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Background More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2nd AIEOP protocol. Methods We considered relapse sites and treatments, that is, various combinations of complete/incomplete surgery, if followed by standard or hypofractionated radiotherapy (RT) ± chemotherapy (CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses. Results The median follow-up was 147 months after diagnosis, 84 months after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse (LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes, it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, the absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse. Conclusions Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well-posed, randomized questions could clarify the numerous issues, orient salvage treatment, and ameliorate prognosis for this group of patients.

Few reports exist about reirradiation (RT2) for recurrent brain tumors in pediatric patients.A monocentric retrospective analysis of 22 patients with reirradiated CNS neoplasms was conducted with the objective to describe clinical outcomes and toxicities associated with RT2. Median age at diagnosis and RT2 was 8.5 years and 11.5 years respectively. Primary diagnoses included ependymoma (n=7, 32%), medulloblastoma (n=5, 23%), DIPG (n=4, 18%), glioblastoma (N=2, 9%), and others (N=4, 18%). The median interval between the first radiotherapy and RT2 was 16.5 months. Two patients underwent in-field RT2 for a secondary tumor. RT2 was administered with a curative intent in 13 patients, with a palliative-only treatment in the remaining 9. Sixteen patients received brain RT2 and 3 patients spine RT2, with a median cumulative dose of 19.9 Gy and 30 Gy respectively. Three patients received combined RT2. Volumetric Modulated Arc Therapy(VMAT) was the most frequent technique used (60%). Eight patients showed neurological symptoms before RT2, 6 had clinical benefit with RT2. Among patients who were asymptomatic before RT2, 5 later showed progressive neurological symptoms (at least partly attributable to RT2). Radionecrosis was radiologically detected in 6 patients, but accompanied by symptoms only in 3. Median event-free survival (EFS) and overall survival(OS) after RT2 was 4.7 and 8.7 months respectively, similarly to previous results. One-year EFS and OS was 13% and 36% respectively. As previously reported, OS appeared to be longer for patients with >12 months elapsed time between first irradiation and RT2 (1-year OS=45% versus 0%, p=0.07). In our cohort RT2 appeared feasible and provided short-term disease control with tolerable short-term toxicity, while providing relief in most symptomatic patients. Larger prospective studies are needed to understand which subsets of patients may benefit from either curative or palliative reirradiation, to provide respectively a longer survival and a significantly improved symptom control.

BackgroundProton beam therapy (PBT) is an effective pediatric brain tumor treatment. However, resulting microstructural changes within and around irradiated tumors are unknown. We retrospectively applied Diffusion-Tensor-Imaging (DTI) and Free-Water-Imaging (FWI) on diffusion-weighted Magnetic Resonance Imaging (dMRI) data to monitor microstructural changes during-PBT and after 8 months, in a pilocytic astrocytoma (PA) and normal-appearing white matter (NAWM).MethodsWe evaluated conventional MRI and dMRI-derived indices from six MRI sessions in a child with a hypothalamic PA: at baseline (t0), during-PBT (t1-t4), and after 8 months (t5). Tumor voxels were classified as “solid” or “fluid” based on FWI.ResultsWhile during PBT tumor volume remained stable, dMRI analyses identified two different response patterns: i) an increase in fluid content and diffusivity with anisotropy reductions in solid voxels at t1, followed by ii) smaller variations in fluid content but higher anisotropy in solid voxels at t2-t4. At follow-up (t5), tumor volume, its fluid content, and diffusivity in solid voxels increased. NAWM showed dose-dependent microstructural changes.ConclusionsThe use of dMRI and FWI showed complex dynamic microstructural changes in the irradiated mass during PBT and at follow-up, opening new avenues in our understanding of radiation-induced pathophysiologic mechanisms in tumor and surrounding tissues.

Metàstasis; Pediatria; Radioteràpia Metástasis; Pediatría; Radioterapia Metastases; Paediatrics; Radiotherapy Purpose/objective About 20% of children with solid tumours (ST) present with distant metastases (DM). Evidence regarding the use of radical radiotherapy of these DM is sparse and open for personal interpretation. The aim of this survey was to review European protocols and to map current practice regarding the irradiation of DM across SIOPE-affiliated countries. Materials/methods Radiotherapy guidelines for metastatic sites (bone, brain, distant lymph nodes, lung and liver) in eight European protocols for rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma, Ewing sarcoma, neuroblastoma and renal tumours were reviewed. SIOPE centres irradiating ≥50 children annually were invited to participate in an online survey. Results Radiotherapy to at least one metastatic site was recommended in all protocols, except for high-risk neuroblastoma. Per protocol, dose prescription varied per site, and information on delineation and treatment planning/delivery was generally missing. Between July and September 2019, 20/27 centres completed the survey. Around 14% of patients were deemed to have DM from ST at diagnosis, of which half were treated with curative intent. A clear cut-off for a maximum number of DM was not used in half of the centres. Regardless of the tumour type and site, conventional radiotherapy regimens were most commonly used to treat DM. When stereotactic radiotherapy was used, a wide range of fractionation regimens were applied. Conclusion Current radiotherapy guidelines for DM do not allow a consistent approach in a multicentre setting. Prospective (randomised) trials are needed to define the role of radical irradiation of DM from paediatric ST. Stichting Kinderen Kankervrij [project no. 343]. KiKa (Children Cancer Free) foundation, grant number 343 and title: Towards optimization of radiotherapy techniques for metastatic lesions in children stage IV disease. The funding source had no role in the study design, collection, analysis and interpretation of data, writing of this manuscript or the decision to submit the article for publication.

Purpose: The aims of patients’ radiological surveillance are to: ascertain relapse; apply second-line therapy; accrue patients in phase 1/2 protocols if second-line therapy is not standardized/curative; and assess/treat iatrogenic effects. To lessen the emotional and socioeconomic burdens for patients and families, we ideally need to establish whether scheduled radiological surveillance gives patients a better outcome than waiting for symptoms and signs to appear. Methods: We analyzed a prospective series of 160 newly-diagnosed and treated pediatric/adolescent patients with intracranial ependymoma, comparing patients with recurrent disease identified on scheduled MRI (the RECPT group; 34 cases) with those showing signs/symptoms of recurrent disease (the SYMPPT group; 16 cases). The median follow-up was 67 months. Results: No significant differences emerged between the two groups in terms of gender, age, tumor grade/site, shunting, residual disease, or type of relapse (local, distant, or concomitant). The time to relapse (median 19 months; range 5–104) and the MRI follow-up intervals did not differ between the SYMPPT and RECPT groups. The presence of signs/symptoms was an unfavorable factor for overall survival (OS) after recurrence (5-year OS: 8% vs. 37%, p = 0.001). On multivariable analysis, an adjusted model confirmed a significantly worse OS in the SYMPPT than in the RECPT patients. Conclusions: Symptomatic relapses carried a significantly worse survival for ependymoma patients than recurrences detected by MRI alone. It would therefore be desirable to identify recurrences before symptoms develop. Radiological follow-up should be retained in ependymoma patient surveillance because there is a chance of salvage treatment for relapses found on MRI

Patients with diffuse intrinsic pontine glioma (DIPG) have a very poor prognosis. Only radiotherapy (XRT) has proven to be effective in delaying the disease progression. Several chemotherapy schedules have been applied so far, but none demonstrated significant improvements in progression and survival. We retrospectively analyzed the clinical data of children diagnosed with DIPG at our center (Pediatric Hospital “Regina Margherita,” Turin, Italy) between 1999 and 2013. Progression-free survival (PFS) and overall survival (OS) were used to describe the outcomes. Twenty-four children were included in our report. Patients diagnosed before March 2003 (n = 12) were treated with XRT and vincristine (VCR); the remaining 12 patients received XRT and temozolomide (TMZ). Progression-free survival was 18.8 % at 1 year (SE = 7.6 %), while overall survival was 44.1 % at 1 year (SE = 9.9 %). Median PFS was 8.1 months, whereas median OS was 11.2 months. No statistically significant difference in PFS or OS was evidenced between the two treatment groups. Radiotherapy followed by VCR or TMZ allows obtaining results that are in line with previous reports, with no advantages over other similar treatment schedules. DIPGs are challenging tumors with a dismal outcome. Further research and newer therapies are urgently needed in order to achieve improvements in survival.

Aims of patient follow-up are: discovering relapse to apply second-line therapy for possible cure, accruing patients in phase 1/2 protocols if second-line therapy is not standardized/curative, evaluating/treating iatrogenic effects. To lessen the patient/family emotional and social economic burdens, we should ideally understand if scheduled radiological follow-up has a better rationale/outcome than the symptomatic relapse. We analyzed the Italian series of 2016 (doi:10.1093/neuonc/now108) comprehending 160 newly diagnosed pediatric/adolescent patients with intracranial ependymoma (EPD) according to relapse status (recurrence at scheduled exam [RECPT]/sign-symptomatic recurring [SYMPPT]). RECPT and SYMPPT were assessed in Cox model as time-dependent variables for overall survival (OS). Differences in characteristics between RECPT and SYMPPT subgroups were assessed by Wilcoxon-Mann-Whitney or Fisher Exact tests. Kaplan-Meier curves depicted event-free survival (EFS) and OS after recurrence according to signs/symptoms. There were 16 SYMPPT /34 RECPT, at a median follow-up of 55 months. No significant differences were found between SYMPPT/RECPT for gender, age, tumor grade/site, shunt, residual disease, radiation boost, type of relapse (local/distant/combined). Time-to-relapse (median:19 months, range 5–104) and treatment adoption did not differ between SYMPPT/RECPT while signs/symptoms depicted an unfavorable factor for OS after relapse (5-year OS: 8% vs 37%). Adjusted model in multivariate analysis confirmed that presence of signs/symptoms was prognostically unfavorable. In order to improve the OS in symptomatic patients, their early identification-in the first two/three years after diagnosis- would be desirable. Perhaps, this could be obtained paying attention to “heuristically detected” subgroup of patients, not just describing general prognostic variables but discovering possible biology differences according to signs/symptoms.

e22508 Background: Advanced OS still represents an unmet medical need. Chemotherapy and targeted therapies have only limited activity in this disease. Moreover, OS is considered a radioresistant tumor at doses conventionally achieved by EBRT. We retrospectively evaluated the impact of palliative EBRT in patients (pts) with advanced OS. Methods: Main inclusion criteria: confirmed histological diagnosis of OS; EBRT for advanced/metastatic disease deemed unresectable after multidisciplinary tumor board discussion; ECOG performance status ≤3, age ≥18 years at RT start; progressive disease at site of irradiation with symptoms (e.g., pain or neurological deficit) or involving critical structures (e.g., superior vena cava compression). Endpoints: progression-free survival (PFS), PFS for RT-treated lesions (RT-PFS), best response with RT, overall survival. All survival endpoints were computed from RT start. We calculated the equivalent total dose in 2 Gy fractions (EQD2). Results: 23 pts, 15 males, median age at diagnosis 33 (17-82), median age at RT start 36 (20-83) were included. All pts had grade 3-4 OS (12 osteoblastic; 6 chondroblastic; 5 other), 7 were metastatic at diagnosis. At time of RT, median metastatic sites were 2 (1-5), 15 pts were symptomatic (11 pain, 4 neurological deficit) and were mainly heavily pretreated [median previous chemotherapies 2 (1-5), median previous surgery 1 (0-2)]. Overall, 45 lesions underwent EBRT. Median EBRT dose per lesion was 33 Gy (IQR 25 - 46.5) with a median dose per fraction of 3 Gy (IQR 3-7.5). Calculated median EQD2 was 50 Gy (IQR 36 - 88). Median PFS, RT-PFS, and overall survival were 5 (95%CI 2-9), 11 (5-15), and 12 months (8-16), respectively. Compared to systemic progression, median progression delay of irradiated lesions was 6 months (95%CI 2 - 12). In 40 lesions evaluable for dimensional response, we observed tumor shrinkage > 30% in 7 lesions, stability in 24, and progression in 9. Conclusions: EBRT might have a role in the treatment of advanced OS. In consideration of the limited activity of medical treatments, EBRT might help in disease control in the advanced setting, delaying progression especially at critical sites.

EPN-02. FINAL RESULTS OF THE 2ND AIEOP PROTOCOL FOR INTRACRANIAL EPENDYMOMA (EPD) Maura Massimino1, Rosalba Miceli1, Felice Giangaspero2,3, Luna Boschetti1, Paolo Ferroli4, Paola Peretta5, Emilia Pecori1, Laura Valentini4, Veronica Biassoni1, Maria Luisa Garre6, Elisabetta Schiavello1, Iacopo Sardi7, Armando Cama6, Silvia Scoccianti8, Maurizio Mascarin9, Lorenzo Genitori7, Daniele Bertin5, Anna Mussano10, Elisabetta Viscardi11, Piergiorgio Modena12, GiuseppinaCalareso1, Salvina Barra13, Giovanni Scarzello14, LuciaQuaglietta15, Giuseppe Cinalli15, Angela Mastronuzzi16, Carlo Giussani17, Carlo Marras16, Rita Balter18, Patrizia Bertolini19, Ermanno Giombelli19, Francesca Buttarelli2, Manila Antonelli2, and Lorenza Gandola1; Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; Universita Sapienza Roma, Roma, Italy; Neuromed Pozzilli, Pozzilli, Italy; Fond IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Ospedale Infantile Regina Margherita, Torino, Italy; Istituto Giannina Gaslini, Genova, Italy; Ospedale Pediatrico Meyer, Firenze, Italy; OspedaleCareggi,Firenze, Italy;CRO,Aviano, Italy;OspedaleS.Anna, Torino, Italy; Clinica di Oncoematologia Pediatrica, Padova, Italy; Genetica, Osp S. Anna, Como, Italy; Istituto dei Tumori, Genova, Italy; Istituto Oncologico del Veneto, Padova, Italy; Ospedale Pausillipon, Napoli, Italy; Ospedale Bambino Gesu, Roma, Italy; Ospedale S. Gerardo, Monza, Italy; Ospedale Borgo Roma, Verona, Italy; Ospedale, Parma, Italy This study stratified patients after surgical resection (complete 1⁄4 NED vs incomplete 1⁄4 ED) and centrally reviewed histology(gr.2 vs gr. 3). Gr2 tumors/NEDpts were focally irradiated with a 3D-conformal technique 1.8Gy/d up to 59.4 Gy, gr3/NED received also 4 VEC(Cyclo,VP16,VCR) after irradiation. EDpts received 1-4 VEC, second-look surgery whenever possible,59.4 Gy followed by 8 Gy boost into 2 fractions on still measurable residue. Children aged 1-3 yrs received the same treatment but for those gr2/NED who could receive only 6 VEC. Between January 2002/December 2014, 160 consecutive children, median age 4.9 years, entered the protocol; follow-up was a median 67 months. M/F was 100/60, infratentorial origin in 110(2 plus metastasis). After surgery, NEDpts were 110,grade 3 was assessed in 84. 100 resections were performed in 46/160 children with another 12 rendered NED after first excision,10 after 1-4 VEC,2 after radiation. Boost was applied to 24/40 still ED patients after surgery/ies and VEC obtaining PFS/OS of 58.1%/68.7% in this severe prognosis subgroup. For the whole series,5-year PFS/OS were 65.4%/81.1% with no toxic deaths. In univariable analysis, female gender, supratentorial origin, NED status before RT, grade 2, shunt absence were favourable for OS, in multivariable NED status and grade 2 were. For PFS, female gender, NED status before RT, grade 2 were significant in univariable, only grade in multivariable. In a multicentric collaboration this trial accrued the highest patient number so far published with comparable results to best monoinstitutional series. Radiation boost was feasible and efficacious in improving local control. Complete surgery, also through multiple excisions, still confirmed its prognostic strength as well as grade. Further biological parameter definition on this series will be the object of next coming studies. Neuro-Oncology 18:iii30–iii39, 2016. doi:10.1093/neuonc/now070.2 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Background This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). Methods WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. Results From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. Conclusions In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports.

The specific goal of this retrospective study is to evaluate the role of total skin electron beam therapy (TSEBT) in the treatment of Mycosis Fungoides (MF) and to assess the most significant prognostic factors in univariate and multivariate analyses.From January 1985 to December 1999, 92 TSEBT (Stanford Standing technique) were performed on a total of 86 patients (63 with Mycosis Fungoides, 6 with Sezary Syndrome and 17 with Cutaneous Lymphomas). This study considers only the Mycosis Fungoides group, which consisted of 60 cases evaluable for response, survival and toxicity. The distribution of patients by stage (MFCG Staging Classification, 1991) was 21, 5, 12, 22 for stages I, II, III and IV, respectively.The overall response rate was 96.6% (58/60) with complete response (CR) in 50/60 patients (83.3%) and partial response (PR) in 8 cases (13.3%). The five-year and ten-year actuarial overall survival (OS) was 50% and 45%, respectively. Local control, intended as control of the disease in the skin, was 35% at five years and 20% at ten years, and was correlated with skin involvement. The prognostic factors confirmed by the multivariate analysis for both overall survival and local control were: T (p0.001) and response after TSEBT (p0.001). The treatment was very well tolerated.Our study showed good results in terms of response and survival with a long follow-up time (mean value 40 months). We confirm that TSEBT yields very good results in early-stage MF; additional trials of combined modality and investigational therapies are needed to improve the outcome for advanced-stage disease.