Craniospinal irradiation as part of re-irradiation for children with recurrent medulloblastoma.

BACKGROUND: Many studies have demonstrated in the last years that once medulloblastoma has recurred, the probability of regaining tumor control is poor despite salvage therapy. Although re-irradiation has an emerging role in other relapsed brain tumors, there is a lack of strong data on re-irradiation for medulloblastoma. METHODS: This is a retrospective cohort study of patients aged 18 years or under, treated at least by a second course of external beam for recurrence medulloblastoma at Garrahan Hospital between 2009 and 2020. Twenty-four patients met eligibility criteria for inclusion. All patients received upfront radiotherapy as part of the curative-intent first radiotherapy, either craniospinal irradiation (CSI) followed by posterior fossa boost in 20 patients or focal posterior fossa radiation in 4 infants. The second course of radiation consisted of CSI in 15 and focal in 9. The 3-year post first failure OS (50% vs. 0%; p = 0.0010) was significantly better for children who received re-CSI compared to children who received focal re-irradiation. Similarly, the 3-year post-re-RT PFS (31% vs. 0%; p = 0.0005) and OS (25% vs. 0%; p = 0.0003) was significantly improved for patients who received re-CSI compared to patients who received focal re-irradiation. No symptomatic intratumoral haemorrhagic events or symptomatic radionecrosis were observed. Survivors fell within mild to moderate intellectual disability range, with a median IQ at last assessment of 58 (range 43-69). CONCLUSIONS: Re-irradiation with CSI is a safe and effective treatment for children with relapsed medulloblastoma; improves disease control and survival compared with focal re-irradiation. However this approach carries a high neurocognitive cost.

Intracranial germ cells tumour: a single institution experience in Argentina.

BACKGROUND: Intracranial germ cell tumor (iGCT) represents a rare and heterogeneous group, with variable incidence and diverse treatment strategies. Although multiagent chemotherapy with reduced radiotherapy strategy has been applied by several cooperative groups in North America and Western Europe, there is a paucity of data to understand if this combined regimen is suitable in low-middle income countries (LMIC). METHODS: We evaluate the outcome in a cohort of iGCT treated by SIOP-CNS-GCT-96 strategy at hospital J.P Garrahan in Argentina over the last 20 years. Radiation field and dose included focal radiotherapy (FRT) before 2009 or focal radiotherapy plus whole ventricular radiotherapy (WVRT) after 2009 for localized germinoma and FRT or FRT plus WVRT or CSI for non germinomatous germ cell tumors (NGGCT) RESULTS: Sixty iGCT were identified; 39 germinoma and 21 NGGCT. Median follow-up was 6.57 years (range 0.13-20.5). 5-year PFS and OS were 83.5% (95% CI [165.53-223.2]) and 88.7% (95% CI [169.84-223.2]) for the germinoma group, while for the NGGCT group were 75% (95% CI [133.27-219.96]) and 64.2% (95% CI [107.38-201.81]) respectively. The localized germinoma group showed poor results between 2000 and 2009 with 5-year PFS and OS of 69 and 75% respectively, and an excellent outcome between 2010 and 2019 with a 5-years PFS and OS of 92.8 and 100%. A univariable analysis identified this difference in survival as related to the field of radiotherapy, specifically whole ventricular radiotherapy. FRT increased the risk of recurrence in localized germinoma, involving not only ventricular relapses; but spinal cord and disseminated disease as well. There were no relapses of localized NGGCT after FRT and FRT plus WVRT. CONCLUSION: Herein we demonstrate that intensive chemotherapy followed by FRT plus WVRT for germinoma is a feasible and effective strategy, warranting further study in the developing world.

[Targeted therapies with BRAF inhibitors for pediatric low- and high-grade gliomas with BRAFv600e mutation. Prof. Dr. Juan P. Garrahan Hospital experience]. / Terapias dirigidas con inhibidores del BRAF en gliomas pediátricos de alto y bajo grado con la mutación BRAFV600E. Experiencia del Hospital Prof. Dr. Juan P. Garrahan.

The BRAFV600E point mutation plays a key role in the tumorigenesis of many gliomas. Inhibiting its product is part of the innovative therapies emerging in recent years. Knowing the role of these treatments is essential. The aim of this experience was to describe the clinical-radiological response of pediatric BRAFV600E mutated gliomas treated with BRAF inhibitors. To this end, a descriptive and retrospective study was performed in patients under 16 years of age with BRAFV600E gliomas, who received vemurafenib or dabrafenib at Hospital Garrahan. Thirteen patients treated in the last 7 years were included: 9 were low-grade and 4 high-grade gliomas. The median age at diagnosis was 8.6 years (0.89-14.04) and at start of targeted therapy was 11.62 years (3.64-15.42). All patients had previously a surgical procedure, and 12/13 had received another therapy prior BRAF inhibition: 11 chemotherapy (in one case, up to 4 different protocols) and 4 radiotherapy. Under targeted therapy, tumour response was obtained in 10 patients (size reduction equal to or greater than 25%), and best response was observed in the first 6 months of treatment in 7 children. Four patients progressed under treatment (all high-grade gliomas) and 2 progressed shortly after stopping the inhibitor (both low-grade gliomas). Five patients had grade 3-4 toxicity, with subsequent full recovery. A good and sustained clinical-radiological response, with acceptable tolerance, is described in patients with BRAFV600E mutated low-grade gliomas treated with BRAFV600E inhibitors. In contrast, the response in patients with high-grade gliomas was intermediate and of short duration, with early tumour progression.

La mutación puntual V600E del gen BRAF juega un papel fundamental en la tumorigénesis de muchos gliomas. La inhibición de su producto forma parte de terapias innovadoras emergentes en los últimos años. Conocer el rol de estos tratamientos resulta imprescindible. El objetivo del trabajo fue describir la respuesta clínico-radiológica en niños con gliomas BRAFV600E mutado tratados con inhibidores BRAF. Para ello se realizó un estudio descriptivo y retrospectivo en pacientes menores de 16 años con gliomas BRAFV600E mutado que recibieron vemurafenib o dabrafenib en el Hospital Garrahan. Trece pacientes tratados en los últimos 7 años fueron incluidos: 9 gliomas de bajo grado y 4 de alto grado. La mediana de edad al diagnóstico fue 8.6 años (0.89-14.04) y del comienzo del inhibidor 11.62 años (3.64-15.42). Inicialmente, todos habían realizado tratamiento quirúrgico, y 12/13 recibieron previamente otra terapia: 11 quimioterapia (eventualmente hasta 4 líneas distintas) y 4 radioterapia. Con la terapia dirigida, 10 pacientes tuvieron una disminución tumoral mayor o igual al 25%, quedando evidenciada en 7 niños la mejor respuesta dentro de los 6 meses del inicio. Hubo 4 progresados intratratamiento (todos alto grado), y 2 progresados prontamente luego de suspender el inhibidor (ambos bajo grado). Cinco presentaron efectos adversos grado 3-4, con recuperación ad-integrum. Se describe una buena y sostenida respuesta clínico-radiológica, con tolerancia aceptable, en pacientes con gliomas de bajo grado BRAFV600E mutado tratados con inhibidores BRAFV600E. En contraste, la respuesta en pacientes con gliomas de alto grado fue intermedia y de poca duración, con progresión tumoral precoz.

Terapias dirigidas con inhibidores del braf en gliomas pediátricos de alto y bajo grado con la mutación brafv600e. Experiencia del hospital Prof. Dr. Juan P. Garrahan / Targeted therapies with BRAF inhibitors for pediatric low- and high-grade gliomas with BRAF v600e mutation. Prof. Dr. Juan P. Garrahan Hospital experience

Resumen La mutación puntual V600E del gen BRAF juega un papel fundamental en la tumorigénesis de muchos gliomas. La inhibición de su producto forma parte de terapias innovadoras emergentes en los últimos años. Conocer el rol de estos tratamientos resulta imprescindible. El objetivo del trabajo fue describir la respuesta clínico-radiológica en niños con gliomas BRAF V600E mutado tratados con inhibidores BRAF. Para ello se realizó un estudio descriptivo y retrospectivo en pacientes menores de 16 años con gliomas BRAF V600E mu tado que recibieron vemurafenib o dabrafenib en el Hospital Garrahan. Trece pacientes tratados en los últimos 7 años fueron incluidos: 9 gliomas de bajo grado y 4 de alto grado. La mediana de edad al diagnóstico fue 8.6 años (0.89-14.04) y del comienzo del inhibidor 11.62 años (3.64-15.42). Inicialmente, todos habían realizado tratamiento quirúrgico, y 12/13 recibieron previamente otra terapia: 11 quimioterapia (eventualmente hasta 4 líneas distintas) y 4 radioterapia. Con la terapia dirigida, 10 pacientes tuvieron una disminución tumoral mayor o igual al 25%, quedando evidenciada en 7 niños la mejor respuesta dentro de los 6 meses del inicio. Hubo 4 progresados intratratamiento (todos alto grado), y 2 progresados prontamente luego de suspender el inhibidor (ambos bajo grado). Cinco presentaron efectos adversos grado 3-4, con recuperación ad-integrum. Se describe una buena y sostenida respuesta clínico-radiológica, con tolerancia aceptable, en pacientes con gliomas de bajo grado BRAF V600E mutado tratados con inhibidores BRAF V600E . En contraste, la respuesta en pacientes con gliomas de alto grado fue intermedia y de poca duración, con progresión tumoral precoz.

Abstract The BRAF V600E point mutation plays a key role in the tumorigenesis of many gliomas. Inhibiting its product is part of the innovative therapies emerging in recent years. Knowing the role of these treatments is essential. The aim of this experience was to describe the clinical-radiological response of pediatric BRAF V600E mutated gliomas treated with BRAF inhibitors. To this end, a descriptive and retrospective study was performed in patients under 16 years of age with BRAF V600E gliomas, who received vemurafenib or dabrafenib at Hospital Garrahan. Thirteen patients treated in the last 7 years were included: 9 were low-grade and 4 high-grade gliomas. The median age at diagnosis was 8.6 years (0.89-14.04) and at start of targeted therapy was 11.62 years (3.64-15.42). All patients had previously a surgical procedure, and 12/13 had received another therapy prior BRAF inhibition: 11 chemotherapy (in one case, up to 4 different protocols) and 4 radiotherapy. Under targeted therapy, tumour response was obtained in 10 patients (size reduction equal to or greater than 25%), and best response was observed in the first 6 months of treatment in 7 children. Four patients progressed under treatment (all high-grade gliomas) and 2 progressed shortly after stopping the inhibitor (both low-grade gliomas). Five patients had grade 3-4 toxicity, with subsequent full recovery. A good and sustained clinical-radiological response, with acceptable tolerance, is described in patients with BRAF V600E mutated low-grade gliomas treated with BRAF V600E inhibitors. In contrast, the response in patients with high-grade gliomas was intermediate and of short duration, with early tumour progression.