Pre-radiation chemotherapy improves survival in pediatric diffuse intrinsic pontine gliomas

Gokce-Samar, Z; Beuriat, P.A.; Faure‐Conter, Cécile; Carrié, C.; Chabaud, Sylvie; Claude, L.; Rocco, F. Di; Mottolèse, C.; Alexandru, Szathmari; Chabert, Charles; Frappaz, Didier

doi:10.1007/s00381-016-3153-8

Cited by 18 publications

(5 citation statements)

References 40 publications

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“…Wagner et al reported a moderately better median PFS in patients with DIPG treated with adjuvant chemotherapy after RT compared with patients treated with RT alone (11.3 months versus 9.5 months) [ 71 ], but no significant improvements in OS. Similar results were reported in other randomized trials [ 72 , 73 ].…”

Section: Current Treatmentssupporting

confidence: 91%

Pediatric Diffuse Midline Gliomas: An Unfinished Puzzle

et al. 2022

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Diffuse midline glioma (DMG) is a heterogeneous group of aggressive pediatric brain tumors with a fatal prognosis. The biological hallmark in the major part of the cases is H3K27 alteration. Prognosis remains poor, with median survival ranging from 9 to 12 months from diagnosis. Clinical and radiological prognostic factors only partially change the progression-free survival but they do not improve the overall survival. Despite efforts, there is currently no curative therapy for DMG. Radiotherapy remains the standard treatment with only transitory benefits. No chemotherapeutic regimens were found to significantly improve the prognosis. In the new era of a deeper integration between histological and molecular findings, potential new approaches are currently under investigation. The entire international scientific community is trying to target DMG on different aspects. The therapeutic strategies involve targeting epigenetic alterations, such as methylation and acetylation status, as well as identifying new molecular pathways that regulate oncogenic proliferation; immunotherapy approaches too are an interesting point of research in the oncology field, and the possibility of driving the immune system against tumor cells has currently been evaluated in several clinical trials, with promising preliminary results. Moreover, thanks to nanotechnology amelioration, the development of innovative delivery approaches to overcross a hostile tumor microenvironment and an almost intact blood–brain barrier could potentially change tumor responses to different treatments. In this review, we provide a comprehensive overview of available and potential new treatments that are worldwide under investigation, with the intent that patient- and tumor-specific treatment could change the biological inauspicious history of this disease.

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Section: Current Treatmentssupporting

confidence: 91%

Pediatric Diffuse Midline Gliomas: An Unfinished Puzzle

et al. 2022

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“…Despite improvements in diagnostic accuracy and multimodal treatments, prognosis for patients with DIPG remains dismal with a median survival of around 1 year. 3 , 4 …”

Section: Introductionmentioning

confidence: 99%

Multi-focal sequencing of a diffuse intrinsic pontine glioma establishes PTEN loss as an early event

et al. 2017

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Improved molecular understanding is needed for rational treatment of diffuse intrinsic pontine gliomas (DIPG). Here, using multi-focal paired tumor and germline exome DNA and RNA sequencing, we uncovered phosphatase and tensin homolog (PTEN) loss as a clonal mutation in the case of a 6-year-old boy with a diffuse intrinsic pontine glioma, and incorporated copy number alteration analyses to provide a more detailed understanding of clonal evolution in diffuse intrinsic pontine gliomas. As well, using the PedcBioPortal, we found alterations in PTEN in 16 of 326 (4.9%) cases of pediatric high-grade glioma (3 of 154 (1.9%) brainstem) for which full sequencing data was available. Our data strengthens the association with PTEN loss in diffuse intrinsic pontine gliomas and provides further argument for the inclusion of PTEN in future targeted sequencing panels for pediatric diffuse intrinsic pontine gliomas and for the development and optimization of mTOR/PI3K inhibitors with optimal central nervous system penetration.

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“…To date, focal irradiation therapy remains the mainstay of therapy for H3K27M glioma, resulting in improved overall survival rates (11). Although additional systemic therapy is generally considered as beneficial (7,12), no therapy regimen has yet been shown to exert superior effects (11,(13)(14)(15). Consequently, novel, improved therapeutic strategies for H3K27M glioma are needed.…”

Section: Introductionmentioning

confidence: 99%

“…Treatment with vinorelbine in combination with nimotuzumab, an antibody directed against EGFR, for example, has been shown to prolong survival, resulting in a median overall survival of 15 months (13). However, other studies with either EGFR-directed small molecules (gefitinib, erlotinib) or antibodies could not confirm this effect for all DMGs but showed individual cases of longer survival (7,15,(22)(23)(24). Similarly, also therapy with dasatinib and crizotinib, two small-molecule PDGFRA inhibitors, has not shown overall survival benefit (25).…”

Section: Introductionmentioning

confidence: 99%

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities

et al. 2020

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Diffuse gliomas with K27M histone mutations (H3K27M glioma) are generally characterized by a fatal prognosis, particularly affecting the pediatric population. Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either Gojo et al.Personalized Treatment of H3K27M Glioma miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma.

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Pre-radiation chemotherapy improves survival in pediatric diffuse intrinsic pontine gliomas

Abstract: The present study confirms that the BSG 98 protocol is one of the most effective current treatment strategies for DIPG. It may be used as the control arm in randomized trials investigating the use of innovative treatments and may be proposed to families who are averse to biopsy.

Cited by 18 publications

References 40 publications

Pediatric Diffuse Midline Gliomas: An Unfinished Puzzle

Pediatric Diffuse Midline Gliomas: An Unfinished Puzzle

Multi-focal sequencing of a diffuse intrinsic pontine glioma establishes PTEN loss as an early event

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities

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