P04.05.B ADJUVANT DOXORUBICIN AS ADD-ON THERAPY IN PEDIATRIC MALIGNANT GLIOMAS: A SINGLE-ARM OPEN-LABEL PHASE 2 INTERVENTIONAL STUDY
Authors: Tellini M , Castelli B , Fonte C , Guidi M , Giunti L , Di Nicola M , Buccoliero A M , Caporalini C , Giordano F , Desideri I , Greto D , Tortora K , Pugi A , Genitori L , Sardi I 
Published: September 2023

Abstract

BACKGROUND
Pediatric high grade gliomas (pHGGs) are leading causes of tumor related death in pediatric age. Beyond surgical and radiotherapy backbone treatment, chemotherapy regimen is a fundamental part of the therapeutic strategy, but its standardization and benefits are still disputed. Recent advances in molecular understanding are promising, nevertheless prognosis remains dismal. After proof-of-concept in vitro and in vivo assays to explore HGG cell lines sensibility to anthracyclines, we aim to introduce doxorubicin (DOX) as add-on therapy to the standard of care.

MATERIAL AND METHODS
Pediatric patients with newly diagnosed, histologically confirmed HGG were randomly assigned to receive radiotherapy plus concomitant and adjuvant temozolomide and valproic acid (as Weller-Stupp 2011 treatment) with or without doxorubicin (DOX) in a monocentric single-arm open-label phase II interventional study. We opted for a 96-hours continuous infusion DOX schedule (25 mg per square meter of body-surface area per day). We initially administered 3 DOX courses during standard radio-chemiotherapy regimen, then reduced to 1 course after 8 weeks from the end of radiotherapy due to an increasing heamatologic toxicities after the third course. The primary end point was safety and tolerability of experimental treatment, the secondary end point was clinical outcome.

RESULTS
From February 2016 to January 2020, 21 patients underwent randomization. 7 (33.3%) patients were affected by glioblastoma, 10 (47,6%) by diffuse intrinsic pontine glioma, 4 (19%) by anaplastic astrocytoma. All patients were Caucasian, 42.9% were females and the mean age was 10 years. 12 patients were treated with doxorubicin (DOX group), whom 2 patients received three doxorubicin (DOX) courses and 10 a single DOX course. 19 of 21 (90.5%) presented at least one serious adverse event (SAEs). 6 of 12 (50%) patients exposed to DOX group had clinically relevant toxic effects related to DOX, mainly as cytopenias, mucositis and febrile neutropenia. After the switch to a 1 DOX course outline the treatment showed a more tolerable toxicity profile. No patients had suspected unexpected serious adverse reactions (SUSAR), early DOX-treatment interruption or death related to DOX. All study withdrawals were related to disease progression and not to investigational drug side effects. 18/21 (85.7%) patients showed disease progression. Among DOX-group, 1 patient show complete remission and 2 showed stable disease. DOX-group show a longer progression free survival (EFS) compared to control group, although this trend was not statistically significative.

CONCLUSION
Adjuvant doxorubicin as add-on therapy to the standard of care treatment of pHGGs is a safe and tolerable option. We need further investigations to optimize the timing and dosing of doxorubicin and to verify the effects on clinical outcome. SAEs must be carefully evaluated.