Recurrent Glioblastoma Multiforme—A Strategy for Long-Term Survival


Recurrent GBM (RGBM) has a highly unfavorable prognosis with majority of patients dying within 6 months and no standard treatments available. Antineoplaston (ANP) A10 and AS2-1 injections underwent Phase II trials in RGBM patients, which reported a long-term overall survival (OS) in a small percentage of patients. The additional Phase II studies BT-07, and BT-21 with ANP in GBM also revealed cases of a long-term OS. ANP shares active ingredients with metabolites of sodium phenylbutyrate (PB), which was used in private practice setting in combination of targeted and chemotherapeutic agents for the treatment of RGBM. The treatment contributed to cases of rapid complete response (CR) and significant OS. This paper provides case studies of three patients treated with ANP under Phase II protocols and two patients treated with PB in combination with targeted therapy, who obtained CR and long-term OS. Based on these studies and basic research on the effects of ANP and PB on the genome of GBM and review of results of preclinical and clinical research on targeted agents, the authors suggest a new strategy for successful treatment of RGBM. They propose Phase I/II clinical trials with ANP and PB in combination with targeted agents, bevacizumab (BVZ), pazopanib, dasatinib and everolimus in patients with RGBM after failure of standard surgery, radiation therapy (RT) and chemotherapy including temozolomide (TMZ) to be conducted to evaluate survival, response and toxicity in these patients.

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Burzynski, S. , Burzynski, G. and Janicki, T. (2014) Recurrent Glioblastoma Multiforme—A Strategy for Long-Term Survival. Journal of Cancer Therapy, 5, 957-976. doi: 10.4236/jct.2014.510101.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Ostrom, Q.T., Gittleman, H., Farah, P., Ondracek, A., Chen, Y., Wolinsky, Y., et al. (2013) CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States 2006-2010. Neuro-Oncology, 15, ii1-ii56.
[2] Louis, N., Ohgaki, H., Wiestler, O.D., Cavenee, W.K., Burger, P.C., Jouvet, A., et al. (2007) The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathologica, 114, 97-109.
[3] Ohka, F. Natsume, A. and Wakabayashi, T. (2012) Current Trends in Targeted Therapies for Glioblastoma Multiforme. Neurology Research International, 2012, Article ID: 878425.
[4] Jemal, A., Siegel, R., Xu, J. and Ward, E. (2010) Cancer Statistics 2010. CA: A Cancer Journal for Clinicians, 60, 277-300.
[5] Olson, J.J., Nayak, L., Ormond, D.R., Wen, P.Y., Kalkanis, S.N. and Ryken, T.C. (2014) The Role of Targeted Therapies in the Management of Progressive Glioblastoma. Journal of Neuro-Oncology, 118, 557-599.
[6] Stupp, R., Mason, W.P., van den Bent, M.J., Weller, M., Fisher, B., Taphoorn, M.J.B., et al. (2005) Radiotherapy PlusConcomitant and Adjuvant Temozolomide for Glioblastoma. The New England Journal of Medicine, 352, 987-996.
[7] Stupp, R., Hegi, M.E., Mason, W.P., van den Bent, M.J., Taphoorn, M.J., Janzer, R.C., et al. (2009) Effects of Radiotherapy with Concomitant and Adjuvant Temozolomide Versus Radiotherapy Alone on Survival in Glioblastoma in a Randomized Phase III Study: 5-Year Analysis of the EORTC-NCIC Trial. The Lancet Oncology, 10, 459-466.
[8] Burzynski, S.R. (1969) Investigations on Unknown Ninhydrin-Reacting Substances in Human Blood Serum. I. Attempts at Identification of Three Such Substances. Experientia, 25, 490-491.
[9] Burzynski, S.R. (1976) Antineoplastons: Biochemical Defense against Cancer. Physiological Chemistry and Physics, 8, 275-279.
[10] Burzynski, S.R. (1986) Antineoplastons—History of the Research (I). Drugs under Experimental and Clinical Research, 12, 1-9.
[11] Burzynski, S.R. (2004) The Present State of Antineoplaston Research (1). Integrative Cancer Therapies, 3, 47-58.
[12] Burzynski, S.R. (2006) Treatments for Astrocytic Tumors in Children: Current and Emerging Strategies. Pediatric Drugs, 8, 167-168.
[13] Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Marszalek, A. (2014) 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. Child’s Nervous System, Published Online.
[14] Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Marszalek, A. (2014) A Phase II Study of Antineoplastons A10 and AS2-1 in Children with High-Grade Glioma. Final Report (Protocol BT-06), and Review of Recent Trials. Journal of Cancer Therapy, 5, 565-577.
[15] Burzynski, S.R. (1986) Synthetic Antineoplastons and Analogs. Drugs of the Future, 11, 679-688.
[16] Burzynski, S.R. (1988) Antineoplastons: Basic Research and Clinical Applications. Advances in Experimental and Clinical Chemotherapies, 6, 1-7.
[17] Burzynski, S.R., Janicki, T.J. and Burzynski, G.S. (2014) A Phase II Study of Antineoplastons A10 and AS2-1 in Adult Patients with Recurrent Glioblastoma Multiforme. Final Report (Protocol BT-21). Journal of Cancer Therapy, in press.
[18] Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Marszalek, A. (2014) A Phase II Study of Antineoplastons A10 and AS2-1 in Children with Recurrent, Refractory or Progressive Primary Brain Tumors. Final Report (Protocol BT-22). Journal of Cancer Therapy, in press.
[19] Sturm, D., Witt, H., Hovestadt, V., Khuong-Quang, D.A., Jones, D.T., Konermann, C., et al. (2012) Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma. Cancer Cell, 22, 425-437.
[20] Kim, Y.W., Koul, D., Kim, S.H., Lucio-Eterovic, A.K., Freire, P.R., Yao, J., et al. (2013) Identification of Prognostic Gene Signatures of Glioblastoma: A Study Based on TCGA Data Analysis. Neuro-Oncology, 15, 829-839.
[21] Burzynski, S.R. and Patil, S. (2014) The Effect of Antineoplastons A10 and AS2-1 and Metabolites of Sodium Phenylbutyrate on Gene Expression in Glioblastoma Multiforme. Journal of Cancer Therapy, in press.
[22] Brusilow, S.W., Danney, M., Waber, L.J., Batshaw, M., Burton, B., Levitsky, L., et al. (1984) Treatment of Episodic Hyperammonemia in Children with Inborn Errors of Urea Synthesis. The New England Journal of Medicine, 310, 1630-1634.
[23] Phuphanich, S., Baker, S.D., Grossman, S.A., Carson, K.A., Gilbert, M.R., Fisher, J.D., et al. (2005) Oral Sodium Phenylbutyrate in Patients with Recurrent Malignant Gliomas: A Dose Escalation and Pharmacologic Study. Neuro-Oncology, 7, 177-182.
[24] Baker, M.J., Brem, S., Daniels, S., Sherman, B. and Phuphanich, S. (2002) Complete Response of a Recurrent, Multicentric Malignant Glioma in a Patient Treated with Phenylbutyrate. Journal of Neuro-Oncology, 59, 239-242.
[25] Weller, M., Cloughesy, T., Perry, J.R. and Wick, W. (2013) Standards of Care for Treatment of Recurrent Glioblastoma—Are We There Yet? Neuro-Oncology, 15, 4-27.
[26] Prados, M.D. (2014) “We Will Know if When We See It;” Bevacizumab and Glioblastoma. Neuro-Oncology, 16, 469-470.
[27] Geison, L. (1995) The Private Science of Louis Pasteur. Princeton University Press, Princeton.
[28] Comfort, N. (2012) The Science of Human Perfection: How Genes Became the Heart of American Medicine. Yale University Press, New Haven.
[29] Kreisl, T.N., Kim, L., Moore, K., Duic, P., Royce, C., Stroud, I., et al. (2009) Phase II Trial of Single-Agent Bevacizumab Followed by Bevacizumab Plus Irinotecan at Tumor Progression in Recurrent Glioblastoma. Journal of Clinical Oncology, 27, 740-745.
[30] Friedman, S., Prados, M.D., Wen, P.Y., Mikkelsen, T., Schiff, D., Abrey, L.E., et al. (2009) Bevacizumab Alone and in Combination with Irinotecan in Recurrent Glioblastoma. Journal of Clinical Oncology, 27, 4733-4740.
[31] Chamberlain, M.C. and Johnston, S.K. (2010) Salvage Therapy with Single Agent Bevacizumab for Recurrent Glioblastoma. Journal of Neuro-Oncology, 96, 259-269.
[32] Burkhardt, J.K., Riina, H., Shin, B.J., Christos, P., Kesavabhotla, K., Hofstetter, C.P., et al. (2012) Intra-Arterial Delivery of Bevacizumab after Blood-Brain Barrier Disruption for the Treatment of Recurrent Glioblastoma: Progression-Free Survival and Overall Survival. World Neurosurgery, 77, 130-134.
[33] Raiser, J.J., Abrey, L.E., Lassman, A.B., Chang, S.M., Lamborn, K.R., Kuhn, J.G., et al. (2010) A Phase II Trial of Erlotinib in Patients with Recurrent Malignant Gliomas and Non-Progressive Glioblastoma Multiforme Postradiation Therapy. Neuro-Oncology, 12, 95-103.
[34] Iwamoto, M., Lamborn, K.R., Robins, H.I., Mehta, M.P., Chang, S.M., Butowski, N.A., et al. (2010) Phase II Trial of Pazopanib (GW786034), and Oral Multi-Targeted Angiogenesis Inhibitor, for Adults with Recurrent Glioblastoma (North American Brain Tumor Consortium Study 06-02). Neuro-Oncology, 12, 855-861.
[35] Galanis, E., Jaeckle, K.A., Maurer, M.J., Reid, J.M., Ames, M.M., Hardwick, J.S., et al. (2009) Phase II Trial of Vorinostat in Recurrent Glioblastoma Multiforme: A North Central Cancer Treatment Group Study. Journal of Clinical Oncology, 27, 2052-2058.
[36] Galanis, E., Buchner, J.C., Maurer, M.J., Kreisberg, J.I., Ballman, K., Boni, J., et al. (2005) Phase II Trial of Temsirolimus (CCI-779) in Recurrent Glioblastoma Multiforme: A North Central Cancer Treatment Group Study. Journal of Clinical Oncology, 23, 5294-5304.
[37] Sathornsumetee, S., Desjardins, A., Vredenburgh, J.J., McLendon, R.E., Marcello, J., Herndon, J.E., et al. (2010) Phase II Trial of Bevacizumab and Erlotinib in Patients with Recurrent Malignant Glioma. Neuro-Oncology, 12, 1300-1310.
[38] Reardon, D.A., Desjardins, A., Vredenburgh, J.J., Gururangan, S., Friedman, A.H., Herndon, J.E., et al. (2010) Phase 2 Trial of Erlotinib Plus Sirolimus in Adults with Recurrent Glioblastoma. Journal of Neuro-Oncology, 96, 219-230.
[39] Lu-Emerson, C., Norden, A.D., Drappatz, J., Quant, E.C., Beroukhim, R., Ciampa, A.S., et al. (2011) Retrospective Study of Dasatinib for Recurrent Glioblastoma after Bevacizumab Failure. Journal of Neuro-Oncology, 104, 287-291.
[40] Reardon, D.A., Vredenburgh, J.J., Desjardins, A., Peters, K., Gururangan, S., Sampson, S.H., et al. (2011) Effect of CYP3A-Inducing Anti-Epileptics on Sorafenib Exposure: Results of a Phase II Study of Sorafenib Plus Daily Temozolomide in Adults with Recurrent Glioblastoma. Journal of Neuro-Oncology, 101, 57-66.
[41] Friday, B., Anderson, S.K., Buckner, J., Yu, C., Giannini, C., Geoffroy, F., et al. (2012) Phase II Trial of Vorinostat in Combination with Bortezomib in Recurrent Glioblastoma: A North Central Cancer Treatment Group Study. Neuro-Oncology, 14, 215-221.
[42] Chang, S.M., Kuhn, J.G., Robins, H.I., Schold, S.C., Spence, A.M., Berger, M.S., et al. (1999) Phase II Study of Phenylacetate in Patients with Recurrent Malignant Glioma: A North American Brain Tumor Consortium Report. Journal of Neuro-Oncology, 17, 984-990.
[43] Goel, L. and Mercurio, A.M. (2013) VEGF Targets the Tumour Cell. Nature Reviews Cancer, 13, 871-882.
[44] Prud’homme, G.J. and Glinka Y. (2012) Neuropilins Are Multifunctional Coreceptors Involved in Tumor Initiation, Growth, Metastasis and Immunity. Oncotarget, 3, 921-939.
[45] Soker, S., Takashima, S., Miao, H.Q., Neufeld, G. and Klagsbrun, M. (1998) Neuropilin-1 Is Expressed by Endothelial and Tumor Cells as an Isoform-Specific Receptor for Vascular Endothelial Growth Factor. Cell, 92, 735-745.
[46] Zachary, I.C., Frankel, P., Evans, I.M. and Pellet-Many, C. (2009) The Role of Neuropilins in Cell Signalling. Biochemical Society Transactions, 37, 1171-1178.
[47] Kolodkin, A.L., Levengood, D.V., Rowe, E.G., Tai, Y.T., Giger, R.J. and Ginty, D.D. (1997) Neuropilin Is a Semaphorin III Receptor. Cell, 90, 735-762.
[48] Neufeld, G., Kessler, O. and Herzog, Y. (2002) The Interaction of Neuropilin-1 and Neuropilin-2 with Tyrosine-Kinase Receptors for VEGF. Advances in Experimental Medicine and Biology, 515, 81-90.
[49] Nakayama, M. and Berger, P. (2013) Coordination of VEGF Receptor Trafficking and Signaling by Coreceptors. Experimental Cell Research, 319, 1340-1347.
[50] Goel, L., Chang, C., Pursell, B., Leav, I., Lyle, S., Xi, .S., et al. (2012) VEGF/Neurophilin-2 Regulation of Bmi-1 and Consequent Repression of IGF-1R Define a Novel Mechanism of Aggressive Prostate Cancer. Cancer Discovery, 2, 906-921.
[51] Lu, V., Chang, J.P., Parachoniak, C.A., Pandika, M.M., Aghi, M.K., Meyronet, D., et al. (2012) VEGF Inhibits Tumor Cell Invasion and Mesenchymal Transition Through a MET/VEGFR2 Complex. Cancer Cell, 22, 21-35.
[52] Rizzolio, S., Rabinowicz, N., Rainero, E., Lanzetti, L., Serini, G., Norman, J., et al. (2012) Neuropilin-1-Dependent Regulation of EGF-Receptor Signaling. Cancer Research, 72, 5801-5811.
[53] Grandclement, C., Pallandre, J.R., Degano, S.V., Viel, E., Bouard, A., Balland, J., et al. (2011) Neuropilin-2 Expression Promotes TGF-β1-Mediated Epithelial to Mesenchymal Transition in Colorectal Cancer Cells. PLoS ONE, 6, Article ID: e20444.
[54] Ginka, Y., Stoilova, S., Mohammed, N. and Prud’homme, G.J. (2011) Neuropilin-1 Exerts Co-Receptor Function for TGF-β-1 on the Membrane of Cancer Cells and Enhances Responses to Both Latent and Active TGF-β. Carcinogenesis, 32, 613-621.
[55] West, C.G., Rees, L., Duchesne, S.J., Patey, C.J., Terry, J.E., Turnbull, J.E., et al. (2005) Interactions of Multiple Heparin Binding Growth Factors with Neuropilin-1 and Potentiation of the Acidity of Fibroblast Growth Factor-2. The Journal of Biological Chemistry, 280, 13457-13464.
[56] Banerjee, S., Sengupta, K., Dhar, K., Mehta, S., D’Amore, P.A., Dhar, G., et al. (2006) Breast Cancer Cells Secreted Platelet-Derived Growth Factor-Induced Motility of Vascular Smooth Muscle Cells in Mediated Through Neuropilin-1. Molecular Carcinogenesis, 45, 871-880.
[57] Byzova, T.V., Goldman, C.K., Pampori, N., Thomas, K.A., Bett, A., Shattil, S.J., et al. (2000) A Mechanism for Modulation of Cellular Responses to VEGF: Activation of the Integrins. Molecular Cell, 6, 851-860.
[58] Wey, S., Gray, M.J., Fan, F., Belcheva, A., McCarty, M.F., Stoeltzing, O., et al. (2005) Overexpression of Neuropilin-1 Promotes Constitutive MAPK Signaling and Chemoresistance in Pancreatic Cancer Cells. British Journal of Cancer, 93, 233-241.
[59] Staton, J., Dutta, S., Zhang, H., Polavaram, N.S., Leontovich, A.A., Honscheid, P., et al. (2013) Autophagy Control by the VEGF-C/NRP-2 Axis in Cancer and Its Implication for Treatment Resistance. Cancer Research, 73, 160-171.
[60] Beck, B., Driessens, G., Goossens, S., Youssef, K.K., Kuchnio, A., Caauwe, A., et al. (2011) A Vascular Niche and a VEGF-Nrp1 Loop Regular the Initiation and Stemness of Skin Tumours. Nature, 478, 399-403.
[61] Snuderl, M., Batista, A., Kirkpatrick, N.D., de Almodovar, C.R., Riedemann, L., Walsh, E.C., et al. (2013) Targeting Placental Growth Factor/Neuropilin 1 Pathway Inhibits Growth and Spread of Medulloblastoma. Cell, 152, 1065-1076.
[62] Ellis, L.M. and Hicklin, D.J. (2008) VEGF-Targeted Therapy: Mechanisms of Anti-Tumour Activity. Nature Reviews Cancer, 8, 579-591.
[63] De Bacco, F., Casanova, E., Medico, E., Pellegatta, S., Orzan, F., Albano, R., et al. (2012) The MET Oncogene Is a Functional Marker of a Glioblastoma Stem Cell Subtype. Cancer Research, 72, 4537-4550.
[64] Bottsford-Miller, J.N., Coleman, R.L. and Sood, A.K. (2012) Resistance and Escape from Antiangiogenesis Therapy: Clinical Implications and Future Strategies. Journal of Clinical Oncology, 30, 4026-4034.
[65] Wick, W., Weller, M., Weiler, M., Batchelor, T., Yung, A.W.K. and Platten, M. (2011) Pathway Inhibition: Emerging Molecular Targets for Treating Glioblastoma. Neuro-Oncology, 13, 566-579.
[66] Chinnaiyan, P., Kensicki, E., Bloom, G., Prabhu, A., Sarcar, B., Kahali, S., et al. (2012) The Metabolomic Signature of Malignant Glioma Reflects Accelerated Anabolic Metabolism. Cancer Research, 72, 5878-5888.

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