Recurrent Diffuse Intrinsic Pontine Glioma Research Articles

Hypofractionated re-irradiation for diffuse intrinsic pontine glioma.

Re-irradiation (reRT) increases survival in locally recurrent diffuse intrinsic pontine glioma (DIPG). There is no standard dose and fractionation for reRT, but conventional fractionation (CF) is typically used. We report our institutional experience of reRT for DIPG, which includes hypofractionation (HF). We reviewed pediatric patients treated with brainstem reRT for DIPG at our institution from 2012 to 2022. Patients were grouped by HF or CF. Outcomes included steroid use, and overall survival (OS) was measured from both diagnosis and start of reRT. Of 22 patients who received reRT for DIPG, two did not complete their course due to clinical decline. Of the 20 who completed reRT, the dose was 20-30Gy in 2-Gy fractions (n=6) and 30-36Gy in 3-Gy fractions (n=14). Median age was 5years (range: 3-14), median interval since initial RT was 8months (range: 3-20), and 12 received concurrent bevacizumab. Median OS from diagnosis was 18months [95% confidence interval: 17-24]. Median OS from start of reRT for HF versus CF was 8.2 and 7.5months, respectively (p=.20). Thirteen (93%) in the HF group and three (75%) in the CF group tapered pre-treatment steroid dose down or off within 2months after reRT due to clinical improvement. There was no significant difference in steroid taper between HF and CF (p=.4). No patients developed radionecrosis. reRT with HF achieved survival duration comparable to published outcomes and effectively palliated symptoms. Future investigation of this regimen in the context of new systemic therapies and upfront HF is warranted.

TRLS-11. A PHASE 1 STUDY OF SAVOLITINIB IN RECURRENT, PROGRESSIVE, OR REFRACTORY MEDULLOBLASTOMA, HIGH-GRADE GLIOMA, DIFFUSE INTRINSIC PONTINE GLIOMA, AND CENTRAL NERVOUS SYSTEM (CNS) TUMORS HARBORING MET ABERRATIONS: A PEDIATRIC BRAIN TUMOR CONSORTIUM TRIAL

Abstract Aberrant mesenchymal epithelial transition receptor (MET) activation leads to neoplasia, promotes invasive tumor growth, angiogenesis, and metastasis. Deregulation of MET signaling pathway is frequently observed in pediatric CNS tumors making MET inhibition a potential therapeutic target in this patient population. A phase 1 first-in-children trial of the MET inhibitor savolitinib was performed in children with recurrent, progressive or refractory medulloblastoma, high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), and other CNS tumors harboring MET aberrations. The study sought to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of savolitinib using a Rolling-6 design given orally once daily continuously, and to describe its toxicity profile and pharmacokinetics (PK). Once the MTD was established, a PK expansion cohort was opened to enrollment. This will be followed by an efficacy expansion cohort for patients whose tumors harbor activating genomic MET aberrations. Tumor tissue and blood were collected as part of correlative studies in consenting subjects. Twenty-eight patients enrolled (median age:12 years; range: 6-21); one patient was deemed ineligible, and 22 patients were evaluable for dose finding. The MTD/RP2D was 350 mg/m2 (dose level 3). Two dose limiting toxicities were reported in 2 subjects and consisted of grade 3 fatigue and grade 3 ALT elevation. The most common grade 3/4 toxicities were: neutropenia (7.7%) and lymphopenia (7.7%). One partial response was observed in a patient with recurrent HGG on dose level 1 (150 mg/m2). As of the most recent data freeze, the patient had completed 35 treatment courses. Sustained stable disease was experienced by 3 other patients with recurrent DIPG who remained on treatment for a median of 9 cycles (range: 4-24). Correlative studies are ongoing and will be presented. Savolitinib was well-tolerated in children with recurrent CNS tumors with an MTD/RP2D of 350 mg/m2. Antitumor activity was observed.

Initial clinical applications treating pediatric and adolescent patients using MR-guided radiotherapy.

To demonstrate the clinical applications and feasibility of online adaptive magnetic resonance image guided radiotherapy (MRgRT) in the pediatric, adolescent and young adult (AYA) population. This is a retrospective case series of patients enrolled onto a prospective study. All pediatric (age < 18) and AYA patients (age< 30), treated on the Elekta Unity MR linear accelerator (MRL) from 2019 to 2021 were enrolled onto a prospective registry. Rationale for MRgRT included improved visualization of and alignment to the primary tumor, re-irradiation in a critical area, ability to use smaller margins, and need for daily adaptive replanning to minimize dose to adjacent critical structures. Step-and-shoot intensity-modulated radiation treatment (IMRT) plans were generated for all Unity patients with a dose grid of 3 mm and a statistical uncertainty of < 1% per plan. A total of 15 pediatric and AYA patients have been treated with median age of 13 years (range: 6 mos - 27 yrs). Seven patients were <10 yo. The clinical applications of MRgRT included Wilms tumor with unresectable IVC thrombus (n=1), Ewing sarcoma (primary and metastatic, n=3), recurrent diffuse intrinsic pontine glioma (DIPG, n=2), nasopharyngeal carcinoma (n=1), clival chordoma (n=1), primitive neuroectodermal tumor of the pancreas (n=1), recurrent gluteo-sacral germ cell tumor (n=1), C-spine ependymoma (n=1), and posterior fossa ependymoma (n=1). Two children required general anesthesia. One AYA patient could not complete the MRgRT course due to tumor-related pain exacerbated by longer treatment times. Two AYA patients experienced anxiety related to treatment on the MRL, one of which required daily Ativan. No patient experienced treatment interruptions or unexpected toxicity. MRgRT was well-tolerated by pediatric and AYA patients. There was no increased use of anesthesia outside of our usual practice. Dosimetric advantages were seen for patients with tumors in critical locations such as adjacent to or involving optic structures, stomach, kidney, bowel, and heart.

DIPG-35. Personalized treatment for molecularly heterogeneous Diffuse midline glioma, H3 k27-altered Paediatric case

Abstract Diffuse midline glioma, H3 k27-altered (DMG) is a type of Paediatric- type diffuse high grade gliomas according to the 2021 WHO CNS tumors Classification. Diffuse intrinsic pontine glioma (DIPG) is another acceptable related term when it located in the pons with fatal prognosis. The combination of H3K27M with BRAF V600 mutations rarely reported in DMG although more commonly in Paediatric-type low grade gliomas (Diffuse low-grade glioma, MAPK pathway-altered). We present a twenty-month-old boy, previously healthy, presented with 2 weeks history of unsteady gait, drooling, cranial nerves palsy MRI imaging showed diffuse pontine mass with classic radiological features of DIPG. 2.6 x 1.6 x 3.2 (AP x TV x CC) with no evidence for spinal metastases. Patient underwent right retro sigmoid approach and open biopsy of lesion he received focal Radiation Therapy 54GY/30fx as stander of care of DIPG with mild neurogical improvement Pathological &amp; molecular Diagnosis was Diffuse midline glioma, H3 k27-altered with Co-occurrence BRAF V600E mutation. Two months after end of radiation, he presented with vomiting, and neurological deterioration with new right-side hemiplegia. Imaging studies showed interval increase in the pontine lesion with increased edema causing narrowing of the fourth ventricle, no active hydrocephalus. He was started on combination therapy BRAF inhibitor Dabrafenib and MEK Inhibitor Trametinib as maintenance therapy the patient gradually showed Marked neurological and clinical improvement. A 6-month MRI after start of targeted therapy showed favorable treatment response with complete resolution of the previous diffusion restriction, reduced tumor volume on MR perfusion ,reduced perilesional edema otherwise almost stabilization of nonenhancing pontine lesion. The poor prognosis of recurrent DIPG is well known but our patient is clinically and radiologically stable with excellent quality of life and well tolerating the therapy . Our case show that personalized treatment approach that address molecular heterogeneity of H3K27M glioma are safe and feasible

Clinical approach to re-irradiation for recurrent diffuse intrinsic pontine glioma.

We present our institutional approach for re-irradiation in diffuse intrinsic pontine glioma and their outcomes. Consecutive patients of recurrent diffuse intrinsic pontine glioma treated with re-irradiation (January 2015-September 2019) were reviewed retrospectively to describe the clinical-response-based approach followed for the dose and volume decision. Outcomes were defined with clinical and steroid response criteria and survival endpoints included progression-free survival and overall survival as cumulative(c) overall survival and re-irradiation overall survival (re-irradiation starting to death). The Kaplan-Meier method and log-rank test were used for survival analysis. Twenty-patient cohort with a median (m) age of 7.5years, m-progression-free survival of 8.4months and m-Lansky performance score of 50 received re-irradiation of which 17 (85%) were called clinical responders. The median re-irradiation-overall survival with 39.6-41.4, 43.2 and 45Gy were 5.8, 7 and 5.3months, respectively. One-month post-re-irradiation steroid independent status was a significant predictor of better survival outcomes (overall survival, P≤0.004). No ≥ grade 3 toxicities were noticed. Two patients succumbed to intra-tumoral hemorrhage. Higher doses of re-irradiation based on a clinical-response-based approach show improvement in survival and steroid dependence rates with acceptable toxicity. Steroid independent status at 1-month post-re-irradiation predicts better outcomes. Prospective studies may validate this with quality of life data.

Immune-stimulatory (TK/Flt3L) gene therapy opens the door to a promising new treatment strategy against brainstem gliomas.

Diffuse intrinsic pontine glioma (DIPG) is a rare brainstem tumor which carries a dismal prognosis. To date. there are no effective treatments for DIPG. Transcriptomic studies have shown that DIPGs have a distinct profile compared to hemispheric high-grade pediatric gliomas. These specific genomic features coupled with the younger median age group suggest that DIPG is of developmental origin. There is a major unmet need for novel effective therapeutic approaches for DIPG. Clinical and preclinical studies have expanded our understanding of the molecular pathways in this deadly disease. We have developed a genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, activin A receptor type I (ACVR1)-G328V (mACVR1) using the sleeping beauty transposon system. DIPG neurospheres isolated from the genetically engineered mouse model were implanted into the pons of immune-competent mice to assess the therapeutic efficacy and toxicity of immunostimulatory gene therapy using adenoviruses expressing thymidine kinase (TK) and fms-like tyrosine kinase 3 ligand (Flt3L). Immunostimulatory adenoviral-mediated delivery of TK/Flt3L in mice bearing brainstem gliomas resulted in antitumor immunity, recruitment of antitumor-specific T cells, and improved median survival by stimulating the host antitumor immune response. Therapeutic efficacy of the immunostimulatory gene therapy strategy will be tested in the clinical arena in a Phase I clinical trial. We also discuss immunotherapeutic interventions currently being implemented in DIPG patients and discuss the profound therapeutic implications of immunotherapy for this patient populations.

Therapeutic Efficacy of Immune Stimulatory Thymidine Kinase and fms-like Tyrosine Kinase 3 Ligand (TK/Flt3L) Gene Therapy in a Mouse Model of High-Grade Brainstem Glioma.

Diffuse intrinsic pontine glioma (DIPG) bears a dismal prognosis. A genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, Activin A receptor type I (ACVR1)-G328V (mACVR1), was developed for testing an immune-stimulatory gene therapy. We utilized the Sleeping Beauty transposase system to generate an endogenous mouse model of mACVR1 brainstem glioma. Histology was used to characterize and validate the model. We performed RNA-sequencing analysis on neurospheres harboring mACVR1. mACVR1 neurospheres were implanted into the pons of immune-competent mice to test the therapeutic efficacy and toxicity of immune-stimulatory gene therapy using adenoviruses expressing thymidine kinase (TK) and fms-like tyrosine kinase 3 ligand (Flt3L). mACVR1 neurospheres expressing the surrogate tumor antigen ovalbumin were generated to investigate whether TK/Flt3L treatment induces the recruitment of tumor antigen-specific T cells. Histologic analysis of mACVR1 tumors indicates that they are localized in the brainstem and have increased downstream signaling of bone morphogenetic pathway as demonstrated by increased phospho-smad1/5 and Id1 levels. Transcriptome analysis of mACVR1 neurosphere identified an increase in the TGFβ signaling pathway and the regulation of cell differentiation. Adenoviral delivery of TK/Flt3L in mice bearing brainstem gliomas resulted in antitumor immunity, recruitment of antitumor-specific T cells, and increased median survival (MS). This study provides insights into the phenotype and function of the tumor immune microenvironment in a mouse model of brainstem glioma harboring mACVR1. Immune-stimulatory gene therapy targeting the hosts' antitumor immune response inhibits tumor progression and increases MS of mice bearing mACVR1 tumors.

The effect of everolimus on CNS penetration and efficacy of dasatinib in the treatment of PDGFRA-driven glioma.

e13508 Background: Pediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. The CNS penetration of PDGFRA inhibitors, such as dasatinib, is limited by the tumor-efflux protein P-glycoprotein (P-gp). We hypothesized that co-treatment with everolimus, which has been shown to block P-gp, will increase CNS penetration and efficacy of dasatinib in in vitro and in vivo models as well as in human PDGFRA-driven glioma. Methods: Tumors were generated in mice using an intra-uterine electroporation (IUE) model [introduction of TP53, PDGFRA and H3K27M mutations in pre-natal cortex]. Dose response, synergism studies, P-GP inhibition and pharmacodynamics/pharmacokinetic studies were then performed on in vitro and in vivo models employing this IUE system. A phase 2 trial employing dasatinib and everolimus was established for children with HGG and diffuse intrinsic pontine glioma (DIPG) that contain PDGFRA alterations (NCT03352427). Paired CSF/plasma samples (before and after addition of everolimus) were collected from enrolled patients. Results: Dasatinib effectively treated mouse HGG cells with an IC50 of 100 nM. Dose-dependent reduction in PDGFRA and pPDGFRA was found. P-gp inhibitor assay confirmed that everolimus strongly blocks P-gp activity at 1 uM (p = 0.0028 vs untreated). Mice treated with dasatinib and everolimus had extended survival as compared to control. Two-hour exposure to everolimus resulted in sub-IC50 dasatinib concentration in cortex (23 nM) and tumor (65 nM). 24-hour exposure to everolimus resulted in greater cortex (235 nM) and tumor (509 nM) concentrations. Two trial patients, recurrent HGG ( PDGFRA-amplified) and recurrent DIPG ( PDGFRA D842V) respectively, survived 6 months and 9 months (ongoing) after progression, which compares very favorably to historical controls. A paired CSF sample from the PDGFRA-amplified patient showed a 50% increase in CSF dasatinib level after addition of everolimus. Conclusions: Dasatinib treatment of PDGFRA-driven HGG is improved with everolimus blockade of P-gp and represents a novel route for improving CNS penetration and efficacy of therapies for HGG. Clinical trial information: NCT03352427.

Reirradiation and PD-1 inhibition with nivolumab for the treatment of recurrent diffuse intrinsic pontine glioma: a single-institution experience

Diffuse intrinsic pontine glioma (DIPG) is a rare, aggressive brain tumor with no known cure. Reirradiation (reRT) at recurrence can prolong survival. The impact of irradiation may be heightened when combined with PD-1 inhibition. We describe our experience using reRT, with or without PD-1 inhibition, in a cohort of patients with recurrent DIPG. We performed a retrospective cohort analysis of children who received reRT with or without concomitant PD-1 inhibition for recurrent DIPG at a single institution between 2005 and 2016. We compared progression-free (PFS) and overall survival (OS) between those who received reRT alone or in combination with PD-1 inhibition. We then compared reRT to a cohort of patients who did not receive reRT. Thirty-one patients were included (8-reRT with nivolumab; 4-reRT alone; 19-no reRT). Patients who received reRT had prolonged OS compared to no reRT (22.9 months-reRT with nivolumab; 20.4months-reRT alone; 8.3months-no reRT; p < 0.0001). Patients who received reRT with nivolumab vs. reRT only had slightly prolonged OS from diagnosis and from reRT (22.9 vs. 20.4months for time from diagnosis; 6.8 vs. 6.0months for time from reRT). All patients receiving reRT with or without nivolumab tolerated the therapy without acute or late toxicity. Our experience demonstrates the tolerability of reRT with concurrent PD-1 inhibition for recurrent DIPG and suggests that combination therapy may offer survival benefit. Future prospective studies are needed to confirm the benefits of this combination therapy.

A Case of Sustained Objective Response of Recurrent/Progressive Diffuse Intrinsic Pontine Glioma with Phenylbutyrate and Targeted Agents

Diffuse intrinsic pontine glioma (DIPG) is the most common type of brainstem glioma and one of the most deadly brain tumors. DIPG in young adult patients is a rare disease for which treatment options are limited. Radiation therapy remains the standard-of-care for newly-diagnosed DIPG, but no established therapies for recurrent disease are available. This paper describes the results of treatment of a young adult patient diagnosed with DIPG that progressed after radiation therapy. Therapy included sodium phenylbutyrate (PB) in combination with the targeted agents: pazopanib, everolimus, erlotinib, and bevacizumab. The patient achieved a rapid partial response, which persisted over a year and five months. The patient opted to discontinue the therapy and thereafter elected chemotherapy, which resulted in a subsequent rapid progression and death within one month. The targeted treatment was associated with minor toxicity that included a Grade 2 skin rash and Grade 1 elevation of transaminases. In conclusion, a combination of PB and currently available targeted drugs may offer extended survival in patients with recurrent DIPG.

Commentary on: "The response and survival of children with recurrent diffuse intrinsic pontine glioma based on phase II study of antineoplastons A10 and AS2-1 in patients with brainstem glioma." By Burzynski et al.

A potential effective therapy for diffuse intrinsic pontine glioma (DIPG) is far to be developed. There are no "shortcuts" to reach this goal. Only a rigid, scientific, and ethically correct approach can help develop effective therapeutic approaches for such a devastating brain tumor. There are no alternative ways. The children affected by DIPG deserve to become the focus of serious collaborative researches. For these children, there are many "lacks" which should be promptly corrected such as the lack of knowledge, the lack of basic and clinical scientists' passion to the problem of finding "the solution" for DIPG, the lack of rigid methods to run research in this frustrating field, the lack of research proposals, and the lack of serious, despite not magic, protocols to offer them.

Comment to the paper: The response and survival of children with recurrent diffuse intrinsic pontine glioma based on phase II study of antineoplastons A10 and AS2-1 in patients with brainstem glioma : Stanislaw R. Burzynski, Tomasz J. Janicki, Gregory S. Burzynski, Ania Marszalek.

Although Burzynski et al. conclude that antineoplastons are a useful treatment, their results do not adequately support their conclusion, and much of what we know about antineoplastons suggests that antineoplastons can have serious and potentially life-threatening side effects, with no evidence of efficacy that could justify that risk. While many of the problems with the paper will be immediately apparent to readers (for instance, the decision to exclude over half of the patients from analysis), readers should also be aware of the context in which the study, BT-11, was conducted. In the 1990s, when the BT-11 trial was initiated, it was one of over 70 clinical trials of antineoplastons that, according Stanislaw Burzynski’s lawyer, Richard Jaffe, would allow Burzynski “to treat almost any patient Burzynski would want to treat!” In all the years since, not a single one of those 70+ clinical trials has culminated in a meaningful paper. For all intents and purposes, the medical community knows nothing more about antineoplastons than they did when the trials opened, and the current paper does not change that. Over the course of these never-ending and apparently unpublishable clinical trials, the US Food and Drug Administration has periodically inspected the Burzynski Research Institute (BRI) and the principal investigator, Stanislaw Burzynski. The FDA have released the observational notes (form 483s) and other documents from these inspections which specifically refer to BT-11, as well as to studies underway at the BRI concurrently with BT-11 and the BRI Institutional Review Board (IRB) that oversaw all of the studies. They are shocking reading, and detail an unbroken string of abysmal FDA site reviews of the Burzynski Research Institute spanning the last 14 years. For instance, a 483 form 2001 noted that “Subjects were started on antineoplaston treatment prior to the protocol-specified interval following prior chemotherapy and/or radiation therapy,” including a patient participating in trial BT-11, who had too recently been treated with etoposide. During the same visit, inspectors observed that “Not all serious adverse events and adverse events are reported to FDA and IRB,” including two patients in BT-11, including one patient who had to be removed from the chemotherapy all together because of recurring pancreatitis. Inspectors also observed a “failure to address and resolve reported patient overdoses in BRI query reports to determine the reason for the possible overdose and to take corrective action to prevent recurrence,” including two patients in BT-11. Additionally, the files of at least two patients in the BT-11 did not record independent tumor measurements by consultants. In the Establishment Inspection Report, the FDA investigator recorded:

Comment to the paper "The response and survival of children with recurrent diffuse intrinsic pontine glioma based on phase II study of antineoplastons A10 and AS2-1 in patients with brain stem glioma" by Burzynski et al.

Comments The authors conducted a single-arm phase II study on antineoplaston (ANP) for the efficacy and safety in the treatment of recurrent pediatric diffuse intrinsic pontine tumors (RPDIPGs) by using a combination of A10 and AS2-1 in a group of 17 patients with mean age of 8.8 years at recurrence. The overall response rate (OR) was 29.5 % with complete response rate (CR) of 6 %, partial response rate (PR) of 23.5 %, stable disease (SD) of 11.8 %, progressive disease of 47 %, and acceptable toxicity. Counting from the first day of ANP administration, the 6-month progression-free survival was 35.3 % and 1-year overall survival was 29.4 % with one long-term survival for more than 15 years. However, the series was small and the enrollment of patients lasted from 1996 to 2006 [1]. In a recently reported series of 31 RPDIPG patients with mean age of 7.8 years at the start of the first treatment for tumor recurrence or progression, the results were as follows: no long-term survival, no CR, PR 12 %, SD 34 %, and PD 53%. The mean event-free survival (EFS) was 2 months. This study highlighted that repeat radiation to the primary tumor was most effective with mean EFS of 3.9 months [2]. Comparing with the treatment results of these two series for RPDIPGs and reports of clinical trials for diffuse intrinsic pontine tumors (DIPGs), although the series of ANP phase II study was small to conclude, the outcome seemed promising [1–3]. There has been a clinical question whether histological grading of DIPGs influences survival and if there are some other diffuse pontine lesions. Referring to a reported study of prognostic factors for DIPGs, stereotactic biopsy and histological diagnosis of high-grade or low-grade gliomas were available in 63 adults and 37 children. This study showed that histological grade was a significant prognostic factor in DIPGs with statistical significance in adult patients (p=0.0001), but there was no statistical significance in pediatric patients (p=0.0755). However, in children, the 1-year actuarial survival rate was higher in low-grade gliomas (80.4± 0.08 %) than high-grade gliomas (48.6±0.14 %). In the same study, the histological diagnosis of stereotactic biopsy of 142 brain stem lesions in adults and children, only 106 cases (74.6 %) were astrocytic tumors [4]. The same study group also reported the histological diagnosis of intrinsic brain stem tumors in children. Biopsies were performed in 44 children with intrinsic brain stem lesion. Histological diagnosis obtained in 41 (93.1 %) patients included 37 diffuse brain stem gliomas, 2 pilocytic astrocytomas, 1 ependymoma, and 1 ganglioglioma [5]. Roujeau et al. reported stereotactic biopsy of diffuse pontine lesions in 24 children. There were 22 highgrade infiltrative astrocytomas (WHO grade III and IV), 1 grade II astrocytoma, and 1 pilocytic astrocytoma [6]. In our unreported experience of biopsy of diffuse pontine tumors in children, the histological diagnosis obtained included five glioblastoma multiformes (GBMs), eight AAs, six astrocytomas, and three pilocytic astrocytomas. The proportion of highgrade and low-grade gliomas varies in different series. Diffuse pontine pilocytic astrocytoma can have long-term survival. There is also a possibility of other pathologies, higher in brain stem lesions in general and sporadic cases in diffuse pontine lesions. In the study series of APN in 17 patients, only four T.<T. Wong (*) Pediatric Neurosurgery, Division of Neurosurgery, Department of Surgery, Cheng Hsin General Hospital, Taipei, Taiwan e-mail: ttwong@vghtpe.gov.tw

The response and survival of children with recurrent diffuse intrinsic pontine glioma based on phase II study of antineoplastons A10 and AS2-1 in patients with brainstem glioma

BackgroundBrainstem gliomas (BSG) are relatively rare tumors of which recurrent pediatric diffuse intrinsic pontine gliomas (RPDIPG) comprise a distinct group. Numerous trials have been conducted on RPDIPG, none of which have resulted in identifying any proven pharmacological treatment benefit. This study included 40 patients diagnosed with different types of BSG, but it was decided to describe first the encouraging results in the most challenging group of RPDIPG.Materials and methodsThis single-arm phase II study evaluated the efficacy and safety of the combination of antineoplastons A10 and AS2-1 (ANP) in patients with RPDIPG. Seventeen patients (median age 8.8 years) were enrolled, and all were diagnosed with RPDIPG. ANP was administered intravenously daily. Efficacy analyses were conducted in this group of patients.ResultsIn this group, complete responses were observed in 6 % of patients, partial responses in 23.5 %, and stable disease in 11.8 %. Six-month progression-free survival was 35.3 %. One-year overall survival was 29.4 %, 2 years 11.8 %, and 5, 10, and 15 years 5.9 %. One patient with DIPG is alive over 15 years post-treatment. Grade 3 and higher toxicities including hypokalemia and fatigue occurred in 6 %, hypernatremia in 18 %, fatigue and urinary incontinence in 6 %, and somnolence in 12 %. In a single patient, grade 4 hypernatremia occurred when he was on mechanical ventilation. He was disconnected from the ventilator and died from brain tumor according to the attending physician. Responding patients experienced improved quality of life.ConclusionThe results suggest that ANP shows efficacy and acceptable tolerability profile in patients with RPDIPG.

Treatment of recurrent diffuse intrinsic pontine glioma: the MD Anderson Cancer Center experience

Recurrent diffuse intrinsic pontine gliomas (DIPG) are traditionally treated with palliative care since no effective treatments have been described for these tumors. Recently, clinical studies have been emerging, and individualized treatment is attempted more frequently. However, an informative way to compare the treatment outcomes has not been established, and historical control data are missing for recurrent disease. We conducted a retrospective chart review of patients with recurrent DIPG treated between 1998 and 2010. Response progression-free survival and possible influencing factors were evaluated. Thirty-one patients were identified who were treated in 61 treatment attempts using 26 treatment elements in 31 different regimens. The most frequently used drugs were etoposide (14), bevacizumab (13), irinotecan (13), nimotuzumab (13), and valproic acid (13). Seven patients had repeat radiation therapy to the primary tumor. Response was recorded after 58 treatment attempts and was comprised of 0 treatment attempts with complete responses, 7 with partial responses, 20 with stable diseases, and 31 with progressive diseases The median progression-free survival after treatment start was 0.16 years (2 months) and was found to be correlated to the prior time to progression but not to the number of previous treatment attempts. Repeat radiation resulted in the highest response rates (4/7), and the longest progression-free survival. These data provide a basis to plan future clinical trials for recurrent DIPG. Repeat radiation therapy should be tested in a prospective clinical study.