Carbon ion reirradiaton for patients with malignant gliomas: Toxicity and first results of the prospective dose-escalation phase I/II CINDERELLA trial.

Abstract

2059 Background: The prospective phase I/II CINDERELLA trial investigates toxicity and effectiveness of a dose escalated reirradiation with carbon ions in patients with recurrent gliomas. Methods: Following a dose escalating protocol, 52 patients with WHO°II-IV gliomas were irradiated with carbon ions with doses of 3 Gy (RBE) in 10 – 16 fractions in 7 dose leels. Median age was 42 years (range: 28 - 69) with 19 female and 33 male participants. Forty-one patients were diagnosed with WHO°III/IV gliomas and 11 patients with WHO°II gliomas. At the time of reirradiation, all patients showed contrast-enhancing recurrences. MRI-based treatment planning encompassed the contrast enhancing lesion (GTV) with additional safety margins of 5 mm (CTV) and 3 mm (PTV). Clinical follow-up visits including contrast-enhanced MRI were scheduled every two months. We used RANO-criteria for diagnosis of progression. Survival rates were analyzed with Kaplan-Meier estimator. Relevant prognostic factors were determined with log rank-test, and toxicity was classified according to CTCAE v4.0. Results: Median time between first irradiation and reirradiation was 9 months (range: 7 – 228). PTV size was 12 – 310 ml. During follow-up ≥°3 toxicities were not observed. Follow-up MRI suggested radiation necrosis in 4 patients. Median overall survival was 352 days and was not influenced by age, gender or radiation dose. A significant trend for improved survival rates was seen in patients with small target volumes (480 days [PTV < 75ml] vs. 322 days [PTV > 75ml], p = 0.06) and initial low grade histology (497 days [WHO °II] vs. 322 days [WHO°III/IV], p = 0.069). During follow-up, 45 patients had local progression, while clinical deterioration was not seen. Median local progression-free survival was 138 days. Twenty-eight patients received chemo-/immunotherapy after reirradiation. Of those, 14 patients were treated with bevacizumab. Progression after reirradiation did not influence overall survival significantly. Conclusions: Carbon ion re-irradiation with 10-16 fractions of 3 Gy for patients with recurrent gliomas is safe; no dose limiting toxicities were observed. Median overall survival with approximately one year is high in comparison to other treatment options. It remains unclear if RANO-criteria is securing the diagnosis of therapy failure after carbon ion reirradiation. Further randomized controlled trials must be awaited to evaluate the effectiveness of reirradiation of carbon ions compared to other treatment options. Clinical trial information: NCT01166308.