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SUPERSELECTIVE INTRAARTERIAL AND INTRATHECAL COMBINATION CHEMOTHERAPY IN THE COMPASSIONATE MANAGEMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA
SILLER AGUIRRE AJ1, GARCÍA DE LA FUENTE JA1
1 INSTITUTO DE ONCOLOGÍA INTERVENCIONISTA (IDOI)
Diffuse Intrinsic Pontine Glioma (DIPG) is an aggressive tumor of the pons with a median overall survival of 11 months in children. 9,6% and 2,2% of the patients are alive at 2 and 5 years after diagnosis, respectively. It represents about 75% of brain stem tumors in children, with no gender prevalence and about 150-300 new diagnoses per year in the United States.
Due to its location, DIPG is unresectable. The different strategies of systemic chemotherapy and radiotherapy have not been effective in significantly improving the overall survival of the patient. Chronic steroid management is palliative.
Combined drug therapy and alternative administration methods have demonstrated their potential to achieve long-term prognosis and reduce side effects.
Superselective Intraarterial chemotherapy is a delivery method that allows higher drug concentrations at the tumor site.
The heterogeneity of the blood brain barrier (BBB) caused by the abnormal tumor vasculature, the invasion of glioma cells and radiotherapy, together with the local administration of hyperosmotic solutions, allow the improved transitory passage of chemotherapeutic agents administered through the BBB.
The administration of chemotherapy by the intrathecal route seeks to prevent tumor implants in the ependyma by neoplastic cells traveling in the subarachnoid space of the central nervous system.
The "compassionate use" of a drug or therapy exists to offer an alternative to patients whose life is immediately threatened with a serious illness or condition, for which there is no satisfactory therapy.
Demonstrate the viability of “IDOI-1” (superselective intraarterial and intrathecal combination chemotherapy, SSIAITCC) as a treatment possibility for pediatric patients with DIPG.
MATERIAL AND METHODS
We conducted a prospective longitudinal analysis of our cohort of pediatric patients diagnosed with DIPG who received IDOI-1 in a single institution between February 2016 and July 2019.
The cohort is comprised of cases from Australia, Belgium, Brazil, Canada, the United States, France, Greece, the Netherlands, Italy, Mexico, Norway, Poland, Sweden, Thailand, the United Kingdom and Uzbekistan.
The overall survival of our cohort patients was estimated using the Kaplan-Meier method (95% confidence interval) and compared with the statistics published by the International DIPG Registry (IDIPGR) and European Society for Pediatric Oncology DIPG Registry (SIOPE -DIPGR).
The overall quality of life was estimated with the Karnofsky / Lansky performance scale (KPS), comparing the initial clinical evaluation and follow-up.
The response to treatment was evaluated with RANO criteria using nuclear magnetic resonance imaging of the brain with gadolinium, spectroscopy and positron emission tomography with 11C-methionine, as necessary.
The SSIAITCC was performed in a hemodynamics unit, under general anesthesia.
A lumbar puncture was performed for intrathecal administration of cytarabine, methotrexate, topotecan and dexamethasone.
A femoral catheterization was performed for intraarterial administration of mannitol, bevacizumab, cabazitaxel, cisplatin, liposomal doxorubicin, irinotecan, gemcitabine, nimotuzumab, temsirolimus.
The treatments were carried out every 3 to 5 weeks until the therapeutic failure or abandonment of the treatment.
69 patients were included in this study, which included 42 female (60.9%) and 27 male (39.1%), with a median age at diagnosis of 6.3 years (range 1.3-17.5 years).
63 of the 69 patients (91.3%) were accepted while the disease was already in progression.
63 of the 69 patients (91.3%) received various treatments, including steroids, radiotherapy and systemic chemotherapy before our intervention.
The IDOI-1 chemotherapy scheme started between day 7 and day 1537 after the initial diagnosis with a median of 215 days.
A median of 9 treatments were performed on each patient.
100% of the patients evaluated presented a positive clinical and radiological response to the treatment, maintaining Stable Disease, with no evidence of tumor progression or the appearance of new clinical symptoms until therapeutic failure or abandonment of treatment.
The cohort presented a median overall survival after the diagnosis of 590 days (19.4 months) and counting to date.
61 of the 69 patients (89.1%) were still alive 1 year after diagnosis.
23 of the 69 patients (33.4%) were still alive 2 years after diagnosis.
The cohort presented a median increase in KPS from 60% in the initial evaluation to a maximum of 90% during our intervention.
As of July 31, 2019, 56 of the 69 patients have died.
The follow-up interval for these results has a median of 337 days from the start of our intervention, with 804 days being the longest follow-up (and counting).
The figure represents the survival function according to the survival time of the patients, by the method of Kaplan Meier.
Fig1. Kaplan-Meier curves representing global survival of DIPG IDOI vs SIOPE DIPGR
13.8 year old male patient is diagnosed with DIPG on December 15, 2017.
Comes to us with neurological impairment qualified with 50% KPS. The pons, comprising the tumor, covers an area of 13.38 cm2, measured on February 20, 2018. It begins IDOI-1 67 days after its diagnosis, receiving a total of 18 sessions conducted every 3 to 5 weeks. Presents overall clinical improvement qualified with KPS 90%. The pons recovers normal anatomy, measuring 8.25 cm2 on April 1, 2019.
Due to clinical improvement and no radiological evidence of tumoral activity, it is decided to suspend treatment, with periodic evaluations.
As of July 31, 2019, 593 days after diagnosis and 2 months after completing our IDOI-1 treatment, the patient continues to improve clinically, has returned to his daily life and does not present evidence of tumor activity.
The use of IDOI-1 (SSIAITCC) in pediatric patients diagnosed with DIPG represents a therapeutic benefit that increases their overall survival and quality of life.
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