Targeted and Systemic therapies for recurrent adult ependymomas: real- world outcomes from a single institution and concise literature review

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This study aimed to retrospectively evaluated outcomes of systemic therapies, including targeted combinations, in a real-world cohort. Methods: Adult patients with intracranial or spinal ependymoma treated at our institution between 2013 and 2025 who received at least one systemic line at recurrence were included. Tumor response was assessed according to RANO criteria. Primary endpoints were disease control rate (DCR) and progression-free survival (PFS). Secondary endpoints were overall survival from the start of the first line treatment(OSt) and overall survival from diagnosis(OS). Results: Among 47 patients, 12 received systemic therapy at recurrence. The median follow up duration for the entire cohort was 28.3 months.Temozolomide (TMZ) was the most commonly used agent (n = 12). TMZ monotherapy achieved a DCR of 57% with 6- and 12-month PFS rates of 85.7% and 57.1%, respectively. Targeted therapy was administered to 7 patients: the TMZ-Lapatinib combination provided limited benefit (DCR 33%, median PFS 2.9 months), bevacizumab-based regimens showed variable efficacy; bevacizumab alone achieved a DCR of 33% with one case of prolonged stabilization (> 58 months), while bevacizumab plus fotemustine yielded a PFS of 14.1 months. Treatments were generally well tolerated, with limited grade 3 toxicities. Sequential systemic therapy, up to five lines, was feasible in selected cases. Median OSt was not reached; 12-month OS was 66.7%. Conclusions: This real-world analysis supports TMZ as a relevant option and suggests potential benefit of bevacizumab-based combinations in recurrent adult ependymomas. Prospective, biomarker-driven multicenter trials are warranted to optimize systemic strategies in this rare disease. ependymomas targeted therapy bevacizumab chemotherapy Figures Figure 1 INTRODUCTION Ependymomas are rare central nervous system (CNS) glial tumors that can arise from ependymal cells lining the cerebral ventricles, the central canal of the spinal cord, or cortical rests[ 1 ]. According to the Central Brain Tumor Registry of the USA(CBTRUS) the annual incidence of ependymomas is estimated to range from 0.25 to 0.48 per 100.000 persons[ 2 ], accounting for 2–3% of all primary CNS tumors and 6.5% of gliomas[ 3 ]. Ependymomas are relatively more common in children, representing about 5.2% of pediatric CNS tumors, compared to 1.9% in adults. The male-to-female ratio is approximately 1.4:1 [ 3 ]. Tumor location is age-dependent. In children they predominantly occur intracranially with two third in the posterior fossa, whereas the spinal cord is the most prevalent site in adults[ 4 ]. Ependymomas were previously classified according to the WHO 2016 classification into grade I, II and III (or anaplastic) on the basis of pathological criteria alone, while the WHO 2021 identifies 10 subgroups according to a combination of histopatological, molecular and clinical features across three tumor locations (supratentorial, infratentorial and spinal), age group, and tumor grade [ 5 , 6 ]. This integrated approach more accurately reflects the biological and clinical heterogenity of these tumors [ 7 – 10 ]. However, this refined classification has not yet translated into the identification of reliable druggable targets.[ 11 ]. Optimal clinical management of adult ependymomas remains undefined. Most treatment paradigms are derived from pediatric studies, while adult data are limited to small retrospective series. Surgery is the cornerstone of treatment, with gross total resection (GTR) consistently associated with improved prognosis [ 12 – 16 ]. The goal is to achieve maximal safe resection without neurological impairment. Regarding radiotherapy(RT), recent studies have demonstrated the efficacy of local fields irradiation in achieving good local control and low risk of spinal disseminations[ 17 – 20 ]. Postoperative radiotherapy is recommended in patients with anaplastic (WHO 2016 grade 3) ependymomas and for those with grade 2 tumors after incomplete resection[ 17 ], while the role of postoperative RT in patients with grade 2 ependymoma who undergo complete resection remains controversial[ 21 ]. No adjuvant chemotherapy has demonstrated efficacy in randomized studies and systemic therapy is generally reserved for recurrent or progressive disease [ 22 ]. According to CBTRUS, the overall relative survival rate is 85.8%, ranging from 91% in patients aged 15–39 to 86.8% in those > 40 years [ 3 ]. Prognosis is influenced by several factors, including extent of resection, tumor grade, location, age < 55 years, and good performance status [ 14 , 19 , 22 , 23 ]. Given the lack of prospective data, real-world analyses may help define the role of systemic therapy and identify signals of activity worth prospective validation. We therefore conducted a retrospective, single-center analysis of systemic therapies, including targeted treatments, administered at our institution to patients with recurrent ependymomas over the past 10 years. In addition, we reviewed current literature on conventional and targeted agents to contextualize our findings and explore emerging therapeutic strategies. MATERIALS and METHODS We conducted a retrospective, single-center study at the Veneto Institute of Oncology (IOV), Padua, Italy, including patients diagnosed with intracranial or spinal ependymoma between April 2013 and April 2025 (data cutoff: April 2025). Clinical records were reviewed to collect demographic and clinical data, including age, sex, tumor location and grade, extent and number of surgical resections, radiotherapy, and systemic treatments. All patient data were anonymized and stored in an institutional database accessible only to authorized personnel. Histopathological classification followed the WHO classification of CNS tumors in use at the time of the patient’s initial diagnosis. The study was approved by the local ethics committee (IOV-2024-ANIMA). Patients were eligible for inclusion in the analysis if they had a histologically confirmed diagnosis of ependymoma, had received at least one line of systemic therapy at disease recurrence or progression, and had available follow-up data for outcome assessment. Radiological follow-up was performed with brain and/or spinal MRI every two to three months, or earlier in case of clinical worsening, according to institutional practice. Tumor response and progression were assessed according to the Response Assessment in Neuro-Oncology (RANO) criteria. Toxicities associated with systemic treatments were retrospectively extracted from clinical charts and laboratory records, and were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The primary endpoints of the study were progression-free survival (PFS), defined as the time from the start of systemic therapy to documented radiological or clinical progression or death from any cause, and disease control rate (DCR), defined as the proportion of patients achieving complete response, partial response, or stable disease as best response to a given systemic therapy. For patients without progression, PFS was censored at the last follow-up or at death in the absence of documented progression. Although systemic treatments and timing varied across the cohort, DCRs were calculated for each regimen for descriptive purposes. Secondary endpoints included overall survival from first-line treatment(OSt), defined as the time from the start of the first systemic therapy to death or last follow-up and overall survival (OS), defined as the time from initial diagnosis to death or last follow-up; Descriptive statistics were used to summarize clinical and treatment-related data. Continuous variables were expressed as medians, interquartile ranges, and ranges, whereas categorical variables were reported as counts and percentages. PFS and OS were estimated using the Kaplan–Meier method. All analyses were descriptive in nature and were performed using R software (version 4.4.0), without formal hypothesis testing. RESULTS A total of 47 adult patients diagnosed with intracranial or spinal ependymoma at our institution between 2013 and 2025 were identified. Among them, 12 patients (26%) who received at least one line of systemic therapy for recurrent disease were included in the present analysis. The median follow up duration for the entire cohort was 28.3 months (95% CI, 8.2- 46.2). The subgroup of 12 patients treated with systemic therapy had a median age at diagnosis of 41 years (range: 18–63), with a slight female predominance (7 females, 5 males). Ten patients had brain tumors (6 supratentorial, 4 posterior fossa) and 2 had spinal lesions. Histologically, 7 patients had WHO grade 3 tumors and 5 had grade 2 at the last surgery. Median Karnofsky Performance Status (KPS) at the time of first line therapy was 70 (range: 60–90). Baseline clinical and treatment characteristics of the 12 patients are summarized in Table 1. Most patients (8/12, 67%) presented with neurological symptoms, such as motor deficits (6 patients), dysarthria (2 patients), seizures (1 patient), dizziness(1 patient), cervical pain(1 patient), or peripheral neuropathy (1 patient), while 2 patients were asymptomatic. All patients had received surgery and radiotherapy as initial treatment. At recurrence, 5 patients underwent reoperation and 4 received radiosurgery. Median time to first-line therapy (mTTT), defined as the time from initial diagnosis to the start of the first sytemic therapy, was 37.8 months (IC 95%: 19,5 – 128,5; IQR 19.77-108.90, range 6.8-287.0). The number of systemic therapy lines ranged from 1 to 5 (median 2). Details of systemic therapies administered and related outcomes are summarized in Table 2 . Temozolomide (TMZ) was the most frequently used agent, administered either as monotherapy (7 patients) or in combination (8 patients). Combination regimens included TMZ with cisplatin (3 patients), TMZ with lapatinib (3 patients), TMZ with bevacizumab (2 patients) and lomustine with procarbazine (1 patient). Other agents included fotemustine (1 patient) and bevacizumab, given either alone (3 patients) or combined (1 patient). The most common first-line regimen was single-agent TMZ. Regardless of the line of therapy, the median progression-free survival (mPFS), progression-free survival rates at 6 and 12 months, and disease control rate (DCR) for each regimen were as follows. Temozolomide (TMZ) monotherapy yielded a mPFS that was not reached (95% CI, 6.9–not estimable; range, 2.7–25.3), with PFS rates of 85.7% (95% CI, 63.3–100) at 6 months and 57.1% (95% CI, 30.1–100) at 12 months, and a DCR of 57% (including one partial response). The combination of TMZ plus cisplatin was associated with a mPFS of 0.89 months (95% CI, 0.8–not estimable; range, 0.8–9.0), with PFS rates of 33% (95% CI, 6.73–100) at 6 months and 0% at 12 months, and a DCR of 33%. TMZ plus lapatinib showed a mPFS of 2.9 months (95% CI, 1.15–not estimable; range, 1.2–5.9), with PFS rates of 0% at 6 and 12 months, respectively, and a DCR of 33%. Bevacizumab monotherapy achieved a mPFS of 1.8 months (95% CI, 1.6–not estimable; range, 1.6–21.0), with PFS rates of 33% (95% CI, 6.7–100) at both 6 and 12 months, and a DCR of 33%, including one patient who achieved stable disease during treatment and remained progression-free at last follow-up (PFS: 58.0 months). The combination of bevacizumab and fotemustine in one patient led to a PFS of 14.1 months with SD as best response. Fotemustine monotherapy resulted in a PFS of 2.4. Bevacizumab plus TMZ showed a mPFS of 9.5 months (95% CI, 3.3–15.7; range, 3.2–15.7), with PFS rates of 50% (95% CI, 0–100) at both 6 and 12 months. Finally, lomustine plus procarbazine (PC) was associated with a PFS of 3.2 months (1 patient). Fig. 1 summarizes the timeline and sequence of systemic treatments administered to the 12 patients, with duration and clinical outcomes indicated for each line of therapy. At the data cut-off in April 2025, six patients were alive: four were in follow-up after stable disease, and two remained on active treatment. Median overall survival from the start of systemic therapy was not reached at the time of analysis. The overall survival rate from the start of systemic therapy rates at 6, 12, and 24 months were 91.7% (95% CI, 53.9–98.8), 66.7% (95% CI, 33.7–86.0), and 58.3% (95% CI, 27.0–80.1), respectively. Median overall survival from diagnosis was 180.9 (95% CI 17.8-NE). The overall survival from diagnosis rates at 6, 12, and 24 months were 100.0% (95% CI, 100.0–100.0), 91.7% (95% CI, 53.9–98.8), and 83.3% (95% CI, 48.2–95.6), respectively(see Supplementary Fig S1 and S2 ). Systemic treatments were generally well tolerated. Hematologic toxicities were the most frequent: thrombocytopenia occurred in 5 patients (including one grade 3), and neutropenia in 2 (both grade 2), mainly during TMZ-based treatments. One case of grade 1 transaminase elevation was reported with TMZ. Bevacizumab was associated with grade 1 hypertension in one case, and grade 2 nausea was observed in a patient treated with TMZ plus cisplatin. No grade ≥4 toxicities or treatment discontinuations occurred. Table 1 Clinical characteristics of 12 patients with recurrent ependymoma treated with systemic therapies Case n. Sex; Age at diagnosis Grade Location Surgery RT (Gy) Pattern of PD KPS Resurgery (n) Re-irradiation Lines of therapy First Line Current status OSt (mo) 1 F;35 G3 supratentorial STR PRT Nodular Leptomeningeal 90 no no 1 TMZ+CIS Dead 0.9 2 F;62 G3 supratentorial STR 60 Local 70 no no 1 TMZ FUP a 28.3+ 3 M;54 G2 spine C2 STR SRS Local 70 no SRS 1 TMZ Dead 8.4 4 F;55 G2 posterior fossa STR CS Local 70 1 SRS 3 TMZ FUP 70.1+ 5 F;18 G3 supratentorial GTR SRT (21) Local 70 12 no 5 TMZ DD +LAP PD b 46.2+ 6 M;23 G2 spine D4-D10 STR CS Local 70 2 no 1 TMZ FUP a 30.6+ 7 F;62 G3 posterior fossa STR 30 Local 70 no no 3 BEV Dead 7.9 8 F;63 G2 posterior fossa+ spine C2 STR PRT Local 70 no no 1 TMZ Treatment ongoing 11.7+ 9 M;35 G3 supratentorial GTR 40 Local 60 4 SRS 1 TMZ Dead 6.3 10 M;22 G3 supratentorial STR 50 Local 70 no no 2 BEV Lost FUP 8.2 11 M;41 G2 supratentorial STR PRT Local 80 no SRS 2 TMZ FUP 24.3 12 F;31 G3 supratentorial STR 50 Local 80 6 no 1 TMZ+CIS Dead 12.9 ᵃPD = progressive disease at last follow-up. ᵇFUP = currently in follow-up after stable disease. “+” indicates censored observation (alive at last follow-up) Abbreviations: PD = Progression, KPS =Karnofsky Performance Status, GTR = gross total resection, STR= subtotal resection, CS = craniospinal radiotherapy, PRT= proton therapy, SRT = stereotactic radiotherapy, SRS= radiosurgery, TMZ= temozolomide, BEV = bevacizumab, TMZ DD = temozolomide dose dense, LAP =lapatinib, CIS =cisplatin FUP= follow up, LOST FUP = lost to follow up OSt: time from start of systemic therapy to death or last follow-up; mo =months Table 2 . Summary of systemic treatment regimens and associated outcomes Therapy Schedule No of pts Median number of cycles (range) mPFS (mo) [95% CI] range PFS-6 (%) [95% CI] PFS-12(%) [95% CI] DCR TMZ Temozolomide 200 mg/mq day 1-5 q4w 7 12 (1-14) NR (7.0–NE) 2.7–25.3 85.7 (63.3–100) 57.1 (30.1–100) 57% (1 PR) TMZ + Cisplatin Temozolomide 150 mg/mq day1-5 + Cisplatin 75 mg/mq q3w 3 2(1-9) 0.9 (0.8–NE) 0.8–9.1 33 (6.7-100) 0 33% (1 SD) TMZ DD+ Lapatinib Temozolomide DD 125mg/mq day 1-7; 15-21 q4w +Lapatinib 1250mg/unit 3 2 (1-5) 2.9 (1.2–NE) 1.2–5.9 0 0 33% (1 SD) TMZ +bevacizumab Temozolomide 200 mg/mq day 1-5 q4w + Bevacizumab 5mg/Kg 2 8(2-14) 9.5 (3.3–15.7) 3.3–15.7 50 (12.5–100) 50 (12.5–100) 0 Bevacizumab alone Bevacizumab 10 mg/kg q2w 3 5(3-37) 1.8 (1.6–NE) 1.6–21.0 33 (6.73-100) 33 (6.7-100) 33% (1SD>3yrs) Bevacizumab+Fotemustine Bevacizumab 5 mg/kg + Fotemustine 80mg/mq q2w 1 28 14.1 (single pt) - 100 100 (SD>1yrs) Fotemustine Fotemustine 80mg/mq q2w for 5 cycles à q4w 1 5 2.40 (single pt) - 0 0 100% (SD) Lomustine +Procarbazine Lomustine (CCNU) 110 mg/m², day 1, q6w Procarbazine 60 mg/m², days 8–21, q6w 1 2 3.22 (single pt) - 0 0 0 Abbreviations: TMZ= Temozolomide; TMZ DD= Temozolomide dose dense; mo = months; yrs= years, pt= patient; NR = not reached, NE = not estimable, DCR = disease control rate, PFS = progression free survival; PFS-6-12 = PFS rates at 6 and 12 months. SD= stable disease, PR = partial response Discussion Recurrent adult ependymomas remain a clinical challenge due to their rarity, biological heterogeneity, and the absence of standardized systemic treatments. Most of the available data come from pediatric populations or small retrospective series, and prospective evidence in adults remains scarce. Table 3 summarizes the main studies evaluating chemotherapy and targeted agents for recurrent ependymoma. In this context, our mono-institutional retrospective analysis of 12 adult patients with recurrent intracranial or spinal ependymomas treated with systemic therapies over a 10-year period provides clinically relevant insights. Temozolomide (TMZ) was the most frequently administered agent, either as monotherapy or in combination. In our cohort, TMZ monotherapy achieved a disease control rate (DCR) of 57% and although the median PFS for temozolomide was not reached by Kaplan–Meier estimation, the observed median follow-up time was 9.4 months, which aligns with findings by Rudà et al. [24], who reported a 22% objective response rate (ORR) and a mPFS of 9.7 months in a retrospective study of 18 adult patients. Conversely, Chamberlain et al.[25] observed limited efficacy of TMZ in platinum-refractory recurrent ependymomas (ORR 4%, mPFS 2 months), suggesting that TMZ is more effective when used earlier in the treatment course and in patients not heavily pretreated. TMZ combinations provided more modest benefit. TMZ plus cisplatin resulted in a DCR of 33% and mPFS of 0.9 in our series, consistent with literature data indicating limited additional efficacy from platinum-based regimens in adults[26]. Interestingly, fotemustine, a nitrosourea similar to lomustine with high CNS penetration, showed promising activity in combination with bevacizumab (PFS 14.1 months) in a heavily pretreated patient, supporting further exploration of this agent. The combination of TMZ and lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, yielded a DCR of 33% and mPFS of 2.9 months in our study. These outcomes were inferior to those reported in a phase II trial conducted by the Collaborative Ependymoma Research Network (CERN), where the dose-dense TMZ plus lapatinib regimen achieved a 16% ORR and mPFS of 7.8 months in 50 adult patients[27]. One potential explanation is the lack of molecular selection in our cohort. In the CERN study, patients with high ErbB2 (HER2) expression appeared to derive greater benefit. Therefore, incorporating molecular profiling, such as EGFR and HER2 status, may optimize patient selection for lapatinib-based treatments. Among targeted therapies, bevacizumab demonstrated noteworthy activity in selected patients. Green et al. [28] reported a 75% ORR and mPFS of 6.4 months in a small adult cohort. Our findings support this observation: one patient achieved 21 months of disease stabilization on bevacizumab monotherapy and remains progression-free 58 months after treatment initiation, despite discontinuation of therapy. Furthermore, the most durable stabilization in our series was achieved in a heavily pretreated patient receiving sequential bevacizumab-containing regimens (bevacizumab plus fotemustine with PFS of 14.13 followed by bevacizumab plus temozolomide with a PFS of 15.67), supporting the potential benefit of bevacizumab-based combinations in this setting.While such outlier responses are rare, they highlight the need to identify predictive markers (e.g., VEGF expression, radiologic features) to select patients more likely to benefit from anti-angiogenic therapy. Conversely, in pediatric trials[29] bevacizumab failed to induce objective responses, though some patients experienced prolonged stable disease. Overall, our data suggest that a subset of adult patients may benefit from targeted treatments. While lapatinib’s efficacy may be limited without patient enrichment strategies, its safety profile and blood-brain barrier permeability justify further investigation in biomarker-driven trials. Bevacizumab, although not universally effective, may provide durable control in angiogenesis-dependent tumors, potentially in combination with nitrosoureas. Notably, the combination of bevacizumab and fotemustine was evaluated for the first time in this pathology in our study, showing encouraging disease stabilization. Another relevant finding from our series is the feasibility of multiple lines of systemic therapy. The number of lines ranged from 1 to 5 (median 2), with some patients achieving prolonged overall survival (OS) beyond 8 years from diagnosis. This challenges the notion that recurrent ependymomas are uniformly aggressive and rapidly fatal. In patients who maintain good clinical condition over time, the use of sequential systemic therapies may contribute to prolonged survival. Although no specific regimen emerged as clearly superior, switching between different chemotherapy classes (e.g., alkylators, nitrosoureas, anti-angiogenics) appears reasonable, given the heterogeneity of treatment response and lack of cross-resistance. This approach is supported by retrospective studies[30] who reported that various chemotherapies, including temozolomide, nitrosoureas, and platinum compounds, achieved disease stabilization in a significant proportion of adult patients with intracranial ependymoma, even across multiple treatment lines, thus supporting the feasibility and potential value of sequential therapeutic strategies. Regarding toxicity, systemic therapies were generally well tolerated. TMZ was associated with manageable hematologic toxicity (thrombocytopenia in 5 patients, including one grade 3; neutropenia in 2 patients, both grade 2). Bevacizumab led to grade 1 hypertension in one case, and no thromboembolic or hemorrhagic complications were observed. Lapatinib did not result in clinically significant adverse events in our cohort, likely due to limited exposure. These findings mirror safety data from the CERN study [27], where the combination of TMZ and lapatinib was well tolerated, with fatigue, nausea, and diarrhea being the most common side effects. Nevertheless, this study has some limitations. First, its retrospective and single-center design limits the generalizability of the findings and may introduce selection biases. Second, the small sample size precludes definitive conclusions on comparative efficacy across treatment regimens. Third, molecular profiling was not routinely performed, preventing correlation between genomic alterations and therapeutic response. Additionally, both spinal and intracranial ependymomas were included, which, despite reflecting real-world heterogeneity, may confound interpretation due to their distinct biological behavior. Radiological assessments were also conducted retrospectively without central review, which may have affected consistency in response evaluation. Furthermore, the same treatment was administered at different lines of therapy across patients, which may have influenced the evaluation of its efficacy, as treatment effectiveness can vary depending on timing and prior exposure. Despite these limitations, our analysis provides clinically relevant, real-world insights into the use of systemic therapies for recurrent adult ependymomas, a rare disease where prospective data are lacking. Our findings emphasize that temozolomide remains a valuable backbone in recurrent ependymoma, while bevacizumab-based strategies and molecularly informed treatments warrant further exploration in prospective multicenter settings. The possibility of administering multiple systemic lines offers a window of opportunity to prolong survival in fit patients. Future research should prioritize the integration of molecular profiling to better guide patient selection for targeted agents, and the design of prospective, multicenter trials specifically dedicated to adults. Novel approaches such as immunotherapy, tumor treating fields, and CAR-T cell strategies are currently under investigation reflecting the growing interest in immuno- and device-based modalities for this rare disease and may offer additional options in the recurrent setting(see Table 3b ). Finally, collaborative real-world registries will be instrumental in defining treatment sequencing and improving outcomes in this rare disease. Table 3 Summary of published studies on systemic therapies for recurrent ependymoma Study (year) Therapy Type Setting N pts Grade(%) RR(%) mPFS (mo) mOS Chemotherapy Rudà[24] 2016 TMZ Retrospective WHO G2 or 3 failing re-operation and/reirradiation 18 II(45) III(55) CR(5) PR(17) 9.7 30.5 Chamberlain[25] 2009 TMZ Retrospective WHO G2 platinum refractory 25 II(100) CR(0) PR(4) 2 3 Gilbert[27] 2021 Dose dense TMZ + Lapatinib Phase II Single arm Recurrent intracranial and spinal 50 I(16) II(32) III(40) CR(4) PR(12) 7.8 27 Brandes[26] 2005 Cisplatin Retrospective Cisplatin-based(46%) vs non cisplatin based (54%) 13 vs 15 II(61) III(39) CR(15,4)vs (0) PR(15,5) vs (13,3) 9.9 vs 10.9 40.7 Gornet[28] 1999 Platinum-based Retrospective Platinum based vs nistrosurea based 6 vs 8 II(50) III(37) PR/MR(67)vs(25) 6 vs 10 - Other therapies Study CT identifier (year) Therapy Type Setting N pts Schedule RR(%) Results NCT01032070 2016 Erlotinib Randomized open label Phase II Recurrent or Refractory pediatric ependymoma 25 Erlotinib 85 mg/m2 daily vs Etoposide 50 mg/m2 daily 3 weeks q4w CR(0) PR(0) SD(15,4) vs CR(0) PR(16,7) MR(8,3) SD(16,7) mPFS 52 vs 65 days NCT01462695 2016 Sunitinib Open label Single arm Phase II Recurrent or Refractory pediatric ependymoma/ HGG 30 Sunitinib 15 mg/m2 4 weeks q6w No ORR mPFS 83 days NCT02155920 2023 Everolimus Open label Single arm Phase II Recurrent or Refractory pediatric posterior fossa and spinal ependymoma 11 Everolimus 4.5 mg/m2 daily q4w No ORR mPFS 48days Green [31] 2009 Bevacizumab Retrospective Recurrent adult ependymoma 8 Bevacizumab10 mg/Kg iv q2w alone or in combination PR(75) 1 SD >8months mTTP 6.4 months mOS 9.4 NCT00883688 2015 Bevacizumab + Lapatinib Phase II Recurrent Pediatric ependymoma 24 Bevacizumab 10 mg/kg iv days q2w + lapatinib 900mg/m2 No ORR Prolonged SD in 4pts mTTP 7.9 weeks NCT02054806 (Keynote 028) Imetelstat Molecular biology Phase II Recurrent medulloblastoma, HGG, ependymoma candidate to surgery 42 (4 ependymomas) Imetelstat 2-h iv at 285 mg/m2 12-24 h before surgery. No ORR Intratumoral and PBMC target inhibition interrupted for toxicity NCT02940483 5-Azacytidine Phase 0 Recurrent ependymoma udergoing maximal safe resection 6 5-AZA 10 mg into the fourth ventricle q1w, 12 cycles No ORR 2pts reduction size one ventricoluar lesion No AE NCT04958486 5 Azacitidine + Trastuzumab Early Phase I Recurrent adult and pediatric with Recurrent or Residual Posterior Fossa Ependymoma 4 5 AZA + Trastuzumab into fourth ventricle NA NA completed, no results available yet NCT03434262 Ribociclib + Gemcitabine Phase I Recurrent brain tumors 11 Ependymomas Ribociclb+ combination molecular driven therapy NA PFS>2 yrs in 1 pt NCT02359565 Pembrolizumab Early phase I Recurrent or progressive diffuse intrinsic pontine glioma, HGG, ependymomas, medulloblastoma or hypermutates brain tumors 13 Ependymomas Pembrolizumab 2mg/kg IV q3w No ORR mPFS 1.38months Abbreviations : CT= clinical trial , TMZ= temozolomide, mPFS = median progression free survival, mOS = median overall survival; TTP= time to progression, RR= Response Rate, ORR= objective response rate, CR= complete response , PR= partial response , MR= minimal response, SD =stabel disease, pts= patients, q1w =weekly, q2w =every 2 weeks, q3w =every 3 weeks, q4w =every 4 weeks, HGG= high grade gliomas, iv= intravenous, icv= intraventricular, AZA= azacitidine, AE= adverse event, NA = not available. Table 3b Ongoing clinical trials for recurrent ependymoma Study CT identifier (year) Drug Type Design Population Status NCT04661384 IL13Ralpha2-CAR T cells Phase I IL13Ralpha2-CAR T Cells icv delivery on day 1 qw for 4 cycles as adjuvant therapy Leptomeningeal disease from glioblastoma, ependymoma, medulloblastoma Active not recruiting NCT02774421 Trastuzumab Phase I Intrathecal trastuzumab + subcutaneus GM-CSF Pediatric recurrent posterior fossa ependymoma Active not recruiting NCT03033992 TTF Not applicable Optune ≥ 18 hours/day for at least 23 days out of 28 days of cycle one Pediatric recurrent/refractorysupratentorial glioma or ependymoma Recruiting NCT01795313 Peptide vaccine + Imiquimod Phase I HLA-A2 restricted tumor antigen vaccine+ Recurrent pediatric Ependymoma Recruiting Abbreviations : GM-CSF= granulocyte-macrophage colony-stimulating factor, HLA= human leukocyte antigen , icv= intraventricular , TTF = tumor treating fields. Declarations Conflicts of interest None declared. Human Ethics and Consent to Participate declarations The study was conducted in accordance with the Declaration of Helsinki and approved by the local Ethics Committee of the Veneto Institute of Oncology (IOV-IRCCS, Padua, Italy; protocol code IOV-2024-ANIMA). Patients still alive at the time of this study provided written informed consent for the collection and use of their anonymized data for scientific purposes. Clinical trial number: not applicable Funding This research received “Ricerca Corrente 2025” funding from the Italian Ministry of Health to cover publication costs (CDC099183). Author Contribution M.M. conceived the study, collected and curated clinical data, performed data analyses, and drafted the manuscript. G.L. supervised the study and critically revised the manuscript. A.B., M.C., M.P., A.G., G.Li., G.P., L.B., F.V., T.I., F.C., L.D. contributed to patient management, data collection, and manuscript review and S.L. provided overall supervision. All authors read and approved the final version of the manuscript. Acknowledgement We gratefully acknowledge Fondazione Celeghin for their partial support of this work and thank Pietro Guerra for his support and advice during the data analysis in R. References Taylor MD, Poppleton H, Fuller C, et al (2005) Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8:323–335. https://doi.org/10.1016/j.ccr.2005.09.001 Price M, Neff C, Nagarajan N, et al (2024) CBTRUS Statistical Report: American Brain Tumor Association & NCI Neuro-Oncology Branch Adolescent and Young Adult Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2016–2020. Neuro-Oncol 26:iii1–iii53. https://doi.org/10.1093/neuonc/noae047 Ostrom QT, Price M, Neff C, et al (2022) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015–2019. Neuro-Oncol 24:v1–v95. https://doi.org/10.1093/neuonc/noac202 McGuire CS, Sainani KL, Fisher PG (2009) Incidence patterns for ependymoma: a Surveillance, Epidemiology, and End Results study: Clinical article. J Neurosurg 110:725–729. https://doi.org/10.3171/2008.9.JNS08117 Kresbach C, Neyazi S, Schüller U (2022) Updates in the classification of ependymal neoplasms: The 2021 WHO Classification and beyond. Brain Pathol 32:e13068. https://doi.org/10.1111/bpa.13068 Pajtler KW, Witt H, Sill M, et al (2015) Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. 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Acta Neuropathol (Berl) 123:727–738. https://doi.org/10.1007/s00401-012-0941-4 Reni M, Brandes AA, Vavassori V, et al (2004) A multicenter study of the prognosis and treatment of adult brain ependymal tumors. Cancer 100:1221–1229. https://doi.org/10.1002/cncr.20074 Rogers L, Pueschel J, Spetzler R, et al (2005) Is gross-total resection sufficient treatment for posterior fossa ependymomas? J Neurosurg 102:629–636. https://doi.org/10.3171/jns.2005.102.4.0629 Metellus P, Barrie M, Figarella-Branger D, et al (2007) Multicentric French study on adult intracranial ependymomas: prognostic factors analysis and therapeutic considerations from a cohort of 152 patients. Brain J Neurol 130:1338–1349. https://doi.org/10.1093/brain/awm046 Metellus P, Guyotat J, Chinot O, et al. Adult intracranial WHO grade II ependymomas: long-term outcome and prognostic factor analysis in a series of 114 patients. Neuro Oncol. 2010;12(9):976–984 https://doi.org/10.1093/neuonc/noq047 Varma A, Giraldi D, Mills S, et al (2018) Surgical management and long-term outcome of intracranial subependymoma. Acta Neurochir (Wien) 160:1793–1799. https://doi.org/10.1007/s00701-018-3570-4 Rudà R, Reifenberger G, Frappaz D, et al (2018) EANO guidelines for the diagnosis and treatment of ependymal tumors. Neuro-Oncol 20:445–456. https://doi.org/10.1093/neuonc/nox166 Wee CW, Kim IH, Park C-K, et al (2020) Postoperative radiotherapy for WHO grade II-III intracranial ependymoma in adults: An intergroup collaborative study (KROG 18-06/KNOG 18-01). Radiother Oncol J Eur Soc Ther Radiol Oncol 150:4–11. https://doi.org/10.1016/j.radonc.2020.05.045 Oya N, Shibamoto Y, Nagata Y, et al (2002) Postoperative radiotherapy for intracranial ependymoma: analysis of prognostic factors and patterns of failure. J Neurooncol 56:87–94. https://doi.org/10.1023/a:1014442106111 Mansur DB, Perry A, Rajaram V, et al (2005) Postoperative radiation therapy for grade II and III intracranial ependymoma. Int J Radiat Oncol Biol Phys 61:387–391. https://doi.org/10.1016/j.ijrobp.2004.06.002 Ghia AJ, Mahajan A, Allen PK, et al (2013) Supratentorial gross-totally resected non-anaplastic ependymoma: population based patterns of care and outcomes analysis. J Neurooncol 115:513–520. https://doi.org/10.1007/s11060-013-1254-8 Iqbal MS, Lewis J (2013) An Overview of the Management of Adult Ependymomas with Emphasis on Relapsed Disease. Clin Oncol 25:726–733. https://doi.org/10.1016/j.clon.2013.07.009 Zhao F, Wu T, Wang L, et al (2021) Survival and Prognostic Factors of Adult Intracranial Ependymoma: A Single-institutional Analysis of 236 Patients. Am J Surg Pathol 45:979. https://doi.org/10.1097/PAS.0000000000001669 Rudà R, Bosa C, Magistrello M, et al (2016) Temozolomide as salvage treatment for recurrent intracranial ependymomas of the adult: a retrospective study. Neuro-Oncol 18:261–268. https://doi.org/10.1093/neuonc/nov167 Chamberlain MC, Johnston SK (2009) Temozolomide for recurrent intracranial supratentorial platinum-refractory ependymoma. Cancer 115:4775–4782. https://doi.org/10.1002/cncr.24524 Brandes AA, Cavallo G, Reni M, et al (2005) A multicenter retrospective study of chemotherapy for recurrent intracranial ependymal tumors in adults by the Gruppo Italiano Cooperativo di Neuro-Oncologia. Cancer 104:143–148. https://doi.org/10.1002/cncr.21110 Gilbert MR, Yuan Y, Wu J, et al (2021) A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma. Neuro-Oncol 23:468–477. https://doi.org/10.1093/neuonc/noaa240 Gornet MK, Buckner JC, Marks RS, et al (1999) Chemotherapy for advanced CNS ependymoma. J Neurooncol 45:61–67. https://doi.org/10.1023/a:1006394407245 DeWire M, Fouladi M, Turner DC, et al (2015) An open-label, two-stage, phase II study of bevacizumab and lapatinib in children with recurrent or refractory ependymoma: a collaborative ependymoma research network study (CERN). J Neurooncol 123:85–91. https://doi.org/10.1007/s11060-015-1764-7 Gramatzki D, Roth P, Felsberg J, Hofer S, Rushing EJ, Hentschel B, Westphal M, Krex D, Simon M, Schnell O, Wick W, Reifenberger G, Weller M. Chemotherapy for intracranial ependymoma in adults. BMC Cancer. 2016 Apr 23;16:287. https://doi.org/10.1186/s12885-016-2323-0 Green RM, Cloughesy TF, Stupp R, DeAngelis LM, Woyshner EA, Ney DE, Lassman AB. Bevacizumab for recurrent ependymoma. Neurology. 2009 Nov 17;73(20):1677-80. https://doi.org/10.1212/wnl.0b013e3181c1df34 Additional Declarations No competing interests reported. Supplementary Files supplementaryfigures.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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1","display":"","copyAsset":false,"role":"figure","size":87575,"visible":true,"origin":"","legend":"\u003cp\u003eTimeline of systemic treatments for the 12 patients\u003c/p\u003e\n\u003cp\u003eEach horizontal bar represents the duration of a systemic therapy. Time is expressed in months from the start of systemic therapy. Different colors correspond to treatment regimens.\u003c/p\u003e\n\u003cp\u003eAbbreviations: \u003cstrong\u003eBEV\u003c/strong\u003e = bevacizumab, \u003cstrong\u003eBEV+FTM\u003c/strong\u003e = bevacizumab + fotemustine, \u003cstrong\u003eBEV+TMZ\u003c/strong\u003e=bevacizumab + temozolomide, \u003cstrong\u003eFTM\u003c/strong\u003e = fotemustine, \u003cstrong\u003ePC\u003c/strong\u003e = lomustine+procarbazine, \u003cstrong\u003eTMZ\u003c/strong\u003e = temozolomide, \u003cstrong\u003eTMZ+CIS\u003c/strong\u003e = temozolomide + cisplatin, \u003cstrong\u003eTMZ+LAP\u003c/strong\u003e = temozolomide dose dense + lapatinib. Symbols indicate clinical events as reported in the legend × = lost to follow-up; ▲ = progressive disease; ● = stable disease (SD); △ = treatment ongoing; ⊗ = death\u003c/p\u003e\n\u003cp\u003e* patient underwent re-operation, ** patient underwent radiosurgery.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7862583/v1/2b2cb3cd1bdb9cbcbb76cd5b.png"},{"id":94988673,"identity":"a2c18445-7fe6-4913-8fcc-c51cbf0f828c","added_by":"auto","created_at":"2025-11-03 07:10:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1378532,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7862583/v1/803336a0-c212-40a1-94c7-ada5d3c0af6e.pdf"},{"id":94823418,"identity":"1a00b374-475e-4d2c-93bc-9ad4b6b1fdcf","added_by":"auto","created_at":"2025-10-31 06:47:19","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":299563,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryfigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-7862583/v1/3fc37ceed17ea16d1ef74db7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Targeted and Systemic therapies for recurrent adult ependymomas: real- world outcomes from a single institution and concise literature review","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eEpendymomas are rare central nervous system (CNS) glial tumors that can arise from ependymal cells lining the cerebral ventricles, the central canal of the spinal cord, or cortical rests[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAccording to the Central Brain Tumor Registry of the USA(CBTRUS) the annual incidence of ependymomas is estimated to range from 0.25 to 0.48 per 100.000 persons[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], accounting for 2\u0026ndash;3% of all primary CNS tumors and 6.5% of gliomas[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Ependymomas are relatively more common in children, representing about 5.2% of pediatric CNS tumors, compared to 1.9% in adults. The male-to-female ratio is approximately 1.4:1 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Tumor location is age-dependent. In children they predominantly occur intracranially with two third in the posterior fossa, whereas the spinal cord is the most prevalent site in adults[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEpendymomas were previously classified according to the WHO 2016 classification into grade I, II and III (or anaplastic) on the basis of pathological criteria alone, while the WHO 2021 identifies 10 subgroups according to a combination of histopatological, molecular and clinical features across three tumor locations (supratentorial, infratentorial and spinal), age group, and tumor grade [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This integrated approach more accurately reflects the biological and clinical heterogenity of these tumors [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, this refined classification has not yet translated into the identification of reliable druggable targets.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOptimal clinical management of adult ependymomas remains undefined. Most treatment paradigms are derived from pediatric studies, while adult data are limited to small retrospective series. Surgery is the cornerstone of treatment, with gross total resection (GTR) consistently associated with improved prognosis [\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The goal is to achieve maximal safe resection without neurological impairment.\u003c/p\u003e\u003cp\u003eRegarding radiotherapy(RT), recent studies have demonstrated the efficacy of local fields irradiation in achieving good local control and low risk of spinal disseminations[\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Postoperative radiotherapy is recommended in patients with anaplastic (WHO 2016 grade 3) ependymomas and for those with grade 2 tumors after incomplete resection[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], while the role of postoperative RT in patients with grade 2 ependymoma who undergo complete resection remains controversial[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNo adjuvant chemotherapy has demonstrated efficacy in randomized studies and systemic therapy is generally reserved for recurrent or progressive disease [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAccording to CBTRUS, the overall relative survival rate is 85.8%, ranging from 91% in patients aged 15\u0026ndash;39 to 86.8% in those\u0026thinsp;\u0026gt;\u0026thinsp;40 years [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Prognosis is influenced by several factors, including extent of resection, tumor grade, location, age\u0026thinsp;\u0026lt;\u0026thinsp;55 years, and good performance status [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eGiven the lack of prospective data, real-world analyses may help define the role of systemic therapy and identify signals of activity worth prospective validation. We therefore conducted a retrospective, single-center analysis of systemic therapies, including targeted treatments, administered at our institution to patients with recurrent ependymomas over the past 10 years. In addition, we reviewed current literature on conventional and targeted agents to contextualize our findings and explore emerging therapeutic strategies.\u003c/p\u003e"},{"header":"MATERIALS and METHODS","content":"\u003cp\u003eWe conducted a retrospective, single-center study at the Veneto Institute of Oncology (IOV), Padua, Italy, including patients diagnosed with intracranial or spinal ependymoma between April 2013 and April 2025 (data cutoff: April 2025). Clinical records were reviewed to collect demographic and clinical data, including age, sex, tumor location and grade, extent and number of surgical resections, radiotherapy, and systemic treatments.\u003c/p\u003e\u003cp\u003eAll patient data were anonymized and stored in an institutional database accessible only to authorized personnel. Histopathological classification followed the WHO classification of CNS tumors in use at the time of the patient\u0026rsquo;s initial diagnosis. The study was approved by the local ethics committee (IOV-2024-ANIMA).\u003c/p\u003e\u003cp\u003ePatients were eligible for inclusion in the analysis if they had a histologically confirmed diagnosis of ependymoma, had received at least one line of systemic therapy at disease recurrence or progression, and had available follow-up data for outcome assessment. Radiological follow-up was performed with brain and/or spinal MRI every two to three months, or earlier in case of clinical worsening, according to institutional practice. Tumor response and progression were assessed according to the Response Assessment in Neuro-Oncology (RANO) criteria.\u003c/p\u003e\u003cp\u003eToxicities associated with systemic treatments were retrospectively extracted from clinical charts and laboratory records, and were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.\u003c/p\u003e\u003cp\u003eThe primary endpoints of the study were progression-free survival (PFS), defined as the time from the start of systemic therapy to documented radiological or clinical progression or death from any cause, and disease control rate (DCR), defined as the proportion of patients achieving complete response, partial response, or stable disease as best response to a given systemic therapy. For patients without progression, PFS was censored at the last follow-up or at death in the absence of documented progression. Although systemic treatments and timing varied across the cohort, DCRs were calculated for each regimen for descriptive purposes.\u003c/p\u003e\u003cp\u003eSecondary endpoints included overall survival from first-line treatment(OSt), defined as the time from the start of the first systemic therapy to death or last follow-up and overall survival (OS), defined as the time from initial diagnosis to death or last follow-up;\u003c/p\u003e\u003cp\u003eDescriptive statistics were used to summarize clinical and treatment-related data. Continuous variables were expressed as medians, interquartile ranges, and ranges, whereas categorical variables were reported as counts and percentages. PFS and OS were estimated using the Kaplan\u0026ndash;Meier method. All analyses were descriptive in nature and were performed using R software (version 4.4.0), without formal hypothesis testing.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 47 adult patients diagnosed with intracranial or spinal ependymoma at our institution between 2013 and 2025 were identified. Among them, 12 patients (26%) who received at least one line of systemic therapy for recurrent disease were included in the present analysis. The median follow up duration for the entire cohort was 28.3 months (95% CI, \u0026nbsp;8.2- 46.2).\u003c/p\u003e\n\u003cp\u003eThe subgroup of 12 patients treated with systemic therapy had a median age at diagnosis of 41 years (range: 18\u0026ndash;63), with a slight female predominance (7 females, 5 males). Ten patients had brain tumors (6 supratentorial, 4 posterior fossa) and 2 had spinal lesions. Histologically, 7 patients had WHO grade 3 tumors and 5 had grade 2 at the last surgery. \u0026nbsp;Median Karnofsky Performance Status (KPS) at the time of first line therapy was 70 (range: 60\u0026ndash;90). Baseline clinical and treatment characteristics of the 12 patients are summarized in \u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eMost patients (8/12, 67%) presented with neurological symptoms, such as motor deficits (6 patients), dysarthria (2 patients), seizures (1 patient), dizziness(1 patient), cervical pain(1 patient), or peripheral neuropathy (1 patient), while 2 patients were asymptomatic. All patients had received surgery and radiotherapy as initial treatment. At recurrence, 5 patients underwent reoperation and 4 received radiosurgery.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMedian time to first-line therapy (mTTT), defined as the time from initial diagnosis to the start of the first sytemic therapy, was \u0026nbsp;37.8 months (IC 95%: 19,5 \u0026ndash; 128,5; IQR 19.77-108.90, range 6.8-287.0).\u003c/p\u003e\n\u003cp\u003eThe number of systemic therapy lines ranged from 1 to 5 (median 2). Details of systemic therapies administered and related outcomes are summarized in \u003cstrong\u003eTable 2\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eTemozolomide (TMZ) was the most frequently used agent, administered either as monotherapy (7 patients) or in combination (8 patients). Combination regimens included TMZ with cisplatin (3 patients), TMZ with lapatinib (3 patients), TMZ with bevacizumab (2 patients) and lomustine with procarbazine (1 patient). Other agents included fotemustine (1 patient) and bevacizumab, given either alone (3 patients) or combined (1 patient). The most common first-line regimen was single-agent TMZ.\u003c/p\u003e\n\u003cp\u003eRegardless of the line of therapy, the median progression-free survival (mPFS), progression-free survival rates at 6 and 12 months, and disease control rate (DCR) for each regimen were as follows. Temozolomide (TMZ) monotherapy yielded a mPFS that was not reached (95% CI, 6.9\u0026ndash;not estimable; range, 2.7\u0026ndash;25.3), with PFS rates of 85.7% (95% CI, 63.3\u0026ndash;100) at 6 months and 57.1% (95% CI, 30.1\u0026ndash;100) at 12 months, and a DCR of 57% (including one partial response). The combination of TMZ plus cisplatin was associated with a mPFS of 0.89 months (95% CI, 0.8\u0026ndash;not estimable; range, 0.8\u0026ndash;9.0), with PFS rates of 33% (95% CI, 6.73\u0026ndash;100) at 6 months and 0% \u0026nbsp;at 12 months, and a DCR of 33%. TMZ plus lapatinib showed a mPFS of 2.9 months (95% CI, 1.15\u0026ndash;not estimable; range, 1.2\u0026ndash;5.9), with PFS rates of 0% at 6 and 12 months, respectively, and a DCR of 33%. Bevacizumab monotherapy achieved a mPFS of 1.8 months (95% CI, 1.6\u0026ndash;not estimable; range, 1.6\u0026ndash;21.0), with PFS rates of 33% (95% CI, 6.7\u0026ndash;100) at both 6 and 12 months, and a DCR of 33%, including one patient who achieved stable disease during treatment and remained progression-free at last follow-up (PFS: 58.0 months). The combination of bevacizumab and fotemustine in one patient led to a PFS of 14.1 months with SD as best response. Fotemustine monotherapy resulted in a PFS of 2.4. Bevacizumab plus TMZ showed a mPFS of 9.5 months (95% CI, 3.3\u0026ndash;15.7; range, 3.2\u0026ndash;15.7), with PFS rates of 50% (95% CI, 0\u0026ndash;100) at both 6 and 12 months. Finally, lomustine plus procarbazine (PC) was associated with a PFS of 3.2 months (1 patient). \u003cstrong\u003eFig. 1\u003c/strong\u003e summarizes the timeline and sequence of systemic treatments administered to the 12 patients, with duration and clinical outcomes indicated for each line of therapy.\u003c/p\u003e\n\u003cp\u003eAt the data cut-off in April 2025, six patients were alive: four were in follow-up after stable disease, and two remained on active treatment. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMedian overall survival from the start of systemic therapy was not reached at the time of analysis. The overall survival rate from the start of systemic therapy rates at 6, 12, and 24 months were 91.7% (95% CI, 53.9\u0026ndash;98.8), 66.7% (95% CI, 33.7\u0026ndash;86.0), and 58.3% (95% CI, 27.0\u0026ndash;80.1), respectively. Median overall survival from diagnosis was 180.9 (95% CI 17.8-NE). The overall survival from diagnosis rates at 6, 12, and 24 months were 100.0% (95% CI, 100.0\u0026ndash;100.0), 91.7% (95% CI, 53.9\u0026ndash;98.8), and 83.3% (95% CI, 48.2\u0026ndash;95.6), respectively(see Supplementary \u003cstrong\u003eFig S1\u003c/strong\u003e and \u003cstrong\u003eS2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eSystemic treatments were generally well tolerated. Hematologic toxicities were the most frequent: thrombocytopenia occurred in 5 patients (including one grade 3), and neutropenia in 2 (both grade 2), mainly during TMZ-based treatments. One case of grade 1 transaminase elevation was reported with TMZ. Bevacizumab was associated with grade 1 hypertension in one case, and grade 2 nausea was observed in a patient treated with TMZ plus cisplatin. No grade \u0026ge;4 toxicities or treatment discontinuations occurred.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e Clinical characteristics of 12 patients with recurrent ependymoma treated with systemic therapies\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCase n.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex; Age at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurgery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRT\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Gy)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePattern of PD\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eKPS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eResurgery\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRe-irradiation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLines of therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFirst Line\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCurrent status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOSt\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(mo)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eF;35\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003esupratentorial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNodular Leptomeningeal\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTMZ+CIS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eF;62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003esupratentorial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTMZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFUP\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e28.3+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eM;54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003espine C2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTMZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eF;55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eposterior fossa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTMZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFUP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e70.1+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eF;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003esupratentorial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSRT\u003c/p\u003e\n \u003cp\u003e(21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTMZ DD +LAP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePD\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e46.2+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eM;23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003espine D4-D10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTMZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFUP\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e30.6+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eF;62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eposterior fossa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBEV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eF;63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eposterior fossa+ spine C2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTMZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTreatment ongoing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11.7+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eM;35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003esupratentorial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTMZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eM;22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003esupratentorial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBEV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLost FUP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8.2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eM;41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003esupratentorial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePRT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTMZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFUP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e24.3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eF;31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eG3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003esupratentorial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSTR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTMZ+CIS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eᵃPD = progressive disease at last follow-up.\u003cbr\u003e\u0026nbsp;ᵇFUP = currently in follow-up after stable disease.\u003cbr\u003e\u0026nbsp;\u0026ldquo;+\u0026rdquo; indicates censored observation (alive at last follow-up)\u003c/p\u003e\n\u003cp\u003eAbbreviations: \u003cstrong\u003ePD\u003c/strong\u003e= Progression, \u003cstrong\u003eKPS\u003c/strong\u003e=Karnofsky Performance Status, \u003cstrong\u003eGTR\u003c/strong\u003e= gross total resection, \u003cstrong\u003eSTR=\u003c/strong\u003e subtotal resection, \u003cstrong\u003eCS\u003c/strong\u003e= craniospinal radiotherapy, \u003cstrong\u003ePRT=\u003c/strong\u003e proton therapy, \u003cstrong\u003eSRT\u003c/strong\u003e= stereotactic radiotherapy, \u0026nbsp;\u003cstrong\u003eSRS=\u003c/strong\u003e radiosurgery, \u003cstrong\u003eTMZ=\u003c/strong\u003etemozolomide, \u003cstrong\u003eBEV\u003c/strong\u003e= bevacizumab, \u003cstrong\u003eTMZ DD =\u0026nbsp;\u003c/strong\u003etemozolomide dose dense, \u003cstrong\u003eLAP\u003c/strong\u003e =lapatinib, \u003cstrong\u003eCIS\u003c/strong\u003e=cisplatin \u003cstrong\u003eFUP=\u003c/strong\u003efollow up,\u003cstrong\u003e\u0026nbsp;LOST FUP\u003c/strong\u003e= lost to follow up \u003cstrong\u003eOSt:\u0026nbsp;\u003c/strong\u003etime from start of systemic therapy to death or last follow-up;\u003cstrong\u003emo\u003c/strong\u003e=months \u0026nbsp;\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. Summary of systemic treatment regimens and associated outcomes\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSchedule\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo of pts\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian number of cycles (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003emPFS (mo)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[95% CI]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003erange\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePFS-6 (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[95% CI]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePFS-12(%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;[95% CI]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDCR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTMZ\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eTemozolomide 200 mg/mq day 1-5 q4w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e12 (1-14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eNR (7.0\u0026ndash;NE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e2.7\u0026ndash;25.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e85.7\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(63.3\u0026ndash;100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e57.1\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(30.1\u0026ndash;100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e57%\u003c/p\u003e\n \u003cp\u003e(1 PR)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; TMZ + Cisplatin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eTemozolomide 150 mg/mq \u0026nbsp;day1-5 + Cisplatin 75 mg/mq q3w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e2(1-9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0.9 (0.8\u0026ndash;NE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e0.8\u0026ndash;9.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(6.7-100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e33%\u003c/p\u003e\n \u003cp\u003e(1 SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTMZ DD+ Lapatinib\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eTemozolomide DD 125mg/mq day 1-7; 15-21 q4w +Lapatinib 1250mg/unit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e2 (1-5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e2.9 (1.2\u0026ndash;NE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e1.2\u0026ndash;5.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e33%\u003c/p\u003e\n \u003cp\u003e(1 SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTMZ +bevacizumab\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eTemozolomide 200 mg/mq day 1-5 q4w +\u003c/p\u003e\n \u003cp\u003eBevacizumab 5mg/Kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e8(2-14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e9.5 (3.3\u0026ndash;15.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e3.3\u0026ndash;15.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e50\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(12.5\u0026ndash;100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(12.5\u0026ndash;100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBevacizumab alone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eBevacizumab 10 mg/kg q2w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e5(3-37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e1.8 (1.6\u0026ndash;NE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e1.6\u0026ndash;21.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(6.73-100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(6.7-100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e33%\u003c/p\u003e\n \u003cp\u003e(1SD\u0026gt;3yrs)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBevacizumab+Fotemustine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eBevacizumab 5 mg/kg + Fotemustine 80mg/mq q2w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e14.1 (single pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e(SD\u0026gt;1yrs)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFotemustine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eFotemustine 80mg/mq q2w for 5 cycles\u0026nbsp;\u0026agrave;\u0026nbsp;q4w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e2.40 (single pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003cp\u003e(SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLomustine +Procarbazine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eLomustine (CCNU) 110 mg/m\u0026sup2;, day 1, q6w Procarbazine 60 mg/m\u0026sup2;, days 8\u0026ndash;21, q6w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e3.22 (single pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 31px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 51px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: \u003cstrong\u003eTMZ=\u003c/strong\u003eTemozolomide; \u003cstrong\u003eTMZ DD=\u0026nbsp;\u003c/strong\u003eTemozolomide dose dense;\u003cstrong\u003emo\u003c/strong\u003e= months; \u003cstrong\u003eyrs=\u003c/strong\u003e years, \u003cstrong\u003ept=\u003c/strong\u003e patient; \u003cstrong\u003eNR\u003c/strong\u003e= not reached, \u003cstrong\u003eNE\u003c/strong\u003e= not estimable, \u003cstrong\u003eDCR\u003c/strong\u003e= disease control rate, \u003cstrong\u003ePFS\u003c/strong\u003e= progression free survival; \u003cstrong\u003ePFS-6-12\u003c/strong\u003e= PFS rates at 6 and 12 months. \u003cstrong\u003eSD=\u0026nbsp;\u003c/strong\u003estable disease, \u003cstrong\u003ePR\u003c/strong\u003e= partial response\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRecurrent adult ependymomas remain a clinical challenge due to their rarity, biological heterogeneity, and the absence of standardized systemic treatments. Most of the available data come from pediatric populations or small retrospective series, and prospective evidence in adults remains scarce.\u0026nbsp;\u003cstrong\u003eTable 3\u003c/strong\u003e summarizes the main studies evaluating chemotherapy and targeted agents for recurrent ependymoma.\u003c/p\u003e\n\u003cp\u003eIn this context, our mono-institutional retrospective analysis of 12 adult patients with recurrent intracranial or spinal ependymomas treated with systemic therapies over a 10-year period provides clinically relevant insights.\u003c/p\u003e\n\u003cp\u003eTemozolomide (TMZ) was the most frequently administered agent, either as monotherapy or in combination. In our cohort, TMZ monotherapy achieved a disease control rate (DCR) of 57% and although the median PFS for temozolomide was not reached by Kaplan\u0026ndash;Meier estimation, the observed median follow-up time was 9.4 months, which aligns with findings by Rud\u0026agrave; et al. [24], who reported a 22% objective response rate (ORR) and a mPFS of 9.7 months in a retrospective study of 18 adult patients. Conversely, Chamberlain et al.[25] observed limited efficacy of TMZ in platinum-refractory recurrent ependymomas (ORR 4%, mPFS 2 months), suggesting that TMZ is more effective when used earlier in the treatment course and in patients not heavily pretreated.\u003c/p\u003e\n\u003cp\u003eTMZ combinations provided more modest benefit. TMZ plus cisplatin resulted in a DCR of 33% and mPFS of 0.9 in our series, consistent with literature data indicating limited additional efficacy from platinum-based regimens in adults[26]. Interestingly, fotemustine, a nitrosourea similar to lomustine with high CNS penetration, showed promising activity in combination with bevacizumab (PFS 14.1 months) in a heavily pretreated patient, supporting further exploration of this agent.\u003c/p\u003e\n\u003cp\u003eThe combination of TMZ and lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, yielded a DCR of 33% and mPFS of 2.9 months in our study. These outcomes were inferior to those reported in a phase II trial conducted by the Collaborative Ependymoma Research Network (CERN), where the dose-dense TMZ plus lapatinib regimen achieved a 16% ORR and mPFS of 7.8 months in 50 adult patients[27]. One potential explanation is the lack of molecular selection in our cohort. In the CERN study, patients with high ErbB2 (HER2) expression appeared to derive greater benefit. Therefore, incorporating molecular profiling, such as EGFR and HER2 status, may optimize patient selection for lapatinib-based treatments.\u003c/p\u003e\n\u003cp\u003eAmong targeted therapies, bevacizumab demonstrated noteworthy activity in selected patients. Green et al.\u0026nbsp;[28]\u0026nbsp;\u0026nbsp;reported a 75% ORR and mPFS of 6.4 months in a small adult cohort. Our findings support this observation: one patient achieved 21 months of disease stabilization on bevacizumab monotherapy and remains progression-free 58 months after treatment initiation, despite discontinuation of therapy. Furthermore, the most durable stabilization in our series was achieved in a heavily pretreated patient receiving sequential bevacizumab-containing regimens (bevacizumab plus fotemustine with PFS of 14.13 followed by bevacizumab plus temozolomide with a PFS of 15.67), supporting the potential benefit of bevacizumab-based combinations in this setting.While such outlier responses are rare, they highlight the need to identify predictive markers (e.g., VEGF expression, radiologic features) to select patients more likely to benefit from anti-angiogenic therapy. Conversely, in pediatric trials[29]\u0026nbsp;bevacizumab failed to induce objective responses, though some patients experienced prolonged stable disease.\u003c/p\u003e\n\u003cp\u003eOverall, our data suggest that a subset of adult patients may benefit from targeted treatments. While lapatinib\u0026rsquo;s efficacy may be limited without patient enrichment strategies, its safety profile and blood-brain barrier permeability justify further investigation in biomarker-driven trials. Bevacizumab, although not universally effective, may provide durable control in angiogenesis-dependent tumors, potentially in combination with nitrosoureas. Notably, the combination of bevacizumab and fotemustine was evaluated for the first time in this pathology in our study, showing encouraging disease stabilization.\u003c/p\u003e\n\u003cp\u003eAnother relevant finding from our series is the feasibility of multiple lines of systemic therapy. The number of lines ranged from 1 to 5 (median 2), with some patients achieving prolonged overall survival (OS) beyond 8 years from diagnosis. This challenges the notion that recurrent ependymomas are uniformly aggressive and rapidly fatal. In patients who maintain good clinical condition over time, the use of sequential systemic therapies may contribute to prolonged survival. Although no specific regimen emerged as clearly superior, switching between different chemotherapy classes (e.g., alkylators, nitrosoureas, anti-angiogenics) appears reasonable, given the heterogeneity of treatment response and lack of cross-resistance. This approach is supported by retrospective studies[30] who reported that various chemotherapies, including temozolomide, nitrosoureas, and platinum compounds, achieved disease stabilization in a significant proportion of adult patients with intracranial ependymoma, even across multiple treatment lines, thus supporting the feasibility and potential value of sequential therapeutic strategies.\u003c/p\u003e\n\u003cp\u003eRegarding toxicity, systemic therapies were generally well tolerated. TMZ was associated with manageable hematologic toxicity (thrombocytopenia in 5 patients, including one grade 3; neutropenia in 2 patients, both grade 2). Bevacizumab led to grade 1 hypertension in one case, and no thromboembolic or hemorrhagic complications were observed. Lapatinib did not result in clinically significant adverse events in our cohort, likely due to limited exposure. These findings mirror safety data from the CERN study [27], where the combination of TMZ and lapatinib was well tolerated, with fatigue, nausea, and diarrhea being the most common side effects.\u003c/p\u003e\n\u003cp\u003eNevertheless, this study has some limitations. First, its retrospective and single-center design limits the generalizability of the findings and may introduce selection biases. Second, the small sample size precludes definitive conclusions on comparative efficacy across treatment regimens. Third, molecular profiling was not routinely performed, preventing correlation between genomic alterations and therapeutic response. Additionally, both spinal and intracranial ependymomas were included, which, despite reflecting real-world heterogeneity, may confound interpretation due to their distinct biological behavior. Radiological assessments were also conducted retrospectively without central review, which may have affected consistency in response evaluation. Furthermore, the same treatment was administered at different lines of therapy across patients, which may have influenced the evaluation of its efficacy, as treatment effectiveness can vary depending on timing and prior exposure.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDespite these limitations, our analysis provides clinically relevant, real-world insights into the use of systemic therapies for recurrent adult ependymomas, a rare disease where prospective data are lacking.\u003c/p\u003e\n\u003cp\u003eOur findings emphasize that temozolomide remains a valuable backbone in recurrent ependymoma, while bevacizumab-based strategies and molecularly informed treatments warrant further exploration in prospective multicenter settings. The possibility of administering multiple systemic lines offers a window of opportunity to prolong survival in fit patients.\u003c/p\u003e\n\u003cp\u003eFuture research should prioritize the integration of molecular profiling to better guide patient selection for targeted agents, and the design of prospective, multicenter trials specifically dedicated to adults. Novel approaches such as immunotherapy, tumor treating fields, and CAR-T cell strategies are currently under investigation reflecting the growing interest in immuno- and device-based modalities for this rare disease and may offer additional options in the recurrent setting(see \u003cstrong\u003eTable 3b\u003c/strong\u003e). Finally, collaborative real-world registries will be instrumental in defining treatment sequencing and improving outcomes in this rare disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u0026nbsp;\u003c/strong\u003eSummary of published studies on systemic therapies for recurrent ependymoma\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"101%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(year)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eType\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSetting\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN pts\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGrade(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRR(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003emPFS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(mo)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003emOS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\" style=\"width: 100px;\"\u003e\n \u003cp\u003eChemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRud\u0026agrave;[24]\u003c/p\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTMZ\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eWHO \u0026nbsp; \u0026nbsp; G2 or 3 failing re-operation and/reirradiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eII(45)\u003c/p\u003e\n \u003cp\u003eIII(55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCR(5)\u003c/p\u003e\n \u003cp\u003ePR(17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eChamberlain[25]\u003c/p\u003e\n \u003cp\u003e2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTMZ\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eWHO G2 platinum refractory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eII(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eCR(0)\u003c/p\u003e\n \u003cp\u003ePR(4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eGilbert[27]\u003c/p\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDose dense TMZ + Lapatinib\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003ePhase II\u003c/p\u003e\n \u003cp\u003eSingle arm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eRecurrent intracranial and spinal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eI(16)\u003c/p\u003e\n \u003cp\u003eII(32)\u003c/p\u003e\n \u003cp\u003eIII(40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eCR(4)\u003c/p\u003e\n \u003cp\u003ePR(12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e7.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eBrandes[26]\u003c/p\u003e\n \u003cp\u003e2005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCisplatin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eCisplatin-based(46%) vs non cisplatin based (54%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e13 vs\u003c/p\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eII(61)\u003c/p\u003e\n \u003cp\u003eIII(39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eCR(15,4)vs (0)\u003c/p\u003e\n \u003cp\u003ePR(15,5) vs (13,3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e9.9 vs\u003c/p\u003e\n \u003cp\u003e10.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e40.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eGornet[28]\u003c/p\u003e\n \u003cp\u003e1999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlatinum-based\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003ePlatinum based vs nistrosurea based\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e6 vs 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eII(50)\u003c/p\u003e\n \u003cp\u003eIII(37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003ePR/MR(67)vs(25)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e6 vs 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\" style=\"width: 100px;\"\u003e\n \u003cp\u003eOther therapies\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCT identifier\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(year)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eType\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSetting\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN pts\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSchedule\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRR(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNCT01032070\u003c/p\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eErlotinib\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRandomized open label\u003c/p\u003e\n \u003cp\u003ePhase II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRecurrent or Refractory pediatric ependymoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eErlotinib 85 mg/m2 daily \u0026nbsp;vs \u0026nbsp;Etoposide 50 mg/m2 daily 3 weeks q4w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCR(0) PR(0) SD(15,4) vs\u003c/p\u003e\n \u003cp\u003eCR(0) PR(16,7) MR(8,3) SD(16,7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003emPFS 52 vs 65 days\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNCT01462695\u003c/p\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSunitinib\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eOpen label\u003c/p\u003e\n \u003cp\u003eSingle arm\u003c/p\u003e\n \u003cp\u003ePhase II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRecurrent or Refractory pediatric ependymoma/ HGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eSunitinib 15 mg/m2 4 weeks q6w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo ORR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003emPFS 83 days\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eNCT02155920\u003c/p\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEverolimus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eOpen label\u003c/p\u003e\n \u003cp\u003eSingle arm\u003c/p\u003e\n \u003cp\u003ePhase II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eRecurrent or Refractory pediatric posterior fossa and spinal ependymoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eEverolimus 4.5 mg/m2 daily q4w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eNo ORR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003emPFS 48days\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eGreen [31]\u003c/p\u003e\n \u003cp\u003e2009\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eBevacizumab\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRecurrent adult\u003c/p\u003e\n \u003cp\u003eependymoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eBevacizumab10 mg/Kg iv q2w alone or in combination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePR(75)\u003c/p\u003e\n \u003cp\u003e1 SD \u0026gt;8months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003emTTP 6.4 months\u003c/p\u003e\n \u003cp\u003emOS 9.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eNCT00883688\u003c/p\u003e\n \u003cp\u003e2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBevacizumab + Lapatinib\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003ePhase II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eRecurrent\u003c/p\u003e\n \u003cp\u003ePediatric ependymoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eBevacizumab 10 mg/kg iv days q2w + lapatinib 900mg/m2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eNo ORR\u003c/p\u003e\n \u003cp\u003eProlonged SD in 4pts\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003emTTP 7.9 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNCT02054806 (Keynote 028)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eImetelstat\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMolecular biology\u003c/p\u003e\n \u003cp\u003ePhase II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRecurrent medulloblastoma, HGG, ependymoma candidate to surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003cp\u003e(4 ependymomas)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eImetelstat\u0026nbsp;2-h iv at 285 mg/m2 12-24 h before surgery.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo ORR\u003c/p\u003e\n \u003cp\u003eIntratumoral and PBMC target inhibition\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003einterrupted for toxicity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNCT02940483\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5-Azacytidine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePhase 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRecurrent ependymoma udergoing maximal safe resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5-AZA 10\u0026nbsp;mg into the fourth ventricle\u0026nbsp;q1w, 12 cycles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo ORR\u003c/p\u003e\n \u003cp\u003e2pts reduction size one ventricoluar lesion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo AE\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNCT04958486\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5 Azacitidine + Trastuzumab\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eEarly Phase I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRecurrent adult and pediatric with Recurrent or Residual Posterior Fossa Ependymoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 AZA + Trastuzumab into fourth ventricle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNA completed, no results available yet\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eNCT03434262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRibociclib + Gemcitabine\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePhase I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRecurrent brain tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003cp\u003eEpendymomas\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRibociclb+ combination molecular driven therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePFS\u0026gt;2 yrs in 1 pt\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNCT02359565\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePembrolizumab\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eEarly phase I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRecurrent or progressive diffuse intrinsic pontine glioma, HGG, ependymomas, medulloblastoma or hypermutates brain tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003eEpendymomas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePembrolizumab 2mg/kg IV q3w\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo ORR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003emPFS 1.38months\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 96px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 40px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations\u003cstrong\u003e: CT=\u0026nbsp;\u003c/strong\u003eclinical trial\u003cstrong\u003e, TMZ=\u0026nbsp;\u003c/strong\u003etemozolomide,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003emPFS\u003c/strong\u003e= median progression free survival, \u003cstrong\u003emOS\u003c/strong\u003e= median overall survival; \u003cstrong\u003eTTP=\u003c/strong\u003e time to progression, \u003cstrong\u003eRR=\u0026nbsp;\u003c/strong\u003eResponse Rate, \u003cstrong\u003eORR=\u003c/strong\u003e objective response rate, \u003cstrong\u003eCR=\u0026nbsp;\u003c/strong\u003ecomplete response\u003cstrong\u003e, PR=\u0026nbsp;\u003c/strong\u003epartial response\u003cstrong\u003e, MR=\u0026nbsp;\u003c/strong\u003eminimal response,\u003cstrong\u003eSD\u003c/strong\u003e=stabel disease,\u003cstrong\u003e\u0026nbsp;pts=\u003c/strong\u003e patients,\u003cstrong\u003eq1w\u003c/strong\u003e=weekly, \u003cstrong\u003eq2w\u003c/strong\u003e=every 2 weeks, \u003cstrong\u003eq3w\u003c/strong\u003e=every 3 weeks,\u003cstrong\u003eq4w\u003c/strong\u003e=every 4 weeks, \u003cstrong\u003eHGG=\u003c/strong\u003e high grade gliomas, \u003cstrong\u003eiv=\u003c/strong\u003e intravenous, \u003cstrong\u003eicv=\u003c/strong\u003e intraventricular, \u003cstrong\u003eAZA=\u003c/strong\u003e azacitidine, \u003cstrong\u003eAE=\u003c/strong\u003e adverse event, \u003cstrong\u003eNA\u003c/strong\u003e= not available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3b\u003c/strong\u003e Ongoing clinical trials for recurrent ependymoma\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"86%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCT identifier\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(year)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDrug\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eType\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDesign\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePopulation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eStatus\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNCT04661384\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIL13Ralpha2-CAR T cells\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePhase I\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eIL13Ralpha2-CAR T Cells\u003c/p\u003e\n \u003cp\u003eicv delivery\u0026nbsp;on day 1 qw for 4 cycles as adjuvant therapy\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003eLeptomeningeal disease from glioblastoma, ependymoma, medulloblastoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eActive not recruiting\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNCT02774421\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTrastuzumab\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePhase I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eIntrathecal trastuzumab + subcutaneus GM-CSF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003ePediatric recurrent posterior fossa ependymoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eActive not recruiting\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNCT03033992\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTTF\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eNot applicable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eOptune \u0026ge; 18 hours/day for at least 23 days out of 28 days of cycle one\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003ePediatric \u0026nbsp; \u0026nbsp; recurrent/refractorysupratentorial glioma or ependymoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eRecruiting\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNCT01795313\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePeptide vaccine + Imiquimod\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003ePhase I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003eHLA-A2 restricted tumor antigen vaccine+\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003eRecurrent pediatric Ependymoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eRecruiting\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations\u003cstrong\u003e:\u0026nbsp;GM-CSF=\u003c/strong\u003egranulocyte-macrophage colony-stimulating factor,\u003cstrong\u003e\u0026nbsp;HLA=\u003c/strong\u003ehuman leukocyte antigen\u003cstrong\u003e, icv=\u0026nbsp;\u003c/strong\u003eintraventricular\u003cstrong\u003e, TTF =\u0026nbsp;\u003c/strong\u003etumor treating fields.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eConflicts of interest\u003c/h2\u003e\u003cp\u003eNone declared.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eHuman Ethics and Consent to Participate declarations\u003c/h2\u003e\u003cp\u003e The study was conducted in accordance with the Declaration of Helsinki and approved by the local Ethics Committee of the Veneto Institute of Oncology (IOV-IRCCS, Padua, Italy; protocol code IOV-2024-ANIMA). Patients still alive at the time of this study provided written informed consent for the collection and use of their anonymized data for scientific purposes.\u003c/p\u003e\u003cp\u003eClinical trial number: not applicable\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis research received \u0026ldquo;Ricerca Corrente 2025\u0026rdquo; funding from the Italian Ministry of Health to cover publication costs (CDC099183).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eM.M. conceived the study, collected and curated clinical data, performed data analyses, and drafted the manuscript. G.L. supervised the study and critically revised the manuscript. A.B., M.C., M.P., A.G., G.Li., G.P., L.B., F.V., T.I., F.C., L.D. contributed to patient management, data collection, and manuscript review and S.L. provided overall supervision. All authors read and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe gratefully acknowledge Fondazione Celeghin for their partial support of this work and thank Pietro Guerra for his support and advice during the data analysis in R.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTaylor MD, Poppleton H, Fuller C, et al (2005) Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8:323\u0026ndash;335. https://doi.org/10.1016/j.ccr.2005.09.001\u003c/li\u003e\n\u003cli\u003ePrice M, Neff C, Nagarajan N, et al (2024) CBTRUS Statistical Report: American Brain Tumor Association \u0026amp; NCI Neuro-Oncology Branch Adolescent and Young Adult Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2016\u0026ndash;2020. Neuro-Oncol 26:iii1\u0026ndash;iii53. https://doi.org/10.1093/neuonc/noae047\u003c/li\u003e\n\u003cli\u003eOstrom QT, Price M, Neff C, et al (2022) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015\u0026ndash;2019. Neuro-Oncol 24:v1\u0026ndash;v95. https://doi.org/10.1093/neuonc/noac202\u003c/li\u003e\n\u003cli\u003eMcGuire CS, Sainani KL, Fisher PG (2009) Incidence patterns for ependymoma: a Surveillance, Epidemiology, and End Results study: Clinical article. J Neurosurg 110:725\u0026ndash;729. https://doi.org/10.3171/2008.9.JNS08117\u003c/li\u003e\n\u003cli\u003eKresbach C, Neyazi S, Sch\u0026uuml;ller U (2022) Updates in the classification of ependymal neoplasms: The 2021 WHO Classification and beyond. Brain Pathol 32:e13068. https://doi.org/10.1111/bpa.13068\u003c/li\u003e\n\u003cli\u003ePajtler KW, Witt H, Sill M, et al (2015) Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell 27:728\u0026ndash;743. https://doi.org/10.1016/j.ccell.2015.04.002\u003c/li\u003e\n\u003cli\u003eLouis DN, Perry A, Wesseling P, et al (2021) The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-Oncol 23:1231\u0026ndash;1251. https://doi.org/10.1093/neuonc/noab106\u003c/li\u003e\n\u003cli\u003eEllison DW, Aldape KD, Capper D, et al (2020) cIMPACT‐NOW update 7: advancing the molecular classification of ependymal tumors. Brain Pathol 30:863\u0026ndash;866. https://doi.org/10.1111/bpa.12866\u003c/li\u003e\n\u003cli\u003eRud\u0026agrave; R, Bruno F, Pellerino A, Soffietti R (2022) Ependymoma: Evaluation and Management Updates. Curr Oncol Rep 24:985\u0026ndash;993. https://doi.org/10.1007/s11912-022-01260-w\u003c/li\u003e\n\u003cli\u003eRaghunathan A, Wani K, Armstrong TS, et al (2013) Histological predictors of outcome in ependymoma are dependent on anatomic site within the central nervous system. Brain Pathol Zurich Switz 23:584\u0026ndash;594. https://doi.org/10.1111/bpa.12050\u003c/li\u003e\n\u003cli\u003eWani K, Armstrong TS, Vera-Bolanos E, et al (2012) A prognostic gene expression signature in infratentorial ependymoma. Acta Neuropathol (Berl) 123:727\u0026ndash;738. https://doi.org/10.1007/s00401-012-0941-4\u003c/li\u003e\n\u003cli\u003eReni M, Brandes AA, Vavassori V, et al (2004) A multicenter study of the prognosis and treatment of adult brain ependymal tumors. Cancer 100:1221\u0026ndash;1229. https://doi.org/10.1002/cncr.20074\u003c/li\u003e\n\u003cli\u003eRogers L, Pueschel J, Spetzler R, et al (2005) Is gross-total resection sufficient treatment for posterior fossa ependymomas? J Neurosurg 102:629\u0026ndash;636. https://doi.org/10.3171/jns.2005.102.4.0629\u003c/li\u003e\n\u003cli\u003eMetellus P, Barrie M, Figarella-Branger D, et al (2007) Multicentric French study on adult intracranial ependymomas: prognostic factors analysis and therapeutic considerations from a cohort of 152 patients. Brain J Neurol 130:1338\u0026ndash;1349. https://doi.org/10.1093/brain/awm046\u003c/li\u003e\n\u003cli\u003eMetellus P, Guyotat J, Chinot O, et al. Adult intracranial WHO grade II ependymomas: long-term outcome and prognostic factor analysis in a series of 114 patients. Neuro Oncol. 2010;12(9):976\u0026ndash;984 https://doi.org/10.1093/neuonc/noq047\u003c/li\u003e\n\u003cli\u003eVarma A, Giraldi D, Mills S, et al (2018) Surgical management and long-term outcome of intracranial subependymoma. Acta Neurochir (Wien) 160:1793\u0026ndash;1799. https://doi.org/10.1007/s00701-018-3570-4\u003c/li\u003e\n\u003cli\u003eRud\u0026agrave; R, Reifenberger G, Frappaz D, et al (2018) EANO guidelines for the diagnosis and treatment of ependymal tumors. Neuro-Oncol 20:445\u0026ndash;456. https://doi.org/10.1093/neuonc/nox166\u003c/li\u003e\n\u003cli\u003eWee CW, Kim IH, Park C-K, et al (2020) Postoperative radiotherapy for WHO grade II-III intracranial ependymoma in adults: An intergroup collaborative study (KROG 18-06/KNOG 18-01). Radiother Oncol J Eur Soc Ther Radiol Oncol 150:4\u0026ndash;11. https://doi.org/10.1016/j.radonc.2020.05.045\u003c/li\u003e\n\u003cli\u003eOya N, Shibamoto Y, Nagata Y, et al (2002) Postoperative radiotherapy for intracranial ependymoma: analysis of prognostic factors and patterns of failure. J Neurooncol 56:87\u0026ndash;94. https://doi.org/10.1023/a:1014442106111\u003c/li\u003e\n\u003cli\u003eMansur DB, Perry A, Rajaram V, et al (2005) Postoperative radiation therapy for grade II and III intracranial ependymoma. Int J Radiat Oncol Biol Phys 61:387\u0026ndash;391. https://doi.org/10.1016/j.ijrobp.2004.06.002\u003c/li\u003e\n\u003cli\u003eGhia AJ, Mahajan A, Allen PK, et al (2013) Supratentorial gross-totally resected non-anaplastic ependymoma: population based patterns of care and outcomes analysis. J Neurooncol 115:513\u0026ndash;520. https://doi.org/10.1007/s11060-013-1254-8\u003c/li\u003e\n\u003cli\u003eIqbal MS, Lewis J (2013) An Overview of the Management of Adult Ependymomas with Emphasis on Relapsed Disease. Clin Oncol 25:726\u0026ndash;733. https://doi.org/10.1016/j.clon.2013.07.009\u003c/li\u003e\n\u003cli\u003eZhao F, Wu T, Wang L, et al (2021) Survival and Prognostic Factors of Adult Intracranial Ependymoma: A Single-institutional Analysis of 236 Patients. Am J Surg Pathol 45:979. https://doi.org/10.1097/PAS.0000000000001669\u003c/li\u003e\n\u003cli\u003eRud\u0026agrave; R, Bosa C, Magistrello M, et al (2016) Temozolomide as salvage treatment for recurrent intracranial ependymomas of the adult: a retrospective study. Neuro-Oncol 18:261\u0026ndash;268. https://doi.org/10.1093/neuonc/nov167\u003c/li\u003e\n\u003cli\u003eChamberlain MC, Johnston SK (2009) Temozolomide for recurrent intracranial supratentorial platinum-refractory ependymoma. Cancer 115:4775\u0026ndash;4782. https://doi.org/10.1002/cncr.24524\u003c/li\u003e\n\u003cli\u003eBrandes AA, Cavallo G, Reni M, et al (2005) A multicenter retrospective study of chemotherapy for recurrent intracranial ependymal tumors in adults by the Gruppo Italiano Cooperativo di Neuro-Oncologia. Cancer 104:143\u0026ndash;148. https://doi.org/10.1002/cncr.21110\u003c/li\u003e\n\u003cli\u003eGilbert MR, Yuan Y, Wu J, et al (2021) A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma. Neuro-Oncol 23:468\u0026ndash;477. https://doi.org/10.1093/neuonc/noaa240\u003c/li\u003e\n\u003cli\u003eGornet MK, Buckner JC, Marks RS, et al (1999) Chemotherapy for advanced CNS ependymoma. J Neurooncol 45:61\u0026ndash;67. https://doi.org/10.1023/a:1006394407245\u003c/li\u003e\n\u003cli\u003eDeWire M, Fouladi M, Turner DC, et al (2015) An open-label, two-stage, phase II study of bevacizumab and lapatinib in children with recurrent or refractory ependymoma: a collaborative ependymoma research network study (CERN). J Neurooncol 123:85\u0026ndash;91. https://doi.org/10.1007/s11060-015-1764-7\u003c/li\u003e\n\u003cli\u003eGramatzki D, Roth P, Felsberg J, Hofer S, Rushing EJ, Hentschel B, Westphal M, Krex D, Simon M, Schnell O, Wick W, Reifenberger G, Weller M. Chemotherapy for intracranial ependymoma in adults. BMC Cancer. 2016 Apr 23;16:287. https://doi.org/10.1186/s12885-016-2323-0\u003c/li\u003e\n\u003cli\u003eGreen RM, Cloughesy TF, Stupp R, DeAngelis LM, Woyshner EA, Ney DE, Lassman AB. Bevacizumab for recurrent ependymoma. Neurology. 2009 Nov 17;73(20):1677-80. https://doi.org/10.1212/wnl.0b013e3181c1df34\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ependymomas, targeted therapy, bevacizumab, chemotherapy","lastPublishedDoi":"10.21203/rs.3.rs-7862583/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7862583/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose:\u003c/h2\u003e\u003cp\u003eRecurrent adult ependymomas lack standard systemic therapies and evidence on chemotherapy and targeted agents is limited. This study aimed to retrospectively evaluated outcomes of systemic therapies, including targeted combinations, in a real-world cohort.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e\u003cp\u003eAdult patients with intracranial or spinal ependymoma treated at our institution between 2013 and 2025 who received at least one systemic line at recurrence were included. Tumor response was assessed according to RANO criteria. Primary endpoints were disease control rate (DCR) and progression-free survival (PFS). Secondary endpoints were overall survival from the start of the first line treatment(OSt) and overall survival from diagnosis(OS).\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e\u003cp\u003eAmong 47 patients, 12 received systemic therapy at recurrence. The median follow up duration for the entire cohort was 28.3 months.Temozolomide (TMZ) was the most commonly used agent (n\u0026thinsp;=\u0026thinsp;12). TMZ monotherapy achieved a DCR of 57% with 6- and 12-month PFS rates of 85.7% and 57.1%, respectively. Targeted therapy was administered to 7 patients: the TMZ-Lapatinib combination provided limited benefit (DCR 33%, median PFS 2.9 months), bevacizumab-based regimens showed variable efficacy; bevacizumab alone achieved a DCR of 33% with one case of prolonged stabilization (\u0026gt;\u0026thinsp;58 months), while bevacizumab plus fotemustine yielded a PFS of 14.1 months. Treatments were generally well tolerated, with limited grade 3 toxicities. Sequential systemic therapy, up to five lines, was feasible in selected cases. Median OSt was not reached; 12-month OS was 66.7%.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e\u003cp\u003eThis real-world analysis supports TMZ as a relevant option and suggests potential benefit of bevacizumab-based combinations in recurrent adult ependymomas. Prospective, biomarker-driven multicenter trials are warranted to optimize systemic strategies in this rare disease.\u003c/p\u003e","manuscriptTitle":"Targeted and Systemic therapies for recurrent adult ependymomas: real- world outcomes from a single institution and concise literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-30 12:04:12","doi":"10.21203/rs.3.rs-7862583/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"519ae5e7-682a-42a6-bc45-ff7b89a9b87a","owner":[],"postedDate":"October 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-01T12:08:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-30 12:04:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7862583","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7862583","identity":"rs-7862583","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}