CA : A Cancer Journal for Clinicians

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

The somatic genomic landscape of glioblastoma

Many cancer patients use therapies promoted as literal alternatives to conventional medical care. Such “alternative” modalities are unproven or were studied and found worthless. These can be harmful. An even greater proportion of cancer patients uses “complementary” therapies along with mainstream cancer treatment. Most are helpful adjunctive approaches that control symptoms and enhance quality of life. This review describes alternative as well as complementary therapies commonly used today by cancer patients. Herbal remedies also are discussed. Evidence regarding the efficacy and safety of complementary/alternative medicine (CAM) is reviewed, and implications for oncologists are discussed. To encourage open communication of CAM use by patients, oncologists should be knowledgeable about the most popular remedies and know where to find reliable information for themselves and for their patients. The Oncologist 2004;9:80-89

Complementary and Alternative Therapies for Cancer

Phase III Randomized Comparison of Gemcitabine Versus Gemcitabine plus Capecitabine in Patients with Advanced Pancreatic Cancer

Ten-year survival in glioblastoma. A systematic review.

Background
Brainstem gliomas (BSG) are relatively rare tumors of which recurrent pediatric diffuse intrinsic pontine gliomas (RPDIPG) comprise a distinct group. Numerous trials have been conducted on RPDIPG, none of which have resulted in identifying any proven pharmacological treatment benefit. This study included 40 patients diagnosed with different types of BSG, but it was decided to describe first the encouraging results in the most challenging group of RPDIPG.

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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

Pediatric gliosarcoma (GS) is a rare variant of glioblastoma multiforme. The authors describe the case of an unusual pontine location of GS in a 9-year-old boy who was initially diagnosed with low-grade astrocytoma (LGA) that was successfully controlled for 4 years. Subsequently, his brain tumor transformed into a GS. Prior treatment of his LGA included subtotal tumor resection 3 times, standard radiation therapy, and Gamma Knife procedure twice. His LGA was also treated with a standard chemotherapy regimen of carboplatin and vincristine, and his GS with subtotal resection, high-dose cyclophosphamide, and thiotepa with stem cell rescue and temozolomide. Unfortunately, he developed disseminated disease with multiple lesions and leptomeningeal involvement including a tumor occupying 80% of the pons. Upon presentation at our clinic, he had rapidly progressing disease. He received treatment with antineoplastons (ANP) A10 and AS2-1 for 6 years and 10 months under special exception to our phase II protocol BT-22. During his treatment with ANP his tumor stabilized, then decreased, and, ultimately, did not show any metabolic activity. The patient’s response was evaluated by magnetic resonance imaging and positron emission tomography scans. His pathology diagnosis was confirmed by external neuropathologists, and his response to the treatment was determined by central radiology review. He experienced the following treatment-related, reversible toxicities with ANP: fatigue, xerostomia and urinary frequency (grade 1), diarrhea, incontinence and urine color change (grade 2), and grade 4 hypernatremia. His condition continued to improve after treatment with ANP and, currently, he complains only of residual neurological deficit from his previous surgery. He achieved a complete response, and his overall and progression-free survival is in excess of 13 years. This report indicates that it is possible to obtain long-term survival of a child with a highly aggressive recurrent GS with diffuse pontine involvement with a currently available investigational treatment.

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Long-term survival (>13 years) in a child with recurrent diffuse pontine gliosarcoma: a case report.

Standard treatment for high-grade glioma involves surgical resection followed by radiation ther- apy and temozolomide. Unfortunately, there are no standard treatment recommendations after recurrence and new therapies are needed for patients whose tumor recurs after first-line treat- ment. This single-arm, two-stage, interventional Phase II study evaluated the efficacy and safety of a combination of antineoplastons A10 and AS2-1. Nineteen patients were enrolled in the study (safety population), but fifteen patients with a median age of 9.4 years who met eligibility criteria were evaluated. The majority of subjects (12/15) were Caucasian and 8/15 (53%) were female. More than half (53%) of patients were diagnosed with glioblastoma and 33% with anaplastic as- trocytoma. All patients had failed standard therapy including surgery, radiation, and chemother- apy. Antineoplastons were administered intravenously every four hours (median dose of A10 6.9 g/kg/d and AS2-1 0.30 g/kg/d) until objective response was documented and thereafter for a fur- ther 8 months. Clinical evaluations were performed every 8 weeks. All patients enrolled in the study were included in the safety analysis but only patients fulfilling the inclusion criteria were included in the efficacy evaluation. The duration of treatment with antineoplastons ranged from 2 weeks to 120 weeks. A complete response was documented in 2/15 (13%), partial response in 2/15 (13%), stable disease in 3/15 (20%). Progression-free survival at six months was 47% and overall survival (OS) at one year was 33.3%. One patient (6.7%) survived 10 years from treatment start. A small group of patients suffered reversible Grade 3 and 4 toxicities including hypernatre- mia 2/19 (11%) and decrease of neutrophils 1/19 (5%). There were no chronic toxicities. There was improvement of quality of life in patients who had objective response. It is concluded that antineoplastons show efficacy with an acceptable profile in this cohort of patients with recurrent high-grade glioma. * Corresponding author.

https://file.scirp.org/pdf/JCT_2014052610203749.pdf

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

Primary malignant brain tumors are a leading cause of cancer-related death in children. This Phase II study evaluated the efficacy and safety of Antineoplastons A10 and AS2-1 (ANP) in children who developed progression during standard treatment. A total of 43 children were recruited to the study, but only 41 met eligibility criteria. There were twelve cases of glioblastoma multiforme (GBM), eight anaplastic astrocytomas (AA), twelve diffuse intrinsic pontine gliomas (DIPG), three supertentorial primitive neuroectodermal tumors (sPNET), three cases of medulloblastoma and one case each of anaplastic ependymoma (AE), atypical teratoid rhabdoid tumor (AT/RT), and disseminated pilocytic astrocytoma (PAD). ANP was administered intravenously daily every four hours (median dose of A10 8.74 g/kg/d and AS2-1 0.35 g/kg/d), until objective response (OR) was documented, and then a further eight months. All enrolled patients were included in safety, but only eligible patients in the efficacy evaluation. A total of 12.2% of patients obtained OR; 2.4% complete response (CR) and 9.8% partial response (PR). Stable disease (SD) was determined in 17.1% and progressive disease (PD) in 43.9% of cases. There were 26.8% of nonevaluable (NE) cases due to premature discontinuation. Out of five OR cases, four patients were diagnosed with recurrent DIPG and one with recurrent AA. Median progression-free survival (PFS) was 2.5 months. Median overall survival was 4.8 months. OS at 6 months was 46.3%, one year was 12.2%, and 4.8% at two, five, and ten years. The longest survivor is a patient diagnosed with DIPG and gliosarcoma who remains alive more than 15 years. A group of eleven patients reported grade 3 and 4 toxicity including hypernatremia in eight cases, somnolence in two cases, and hypokalemia in one case. There were no chronic toxicities, and the quality of life was very good. The largest group of patients were represented by DIPG, GBM, and AA. The best results were obtained in the DIPG and AA groups. In the DIPG group, CR was in 8.3%, PR was 25%, median PFS was 4.8 months,

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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)

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.

/pdf/recurrent-glioblastoma-multiforme-a-strategy-for-long-term-3koxq82n67.pdf

Tomasz J. Janicki

Papers

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

Long-term survival (>13 years) in a child with recurrent diffuse pontine gliosarcoma: a case report.

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

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)

Recurrent Glioblastoma Multiforme—A Strategy for Long-Term Survival