radiotherapy (RT), but is infrequent and does not typically interfere with the ability to deliver treatment. We seek to determine the rate of phantosmia for patients treated with proton craniospinal irradiation (CSI) and identify any potential clinical or treatment-related associations. We performed a retrospective review of 127 pediatric patients treated with CSI, followed by a boost to the brain for primary brain tumors in a single institution between 2016 and 2021. Proton CSI was delivered with passive scattering (PS) proton technique (n=53) or pencil beam scanning technique (PBS) (n=74). Within the PBS group, treatment delivery to the CSI utilized a single posterior (PA) field (n=24) or two posterior oblique fields (n=50). We collected data on phantom smell, nausea/vomiting, and the use of medical intervention. Our cohort included 80 males and 47 females. The median age of patients was 10years (range: 3-21). Seventy-one patients (56%) received concurrent chemotherapy. During RT, 104 patients (82%) developed worsening nausea, while 63 patients (50%) reported episodes of emesis. Of those patients who were awake during CSI (n=59), 17 (29%) reported phantosmia. In the non-sedated group, we found a higher rate of phantosmia in patients treated with PBS (n=16, 42%) than PS (n=1, 4.7%) (p=.002). Seventy-eight patients (61%) required medical intervention after developing nausea/vomiting or phantosmia during RT. Two patients required sedation due to the malodorous smell during CSI. We did not find any significant difference in nausea/vomiting based on treatment technique. Proton technique significantly influenced olfactory perception with greater rates of phantosmia with PBS compared to PS. Prospective studies should be performed to determine the cause of these findings and determine techniques to minimize phantosmia during radiation therapy.

Proton PBS Planning Techniques, Robustness Evaluation, and OAR Sparing for the Whole-Brain Part of Craniospinal Axis Irradiation.

Proton therapy is a promising modality for craniospinal irradiation (CSI), offering dosimetric advantages over conventional treatments. While significant attention has been paid to spine fields, for the brain fields, only dose reduction to the lens of the eye has been reported. Hence, the objective of this study is to assess the potential gains and feasibility of adopting different treatment planning techniques for the entire brain within the CSI target. To this end, eight previously treated CSI patients underwent retrospective replanning using various techniques: (1) intensity modulated proton therapy (IMPT) optimization, (2) the modification/addition of field directions, and (3) the pre-optimization removal of superficially placed spots. The target coverage robustness was evaluated and dose comparisons for lenses, cochleae, and scalp were conducted, considering potential biological dose increases. The target coverage robustness was maintained across all plans, with minor reductions when superficial spot removal was utilized. Single- and multifield optimization showed comparable target coverage robustness and organ-at-risk sparing. A significant scalp sparing was achieved in adults but only limited in pediatric cases. Superficial spot removal contributed to scalp V30 Gy reduction at the expense of lower coverage robustness in specific cases. Lens sparing benefits from multiple field directions, while cochlear sparing remains impractical. Based on the results, all investigated plan types are deemed clinically adoptable.

Performance analysis and knowledge-based quality assurance of critical organ auto-segmentation for pediatric craniospinal irradiation

Craniospinal irradiation (CSI) is a vital therapeutic approach utilized for young patients suffering from central nervous system disorders such as medulloblastoma. The task of accurately outlining the treatment area is particularly time-consuming due to the presence of several sensitive organs at risk (OAR) that can be affected by radiation. This study aimed to assess two different methods for automating the segmentation process: an atlas technique and a deep learning neural network approach. Additionally, a novel method was devised to prospectively evaluate the accuracy of automated segmentation as a knowledge-based quality assurance (QA) tool. Involving a patient cohort of 100, ranging in ages from 2 to 25 years with a median age of 8, this study employed quantitative metrics centered around overlap and distance calculations to determine the most effective approach for practical clinical application. The contours generated by two distinct methods of atlas and neural network were compared to ground truth contours approved by a radiation oncologist, utilizing 13 distinct metrics. Furthermore, an innovative QA tool was conceptualized, designed for forthcoming cases based on the baseline dataset of 100 patient cases. The calculated metrics indicated that, in the majority of cases (60.58%), the neural network method demonstrated a notably higher alignment with the ground truth. Instances where no difference was observed accounted for 31.25%, while utilization of the atlas method represented 8.17%. The QA tool results showed that the two approaches achieved 100% agreement in 39.4% of instances for the atlas method and in 50.6% of instances for the neural network auto-segmentation. The results indicate that the neural network approach showcases superior performance, and its significantly closer physical alignment to ground truth contours in the majority of cases. The metrics derived from overlap and distance measurements have enabled clinicians to discern the optimal choice for practical clinical application.

The clinical significance of sub-total surgical resection in childhood medulloblastoma: a multi-cohort analysis of 1100 patients

Medulloblastoma patients with a sub-total surgical resection (STR; >1.5cm2 primary tumour residuum post-surgery) typically receive intensified treatment. However, the association of STR with poor outcomes has not been observed consistently, questioning the validity of STR as a high-risk disease feature. We collected extent of resection (EOR) data from 1110 patients (from UK CCLG centres (n=416, collected between September 1990 and July 2014) and published (n=694) cohorts), the largest cohort of molecularly and clinically annotated tumours assembled to specifically assess the significance of EOR. We performed association and univariable/multivariable survival analyses, assessing overall survival (OS) cohort-wide and with reference to the four consensus medulloblastoma molecular groups and clinical features. STR was reported in 20% (226/1110) of patients. Non-WNT (p=0.047), children <5 years at diagnosis (p=0.021) and metastatic patients (p<0.0001) were significantly more likely to have a STR. In cohort-wide analysis, STR was associated with worse survival in univariable analysis (p<0.0001). Examination of specific disease contexts showed that STR was prognostic in univariate analysis for patients receiving cranio-spinal irradiation (CSI) and chemotherapy (p=0.016) and for patients with Group 3 tumours receiving CSI (p=0.039). STR was not independently prognostic in multivariable analyses; outcomes for patients who have STR as their only risk-feature are as per standard-risk disease. Specifically, STR was not prognostic in non-metastatic patients that received upfront CSI. In a cohort of 1100 molecularly characterised medulloblastoma patients, STR (n=226) predicted significantly lower OS in univariable analysis, but was not an independent prognostic factor. Our data suggest that maximal safe resection can continue to be carried out for patients with medulloblastoma and suggest STR should not inform patient management when observed as a sole, isolated risk-feature. Cancer Research UK, Newcastle Hospitals Charity, Children's Cancer North, British Division of the International Academy of Pathology.

Developing a comparative photon-proton planning service in Victoria: the experience at Peter MacCallum Cancer Centre.

Proton-beam therapy (PBT) is a cutting-edge radiation therapy modality that is currently not available in Australia. Comparative photon-proton (CPP) planning is required for the medical treatment overseas programme (MTOP) and will be required for access to PBT in Australia in the future. Comparative planning brings professional development benefits to all members of the radiation therapy team. This service was also created to support future proposals for a PBT facility in Victoria. We report our experience developing an in-house CPP service at Peter MacCallum Cancer Centre. A set of resources to support CPP planning was established. Training of relevant staff was undertaken after which an in-house training programme was developed. A standard protocol for PBT planning parameters was established. All CPP plans were reviewed. Future goals for the CPP planning programme were described. In total, 62 cases were comparatively planned over 54 months. Of these, 60% were paediatric cases, 14% were adolescents and young adults (15-25 years) and 26% were adults. The vast majority (over 75%) of patients comparatively planned required irradiation to the central nervous system including brain and cranio-spinal irradiation. A variety of proton plans were reviewed by international PBT experts to confirm their deliverability. Our team at Peter MacCallum Cancer Centre has gained significant experience in CPP planning and will continue to develop this further. Local expertise will help support decentralisation of patient selection for proton treatments in the near future and the PBT business case in Victoria.

Maintaining Survival While Improving Quality of Life: An Advanced Practitioner–Led Pilot Feasibility Study to Reduce Radiation Dose in Children With Brain Tumors

Purpose: Oncology advanced practitioners (APs) are on the front line in treating adverse effects. Among children with brain tumors, treatments such as craniospinal irradiation (CSI) cause neurocognitive injury, endocrinopathies, and ototoxicity. High-dose CSI with concurrent chemotherapy allows high-risk embryonal tumors (non-anaplastic) good survival (70%), but significant distressing effects are commonly treated by APs in multidisciplinary long-term follow-up. The aim of this study was to test feasibility of reducing radiation dose with an AP-led protocol. Methods: An interdisciplinary team developed this pilot study with the primary outcome of fewer than two deaths in 10 patients (80% survival). Secondary outcomes were feasibility of an AP-led treatment protocol and acute/late effects of treatment. The AP held a pioneering role as principal investigator of a tumor treatment study. Exclusion criteria included age less than 3 years and anaplasia. The CSI was reduced from 36 to 24 Gy. All other treatment was standard. Results: Survival rate exceeded the primary outcome threshold (88%); the accrual rate (80%) and follow-up neurocognitive testing rate (75%) were acceptable. Eight children ages 3 to 19 years (M = 8) with tumors of varied molecular subtyping were enrolled. The single death occurred 2.5 years from diagnosis of multiorgan failure (without evidence of tumor). The mean survival is 11 years, with two college and one graduate degrees. Acute and late effects were decreased compared with the higher-dose CSI. Conclusion: APs who treat cancer adverse effects can also conduct clinical prospective studies to maintain survival rates and improve quality-of life-outcomes.

Proton Craniospinal Irradiation with Immunotherapy in Two Patients with Leptomeningeal Disease from Melanoma.

Proton craniospinal irradiation (pCSI) is a treatment option for leptomeningeal disease (LMD), which permits whole neuroaxis treatment while minimizing toxicity. Despite this, patients inevitably experience progression. Adding systemic therapy to pCSI may improve outcomes. In this single-institution retrospective case series, we present the feasibility of treatment with pCSI (30Gy, 10 fractions) and an immune checkpoint inhibitor (ICI) in two sequential patients with LMD from melanoma. The first patient developed LMD related to BRAF V600E-mutant melanoma after prior ICI and BRAF-targeted therapy. After pCSI with concurrent nivolumab, the addition of relatlimab, and BRAF-targeted therapy, he remained alive 7 months after LMD diagnosis despite central nervous system progression. The second patient developed LMD related to BRAF-wildtype melanoma after up-front ICI. He received pCSI with concurrent ipilimumab and nivolumab, then nivolumab maintenance. Though therapy was held for ICI hepatitis, the patient remained progression-free 5 months after LMD diagnosis. Adding an ICI to pCSI is feasible for patients with LMD and demonstrates a tolerable toxicity profile. While prospective evaluation is ultimately warranted, pCSI with ICI may confer survival benefits, even after prior ICI.

Craniospinal irradiation for CNS leukemia: rates of response and durability of CNS control.

Management of CNS involvement in leukemia may include craniospinal irradiation (CSI), though data on CSI efficacy are limited. We retrospectively reviewed leukemia patients who underwent CSI at our institution between 2009 and 2021 for CNS involvement. CNS local recurrence (CNS-LR), any recurrence, progression-free survival (PFS), CNS PFS, and overall survival (OS) were estimated. Of thirty-nine eligible patients treated with CSI, most were male (59%) and treated as young adults (median 31 years). The median dose was 18Gy to the brain and 12Gy to the spine. Twenty-five (64%) patients received CSI immediately prior to allogeneic hematopoietic cell transplant, of which 21 (84%) underwent total body irradiation conditioning (median 12Gy). Among 15 patients with CSF-positive disease immediately prior to CSI, all 14 assessed patients had pathologic clearance of blasts (CNS-response rate 100%) at a median of 23 days from CSI start. With a median follow-up of 48 months among survivors, 2-year PFS and OS were 32% (95% CI 18-48%) and 43% (95% CI 27-58%), respectively. Only 5 CNS relapses were noted (2-year CNS-LR 14% (95% CI 5-28%)), which occurred either concurrently or after a systemic relapse. Only systemic relapse after CSI was associated with higher risk of CNS-LR on univariate analysis. No grade 3 or higher acute toxicity was seen during CSI. CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Control of systemic disease after CSI may be important for CNS local control. CNS recurrence may reflect reseeding from the systemic space.

Proton versus photon craniospinal irradiation for adult medulloblastoma: A dosimetric, toxicity, and exploratory cost analysis.

This study aimed to determine whether proton craniospinal irradiation (CSI) decreased the dose to normal tissue and resulted in less toxicity than photon CSI for adult patients. This single-institution retrospective analyzed differences in radiation doses, acute toxicity, and cost between proton and CSI for adult medulloblastoma patients. Of 39 total patients, 20 were treated with photon CSI prior to 2015, and 19 were treated with proton CSI thereafter. Median age was 28 years (range 18-66). The molecular subtype was most commonly sonic hedgehog (68%). Patients most commonly received 36 Gy CSI in 20 fractions with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to cochleae, lacrimal glands, lens, parotid glands, pharyngeal constrictors, esophagus, lungs, liver, and skin (all P < .001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% versus 35%, P = .044) and decreased median weight loss during radiation (+1.0 versus -2.8kg, P = .011). Weight loss was associated with acute hospitalization (P = .009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At the last follow-up, 5 photon patients had died (2 of progressive disease, 3 without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. This study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.

Treatment outcomes and risk factors of patients with intracranial germ cell tumour with choriocarcinoma element or β-HCG level higher than 500IU/L.

In previous studies, patients with intracranial germ cell tumour (iGCT) with pure choriocarcinoma or mixed germ cell tumours with choriocarcinoma element showed similar dismal prognoses, with median overall survival (OS) of 22months and 1-year survival rate of approximately 60%. However, these conclusions need to be updated because radiotherapy, which is the mainstay for this disease, was not applied in a number of patients. Additionally, prognostic factors need to be explored in this population. Clinical data of patients with iGCTs with histologically confirmed choriocarcinoma element or beta-human chorionic gonadotropin (β-HCG) > 500IU/L were collected from the archives of our institution and retrospectively studied. A total of 76 patients were eligible for this study. Except for two early deaths, all patients received radiotherapy (craniospinal irradiation [CSI], n = 23; non-CSI, n = 51). The median follow-up duration for the entire series was 63months (range, 6-188months). The 5-year event-free survival (EFS) and OS rates were 81.5% and 84.1%, respectively. Among patients who did not have early death or progressive disease after induction chemotherapy, multivariate analysis revealed that chemotherapy cycles (> 4 vs. ≤ 4) (hazard ratio [HR] for EFS 0.144, p = 0.020; HR for OS 0.111, p = 0.028) and β-HCG levels (> 3000IU/L vs. ≤ 3000IU/L) (HR for EFS 4.342, p = 0.059; HR for OS 6.614, p = 0.033) were independent factors for survival. Patients with iGCTs with choriocarcinoma element or β-HCG > 500IU/L showed improved survival with radiotherapy-based treatments. Additional chemotherapy cycles could result in additional survival benefits. Patients with β-HCG level > 3000IU/L had poorer prognosis.