Medical Policy

 

Subject: Antineoplaston Therapy
Document #: MED.00085 Publish Date:    12/27/2017
Status: Reviewed Last Review Date:    11/02/2017

Description/Scope

This document addresses the use of antineoplaston therapy including the use of sodium phenylbutyrate (Buphenyl®, Pharmaceutics International, Inc., Hunt Valley, MD), a pro-drug that is metabolized in the liver into phenylacetate, when used as an antineoplaston.

Antineoplastons are a group of chemical compounds typically found in urine and blood (National Cancer Institute [NCI], 2015).  The antineoplastons are mainly comprised of medium and small size synthetic peptides and amino acid derivatives thought to be components of a biochemical defense system which functions by activating neoplastic cells to switch back to a path of normal cell development.  Antineoplastons A10 (3-phenylacetylamino-2, 6-piperidinedione) and AS2-1 (phenylacetic acid/phenylacteyl glutamate) have been most commonly researched as a treatment for a wide variety of malignancies.  

Position Statement

Investigational and Not Medically Necessary:

Antineoplaston therapy, including, but not limited to, antineoplaston A10 and AS2-1, is considered investigational and not medically necessary for all conditions, including but not limited to any malignancy.

Rationale

Originally isolated from human blood and urine, the Burzynski Research Institute in Houston, Texas, developed antineoplastons as synthetic compounds made up of naturally occurring peptides, amino acid derivatives and organic acids (namely, glutamine, isoglutamine and phenylacetic acid).  It has been postulated antineoplastons function as molecular switches that inhibit, or turn off, neoplastic cancer cells while sparing normal cells.  Peptides are considered carriers of instructions within the body, and became the focus of research (NCI, 2015).

Peptide fractions and amino acids in the blood of healthy individuals and those suffering from a variety of diseases were analyzed.  It was noted individuals with cancer had significant deficiencies in serum peptide content and peptide fractions identified in their urine.  It was proposed that the peptide fractions were synthesized in tissues and passed into the blood and urine (Burzynski, 2004).  Investigators separated urinary peptides into fractions and studied the effect on the growth of neoplastic and normal cells.  Peptide fractions that inhibited the development of neoplastic cells were named “antineoplastons” and were postulated to be a component in the biochemical defense system against abnormal cell growth (Burzynski, 2004).  Initially, antineoplastons A1, A2, A3, A4 and A5 were investigated in phase 1 studies, and there was suggested activity with A2.  The active compound in A2 was determined to be 3-phenylactylamino-2, 6-piperidinedione and was named antineoplaston A10.

According to Burzynski (2004), A10 has been reproduced by synthesis involving condensation of l-glutamine with phenylacetyl chloride and subsequent cyclization of phenylacetylglutamine (PG).  In the human body, it is thought metabolism of A10 yields PG, phenylacetylisoglutamine (isoPG) and phenylacetate (PN).  These ingredients were reproduced synthetically and formulated into antineoplaston A10 injections.  Additional compounds also obtained from A10 include: AS2-5 (phenylacetylglutamine [PAG]), AS2-1 (a 4:1 mixture of phenyl acid [PA] and PAG) and A5 (which is PA and an aromatic fatty acid (NCI, 2015).  The NCI (2015) also reported “there have been no independent analyses of which amino acids comprise the antineoplastons used in any of the reported studies.” 

At this time, there is no antineoplaston approved by the U. S. Food and Drug Administration (FDA).  Formulations of antineoplastons utilized in phase II studies include: antineoplaston A10 capsules and injection; AS2-1 capsules and injection (Burzynski, 2004; National Cancer Institute, 2015).

Antineoplaston therapy has adverse effects that have been documented in phase I and phase II trials.  The side effects have ranged from mild symptoms with short duration, to severe neurologic toxicity (such as sleepiness, confusion, seizures, and swelling near the brain) which resulted in discontinuation of therapy in some individuals (NCI, 2015).

A search of the literature did not identify any controlled studies of antineoplaston therapy.  The bulk of the literature consists of case reports, case series and non-randomized data from single institution phase II trials.  There are no data published from large, prospective, phase III, randomized controlled trials of cancer diagnoses treated with antineoplaston therapy.  A phase III randomized study of antineoplaston therapy versus temozolomide in subjects with recurrent and/or progressive optic pathway glioma was posted in 2010, but is not yet open for participant recruitment at the Burzynski Research Institute.  Currently, there are ongoing phase II trials studying the use of antineoplastons as a treatment for a variety of oncologic indications, but there have been no published data from these trials.  In summary, there is inadequate published peer-reviewed data from controlled clinical trials to permit scientific conclusions regarding the safety and efficacy of antineoplaston therapy.

The FDA has approved sodium phenylbutyrate as a treatment to remove ammonia from the bloodstream in individuals with urea cycle disorders.  According to the Product Information Label (2009), the overall disposition of sodium phenylbutyrate and its metabolites has not been fully characterized.  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 individuals with primary or recurrent malignant glioma.  However, the FDA has not conferred marketing approval for the orphan designations.  The published peer reviewed literature regarding off-label use of sodium phenylbutyrate as a form of antineoplaston to treat malignancies includes case series, phase I and pilot studies.  This is not sufficient evidence to draw reasonable conclusions regarding the safety or the efficacy of sodium phenylbutyrate as a treatment for malignancy.  Prospective, randomized control trials are needed to determine the clinical effectiveness of sodium phenylbutyrate as a cancer treatment.

Note: In general, prescribed oral medications are covered under the pharmacy benefit plan and excluded from coverage under the medical benefit plan.  The above description of oral drugs being used as antineoplaston therapy is not intended to confer or imply that oral medications are covered under the medical benefit.

Background/Overview

For many years, the Burzynski Research Institute has utilized antineoplaston therapy to treat individuals with a variety of cancers.  In 1991, the clinical responses of individuals treated with antineoplastons at the Burzynski Research Institute were reviewed by the National Cancer Institute (NCI, 2015).

The NCI performed a retrospective review of medical records of 7 individuals with brain tumors who were thought to have benefited from treatment with antineoplastons.  This “best case series” analysis did not constitute a clinical trial.  After the reviewers found some evidence of antitumor activity, the NCI proposed that formal clinical trials be conducted on adults with advanced brain tumors, to further evaluate the response rate and toxicity of antineoplastons.

The NCI sponsored two phase II clinical trials at several cancer centers which included Memorial Sloan-Kettering Cancer Center, the Mayo Clinic, and the Warren Grant Magnuson Clinical Center at the National Institutes of Health.  These NCI-sponsored studies were developed with review and input from Dr. Burzynski and the trials began in 1993.  However, by 1995, only 9 individuals had enrolled in the trials.  On August 18, 1995, the studies were closed prior to completion when attempts to reach a consensus on proposed changes to increase accrual could not be reached by Dr. Burzynski, NCI staff, and investigators.  The NCI concluded that no definitive conclusions can be drawn about the effectiveness of treatment with antineoplastons as a result of the small number of individuals enrolled in the studies.

In 2006, Burzynski and colleagues reported data on antineoplaston therapy for high-grade, recurrent and progressive brainstem gliomas consolidated from four trials.  The resulting non-randomized, uncontrolled case studies involved 18 evaluable individuals and only 3 participants were alive at the last evaluation.  Larger, randomized, controlled studies are needed to demonstrate the efficacy of antineoplaston therapy.

Information about many of these trials is available from the National Cancer Institute’s web site of clinical trials.  The list of trials includes multiple phase II trials using antineoplastons for a variety of cancers.  Currently, there are no antineoplaston products approved for use by the U.S. Food and Drug Administration (FDA).

Definitions

Neoplastic: An abnormal, uncontrolled cell growth.

Synthetic peptide: A compound containing two or more amino acids that are produced artificially.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT

 

96549

Unlisted chemotherapy procedure [when specified as administration of antineoplaston therapy]

 

 

HCPCS

 

J3490

Unclassified drugs [when specified as antineoplastons]

J8499

Prescription drug, oral, non-chemotherapeutic, NOS [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-10 Diagnosis

 

 

All diagnoses

References

Peer Reviewed Publications:

  1. Buckner JC, Malkin MG, Reed E, et al. Phase II study of antineoplaston A10 and AS2-1 in patients with recurrent glioma. Mayo Clin Proc. 1999; 74(2):137-145.
  2. Burzynski SR. The present state of antineoplaston research. Integr Cancer Ther. 2004; 3(1):47-58.
  3. 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.
  4. Burzynski SR, Lewy RI, Weaver R, et al. Long-term survival and complete response of a patient with recurrent diffuse intrinsic brain stem glioblastoma multiforme. Integr Cancer Ther. 2004; 3(3):257-261.
  5. 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.
  6. Camacho LH, Olson J, Tong WP, et al. Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors. Invest New Drugs. 2007; 25:131-138.
  7. 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.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Sodium Phenylbutyrate Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised January 1, 2009. Accessed on August 18, 2016.
  2. Buphenyl (Ucyclyd Pharma, Inc., Scottsdale, AZ). Revised March 31, 2009. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020572s016,020573s015lbl.pdf. Accessed on September 18, 2017.
  3. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium(electronic version). For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 18, 2017.
  4. NCCN Clinical Practice Guidelines in Oncology. © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 18, 2017.
  5. Sodium phenylbutyrate. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated November 16, 2016. Available at: http://www.micromedexsolutions.com. Accessed on September 18, 2017.
Websites for Additional Information
  1. National Cancer Institute. Antineoplastons PDQ®. Updated March 19, 2015. Available at: http://www.cancer.gov/about-cancer/treatment/cam/patient/antineoplastons-pdq. Accessed on September 18, 2017.
Index

A10
Antineoplaston Therapy
AS2-1
Buphenyl®
Phenylacetic acid
Sodium phenylbutyrate

Document History

Status

Date

Action

Reviewed

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review.

Reviewed

11/01/2017

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated References and Websites sections.

Reviewed

11/03/2016

MPTAC review.

Reviewed

11/02/2016

Hematology/Oncology Subcommittee review. Updated References and Websites sections.

Reviewed

11/05/2015

MPTAC review.

Reviewed

11/04/2015

Hematology/Oncology Subcommittee review. Updated Rationale, Background/Overview, References and Websites sections. Updated Coding section to include additional NOC code J8499; removed ICD-9 codes.

Reviewed

11/13/2014

MPTAC review.

Reviewed

11/12/2014

Hematology/Oncology Subcommittee review. Updated References and Websites sections.

 

04/01/2014

Updated Coding section to include additional NOC codes J3490, J8999.

Reviewed

11/14/2013

MPTAC review.

Reviewed

11/13/2013

Hematology/Oncology Subcommittee review. Updated Description/Scope, Rationale, References and Websites sections.

Reviewed

11/08/2012

MPTAC review.

Reviewed

11/07/2012

Hematology/Oncology Subcommittee review. Updated References and Websites.

Reviewed

11/17/2011

MPTAC review.

Reviewed

11/16/2011

Hematology/Oncology Subcommittee review. Updated Rationale, References and Websites.

Reviewed

11/18/2010

MPTAC review.

Reviewed

11/17/2010

Hematology/Oncology Subcommittee review. Updated rationale, references and websites.

Reviewed

11/19/2009

MPTAC review.

Reviewed

11/18/2009

Hematology/Oncology Subcommittee review. Updated rationale, references and websites.

Revised

11/20/2008

MPTAC review.

Revised

11/19/2008

Hematology/Oncology Subcommittee review. Updated rationale, references and websites. Removed human immunodeficiency virus from the investigational and not medically necessary statement.

Reviewed

11/29/2007

MPTAC review.

Reviewed

11/28/2007

Hematology/Oncology Subcommittee review. No change to position. The phrase “investigational/not medically necessary” was clarified to read “investigational and not medically necessary.”

Reviewed

08/23/2007

MPTAC review. Updated references and websites. No change to position

Reviewed

09/14/2006

MPTAC review. Updated references. No change to position.

New

09/22/2005

MPTAC initial document development.