Tumour Review Diffuse intrinsic pontine gliomas: A systematic update on clinical trials and biology M.H.A. Jansen a,c,⇑ , D.G. van Vuurden a,c,1 , W.P. Vandertop b,c,2 , G.J.L. Kaspers a,c,3 a Department of Pediatrics, Division of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands b Neurosurgical Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands c Neuro-Oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands article info Article history: Received 9 February 2011 Received in revised form 17 May 2011 Accepted 25 June 2011 Keywords: Brain stem Molecular targeted therapy Pontine tumors Pontine glioma Glioma abstract Patients with diffuse intrinsic pontine gliomas (DIPG) have a poor prognosis. Although DIPG constitute only 10–15% of all pediatric brain tumors, they are the main cause of death in this group. Despite 26 clin- ical trials in newly diagnosed DIPG in the past 5 years (including several targeted agents), there is no clear improvement in prognosis. However, knowledge on DIPG biology is increasing, mainly due to the (re)introduction of biopsies and autopsies, the possibility of gene expression profiling, and the develop- ment of in vivo models. Translation of this knowledge into clinical trials in combination with improved drug distribution methods may eventually lead to more effective treatment of this devastating disease. Ó 2011 Elsevier Ltd. All rights reserved. Background Effective treatment of diffuse intrinsic pontine gliomas (DIPG) in children remains elusive. DIPG comprise 10–15% of childhood brain tumors but are the main cause of death in this young group. Despite several treatment regimens being studied over the last 25 years, prognosis has not improved and <10% of patients are alive two years after diagnosis. 1 In 2006, Hargrave et al. reviewed all clinical studies performed in DIPG patients from 1984 to 2005: 29 studies were reported including a total of 973 patients. 1 Most studies were non-random- ized and comparison was difficult due to unclearly defined inclu- sion criteria. In these studies, the median overall survival (OS) ranged from 7–16 months; when only studies with detailed clini- cal and radiological eligibility criteria were included, the median OS ranged from 8–11 months with a progression-free survival (PFS) of 5–9 months. The use of hyperfractionated radiotherapy, pre-irradiation chemotherapy, concurrent chemo-radiotherapy and radiosensitizers has not increased long-term OS. In addition, adjuvant chemotherapy and high-dose chemotherapy regimens have also failed to improve long-term prognosis. Historically, DIPG were diagnosed radiologically and biopsies were not performed due to perceived morbidity. 2 This was later shown to be overestimated and biopsies are now more widely practiced. 3–5 Biopsies, together with autopsy material, have paved the way for biological studies in DIPG. Studies published in the past five years will probably be the basis for a more rational drug treat- ment of these tumors. The present study is an update on the clinical trials (including recently completed and ongoing studies) and presents current knowledge on DIPG biology with regard to potential future tar- geted therapy. Methods A search was made in PubMed, the Cochrane Central Register of Controlled Trials and Embase covering the period from 1 January 2005 until 1 March 2011. The following terms were used (with synonyms and closely related words): ‘‘brain stem’’ and ‘‘gliomas’’ or ‘‘tumors’’ and ‘‘RCT’s’’ or ‘‘reviews’’ or ‘‘meta-analyses’’ or ‘‘sys- tematic reviews’’ and ‘‘children’’. Two reviewers (MJ and GJK) inde- pendently screened the references for eligible articles by reading 0305-7372/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2011.06.007 Abbreviations: CNS, central nervous system; DIPG, diffuse intrinsic pontine gliomas; EGFR, epidermal growth factor receptor; HGG, high-grade glioma; ITH, intratumoral hemorrhage; IV, intravenous; MTD, maximum tolerated dose; OS, overall survival; PDGFR, platelet-derived growth factor receptor; PFS, progression- free survival; PO, orally; VEGFR, vascular endothelial growth factor receptor. ⇑ Corresponding author. Address: Department of Pediatrics, Division of Oncology/ Hematology, VU University Medical Center, Room PK 4x027, De Boelelaan 1118, 1007MB Amsterdam, The Netherlands. Tel.: +31 20 4446201; fax: +31 20 4442422. E-mail addresses: mh.jansen@vumc.nl (M.H.A. Jansen), dg.vanvuurden@vumc.nl (D.G. van Vuurden), wp.vandertop@vumc.nl (W.P. Vandertop), gjl.kaspers@vumc.nl (G.J.L. Kaspers). 1 Tel.: +31 20 44 42420x7212; fax: +31 20 44 42422. 2 Tel.: +31 20 44 43725; fax: +31 20 44 43784. 3 Tel.: +31 20 44 42420; fax: +31 20 44 42422. Cancer Treatment Reviews 38 (2012) 27–35 Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv