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, Stanislaw R Burzynski, Tomasz J Janicki, Gregory S Burzynski, Ania Marszalek

Abstract

Background: Brainstem 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 methods: This 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.

Results: In 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.

Conclusion: The results suggest that ANP shows efficacy and acceptable tolerability profile in patients with RPDIPG.

Figures

Fig. 1
Fig. 1
Proposed mechanism of action of antineoplastons A10 and AS2-1. The ingredients of antineoplastons A10 and AS2-1, PN and PG, affect signal transmission through AKT and RAS pathways, promote apoptosis, and interrupt cell cycle progression at G1/S and G2/M checkpoints
Fig. 2
Fig. 2
DIPG in a 10-year-old male (case 8) which recurred two times after partial surgical resection. MRI of the head: 1—T1 nonenhanced, 2—contrast-enhanced, 3—T2W, and 4—FLAIR images. PR was documented by the MRI and CR was established by the normalization of the follow-up PET scans. Arrows indicate tumors
Fig. 3
Fig. 3
DIPG in a 7-year-old female (case 9) which recurred after radiation therapy and chemotherapy with etoposide. MRI of the head: 1—T1 nonenhanced, 2—contrast-enhanced, and 3—T2W images. MRI documented PR. Arrows indicate tumors
Fig. 4
Fig. 4
The Kaplan-Meier survival curves from the start of treatment for recurrent pediatric DIPG

References

    1. Hargrave D, Bartels U, Bouffet E. Diffuse brainstem glioma in children: critical review of clinical trials. Lancet. 2006;7:241–248. doi: 10.1016/S1470-2045(06)70615-5.
    1. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009 (2012). Central Brain Tumor Registry of the United States (CBTRUS), Hinsdale, IL, 14:201.
    1. Burzynski SR. Recent clinical trials in diffuse intrinsic brainstem glioma. Cancer Ther. 2007;5:379–390.
    1. Khuong-Quang D-A, Buczkowicz P, Rakopoulos P, Liu X-Y, Fontebasso AM, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 2012;124:439–447. doi: 10.1007/s00401-012-0998-0.
    1. Burzynski SR. The present state of antineoplaston research (1) Integr Cancer Ther. 2004;3:47–58. doi: 10.1177/1534735403261964.
    1. Burzynski SR. Targeted therapy for brain tumors. In: Yang A, editor. Brain cancer: therapy and surgical interventions. New York: Nova Science Publishers; 2006.
    1. Patil SS, Burzynski SR, Mrowczynski E, Grela K, Chittur S. Phenylacetylglutaminate in combination with phenylacetate causes cell cycle blockade and apoptosis by upregulating VDUP1 in U-87 glioblastoma cells. J Cancer Ther. 2012;3:192–200. doi: 10.4236/jct.2012.33028.
    1. Han SH, Jeon JH, Ju HR, Jung U, Kim KY, Yoo HS, Lee YH, Song KS, Hwang HM, Na YS, Yang Y, Lee KN, Choi I. VDUP1 upregulated by TGF-β1 and 1,25-dihydorxyvitamin D3 inhibits tumor cell growth by blocking cell-cycle progression. Oncogene. 2003;22:4035–4046. doi: 10.1038/sj.onc.1206610.
    1. Hui STY, Andres AM, Miller AK, Spann NJ, Potter DW, Post NM, Chen AZ, Sachithanantham S, Jung DY, Kim JK, Davis RA. Txnip balances metabolic and growth signaling via PTEN disulfide reduction. PNAS. 2008;105:3921–3926. doi: 10.1073/pnas.0800293105.
    1. Mure H, Matsuzaki K, Kitazato KT, Mizobuchi Y, Kuwayama K, Kageji T, Nagahiro S. Akt2 and Akt3 play a pivotal role in malignant gliomas. Neuro-Oncol. 2010;12:221–232. doi: 10.1093/neuonc/nop026.
    1. Gilmore AP. Anoikis. Cell Death Differ. 2005;12:1473–1477. doi: 10.1038/sj.cdd.4401723.
    1. Zhou BB, Anderson HJ, Roberge M. Targeting DNA checkpoint kinases in cancer therapy. Cancer Biol Ther. 2003;2:16–22. doi: 10.4161/cbt.200.
    1. Sanchez Y, Bachant J, Wang H, Hu F, Liu D, Tetzlaff M, et al. Control of the DNA damage checkpoint by Chk1 and Rad53 protein kinases through distinct mechanisms. Science. 1999;286(5442):1166–1171. doi: 10.1126/science.286.5442.1166.
    1. Gabai VL, O’Callaghan-Sunol C, Meng L, Sherman MY, Yaglom J. Triggering senescence programs suppresses Chk1 kinase and sensitizes cells to genotoxic stresses. Cancer Res. 2008;68:1834–1842. doi: 10.1158/0008-5472.CAN-07-5656.
    1. Patil S, Burzynski SR, Mrowczynski E, Grela K. Antineoplastons initiate caspase induced apoptosis by suppressing survivin expression in U87 glioblastoma cells. Neuro-Oncol. 2010;12:ii87. doi: 10.1093/neuonc/nop017.
    1. Patil S, Burzynski SR, Mrowczynski E, Grela K. CB-15. Targeting microRNAs in glioma cells with antineoplastons. Neuro-Oncol. 2010;12:iv10.
    1. Paugh BS, Broniscer A, Qu C, Miller CP, Zhang J, Tatevossian RG, Olson JM, Geyer JR, Chi SN, Saba da Silva N, Onar-Thomas A, Baker JN, Gajjar A, Ellison DW, Baker SJ. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J Clin Oncol. 2011;29:3999–4006. doi: 10.1200/JCO.2011.35.5677.
    1. Gilbertson RJ, Hill DA, Hernan R, Kocak M, Geyer R, Olson J, Gaijar A, Rush L, Hamilton RL, Finkelstein SD, Pollack IF. ERBB1 is amplified and overexpressed in high-grade diffusely infiltrative pediatric brain stem glioma. Clin Cancer Res. 2003;9:3620–3624.
    1. Burzynski SR, Kubove E. Toxicology studies on antineoplaston A10 injections in cancer patients. Drugs Exp Clin Res. 1986;12:47–55.
    1. Burzynski SR, Kubove E, Burzynski B. Phase II clinical trials of antineoplastons A10 and AS2-1 infusions in astrocytoma. In: Adam D, editor. Recent advances in chemotherapy. Munich: Futuramed Publishers; 1992.
    1. Hawkins MG, Friedman MA. National Cancer Institute’s evaluation of unconventional cancer treatments. J Natl Cancer Inst. 1992;84:1699. doi: 10.1093/jnci/84.22.1699.
    1. Burzynski SR, Conde AB, Peters A, Saling B, Ellithorpe R, Daugherty JP, Nacht CH. A retrospective study of antineoplastons A10 and AS2-1 in primary brain tumours. Clin Drug Investig. 1999;18:1–10. doi: 10.2165/00044011-199918010-00001.
    1. Burzynski SR, Janicki TJ, Burzynski GS, Marszalek A (2014) Long term survival (>13 years) in a child with recurrent diffuse pontine gliosarcoma: a case report. J Pediatr Hematol Oncol. doi:10.1097/MPH.0000000000000020
    1. Packer RJ, Boyett JM, Zimmerman RA, et al. Hyperfractionated radiation therapy (72 Gy) for children with brain stem gliomas. A Children’s Cancer Group Phase I/II Trial. Cancer. 1993;72:1414–1421. doi: 10.1002/1097-0142(19930815)72:4<1414::AID-CNCR2820720442>;2-C.
    1. Albright AL, Packer RJ, Zimmerman R, Rorke LB, Boyett J, Hammond GD. Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children’s Cancer Group. Neurosurgery. 1993;33:1026–1030. doi: 10.1227/00006123-199312000-00010.
    1. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in Neuro-oncology Working Group. J Clin Oncol. 2010;28:1963–1972. doi: 10.1200/JCO.2009.26.3541.
    1. Chang SM, et al. Phase II study of phenylacetate in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report. J Clin Oncol. 1999;17:984–990.
    1. Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma—are we there yet? Neuro Oncol. 2013;15:4–27. doi: 10.1093/neuonc/nos273.
    1. Burzynski SR. Treatments for astrocytic tumors in children: current and emerging strategies. Pediatr Drugs. 2006;8:167–168. doi: 10.2165/00148581-200608030-00003.
    1. Lashford LS, Thiesse P, Jouvet A, Jaspan T, Couanet D, et al. Temozolomide in malignant gliomas of childhood: a United Kingdom Children’s Cancer Study Group and French Society for Pediatric Oncology Intergroup Study. J Clin Oncol. 2002;20:4684–4691. doi: 10.1200/JCO.2002.08.141.
    1. Dreyer ZE, Kadota RP, Stewart CF, Friedman HS, Mahoney DH, et al. Phase 2 study of idarubicin in pediatric brain tumors: Pediatric Oncology Group study POG 9237. Neuro Oncol. 2003;5:261–267. doi: 10.1215/S115285170200056X.
    1. Warren K, Jakacki R, Widemann B, Aikin A, Libucha M, et al. Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children’s Oncology Group. Cancer Chemother Pharmacol. 2006;58:343–347. doi: 10.1007/s00280-005-0172-7.
    1. Fouladi M, Nicholson HS, Zhou T, Laningham F, Helton KJ, et al. A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: a Children’s Oncology Group study. Cancer. 2007;110:2535–2541. doi: 10.1002/cncr.23078.
    1. Gururangan S, Chi SN, Young Poussaint T, Onar-Thomas A, Gilbertson RJ, et al. Lack of efficacy of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse brainstem glioma: a Pediatric Brain Tumor Consortium study. J Clin Oncol. 2010;2010(28):3069–3075. doi: 10.1200/JCO.2009.26.8789.
    1. Minturn JE, Janss AJ, Fisher PG, Allen JC, Patti R, et al. A phase II study of metronomic oral topotecan for recurrent childhood brain tumors. Pediatr Blood Cancer. 2011;56:39–44. doi: 10.1002/pbc.22690.
    1. Warren KE, Gururangan S, Geyer JR, McLendon RE, Poussaint TY, et al. A phase II study of 06-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain tumor Consortium study. J Neurooncol. 2012;106:643–649. doi: 10.1007/s11060-011-0709-z.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe