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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.

BACKGROUND: The purposes of this trial were to evaluate the feasibility, response, PFS/OS of a randomized study comparing two different RT schedules for DIPG while administering the same systemic treatment. METHODS: Patients: 2-21 years-old with a not-pretreated radiologically verified DIPG (MRI blindly reviewed at diagnosis and every 12 weeks thereafter) and symptoms duration below 6 months. Biopsy was required if suggested by atypical imaging. Vinorelbine 20 mg/m2+nimotuzumab 150 mg/m2 were administered weekly for 12 weeks; thereafter every other week until tumor progression or for up to 2 years. Standard(ST) arm included focal RT at total dose of 54Gy (1.8Gy/day); for local progression re-irradiation was proposed at 19.8Gy, in case of dissemination craniospinal irradiation(CSI) at 36Gy was adopted. Experimental(SP) arm included three elective courses of RT at defined timepoints at 36Gy, 19.8Gy and 19.8Gy with possible reirradiation for relapse at 9 Gy. Incidences of local(L) and distant(D) progression were assessed in a competing risk setting. RESULTS: Aggregated preliminary results are given for 4 Italian centers. 54 pts were screened and 51 included, 27 in ST, 28 males, median age 7 years (range 3-17). Median time of observation was 17.9 months. Twelve patients needed a shunt, 10 during treatment; 20 were biopsied, in 18 cases according local protocols. 19/20 tumors had H3.3 K27 mutation. 41 relapsed, 28 locally, 13 with a component of dissemination. 36 died, one for tracheotomy bleeding. SP irradiation was feasible and never produced significant radionecrosis. Median EFS/OS were 7.3/12.9 months, respectively; EFS/OS at 1 year were 19.0%/57.3%, not differing between patients with local vs. disseminated relapses. Patients submitted to biopsies had more dissemination (P=0.04) and less local progression (P=0.077). CONCLUSIONS: Treatment was feasible and OS confirmed previous results obtained in a single center. Randomization results will be later reported.