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Metronomics for paediatric brain tumours at ISPNO 2018

The International Symposium on Pediatric Neuro-Oncology (ISPNO) is the major biennial global meeting of the multi-disciplinary international community of professionals involved in the scientific research, diagnosis, treatment, rehabilitation of infants, children and young people with CNS tumors. The ISPNO took place Friday, June 29 to Tuesday, July 3, 2018. in Denver.

Four communications concerned metronomics:

- 1 communication from the Tata Memorial in Mumbai presented un update of their experience with the modified COMBAT regimen as a maitenance for high-risk brain tumours.
- 1 communication from Buenos Aeres reported the use of a 5 drugs metronomic regimen combined with bevacizumab in children with recurrent ependymoma
- 2 communication from Hartfort for patients with refractory ependymoma treated according to the MEMMAT regimen.
- 1 communication from Vienna summarizing their experience with 71 patients treated with the MEMMAT regimen.

The detailed abstrcts are pasted bellow.


Girish Chinnaswamy, Hari Sankaran, Vasudev Bhat, Anand KC,
Megha Saroha, Maya Prasad, Tushar Vora, Ayushi Sahay, Rahul Krishnatry, Sona Pungavkar, Amit Janu, Tejpal Gupta, Rakesh Jalali, and Shripad Banavali; Tata Memorial Centre, Mumbai, India

OBJECTIVE: We retrospectively reviewed the ef cacy and feasibility of COMBAT metronomic chemotherapy in high risk and relapsed medul- loblastoma from April 2011 to December 2016. METHODS: Post-sur- gery high risk medulloblastoma or relapsed medulloblastoma who were started on COMBAT regimen after completion of conventional therapy were included in this analysis. COMBAT regimen consists of low dose temozolomide, etoposide, sodium valproate and 13-cisretinoic acid admin- istered in 12-weekly cycles. RESULTS: 39 children (median age, 9 years; median follow-up, 27.7 months; male:female ratio, 5.5:1) were started on COMBAT during the study period, of which 19 (48.7%) were started after completion of conventional therapy and 20 (51.3%) were started at relapse. Molecular data was available for 17 children (WNT – n=2; SHH, n=3; Group 3, n=5; Group 4, n =7). 2-year progression free sur- vival (PFS) after starting COMBAT was 83.9% (95%CI: 49.4–95.7) and 25.8% (95% CI: 6.5–51.1%) for upfront therapy and relapsed medullo- blastoma at presentation respectively. 2-year overall survival was 92.3% (95% CI: 56.6–98.9%) and 67.4% (95% CI: 41.0–84.0%) for upfront therapy and relapsed medulloblastoma at presentation respectively. Only 1 child developed secondary AML and warranted discontinuation of COM- BAT therapy. CONCLUSION: COMBAT regimen is a well-tolerated and effective treatment option after completion of conventional treatment for children with high risk medulloblastoma. Future ongoing studies will fur- ther delineate the role of COMBAT in high risk medulloblastoma based on molecular subtypes.


Daniel Alderete, Lorena Baroni, Claudia Sampor, Candela Freytes, and Carla Pennella; Hospital Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina

Patients with relapse ependymoma have few therapy options and a short median survival time regardless of salvage treatment. The aim of this study is to evaluate the activity of multidrug antiangiogenic treatment in recurrent ependymoma patients. We evaluated the use of biweekly intravenous bevacizumab in combination with fivve oral drugs (thalidomide, celecoxib, fenofibrate, and oral etoposide/cyclophosphamide) in 9 recurrent ependymoma patients between September 2015 and August 2017. The median aged at beginning of treatment was 7.7y (3.7–11.8). 8 patients began therapy for progression disease (6 local/2 metastatic; 1 rst/7 multiple) and 1 because residual tumor after conventional treatment. Objective tumor response was 88% (8), including 5 with partial response and 3 with stable disease. Best response was observed 4.4 months (2.8–5.4) since starting treatment. The median treatment time was 10.6 months (3.4–21). Median time to progression(PFS) was 10.7 months. Median overall survival(OS) was 14.4 months (3.4–27.8). The OS and PFS after 6 months was 100% and 87% respectively; and after 12 months 50% and 37%. At last follow-up, 4 patients (44%) are alive including 2 still undergoing treatment. One patients remain alive and progression free at 16 months and another is alive with disease at 27 months. Therapy was generally well tolerated. This 5-drug regimen plus Bevacizumab produces objective responses with minimal toxicity in children with recurrent ependymoma. This antiangiogenic metronomic therapy could be an evolving alternative approach to recurrent ependymoma and it would be included as part of conventional treatment for unresectable ependymoma.


Eileen Gillan and Markus Bookland; Connecticut Children’s Medical Center, Hartford, CT, USA

Recurrent ependymomas have a dismal prognosis (2 year survival rates 29% OS and 23% EFS) and are relatively resistant to conventional chemo- therapy. An alternative approach to conventional chemotherapy can be antiangiogenic or metronomic chemotherapy which inhibits endothelial cell function and resultant neovascularization. From November 2011 to Feb 2018 five patients (median age:28 months) with recurrent (3 first, 2 multiple) anaplastic ependymomal brain tumors were treated with an antiangiogenic multidrug combination regimen (bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide, and cyclophophamide) and additional intraventricular therapy (etoposide and liposomal cytarabine) for a median of 12 months. Currently all patients are alive without evidence of recurrent disease at a median of 14 months. Toxicities were manageable and therapy was generally well tolerated with the exception of 1 patient who suffered developmental regression necessitating discontinuation of treatment. Our results suggest that the chosen antiangiogenic drug combination is particularly bene cial for patients with recurrent ependymoma and warrants further investigation as an alternative to conventional chemotherapy in relapsed patients.


Irene Slavc1, Andreas Peyrl1, Monika Chocholous1, Dominik Reisinger1, Lisa Mayr1, Amedeo Azizi1, Karin Dieckmann1, Christine Haberler1, and Thomas Czech1; 1Medical University of Vienna, Department of Pediatrics, Vienna, Austria, 2Medical University of Vienna, Department of Radiotherapy., Vienna, Austria, 3Medical University of Vienna, Institute of Neurology, Vienna, Austria, 4Medical University of Vienna, Department of neurosurgery, Vienna, Austria

Patients with recurrent malignant CNS tumors have a poor prognosis irrespective of salvage therapy applied. We used a metronomic antiangio- genic combination therapy and report on the response of individual tumor types to this approach. Since 2006, 81 patients with various recurrent malignant brain tumors started treatment with an antiangiogenic multidrug- regimen at the Medical University of Vienna. Therapy consisted of daily oral thalidomide, feno brate, celecoxib, and 21-day cycles of low dose oral etoposide alternating with cyclophosphamide augmented with IV bevaci- zumab and intraventricular therapy (etoposide and liposomal cytarabine). Excluding the 10 patients with recurrent medulloblastoma treated in the formal international protocol (MEMMAT; Identi er: NCT01356290), 71 patients were treated according to the same strategy “off trial”. Diagnoses were medulloblastoma (n=20), atypical teratoid rhab- doid tumor (ATRT) (n=11), ependymoma (n=9), high grade glioma/diffuse intrinsic pontine glioma (HGG/DIPG) (n=9), and various other entities in the remaining patients. As of the end of 2017, 3-year and 5-year OS for the 20 patients with recurrent medulloblastoma was 64.2 ± 10.9% and for the 11 patients with recurrent ATRT 45.7 ± 16.6% and 30.5 ± 16.7%, respec- tively. Remission could be maintained after discontinuation of treatment in a certain percentage of patients with medulloblastoma, ATRT and epend- ymoma. Patients with HGG and DIPG did not respond to this approach. The proposed antiangiogenic regimen seems most promising in medulloblastoma and ATRT and possibly also ependymoma. In a number of other tumor enti- ties time to progression could be prolonged while maintaining good quality of life.


Eileen Gillan, Jeanne Walczak, and Heather Rea; Connecticut Children’s Medical Center, Hartford, CT, USA

Metronomic chemotherapy can be an alternative approach to conven- tional chemotherapy by inhibition of endothelial cell function and result- ant neovascularization. During the last 3 years our center has successfully treated 5 patients with either high grade glioma or recurrent ependymomal brain tumors. The antiangiogenic multidrug combination regimen consists of IV bevacizumab, 5 oral drugs; thalidomide, celecoxib, feno brate, etopo- side, and cyclophophamide plus intraventricular therapy (etoposide and liposomal cytarabine). This drug regimen has a complicated schedule with the administration of 5 oral drugs on varying schedules with modi cations based on blood counts plus IV and IT medications. In an effort to improve patient/parent understanding of regimen and subsequent compliance we chose a mobile app for iOS and Android. named CareZone. Based upon patient and staff comments the CareZone app was the most comprehensive in simplifying this regimen with improved patient sati cation and adher- ence to drug administration. This app has the following features that are desirable in our pediatric oncology population: 1) the bottle barcode can be photographed and converted directly into text 2) roadmaps and other documents can be photographed into app 3) reminders for med adminis- tration with administration documentation is available to share with other caregivers and providers, 4) reminders for drug re ll dates and speciality pharmacy contact information 5) lab owsheets are to be added by devel- oper for oncology population. Mobile apps are familiar with patient and care providers and simplify complicated metronomic drug administration and compliance data for physicians.