Antineoplaston Therapy and Sodium Phenylbutyrate - CAM 024
Antineoplaston therapy is a complementary/alternative cancer treatment that involves using a group of synthetic chemicals called antineoplastons intended to protect the body from disease. Antineoplastons are made up mostly of peptides and amino acids originally taken from human blood and urine. Sodium phenylbutyrate is used together with a proper diet to help treat urea cycle disorders (including a specific liver enzyme deficiency) that help remove ammonia from the body.
Antineoplaston therapy (auto-urine therapy) and associated medical services is investigaional and/or unproven and therefore is considered NOT MEDICALLY NECESSARY because there is insufficient evidence published in the peer-reviewed medical literature validating the effectiveness of antineoplaston therapy for any indication.
Services associated with antineoplaston therapy are investigational and/or unproven and therefore are considered NOT MEDICALLY NECESSARY, including:
Ancillary diagnostic laboratory, X-rays, MRI or CT scans done to monitor antineoplaston therapy
Infusion pump and intravenous supplies for use with the infusion pump
Placement of Hickman catheter
Oral antineoplaston therapy or associated physician services for administering and monitoring oral antineoplaston therapy are investigational and/or unproven and are therefore considered NOT MEDICALLY NECESSARY
Sodium phenylbutyrate is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for the treatment of breast cancer and prostate cancer
Sodium phenylbutyrate is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for the treatment of amyotrophic lateral sclerosis, beta-thalassemia, insulin resistance and beta-cell dysfunction, maple syrup urine disease, sickle cell anemia, spinal muscular atrophy and for all other indications
Antineoplastons are a group of naturally occurring peptides, which have been hypothesized to have anti-tumor activity. Antineoplaston treatment is offered by the Burzynski Research Institute in Houston, Texas, and has long been a controversial treatment for various types of malignancy. This therapy is not approved by the FDA for any indication. Of note, there are no controlled, peer-reviewed clinical trials indicating that antineoplaston therapy is effective for any indication.
Primitive neuroectodermal tumors (PNETs) are often treated with cranio-spinal radiation and chemotherapy. However, difficulties with conventional therapies can be encountered in very young children, in adult patients at high-risk of complication from standard treatment, as well as in patients with recurrent tumors. In a phase II clinical trial, Burzynski et al. (2005) studied the effect of antineoplaston (ANP) therapy in 13 children, either with recurrent disease or high-risk disease (median age of five years and seven months, with a range of 1 to 11 years). Medulloblastoma was diagnosed in eight patients, pineoblastoma in three patients and other PNET in two patients. Prior therapies included surgery in 12 patients (1 had biopsy only, suboccipital craniotomy), chemotherapy in six patients and radiation therapy in six patients. Six patients had not received chemotherapy or radiation. The treatment consisted of intravenous infusions of two formulations of ANP, A10 and AS2-1, and was administered for an average of 20 months. The average dosage of A10 was 10.3 g/kg/day and of AS2-1 was 0.38 g/kg/day. Complete response was accomplished in 23 percent, partial response in eight percent, stable disease in 31 percent and progressive disease in 38 percent of cases. Six patients (46 percent) survived more than five years from initiation of ANP; five were not treated earlier with radiation therapy or chemotherapy. Serious side effects included single occurrences of fever, anemia and granulocytopenia. Investigators noted that the percentage of patients' response is lower than for standard treatment of favorable PNET, but long-term survival in poor-risk cases and reduced toxicity makes ANP therapy promising for very young children, patients at high-risk of complication of standard therapy and patients with recurrent tumors.
Sodium phenylbutyrate (Buphenyl) taken orally metabolizes in the liver into a combination of phenylacetylglutamine and phenylacetate, which then enter the bloodstream. Those two chemicals are the prime ingredients of antineoplaston AS2-1.
Sodium phenylbutyrate removes ammonia from the bloodstream. It has been approved by the FDA for use in patients with urea cycle disorders and has also received an orphan drug designation by the FDA for treatment of acute promyelocytic leukemia. Sodium phenylbutyrate was given an orphan drug designation by the FDA for use as an adjunct to surgery, radiation therapy and chemotherapy for treatment of patients with primary or recurrent malignant glioma.
Since sodium phenylbutyrate has been approved by the FDA for treatment of other indications, physicians can prescribe it for patients without any danger of legal sanctions or need for compassionate use exemptions. However, there is no adequate evidence in the peer-reviewed published medical literature demonstrating that the use of sodium phenylbutyrate improves the clinical outcomes of patients with cancers of the prostate, breast or cancers other than acute promyelocytic leukemia and malignant glioma. Current evidence is limited to in-vitro and in-vivo studies and phase I studies. Prospective phase III clinical outcome studies are necessary to determine the clinical effectiveness of sodium phenylbutyrate for cancer.
Wirth et al. (2006) stated that the molecular genetic basis of SMA is the loss of function of SMN1. The SMN2 gene, a nearly identical copy of SMN1, has been detected as a promising target for SMA therapy. Both genes encode identical proteins, but differ markedly in their splicing patterns, with SMN1 producing full-length (FL)-SMN transcripts only, while the majority of SMN2 transcripts lack exon seven. Transcriptional SMN2 activation or modulation of its splicing pattern to increase FL-SMN levels is thought to benefit patients with SMA. Drugs such as valproic acid, phenylbutyrate, sodium butyrate, M344 and SAHA can stimulate the SMN2 gene transcription and/or restore the splicing pattern, thereby raising the levels of FL-SMN2 protein. Phase II clinical trials have shown promising results. However, phase III double-blind placebo-controlled studies are needed to prove the effectiveness of these drugs.
In a phase I clinical trial, Lin and associates (2009) determined the minimal effective dose and optimal dose schedule for 5-azacytidine (5-AC) in combination with sodium phenylbutyrate in patients with refractory solid tumors. The pharmacokinetics, pharmacodynamics and antineoplastic effects were also studied. Three dosing regimens were studied in 27 patients with advanced solid tumors, and toxicity was recorded. The pharmacokinetics of the combination of drugs was evaluated. Repeat tumor biopsies and peripheral blood mononuclear cells (PBMC) were analyzed to evaluate epigenetic changes in response to therapy. Epstein Barr virus titers were evaluated as a surrogate measure for gene re-expression of epigenetic modulation in PBMC. The 3-dose regimens of 5-AC and phenylbutyrate were generally well-tolerated and safe. A total of 48 cycles was administrated to 27 patients. The most common toxicities were bone marrow suppression-related neutropenia and anemia, which were minor. The clinical response rate was disappointing for the combination of agents. One patient showed stable disease for five months, whereas 26 patients showed progressive disease as the best tumor response. The administration of sodium phenylbutyrate and 5-AC did not seem to alter the pharmacokinetics of either drug. Although there were individual cases of targeted DNA methyltransferase activity and histone H3/4 acetylation changes from paired biopsy or PBMC, no conclusive statement can be made based on these limited correlative studies. The authors concluded that the combination of 5-AC and sodium phenylbutyrate across 3-dose schedules was generally well-tolerated and safe, yet lacked any real evidence for clinical benefit.
- Green S. 'Antineoplastons' An unproved cancer therapy. JAMA. 1992;267:2924-2928.
- Burzynski Clinic [website]. Houston, TX: Burzynski Clinic; 2001.
- Juszkiewicz M, Chodkowska A, Burzynski SR, et al. The influence of antineoplaston A5 on particular subtypes of central dopaminergic receptors. Drugs Exp Clin Res. 1995;21(4):153-156.
- Tsuda H, Hara H, Eriguchi N, et al. Toxicological study on antineoplastons A-10 and AS2-1 in cancer patients. Kurume Med. J 1995;42(4):241-249.
- Tsuda H, Iemura A, Sata M, et al. Inhibitory effect of antineoplaston A10 and AS2-1 on human hepatocellular carcinoma. Kurume Med J. 1996;43(2):137-147.
- Sugita Y, Tsuda H, Maruiwa H, et al. The effects of Antineoplaston, a new antitumor agent on malignant brain tumors. Kurume Med J. 1995;42(3):133-140.
- Burzynski SR. Potential of antineoplastons in diseases of old age. Drugs Aging. 1995;7(3):157-167.
- Soltysiak-Pawluczuk D, Burzynski SR. Cellular accumulation of antineoplaston AS21 in human hepatoma cells. Cancer Lett. 1995;88(1):107-112.
- Kumabe T. Antineoplaston treatment for advanced hepatocellular carcinoma. Oncology Rep. 1998;5(6):1363-1367.
- Buckner JC, Malkin MG, Reed E, et al. Phase II study of antineoplastons A1O (NSC 648539) and AS2-1 (NSC 620261) in patients with recurrent glioma. Mayo Clinic Proc. 1999;74(2):137-145.
- Tsuda H, Sata M, Kumabe T, et al. Quick response of advanced cancer to chemoradiation therapy with antineoplastons. Oncology Rep. 1998;5(3):597-600.
- Choi BG. Synthesis of antineoplaston A10 as potential antitumor agents. Arch Pharm Res. 1998;21(2):157-163.
- Tweddle S, James N. Lessons from antineoplaston. Lancet. 1997;349(9063):1481.
- Badria F, Mabed M, El-Awadi M, et al. Immune modulatory potentials of antineoplaston A-10 in breast cancer patients. Cancer Lett. 2000;157(1):57-63.
- Congress of the United States, Office of Technology Assessment. Unconventional Cancer Treatments. OTA-H-405. Washington, DC: U.S. Government Printing Office; September 1990.
- National Cancer Institute (NCI). Antineoplastons. Cancer Facts. Bethesda, MD: NCI; revised May 20, 2002.
- BC Cancer Agency. Unconventional Therapies - Antineoplastons. Patient/Public Information. Vancouver, BC: BC Cancer Agency; revised February 2000.
- U.S. Food and Drug Administration (FDA). List of Orphan Drug Designations for January 2000. Rockville, MD: FDA; February 4, 2000.
- U.S. Pharmacopeial Convention Inc. Sodium phenylbutyrate (systemic). In: USP DI: Drug Information for the Healthcare Professional. Greenwood Village, CO: Micromedex; 2002.
- Gore SD, Weng LJ, Figg WD, et al. Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res. 2002;8(4):963-970.
- Carducci MA, Gilbert J, Bowling MK, et al. A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule. Clin Cancer Res. 2001;7(10):3047-3055.
- Gore SD, Weng LJ, Zhai S, et al. Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res. 2001;7(8):2330-2339.
- Gilbert J, Baker SD, Bowling MK, et al. A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin Cancer Res. 2001;7(8):2292-2300.
- Boudoulas S, Lush RM, McCall NA, et al. Plasma protein binding of phenylacetate and phenylbutyrate, two novel antineoplastic agents. Ther Drug Monit. 1996;18(6):714-720.
- Tsuda H, Sata M, Ijuuin H, et al. A novel strategy for remission induction and maintenance in cancer therapy. Oncol Rep. 2002;9(1):65-68.
- Piscitelli SC, Thibault A, Figg WD, et al. Disposition of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine. J Clin Pharmacol. 1995;35(4):368-373.
- Linz U. Complete response of a recurrent, multicentric malignant glioma in a patient treated with phenylbutyrate. J Neurooncol. 2004;66(1-2):251.
- Finzer P, Stohr M, Seibert N, Rosl F. Phenylbutyrate inhibits growth of cervical carcinoma cells independent of HPV type and copy number. J Cancer Res Clin Oncol. 2003;129(2):107-113.
- Svechnikova I, Gray SG, Kundrotiene J, et al. Apoptosis and tumor remission in liver tumor xenografts by 4-phenylbutyrate. Int J Oncol. 2003;22(3):579-588.
- Kennedy C, Byth K, Clarke CL, deFazio A. Cell proliferation in the normal mouse mammary gland and inhibition by phenylbutyrate. Mol Cancer Ther. 2002;1(12):1025-1033.
- Boivin AJ, Momparler LF, Hurtubise A, Momparler RL. Antineoplastic action of 5-aza-2'-deoxycytidine and phenylbutyrate on human lung carcinoma cells. Anticancer Drugs. 2002;13(8):869-874.
- Baker MJ, Brem S, Daniels S, et al. Complete response of a recurrent, multicentric malignant glioma in a patient treated with phenylbutyrate. J Neurooncol. 2002;59(3):239-242.
- Dyer ES, Paulsen MT, Markwart SM, et al. Phenylbutyrate inhibits the invasive properties of prostate and breast cancer cell lines in the sea urchin embryo basement membrane invasion assay. Int J Cancer. 2002;101(5):496-499.
- Andratschke N, Grosu AL, Molls M, Nieder C. Perspectives in the treatment of malignant gliomas in adults. Anticancer Res. 2001;21(5):3541-3550.
- Reynolds S, Cederberg H, Chakrabarty S. Inhibitory effect of 1-O (2 methoxy) hexadecyl glycerol and phenylbutyrate on the malignant properties of human prostate cancer cells. Clin Exp Metastasis. 2000;18(4):309-312.
- Calvaruso G, Carabillo M, Giuliano M, et al. Sodium phenylbutyrate induces apoptosis in human retinoblastoma Y79 cells: The effect of combined treatment with the topoisomerase I-inhibitor topotecan. Int J Oncol. 2001;18(6):1233-1237.
- Walczak J, Wood H, Wilding G, et al. Prostate cancer prevention strategies using antiproliferative or differentiating agents. Urology. 2001;57(4 Suppl 1):81-85.
- Pili R, Kruszewski MP, Hager BW, et al. Combination of phenylbutyrate and 13-cis retinoic acid inhibits prostate tumor growth and angiogenesis. Cancer Res. 2001;61(4):1477-1485.
- Gore SD, Carducci MA. Modifying histones to tame cancer: Clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors. Expert Opin Investig Drugs. 2000;9(12):2923-2934.
- Nieder C, Nestle U. A review of current and future treatment strategies for malignant astrocytomas in adults. Strahlenther Onkol. 2000;176(6):251-258.
- Huang Y, Horvath CM, Waxman S. Regrowth of 5-fluorouracil-treated human colon cancer cells is prevented by the combination of interferon gamma, indomethacin, and phenylbutyrate. Cancer Res. 2000;60(12):3200-3206.
- Wargovich MJ, Jimenez A, McKee K, et al. Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression. Carcinogenesis. 2000;21(6):1149-1155.
- Chung YL, Lee YH, Yen SH, Chi KH. A novel approach for nasopharyngeal carcinoma treatment uses phenylbutyrate as a protein kinase C modulator: Implications for radiosensitization and EBV-targeted therapy. Clin Cancer Res. 2000;6(4):1452-1458.
- Ng AY, Bales W, Veltri RW. Phenylbutyrate-induced apoptosis and differential expression of Bcl-2, Bax, p53 and Fas in human prostate cancer cell lines. Anal Quant Cytol Histol. 2000;22(1):45-54.
- Witzig TE, Timm M, Stenson M, et al. Induction of apoptosis in malignant B cells by phenylbutyrate or phenylacetate in combination with chemotherapeutic agents. Clin Cancer Res. 2000;6(2):681-692.
- Lea MA, Randolph VM, Hodge SK. Induction of histone acetylation and growth regulation in eryrthroleukemia cells by 4-phenylbutyrate and structural analogs. Anticancer Res. 1999;19(3A):1971-1976.
- Yu KH, Weng LJ, Fu S, et al. Augmentation of phenylbutyrate-induced differentiation of myeloid leukemia cells using all-trans retinoic acid. Leukemia. 1999;13(8):1258-1265.
- DiGiuseppe JA, Weng LJ, Yu KH, et al. Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: Structure-function analysis. Leukemia. 1999;13(8):1243-1253.
- Bar-Ner M, Thibault A, Tsokos M, et al. Phenylbutyrate induces cell differentiation and modulates Epstein-Barr virus gene expression in Burkitt's lymphoma cells. Clin Cancer Res. 1999;5(6):1509-1516.
- Wang J, Saunthararajah Y, Redner RL, Liu JM. Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. Cancer Res. 1999;59(12):2766-2769.
- Melchior SW, Brown LG, Figg WD, et al. Effects of phenylbutyrate on proliferation and apoptosis in human prostate cancer cells in vitro and in vivo. Int J Oncol. 1999;14(3):501-508.
- Melichar B, Ferrandina G, Verschraegen CF, et al. Growth inhibitory effects of aromatic fatty acids on ovarian tumor cell lines. Clin Cancer Res. 1998;4(12):3069-3076.
- Shack S, Miller A, Liu L, et al. Vulnerability of multidrug-resistant tumor cells to the aromatic fatty acids phenylacetate and phenylbutyrate. Clin Cancer Res. 1996;2(5):865-872.
- Carducci MA, Nelson JB, Chan-Tack KM, et al. Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate. Clin Cancer Res. 1996;2(2):379-387.
- Prasanna P, Shack S, Wilson VL, Samid D. Phenylacetate in chemoprevention: in vitro and in vivo suppression of 5-aza-2'-deoxycytidine-induced carcinogenesis. Clin Cancer Res. 1995;1(8):865-871.
- Gore SD, Samid D, Weng LJ. Impact of the putative differentiating agents sodium phenylbutyrate and sodium phenylacetate on proliferation, differentiation, and apoptosis of primary neoplastic myeloid cells. Clin Cancer Res. 1997;3(10):1755-1762.
- Warrell RP Jr, He LZ, Richon V, et al. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst. 1998;90(21):1621-1625.
- Huang Y, Waxman S. Enhanced growth inhibition and differentiation of fluorodeoxyuridine-treated human colon carcinoma cells by phenylbutyrate. Clin Cancer Res. 1998;4(10):2503-2509.
- Pelidis MA, Carducci MA, Simons JW. Cytotoxic effects of sodium phenylbutyrate on human neuroblastoma cell lines. Int J Oncol. 1998;12(4):889-893.
- Samid D, Hudgins WR, Shack S, et al. Phenylacetate and phenylbutyrate as novel, nontoxic differentiation inducers. Adv Exp Med Biol. 1997;400A:501-505.
- Engelhard HH, Homer RJ, Duncan HA, Rozental J. Inhibitory effects of phenylbutyrate on the proliferation, morphology, migration and invasiveness of malignant glioma cells. J Neurooncol. 1998;37(2):97-108.
- Liu L, Hudgins WR, Miller AC, et al. Transcriptional upregulation of TGF-alpha by phenylacetate and phenylbutyrate is associated with differentiation of human melanoma cells. Cytokine. 1995;7(5):449-456.
- U.S. Food and Drug Administration (FDA). Orphan Products Designations and Approvals List Through February 2001. Rockville, MD: FDA; April 16, 2001.
- Burzynski SR, Lewy RI, Weaver RA, et al. Phase II study of antineoplaston A10 and AS2-1 in patients with recurrent diffuse intrinsic brain stem glioma: A preliminary report. Drugs R D. 2003;4(2):91-101.
- Burzynski SR, Weaver RA, Lewy RI, et al. Phase II study of antineoplaston A10 and AS2-1 in children with recurrent and progressive multicentric glioma: A preliminary report. Drugs R D. 2004;5(6):315-326.
- Burzynski SR. The present state of antineoplaston research. Integr Cancer Ther. 2004;3(1):47-58.
- Burzynski SR, Weaver RA, Janicki T, et al. Long-term survival of high-risk pediatric patients with primitive neuroectodermal tumors treated with antineoplastons A10 and AS2-1. Integr Cancer Ther. 2005;4(2):168-177.
- Phuphanich S, Baker SD, Grossman SA, et al. Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: A dose escalation and pharmacologic study. Neuro-oncol. 2005;7(2):177-182.
- Burzynski SR. Treatments for astrocytic tumors in children: Current and emerging strategies. Paediatr Drugs. 2006;8(3):167-178.
- Burzynski SR, Janicki TJ, Weaver RA, Burzynski B. Targeted therapy with antineoplastons A10 and AS2-1 of high-grade, recurrent, and progressive brainstem glioma. Integr Cancer Ther. 2006;5(1):40-47.
- Fujii T, Yokoyama G, Takahashi H, et al. Preclinical studies of molecular-targeting diagnostic and therapeutic strategies against breast cancer. Breast Cancer. 2008;15(1):73-78.
- Perrine SP. Fetal globin stimulant therapies in the beta-hemoglobinopathies: Principles and current potential. Pediatr Ann. 2008;37(5):339-346.
- Lin J, Gilbert J, Rudek MA, et al. A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors. Clin Cancer Res. 2009;15(19):6241-6249.
- Burzynski SR. Stanislaw R. Burzynski, MD, PhD: Novel cancer research and the fight to prove its worth. Altern Ther Health Med. 2012;18(3):54-61
|CPT||96549||Unlisted chemotherapy procedure (when specified as administration of antineoplaston therapy)|
|HCPCS||J3490||Unclassified drugs (when specified as antineoplastons)|
|J8999||Prescription drug, oral, chemotherapeutic, NOS (when specified as antineoplastons)|
|J9999||Not otherwise classified, antineoplastic drugs (when specified as antineoplastons)|
|ICD-9 Diagnosis||All diagnoses|
|ICD-10-CM (effective 10/01/15)||All diagnoses|
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.
"Current Procedural Terminology © American Medical Association. All Rights Reserved"
History From 2014 Forward
Annual review, no change to policy intent.
Annual review, no change to policy intent.
Annual review, updating policy verbiage from stating investigational to all uses of these treatments to be investigational and/or unproven and are therefore considered not medically necessary. No other changes.
Annual review, no change to policy intent.
Annual review, no change to policy intent.
Annual review, no change to policy intent.
Change Category from Medicine to Prescription Drug.
Annual review, no change to policy intent. Addied coding.
Annual review, no changes made.