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Efficacy of Antineoplastons A10 and AS2-1: In Response

      Dr Burzynski raises 3 important issues in evaluating treatment outcomes in patients with recurrent gliomas: the relationship between dose and response, the evaluation of objective response, and the meaning of tumor necrosis after both radiation and drug therapy. In our study, we used a gradually escalating dosing scheme over 4 days to the target dosages of 10 g/kg per day for antineoplaston A10 and 0.4 g/kg per day for antineoplaston AS2-1, which resulted in a dosage of 320 mg/kg per day of phenylacetate. Both the NCI and the Burzynski Research Institute agreed to this plan before the study was initiated. Furthermore, in 7 of the 9 patients enrolled in this trial, size of their tumor fulfilled the criteria agreed on at the time of study initiation (contrast-enhancing tumor of 5 cm or less in maximal diameter). All patients received treatment until either tumor progression or unacceptable toxic effects occurred.
      The issue of appropriate dosing is relevant because preclinical data suggest that increasing the concentration of phenylacetate, a major component of AS2-1, results in increased inhibition of cellular proliferation in vitro. In contrast, there is minimal, if any, effect on cell proliferation with increasing concentrations of phenylacetylglutamine.
      • Samid D
      • Shack S
      • Sherman LT
      Phenylacetate: a novel nontoxic inducer of tumor cell differentiation.
      • Danesi R
      • Nardini D
      • Basolo F
      • Del Tacca M
      • Samid D
      Myers CEo Phenylacetate inhibits protein isoprenylation and growth of the androgen-independent LNCaP prostate cancer cells transfected with the T24 Ha-ras oncogene.
      Our study cannot address the issue of whether higher doses may have been more effective. We documented that plasma concentrations of phenylacetate increased with increasing doses of AS2-1 and A10. Similarly, central nervous system toxicity was associated with higher serum concentrations of phenylacetate. Other investigators have noted similar toxic effects with continuous infusion of phenylacetate in patients with recurrent gliomas. Chang et al
      • Chang SM
      • Kuhn LG
      • Robins HI
      • et al.
      Phase II study of phenyl-acetate in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report.
      reported central nervous system toxicity manifested primarily by disorientation and somnolence as well as malaise, fatigue, and lethargy after administration of 400 mg/kg per day of phenylacetate. The toxic effects were predominantly mild to moderate but occasionally severe, and they were reversible with discontinuation of phenylacetate. The mean phenyl acetate concentration reported in their study was 164 μg/mL, similar to that reported in our study (177 μg/ml.). Similarly, Thibault et al
      • Thibault A
      • Cooper MR
      • Figg WD
      • et al.
      A phase I and pharmacoki-netic study of intravenous phenylacetate in patients with cancer.
      noted dose-related central nervous system toxic effects in patients with various types of cancer who were receiving continuous infusion of phenylacetate. Dose-limiting toxicity consisted of reversible central nervous system depression pre- ceded by emesis. These investigators suggested that concentrations of 200 to 300 μg/mL of phenylacetate could be maintained in their patients, 1 of whom had a brain tumor, by using adaptive control dosing (266 ± 40 mg/kg per day of phenylacetate). Maintenance of plasma phenylacetate concentrations at 400 μg/mL proved to be too toxic. Because patients with recurrent gliomas often have underlying central nervous system injury as a consequence of tumor or previous treatment (or both), they may be unable to tolerate higher concentrations of phenylacetate because of toxic effects. The safety of higher concentrations of phenylacetate in patients with recurrent gliomas has not been documented in appropriately designed trials published in peer-reviewed journals.
      Interpretation of tumor response in patients with recurrent gliomas is complicated by multiple factors. Most patients have had prior radiation, and radiation can cause both subacute and late changes on magnetic resonance imaging, which may mimic tumor progression. These changes may resolve spontaneously or with use of corticosteroids. Thus, in any study on recurrent gliomas, some patients may not have recurrent glioma but only delayed treatment effect. Moreover, changes in doses of corticosteroids, changes related to prior surgery, and variability in scan technique can all mimic either tumor progression or tumor regression. An appropriate review of study methods is necessary to interpret reports of tumor responses in any study on recurrent gliomas. Burzynski states that 4 of 8 evaluable patients with astrocytoma had objective responses in an ongoing clinical trial. Chang et al
      • Chang SM
      • Kuhn LG
      • Robins HI
      • et al.
      Phase II study of phenyl-acetate in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report.
      found that only 7.5% of 40 patients had any evidence of transient tumor shrinkage with continuous infusion of phenylacetate. This low response rate may reflect not only true biologic activity of phenylacetate but also other influences on neuroimaging studies. Neuroimaging technology has major limitations. Interpretations of tumor regression in studies on recurrent gliomas should be viewed cautiously and in the context of these limitations.
      Finally, interpretation of tumor necrosis after both radiation therapy and drug therapy is problematic. Radiation necrosis after external-beam radiation, especially after stereotactic radio-surgery, is well documented. With the exception of studies using direct intra-arterial administration of chemotherapy, tumor necrosis after drug therapy is poorly documented. Because necrosis was proved by biopsy in 2 of our patients after stereotactic radio-surgery, we believe the more likely cause was the radiation rather than drug effect.

      References

        • Samid D
        • Shack S
        • Sherman LT
        Phenylacetate: a novel nontoxic inducer of tumor cell differentiation.
        Cancer Res. 1992; 52: 1988-1992
        • Danesi R
        • Nardini D
        • Basolo F
        • Del Tacca M
        • Samid D
        Myers CEo Phenylacetate inhibits protein isoprenylation and growth of the androgen-independent LNCaP prostate cancer cells transfected with the T24 Ha-ras oncogene.
        Mol Pharmacal. 1996; 49: 972-979
        • Chang SM
        • Kuhn LG
        • Robins HI
        • et al.
        Phase II study of phenyl-acetate in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report.
        J Clin Oneal. 1999; 17: 984-990
        • Thibault A
        • Cooper MR
        • Figg WD
        • et al.
        A phase I and pharmacoki-netic study of intravenous phenylacetate in patients with cancer.
        Cancer Res. 1994; 54: 1690-1694

      Linked Article

      • Efficacy of Antineoplastons A10 and AS2-1
        Mayo Clinic ProceedingsVol. 74Issue 6
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          To the Editor: I read with interest the article by Buckner et al, in the February 1999 issue of Mayo Clinic Proceedings (pages 137 to 145), on the efficacy of antineoplastons A10 and AS2-1. Although the study results were not conclusive, the study tested a dosing regimen known to be ineffective. Specifically, the dosages of A10 and AS2–1 used in the study were meant for the treatment of a single small lesion (<5 cm). Five of the 6 evaluable patients had either multiple nodules or tumors larger than 5 cm.
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