Phase I Toxicity Studies for Specific Antineoplastons
        Antineoplaston A
        Antineoplaston A10
        Antineoplaston AS2-1
        Antineoplastons A10 and AS2-1
        Antineoplaston AS2-5
        Antineoplaston A2
        Antineoplaston A3
        Antineoplaston A5
Studies of Specific Malignancies Treated with Antineoplastons
        Brain tumors
        Prostate cancer
        Hepatocellular (liver) cancer

To date, no phase III randomized, controlled trials of antineoplastons as a treatment for cancer have been conducted. Publications have taken the form of case reports, phase I clinical trials, toxicity studies, and phase II clinical trials. Phase I toxicity studies are the first group discussed below. The studies are categorized by the antineoplaston investigated. The second group of studies involves patients with various malignancies. Table 1 is a summary of dose regimens for all human studies. Table 2 summarizes the following clinical trials and appears at the end of this section.

The studies discussed below are phase I toxicity studies in patients with various types of malignancies, including bladder cancer, breast cancer, and leukemias. The studies are listed by the antineoplastons administered. The effect of a specific antineoplaston under investigation is difficult to ascertain because of the confounding effect of previous therapies. Unless specifically noted, all studies were conducted by the developer and his associates at his research institute.

A 1977 article reported on 21 patients with advanced cancer or leukemia who were treated with antineoplaston A and followed for up to 9 months. Patients ranged in age from 14 to 75 years and had cancers of various types. Eight patients received no previous therapies, and 13 patients had been previously treated with chemotherapy and radiation therapy.[1] Antineoplaston A was administered intravenously (IV), intramuscularly (IM), rectally, by bladder instillation, intrapleurally, and by application to the skin. Tolerance to antineoplaston A depended on the method of administration and the type of neoplasm.

Fever and chills, the main side effects, occurred only after IV or IM administration at the beginning of treatment. Fever lasted for a few hours, followed by subnormal temperatures and lowered blood pressure. Premedication with salicylates, adrenocorticotrophic hormone, or corticosteroids were used to treat the fever or suppress it. Only patients with chronic lymphocytic leukemia, transitional cell carcinoma of the bladder, metastatic adenocarcinoma of the rectum, squamous cell carcinoma of the cervix, and synovial sarcoma reacted with fever to low doses of antineoplaston A. No severe adverse reactions were reported, even when patients were treated with very high doses of the formulation (refer to Table 1). No toxicities were reported in any patient. Platelet and white blood cell counts were elevated after a month of treatment but gradually returned to normal.

Four patients obtained complete tumor response (two cases of bladder cancer, one case of breast cancer, and one case of acute lymphocytic leukemia); four patients obtained partial tumor response (two cases of chronic lymphocytic leukemia, one case of rectosigmoid adenocarcinoma, and one case of synovial sarcoma); six patients had stable disease; and two patients discontinued treatment. There were five deaths during the study that were not attributed to antineoplaston A toxicity.[1]

In 1986, a toxicity study of antineoplaston A10 reported on 18 patients with 19 malignancies. Patients ranged in age from 19 to 70 years. Only patients who completed 6 or more weeks of antineoplaston A10 injections were included in the results. Six of the 18 patients received other antineoplastons in addition to A10. Four patients were administered additional drugs such as antibiotics, analgesics, and anticonvulsants.[2]

Treatment duration ranged from 52 to 640 days. No major toxicities were reported. As with the antineoplaston A study described above, chills and fever were reported in nine patients and occurred only once during the course of treatment. Other side effects noted were muscle and joint pain, abdominal pain, nausea, dizziness, and headache. Partial remission occurred in one patient with chondrosarcoma, and mixed response was obtained in three other cases. Eight patients attained stable disease, and six patients had disease progression. Ten patients discontinued treatment during the study; no reasons were reported. Ten of the 18 patients had died by the time of study publication, 4 years after the start of the study.[2]

A 1986 study examined the toxicity of injectable antineoplaston AS2-1.[3] Twenty patients ranging in age from 17 to 74 years received antineoplaston injections for 21 malignancies. Patients were followed for 5 years. Eight patients received antineoplaston AS2-1 alone. The remaining 12 received other antineoplastons in combination with AS2-1 at different times during treatment.

Side effects associated with AS2-1 treatment included nausea and vomiting, rash, moderate blood pressure elevation, mild electrolyte imbalance, and slightly lowered white blood cell count. Although complete remission was reported in six cases (one case each of stage IV lymphocytic lymphoma, glioma, myelocytic leukemia, intraductal carcinoma of the breast, stage IA uterine cervix carcinoma, and metastatic breast carcinoma), one patient with breast carcinoma could not be considered evaluable for response because she had undergone radical mastectomy and had no measurable disease at the beginning of treatment with AS2-1; the cervical cancer patient had received prior radiation therapy, which could not be ruled out as producing a beneficial effect.

Partial remissions were reported in two cases, one each of stage III lung adenocarcinoma and chronic myelogenous leukemia in blastic phase. The patient with lung cancer had received prior radiation therapy; both patients developed disease progression and had died by the time of study publication. Seven cases were reported as having stable disease, and six patients had disease progression. Ten patients discontinued antineoplaston therapy during the study: two who were in complete remission, one in partial remission, and seven with stable disease.[3]

A 1998 case series from Japan discussed three patients enrolled in a phase I study of antineoplastons A10 and AS2-1. Diagnoses included one case of breast cancer metastatic to the lung, one case of an anaplastic astrocytoma/thalamic glioma, and one case of large cell lung carcinoma (stage IIIB). All patients also received chemotherapy and radiation therapy.[4]

In the patient with metastatic breast cancer, A10 was added to a variety of chemotherapeutics. Rapid tumor growth was followed by the addition of antineoplaston AS2-1 and additional chemotherapy to the treatment regimen. Two weeks following this treatment, a chest x-ray showed marked reduction in size and number of metastatic tumors, and tumor sizes decreased further over the next 5 months.[4]

The patient with anaplastic astrocytoma received antineoplaston AS2-1 in addition to other chemotherapy and radiation. An MRI 6 weeks after diagnosis showed a 50% reduction in tumor diameters.[4]

The third patient with metastatic lung cancer received antineoplaston A10 in addition to chemotherapy followed by radiation. Although initially diagnosed as inoperable, after 1 month of this treatment the patient was reconsidered and underwent a middle and lower lobectomy. Follow-up showed the patient in good condition, and a CT scan had confirmed no trace of tumor postoperatively.[4]

The addition of other therapies to the administration of antineoplastons is a confounding factor in assessing the results of antineoplaston treatment.

Information about ongoing clinical trials on A10 and AS2-1 is available from the NCI Web site.

In a 1986 study, antineoplaston AS2-5 injections were administered to 13 patients with 15 various malignancies (two patients each had two different malignancies).[5] All patients had stage IV disease and ranged in age from 20 to 64 years. Only patients who had an expected survival longer than 1 month were eligible for the study.

In addition to antineoplaston AS2-5 injections, two patients also received injections of antineoplaston AS2-1, and one patient received antineoplaston A10 after surgical intervention for a recurrence. Patients received other drugs such as antibiotics, analgesics, anti-inflammatory agents, anti-emetics, bronchial dilators, diuretics, corticosteroids, antihistamines, and uricosuric agents.

Side effects included chills and fever in two patients; swelling of the joints, bone pain, and redness of hands and feet in one patient; increase in platelet count in one patient; and an increase in plasma globulin in one patient.

Two patients were classified as having achieved complete remission, four patients were classified as having stable disease, six had disease progression, and one patient had a mixed response. During the study, eight patients discontinued treatment and were lost to follow-up, and three patients died. At the time of study publication, one patient who was given A10 after surgical intervention for recurrence was reported to be free of cancer for a period of slightly more than 4 years.[5]

In a 1987 study, 15 patients received antineoplaston A2 through intravenous subclavian catheter. Minor side effects were noted in four patients: fever, chills, and muscle pain. Of the 15 patients, 9 had objective response to treatment: complete tumor response in 7 and partial tumor response in 2. Five patients had stable disease, and one had disease progression. Follow-up showed three patients with complete response were cancer-free 5 years after treatment, and three patients were known to have survived for 4 years from the beginning of the study. Three patients were followed for 2 years, at which time they discontinued AS2-1 therapy. Five patients died within 2 years of the start of the study, and one patient was lost to follow-up.[6]

In 1987, 24 patients with 25 various malignancies participated in a retrospective nonconsecutive case series study of antineoplaston A3. Patients who had more than 6 weeks’ anticipated survival and who continued the treatment for more than 6 weeks were eligible. Antineoplaston A3 was administered through subclavian vein catheter in 23 patients. One patient received IM injections. Length of treatment was 44 to 478 days. Side effects, which occurred only once during treatment, included fever and chills in four patients, vertigo in two patients, headache in two patients, flushing of the face in one patient, nausea in one patient, and tachycardia in one patient. In addition, there was an increase in platelets, white blood cell counts, and reticulocyte counts. Tumor response was complete in five patients, and partial response was seen in five patients. Stable disease was reported in nine patients, while six patients had disease progression. One patient received radiation therapy before entering the study, so tumor response cannot be attributed solely to A3. Six patients discontinued treatment during the study; no reasons were reported.[7]

In 1987, patients with a variety of advanced malignancies participated in a retrospective selective case series study of antineoplaston A5. Patients ranged in age from 43 to 71 years. Only patients who were expected to survive for at least 6 weeks and who continued the treatment for at least 6 weeks were eligible. Patients received A5 through IV subclavian vein catheter. Treatment lasted from 47 to 130 days. Side effects included chills and fever in five patients, arthralgia in one patient, and premature heart beats and chest pressure in one patient. An increase in platelets and white blood cell counts were noted, as was hypertrophy of the epidermis. One patient had complete tumor response, and there were two partial responses. Stable disease was reported in seven patients. Disease progression occurred in four patients.[8]

A 1995 phase I study from Japan investigated the use of antineoplastons in conjunction with radiochemotherapy and surgical resection in patients with malignant brain tumors.[9] Nine patients were diagnosed with the following brain tumors: three cases of glioblastoma, two cases of anaplastic astrocytoma, one pontine glioma, one medulloblastoma, one metastatic brain tumor, and one case of multiple brain metastases. All patients received some form of chemotherapy and radiation, with the exception of the patient with multiple brain metastases. Most patients underwent surgical resection of the tumor, with the exception of the cases of pontine glioma, multiple brain metastases, and metastatic brain tumor. Patients with glioma were treated with remission maintenance therapy. Nimustine or ranimustine was administered over intervals of several months; at 2-week intervals, the patients received interferon-beta and an antineoplaston. The study does not indicate which antineoplastons were used.[9]

One complete response was achieved in a patient with anaplastic astrocytoma. This response was seen within 4 weeks and lasted for 6 months, at which time the patient developed recurrence in another part of the brain. Two patients (one case of pontine glioma and one case of metastatic brain tumor) achieved a partial response. In two patients, no change in disease status was reported, while four patients had disease progression. Adverse effects of antineoplaston therapy included itchy skin rash, stiff finger joints, flatulence, and mild myelosuppression.[9]

A multicenter phase II study conducted by the departments of Oncology and Neurology at the Mayo Clinic attempted to assess the pharmacokinetics, toxicity, and efficacy of antineoplastons A10 and AS2-1.[10] Slow patient accrual caused the trial to be closed early. Nine adult patients with anaplastic oligoastrocytoma, anaplastic astrocytoma, or glioblastoma multiforme that had recurred after radiation therapy received escalating doses of A10 and AS2-1, to a target daily dose of 1.0 g/kg for A10 and 0.4 g/kg for AS2-1. Six of the patients experienced a second tumor recurrence, while the remaining three patients experienced their first tumor recurrence.[10]

Of the nine patients enrolled in the trial, six could be evaluated for objective tumor response in accordance with the protocol. At the time of study publication, all patients had died. The median survival time was 5.2 months and the mean survival time was 7.2 months. All patients except one died of tumor progression. The remaining patient died of sepsis related to complications from chemotherapy, which was administered after antineoplaston treatment was discontinued.[10]

None of the six assessable patients showed evidence on computed tomography (CT) scan or magnetic resonance imaging (MRI) of tumor regression associated with antineoplaston treatment; however, all nine patients showed evidence of tumor progression. Antineoplaston treatment was administered for 6 to 66 days, after which treatment was discontinued. Toxicity caused three patients to discontinue treatment and subsequent scans of these patients showed tumor progression. The mean time to treatment failure (progression or unacceptable toxicity) was 29 days.[10]

Burzynski has stated that the results of this study were inconclusive because (1) the duration of treatment was too short and (2) researchers used a dosing regimen known to be ineffective against brain tumors as large as those of the study participants.[11] However, in response, the study authors have stated that all patients in this study received treatment until either tumor progression or unacceptable toxic effects occurred.[11] The National Cancer Institute and the Burzynski Institute agreed to the dosage regimen and study plan before the study was initiated, and the tumor size in seven of the nine patients was within the specified limits.[11]

Steady-state plasma concentrations of phenylacetate and phenylacetylglutamine were measured during antineoplaston treatment in this study (refer to Table 1). High serum concentrations of phenylacetate were associated with central nervous system toxic effects.[11] Treatment-related neurologic toxicity included excessive somnolence, somnolence plus confusion, and increased frequency of underlying focal motor seizures. MRI scans also revealed increased cerebral edema in two patients. One of the nine patients had findings suggestive of a diffuse metabolic encephalopathic process; this patient and one other had antineoplaston treatment interrupted and received dexamethasone for their symptoms, which resolved within 48 hours. These patients resumed their treatment with a 25% decrease in dose and had no recurrence of neurologic toxicity. Another patient manifested persistent confusion that stopped after discontinuation of antineoplastons. Other toxicities included nausea and vomiting, headache, myalgia, and edema. These effects were reported as usually mild to moderate, except for headache, which was severe in two patients. The patient who experienced persistent confusion also developed severe cutaneous erythema, pruritus, and facial edema, at which time treatment was permanently discontinued. Another patient had treatment discontinued because of edema of the extremities and face that was unresponsive to diuretics. The edema resolved after discontinuation of antineoplastons.[10]

A phase II study also conducted by the developer and his associates at his clinic reported on 12 patients with recurrent and diffuse intrinsic brain stem glioma. Of the ten patients who were evaluable, two achieved complete tumor response, three had partial tumor response, three had stable disease, and two had progressive disease. Patients ranged in age from 4 to 29 years. Treatment with escalating intravenous bolus injections of antineoplastons A10 and AS2-1 continued for 6 months. The average dose of A10 was 11.3 g/kg daily, and the average dose of AS2-1 was 0.4 g/kg daily. Adverse effects included skin allergy, anemia, fever and hypernatremia, agranulocytosis, hypocalcemia, hypoglycemia, numbness, tiredness, myalgia, and vomiting.[12]

A similar study of 12 pediatric patients with recurrent and progressive brain tumors was conducted by the developer and his associates at his clinic. Six patients were diagnosed with pilocytic astrocytoma, four had low-grade glioma, one had grade 2 astrocytoma, and one had visual pathway glioma. Both A10 and AS2-1 were administered intravenously and later orally, for an average duration of 16 months. The average dose of A10 was 7.95 g/kg daily, and the average dose of AS2-1 was 0.33 g/kg daily. Injections were discontinued after the patients showed stable disease or partial or complete tumor response. The patients then received oral administration of A10 and AS2-1 for an average duration of 19 months. Average doses for both A10 and AS2-1 were 0.28 g/kg daily. Of the 12 patients, one was nonevaluable, three were still in the study at the time of publication, and two achieved complete response. The remaining six patients requested removal from the study.[13]

Another study by the developer and associates reported on the long-term survival of high-risk pediatric patients with central nervous system primitive neuroectodermal tumors treated with a combination of AS2-1 and A10 for an average duration of 20 months (range, 1.2–67 months). The average dose of A10 was 10.3 g/kg daily, and the average dose of AS2-1 was 0.38 g/kg daily. Of 13 patients (age range, 1–11 years) with recurrent or high-risk disease given intravenous infusions of the antineoplaston combination, six patients survived more than 5 years from the start of antineoplaston therapy, and three of these six survived more than 7 years. These three patients received no chemotherapy or radiation after their initial partial tumor resection and before treatment with antineoplastons. A complete response was seen in two of the long-term survivors.[14] Reported adverse effects included fever, granulocytopenia (reversible), and anemia.

A 2006 report from the developer and associates summarizes the results from four phase II trials of antineoplaston treatment for high-grade, recurrent, and progressive brainstem glioma. Two of the 18 patients in this report were included in a previously published study.[15] Patients were treated with a combination of AS2-1 and A10 for an average of 216 days (range, 1.53–18.36 months). Doses of A10 ranged from 0.78 g/kg daily to 19.44 g/kg daily; doses of AS2-1 ranged from 0.2 g/kg daily to 0.52 g/kg daily.

Complete responses were observed in two cases, partial response in two cases, stable disease in seven cases, and progressive disease in seven cases. Reversible anemia, the only reported adverse effect, occurred in three patients. Survival from the start of antineoplaston treatment ranged from 2.6 months to 68.4 months among the newly reported cases.[16]

A phase II clinical trial using antineoplaston AS2-1 in conjunction with low-dose diethylstilbestrol (DES) was conducted by the developer and his associates in 14 patients with hormonally refractory prostate cancer.[17] Thirteen patients were diagnosed with stage IV prostate cancer, and one patient was diagnosed with stage II prostate cancer. Ages ranged from 54 to 88 years. Previous therapy included prostatectomy, orchiectomy, radiation therapy, and treatment with DES, luteinizing hormone-releasing hormone (LHRH) agonists, flutamide, aminoglutethimide, and immunotherapy. Patients all showed disease progression after initial response to treatment. During the study, all 14 patients received oral AS2-1 in doses ranging from 97 to 130 mg/kg daily and DES in doses ranging from 0.01 to 0.02 mg/kg daily. Patients exhibited few significant side effects.

Overall, there were two complete remissions, three partial remissions, seven cases of stable disease, and two cases of disease progression. All patients were known to be alive 2 years after the beginning of the study. The two patients who showed disease progression discontinued AS2-1 treatment.[17] The use of DES in conjunction with AS2-1 is a confounding factor in interpreting any results of tumor response.

A case report from Japan discussed two patients with advanced hepatocellular carcinoma who received antineoplaston A10 in addition to other treatments. Although both patients died—one from hemorrhagic pancreatic necroses and the other from hepatic failure brought on by esophageal varices—both appeared to tolerate A10 with few serious side effects. CT scans indicated that one patient exhibited inhibition of tumor growth and slight shrinkage of the tumor after oral administration and infusion of A10.[18]

To date, no randomized controlled trials examining the use of antineoplastons in patients with cancer have been reported in the literature. Existing publications have taken the form of case reports or series, phase I clinical trials, and phase II clinical trials, conducted mainly by the developer and his associates. While these publications have reported on successful remissions with the use of antineoplastons, other investigators have been unable to duplicate these results [10] and suggest that interpreting effects of antineoplaston treatment in patients with recurrent gliomas may be confounded by pre-antineoplaston treatment as well as imaging artifacts.[11,14,16] Reports originating from Japan on the effect of antineoplaston treatment on brain and other types of tumors have been mixed, and in some Japanese studies the specific antineoplastons used are not named.[9] In many of the reported studies, several or all patients received concurrent or recent radiation therapy, chemotherapy, or both, confounding interpretability.

Table 1 summarizes the dose ranges of antineoplastons used in the studies discussed above.

Table 2 summarizes the clinical trials used in the studies discussed above.

References

1. Burzynski SR, Stolzmann Z, Szopa B, et al.: Antineoplaston A in cancer therapy. (I). Physiol Chem Phys 9 (6): 485-500, 1977.  [PUBMED Abstract]
   
   
2. Burzynski SR, Kubove E: Toxicology studies on antineoplaston A10 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 47-55, 1986.  [PUBMED Abstract]
   
   
3. Burzynski SR, Burzynski B, Mohabbat MO: Toxicology studies on antineoplaston AS2-1 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 25-35, 1986.  [PUBMED Abstract]
   
   
4. Tsuda H, Sata M, Kumabe T, et al.: Quick response of advanced cancer to chemoradiation therapy with antineoplastons. Oncol Rep 5 (3): 597-600, 1998 May-Jun.  [PUBMED Abstract]
   
   
5. Burzynski SR: Toxicology studies on antineoplaston AS2-5 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 17-24, 1986.  [PUBMED Abstract]
   
   
6. Burzynski SR, Kubove E: Initial clinical study with antineoplaston A2 injections in cancer patients with five years' follow-up. Drugs Exp Clin Res 13 (Suppl 1): 1-11, 1987.  [PUBMED Abstract]
   
   
7. Burzynski SR, Kubove E: Phase I clinical studies of antineoplaston A3 injections. Drugs Exp Clin Res 13 (Suppl 1): 17-29, 1987.  [PUBMED Abstract]
   
   
8. Burzynski SR, Kubove E, Burzynski B: Phase I clinical studies of antineoplaston A5 injections. Drugs Exp Clin Res 13 (Suppl 1): 37-43, 1987.  [PUBMED Abstract]
   
   
9. Sugita Y, Tsuda H, Maruiwa H, et al.: The effect of Antineoplaston, a new antitumor agent on malignant brain tumors. Kurume Med J 42 (3): 133-40, 1995.  [PUBMED Abstract]
   
   
10. Buckner JC, Malkin MG, Reed E, et al.: Phase II study of antineoplastons A10 (NSC 648539) and AS2-1 (NSC 620261) in patients with recurrent glioma. Mayo Clin Proc 74 (2): 137-45, 1999.  [PUBMED Abstract]
    
    
11. Burzynski SR: Efficacy of antineoplastons A10 and AS2-1. Mayo Clin Proc 74 (6): 641-2, 1999.  [PUBMED Abstract]
    
    
12. 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 4 (2): 91-101, 2003.  [PUBMED Abstract]
    
    
13. 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 5 (6): 315-26, 2004.  [PUBMED Abstract]
    
    
14. 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 4 (2): 168-77, 2005.  [PUBMED Abstract]
    
    
15. Burzynski SR, Conde AB, Peters A, et al.: A retrospective study of antineoplastons A10 and AS2-1 in primary brain tumors. Clin Drug Investig 18 (1): 1-10, 1999. 
    
    
16. Burzynski SR, Janicki TJ, Weaver RA, et al.: Targeted therapy with antineoplastons A10 and AS2-1 of high-grade, recurrent, and progressive brainstem glioma. Integr Cancer Ther 5 (1): 40-7, 2006.  [PUBMED Abstract]
    
    
17. Burzynski SR, Kubove E, Burzynski B: Treatment of hormonally refractory cancer of the prostate with antineoplaston AS2-1. Drugs Exp Clin Res 16 (7): 361-9, 1990.  [PUBMED Abstract]
    
    
18. Kumabe T, Tsuda H, Uchida M, et al.: Antineoplaston treatment for advanced hepatocellular carcinoma. Oncol Rep 5 (6): 1363-7, 1998 Nov-Dec.  [PUBMED Abstract]
    
    
19. Tsuda H, Hara H, Eriguchi N, et al.: Toxicological study on antineoplastons A-10 and AS2-1 in cancer patients. Kurume Med J 42 (4): 241-9, 1995.  [PUBMED Abstract]
    
    

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