Choroid plexus neoplasms (CPNs) are uncommon and have three types: papilloma, atypical papilloma, and carcinoma (CPC). There is no established treatment for recurrent/disseminated CPC. Objectives: CPN patients received treatment at the Burzynski Clinic (BC) according to the phase II protocol, BT-26, which aimed to evaluate the antitumor activity of ANP and to evaluate patient tolerance to ANP. Tumor response was assessed by sequential brain and spine MRIs utilizing gadolinium enhancement. Findings: After gross total resection of her CPC at another facility, this one-year and nine-month-old child, along with her parents, came to the BC for evaluation and treatment of the child’s recurrent/disseminated CPC. Baseline MRI of the brain (September 15, 2000) showed four enhancing lesions totaling 2.16 cm² in size. Baseline MRI of the spine (August 28, 2000) showed enhancing but non-measurable dural lesions. Subsequent MRIs (December 14, 2000) showed enhancing brain tumors totaling 3.03 cm² in size (a 40.3% increase from baseline) and enhancing dural lesions of the spine totaling 0.81 cm² in size, indicating progressive disease. However, following ANP, this child has enjoyed > 23.6 years overall survival while experiencing good health. Conclusions: A very rare long-term survival with recurrent/disseminated CPC is presented and the usefulness of ANP is discussed.

Abbreviations: ANP: Antineoplaston therapy; Antineoplastons: Antineoplastons A10 and AS2-1; A10: Atengenal; AS2-1: Astugenal; BC: Burzynski Clinic; CPN: Choroid plexus neoplasm; CPC: Choroid plexus carcinoma; CR: Complete response; CSF: Cerebrospinal fluid; PD: Progressive disease; FDA: Food and Drug Administration; GBM: Glioblastoma; GTR: Gross total resection; ICH: International Conference on Harmonization; IND: Investigational new drug; LPS: Lansky Performance Score; MRI: Magnetic resonance imaging; OR: Objective response; OS: Overall survival; PR: Partial response; RT: Radiation therapy; SAE: Serious adverse event; WHO: World Health Organization

Choroid plexus neoplasms (CPNs) are rare but account for 12–20% of brain tumors in children less than one year of age. [1,2]. The choroid plexus consists of highly vascularized tissue, which covers the walls of the ventricles. [3,4] This tissue produces cerebrospinal fluid (CSF) and contains stem cells. [3] The World Health Organization (WHO) classifies a CPN as either a choroid plexus papilloma, an atypical choroid plexus papilloma, or a choroid plexus carcinoma (CPC). [5] 

CPCs, the focus of this paper, show elevated mitotic activity, dense cellularity, and brain invasion [6]. Craniospinal dissemination occurs in 12–30% of cases. [6] CPCs have five-year survival rates of 71%, but surviving patients frequently demonstrate developmental and cognitive disabilities. Survival data for recurrent/disseminated CPC is not available. [6] Gross total resection (GTR) of the tumor is the current treatment of choice for CPC. [7] Treatment of hydrocephalus is required in most cases. [7] Radiation therapy (RT) and chemotherapy are also utilized depending on the clinical circumstances. However, further data is needed concerning these treatment modalities. [8] Serial magnetic resonance imaging (MRI) of the brain are used in follow-up after primary therapy. [9]

CPNs are best imaged by MRI scans of the brain with gadolinium. Forty percent of CPNs are in the lateral ventricles. [9] They are hypo- or isointense on T1 weighted images, hyper- or isointense on T2 weighted images, and moderately or strongly enhanced on post-contrast images. [9] Hydrocephalus, seen in approximately 60% of cases, is primarily a result of obstruction, but is also due to increased CSF production and decreased reabsorption. [9]

Ventricular CPNs present with symptoms specifically due to their producing hydrocephalus with increased intracranial pressure. These symptoms include a bulging frontal fontanelle, increased cranial size, headache, nausea and vomiting, and papilledema. [7]

We present here the use of ANP (IV Antineoplaston therapy), which consists of Antineoplaston A10 (Atengenal) and Antineoplaston AS2-1 (Astugenal), in the treatment of a recurrent/disseminated CPC in a one-year and nine-month-old child following GTR.

A one-year and 9-month-old female child was in good health until July 2000, when she developed intermittent vomiting and increased head circumference. She underwent an MRI of the brain elsewhere on August 13, 2000, which showed a left-sided intraventricular tumor with hydrocephalus. That same day, the child underwent GTR and placement of an external ventriculostomy. An Ommaya reservoir was subsequently placed. Examination of the microscopic sections of the surgical specimen revealed a CPC. Follow-up MRI of the brain on August 31, 2000, showed progressive/disseminated disease and the child’s parents determined that their daughter be treated at the Burzynski Clinic (BC). She was evaluated there on September 21, 2000, having had only surgical treatment up to that time. The child’s mother described her daughter as having headaches, weakness, and balance problems. The physical examination was essentially normal except for a surgical scar and an Ommaya reservoir in the left parietal region.  

The patient had a low LPS, and following baseline MRIs (see “Results”), started treatment on September 22, 2000, as a Special Exception, according to Protocol BT-26, “Phase II Study of Antineoplastons A10 and AS2-1 Infusions in Patients with Choroid Plexus Neoplasms”. In this single arm study, ANP was delivered every four hours via a subclavian catheter and a programmable infusion pump.

The objectives of BT-26 were to 1) “demonstrate the antitumor activity of Antineoplastons A10 and AS2-1 in the treatment of patients with choroid plexus neoplasms by determining the proportion of patients who experience an objective tumor response” and 2) “evaluate the adverse effects and tolerance of Antineoplastons A-10 and AS2-1 in these patients”. Eligibility criteria for BT-26 included 1) Histologic diagnosis of a CPN; 2) Tumor size ≥ 5mm; 3) Age ≥ 6 months; 4) Lansky Performance Status (LPS) of 60% to 100%; and 5) Life expectancy ≥ 2 months.

Gadolinium-enhanced MRI of the brain and spine were used in the diagnosis and follow-up of the patient’s CPC. They were performed every 8 weeks for the first two years and then less frequently. T2-weighted, T2-fluid attenuated inversion recovery (T2-FLAIR), T1 weighted, and T1-weighted contrast-enhanced images were obtained. CPCs exhibit patchy gadolinium-enhancing and sequential T1-weighted contrast-enhanced images were utilized to determine the effect of therapy. [10]

As determined by MRI of the brain, the product of the two greatest perpendicular diameters of each measurable (≥ 5mm) and enhancing lesion was calculated. Tumor size was defined as the sum of these products [11,12]. The response criteria were as follows: a complete response (CR) indicated complete disappearance of all enhancing tumor while a partial response (PR) indicated a 50% or greater reduction in total measurable and enhancing tumor size. CR and PR required a confirmatory brain MRI performed at least four weeks after the initial finding. Progressive disease (PD) indicated a 25% or greater increase in total measurable and enhancing tumor size, or new measurable and enhancing disease, while stable disease (SD) did not meet the criteria for PR or PD [11].

This Phase II trial was conducted in accordance with the U.S. Code of Federal Regulations, Title 21, Parts 11, 50, 56 and 312; the Declaration of Helsinki (1964) including all amendments and revisions; the Good Clinical Practices: Consolidated Guideline (E6), International Conference on Harmonization (ICH) and Guidance for Industry (FDA). By participating in this study protocol, the investigators agreed to provide access to all appropriate documents for monitoring, auditing, IRB review and review by any authorized regulatory agency.

Baseline MRI of the brain performed September 15, 2000, and spine, performed August 28, 2000, (Figure 1) showed four measurable and enhancing brain lesions (right temporal, left temporal, left sylvian fissure, and left occipital) totaling 2.16 cm² in size and enhancing, but non-measurable dural lesions at the level of the third and fourth thoracic vertebrae and the first and fifth lumbar vertebrae. As described above, this one-year and nine-month-old child was accrued to BT-26, as a Special Exception, and began treatment on September 22, 2000. The starting dose of A10 was 0.79 g/kg/d. It was gradually increased to 23.00 g/kg/d and subsequently reduced to 18.14 g/kg/d. The starting dose of AS2-1 was 0.21 g/kg/d. It was gradually increased to 0.65 g/kg/d and subsequently reduced to 0.56 g/kg/d.

On December 14, 2000, MRIs showed enhancing brain tumors totaling 3.03 cm² in size (a 40.3% increase from baseline) and enhancing dural lesions of the spine totaling 0.81 cm² in size, indicating PD. ANP was discontinued on July 3, 2001. Final MRIs performed on December 14, 2001, showed enhancing brain tumors totaling 23.80 cm (a 1001.9% increase from baseline) and enhancing dural lesions of the spine totaling 1.12 cm² in size indicating further progression of disease. The patient has subsequently received no anti-cancer therapy. The date of last contact was April 17, 2024, the patient was doing well and enjoying life. Her overall survival (OS) at that time was 26.6 years.

Adverse events were graded according to the Common Terminology Criteria for Adverse Events Version 3.0. The patient presented here experienced six serious adverse events (SAEs), of which two were thought to be related to ANP (diarrhea, hypokalemia). She fully recovered from all SAEs.

Consent was obtained from the patient for publication of the brain/spine MRI images (Figure 1) and the post-therapy photograph (Figure 2) presented in this report.

Chemotherapy, RT, and a second surgical procedure have been utilized in the treatment of recurrent CPC. The use of chemotherapy and RT in recurrent/disseminated CPC requires further study as the existing data is sparse. Information on the demographics and treatment of CPN in general can be illustrated by a single institution’s experience – see below.

Hosmann and colleagues, in a retrospective review, studied the demographics and treatment of CPNs in 36 consecutive pediatric and adult patients treated at the Medical University of Vienna between 1991 and 2016. [7] This review included 17 children, with a median age of 1.2 years, and 19 adults, with a median age of 48.5 years, in cohorts of 21 choroid plexus pappilomas, 11 atypical papillomas, and four CPCs, all of which were diagnosed in children, but none of these were ≤ 6 months of age. [7]

GTR was achieved in 91.7% of patients. A 25% tumor recurrence rate was associated with histological grading (p = 0.004), subtotal resection (p = 0.002), and tumor infiltration into brain parenchyma (p = 0.001). Adjuvant therapy was performed in 19.4% of patients, most of whom had a CPC. OS was dependent on the extent of resection (p = 0.001), tumor progression (p = 0.04), and the presence of leptomeningeal metastases (p = 0.002). [7] Hence, patients with CPC, tumor progression, and leptomeningeal metastases, such as the child we present here, were in a very high-risk category.

Hossman and colleagues concluded that GTR was the most important predictor of OS. In addition, tumor location and vascularization, along with hydrocephalus and patient age, were important determinates of perioperative morbidity. [7]

The utility of neoadjuvant or adjuvant RT and chemotherapy in CPC awaits resolution. In the future, epigenetic patterns [12], methylation profiling [13], proliferation markers (Ki-67/MIB-1) and tumor suppressor proteins (p53), [14, 15, 16], as well as age-related chromosomal alterations [17] may predict clinical outcome and provide insight into the use of neoadjuvant or adjuvant therapies.

We present here the use of ANP in the treatment of recurrent/disseminated CPC in a one-year and nine-month-old child following prior GTR of the tumor performed elsewhere. In the absence of any standardized therapy, the use of ANP avoided the negative sequalae of chemotherapy, RT, and/or second surgery. Despite PD the patient has obtained an OS of > 23.6 years. This may be due to an ANP effect on the invasiveness of the recurrent/disseminated CPC. We previously reported the case of a patient with glioblastoma (GBM) who obtained a PR with ANP and then underwent GTR of the persistent GBM. At the time of surgery there was no evidence of involvement of the underlying brain parenchyma suggesting an ANP effect on the tumor’s invasive potential. Now, > 23.6 years later, the patient is experiencing good health and showing no evidence of tumor recurrence. [18] The prolonged OS in these patients, with less than a CR, suggests that OS is the most important endpoint for clinical trials of ANP.

Antineoplaston research began in 1967, when significant deficiencies were noticed in the peptide content of the serum of patients with cancer compared with healthy persons. Initially Antineoplastons were isolated from blood and later from urine [19]. Subsequent studies of the isolated Antineoplastons demonstrated that Antineoplaston A10 and Antineoplaston AS2-1 were the most active ANPs. The chemical name of Antineoplaston A10 is 3-phenylacetylamino-2,6-piperidinedione. It consists of the cyclic form of L-glutamine connected by a peptide bond to phenylacetyl residue. When given orally, Antineoplaston A10 resists the attack of gastric enzymes. In the small intestine, under alkaline conditions, 30% is digested into phenylacetylglutamine (PG) and phenylacetylisoglutaminate (isoPG) in a ratio of approximately 4:1. The mixture of synthetic PG and isoPG in a 4:1 ratio, dissolved in sterile water constitutes Antineoplaston A10 IV injection. Further metabolism of Antineoplaston A10 results in phenylacetate (PN). Both metabolites, PG and PN, have anticancer activity. The mixture of PN and PG in a 4:1 ratio, dissolved in sterile water constitutes Antineoplaston AS2-1 IV injection. [20]

ANP’s mechanism of action differs from that of RT or cytotoxic chemotherapy. Growth of normal cells is controlled by cell cycle progression genes (oncogenes) and by cell cycle arrest genes (tumor suppressor genes). In cancer, alteration of these control genes in malignant cells favors aggressive cell proliferation. Evidence suggests that ANP affects 400 mutated genes in the malignant genome and functions as a “molecular switch” which “turns on” tumor-suppressor genes and “turns off” oncogenes [21/22]. Hence, the ntineoplastic action of ANP involves restoration of cell cycle control, induction of programmed cell death, and interference with cancer cell metabolism and nuclear transport.

We have presented the case of a one-year and nine-month-old female with a recurrent/disseminated CPC who despite PD has obtained an OS of greater than 23.6 years and good health following ANP, which may be due to an ANP effect on the invasiveness of the recurrent/disseminated CPC. ANP has proved to be an attractive option for patients with persistent, recurrent, disseminated, and/or metastatic brain tumors as it produces ORs and avoids the negative sequalae of chemotherapy, RT, and/or second surgery. Multiple Phase II clinical studies of ANP in a variety of low-and high-grade brain tumors under the Burzynski Research Institute’s IND # 43,742 have now been completed and numerous articles have been published [23-68]. Based on our findings, we propose a multi-institutional Phase II clinical study of ANP in CPC.

Acknowledgements
The authors express their appreciation to Carolyn Powers for preparation of the manuscript and to Ramiro Rivera, Mohamed Khan, Jennifer Pineda, and Adam Golunski for their involvement.