Repeat irradiation for children with supratentorial high‐grade glioma

Tsang, Derek S.; Oliveira, Carol; Bouffet, Éric; Hawkins, Cynthia; Ramaswamy, Vijay; Yee, Ryan; Tabori, Uri; Bartels, Ute; Huang, Annie; Millar, B; Crooks, Bruce; Bowes, Lynette; Zelcer, Shayna; Laperrière, Normand

doi:10.1002/pbc.27881

Cited by 20 publications

(12 citation statements)

References 26 publications

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“…though this is changing as recent studies demonstrate superior median survival times from re-irradiation which was welltolerated in pHGG (110); re-irradiation is currently being trialled for progressive or recurrent DIPG (111). Studies are investigating combination of immunotherapies such as PD-1 immune checkpoint inhibitors with re-irradiation (112).…”

Section: Neurocognitivementioning

confidence: 99%

Molecular Genetics and Targeted Therapies for Paediatric High-grade Glioma

Rallis

George

Woźniak

et al. 2022

Cancer Genomics Proteomics

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Brain tumours are the leading cause of paediatric cancer-associated death worldwide. High-grade glioma (HGG) represents a main cause of paediatric brain tumours and is associated with poor prognosis despite surgical and chemoradiotherapeutic advances. The molecular genetics of paediatric HGG (pHGG) are distinct from those in adults, and therefore, adult clinical trial data cannot be extrapolated to children. Compared to adult HGG, pHGG is characterised by more frequent mutations in PDGFRA, TP53 and recurrent K27M and G34R/V mutations on histone H3. Ongoing trials are investigating novel targeted therapies in pHGG. Promising results have been achieved with BRAF/MEK and PI3K/mTOR inhibitors. Combination of PI3K/mTOR, EGFR, CDK4/6, and HDAC inhibitors are potentially viable options. Inhibitors targeting the UPS proteosome, ADAM10/17, IDO, and XPO1 are more novel and are being investigated in early-phase trials. Despite preclinical and clinical trials holding promise for the discovery of effective pHGG treatments, several issues persist. Inadequate blood-brain barrier penetration, unfavourable pharmacokinetics, dose-limiting toxicities, long-term adverse effects in the developing child, and short-lived duration of response due to relapse and resistance highlight the need for further improvement. Future pHGG management will largely depend on selecting combination therapies which work synergistically based on a sound knowledge of the underlying molecular target pathways. A systematic investigation of multimodal therapy with chemoradiotherapy, surgery, target agents and immunotherapy is paramount. This review provides a comprehensive overview of pHGG focusing on molecular genetics and novel targeted therapies. The diagnostics, genetic discrepancies with adults and their clinical implications, as well as conventional treatment approaches are discussed.Intracranial and intraspinal tumours are the most common solid tumours in paediatrics (1). They are the second leading cause of cancer-associated death in children and adolescents under the age of 19 in the USA and Canada (1), with an average annual age-adjusted incidence of 6.06 per 100,000 in the USA between 2012 and 2016 (2). Brain tumours are now the leading cause of paediatric-cancer-associated death worldwide, surpassing deaths from childhood leukaemia (3). Gliomas represent the highest proportion of childhood brain tumours (4, 5) accounting for 60% of paediatric brain tumour cases (5, 6), of which approximately half are classified as high grade (6, 7).

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Section: Neurocognitivementioning

confidence: 99%

Molecular Genetics and Targeted Therapies for Paediatric High-grade Glioma

Rallis

George

Woźniak

et al. 2022

Cancer Genomics Proteomics

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“…A marginal relapse occurred in 7/21 cases (33.3%) plus another with also a concomitant distant relapse. Marginal relapse was reported without a precise de nition in 50% of cases in the German series [19] while it was described in only 9.3% in the St. Jude's series [7] and not reported in the Canadian one [20]. Marginal relapses after re-RT were seen again in 3/12 locally relapsing patients of our series (Fig.…”

Section: Discussionmentioning

confidence: 49%

How ten-years of reirradiation for paediatric high-grade glioma can shed light on first line treatment

Massimino

Vennarini

Barretta

et al. 2022

Preprint

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Purpose. Recurrence incidence for paediatric/adolescent high-grade glioma(HGG) exceeds 80%. Reirradiation(reRT) palliates symptoms and delays further progression. Strategies for reRT are scarce: we retrospectively analysed our series to develop rational future approaches.Methods. We re-evaluated MRI+RT plans of 21 relapsed HGG-patients, accrued 2010-2021, aged under 18 years. All underwent surgery and RT+chemotherapy at diagnosis. Pathologic/molecular re-evaluation allowed classification based on WHO 2021 criteria in 20/21 patients. Survival analyses and association with clinical parameters were performed. Results. Relapse after 1st RT was local in 12(7 marginal), 4 disseminated, 5 local+disseminated. Re-RT obtained 8 SD, 1 PR, 1PsPD, 1 mixed response, 10 PD; neurological signs/symptoms improved in 8. Local reRT was given to 12, followed again by 6 local(2 marginal) and 4 local+disseminated second relapses in 10/12 re-evaluated. The 4 with dissemination had 1 whole brain, 2 craniospinal irradiation(CSI), 1 spine reRT and further relapsed with dissemination and local+dissemination in 3/four assessed. Five local+disseminated tumours had 3 CSI, 1 spine reRT, further progressing locally(2), disseminated(1), n.a.(1). Three had a third RT; three were alive at 19.4, 29, 50.3 months after diagnosis. Median times to progression/survival after re-RT were 3.7 months (0.6-16.2 months)/6.9 months (0.6-17.9 months), improved for longer interval r between 1st RT and re-RT(P=0.017) and for non-PD after reRT(P< 0.001). First marginal relapse showed potential association with dissemination after re-RT(P= 0.081) Conclusions. This is the biggest series of re-RT in paediatric HGG. Considering the dissemination relapse incidence observed, our results could prompt the investigation of first RT fields in a randomized trial.

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“…18 Re-irradiation with 30-54 Gy led to clinical and survival improvement in pHGG patients including DIPG, especially when the interval between the rst and second irradiation was longer than one year. 8, 19,20,24,25 Although the role of craniospinal irradiation in disseminated disease remains unclear and haematological toxicity has to be expected, its feasibility has been reported. 26 In the present survey, two thirds of experts recommended CSI (preferably after deferral through chemotherapy) in a young child with disseminated spinal cord infant HGG.…”

Section: Discussionmentioning

confidence: 99%

“…1,2,[6][7][8]10,[12][13][14][15][16][17] Recurrent/progressing pHGG are virtually incurable, thus usually indicating a palliative treatment situation: Despite multiple efforts and trials investigating new therapeutic approaches, median survival following recurrence is a few months, and there is no established standard of care regimen since many centres pursue a different strategy, most patients undergoing multimodality treatment with very limited success. [18][19][20] Hence, the present Europe-wide online survey study was set up to collect different views and concepts on treatment options and goals in children and adolescents with recurrent/progressing HGG in representative real-world treatment situations. As the target group of respondents, clinicians with distinct experience in paediatric neuro-oncology were chosen.…”

Section: Introductionmentioning

confidence: 99%

How I treat recurrent paediatric high-grade glioma (pHGG): A Europe-wide survey study

Perwein

Giese

Nussbaumer

et al. 2022

Preprint

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BACKGROUND: As there is no standard of care treatment for recurrent/progressing paediatric high-grade gliomas (pHGG), we aimed to gain an overview of different treatment strategies. METHODS: In a web-based questionnaire, members of the SIOPE-BTG and the GPOH were surveyed on therapeutic options in four case scenarios (children/adolescents with recurrent/progressing HGG).RESULTS: Most respondents (139 clinicians from 22 European countries) preferred further oncological treatment in three out of four cases and chose palliative care in one case with marked symptoms. Depending on the case, 8-92% would initiate a re-resection (preferably hemispheric pHGG), combined with molecular diagnostics. Throughout all case scenarios, 55-77% recommended (re-)irradiation, preferably local radiotherapy >20 Gy, and most respondents would participate in clinical trials and use targeted therapy (79-99%), depending on molecular genetic findings (BRAF alterations: BRAF/MEK inhibitor, 64-88%; EGFR overexpression: anti-EGFR treatment, 46%; CDKN2A deletion: CDK inhibitor, 18%; SMARCB1 deletion: EZH2 inhibitor, 12%). 31-72% would administer chemotherapy (CCNU, 17%; PCV, 8%; temozolomide, 19%; oral etoposide/trofosfamide, 8%), and 20-69% advocated immunotherapy (checkpoint inhibitors, 30%; tumour vaccines, 16%). Depending on the individual case, respondents would also include bevacizumab (6-18%), HDAC inhibitors (4-15%), tumour-treating fields (1-26%), and intraventricular chemotherapy (4-24%). CONCLUSIONS: In each case, experts would combine conventional multimodal treatment concepts, including reirradiation, with targeted therapy based on molecular genetic findings. International cooperative trials combining a (chemo-)therapy backbone with targeted therapy approaches for defined subgroups may help to gain valid clinical data and improve treatment in paediatric patients with recurrent/progressing HGG.

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Repeat irradiation for children with supratentorial high‐grade glioma

Cited by 20 publications

References 26 publications

Molecular Genetics and Targeted Therapies for Paediatric High-grade Glioma

Molecular Genetics and Targeted Therapies for Paediatric High-grade Glioma

How ten-years of reirradiation for paediatric high-grade glioma can shed light on first line treatment

How I treat recurrent paediatric high-grade glioma (pHGG): A Europe-wide survey study

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