antineoplastons for astrocytic tumours pediatrics by Kirk Andrew

Pediatr Drugs 2006; 8 (3): 167-178 1174-5878/06/0003-0167/$39.95/0

THERAPY IN PRACTICE

Treatments for Astrocytic Tumors in Children Current and Emerging Strategies Stanislaw R. Burzynski Burzynski Clinic, Houston, Texas, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 1. Therapeutic Approaches to Different Types of Astrocytomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 1.1 Low-Grade Astrocytomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 1.1.1 Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 1.1.2 Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 1.1.3 Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 1.1.4 Targeted Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 1.2 Optic Pathway Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 1.2.1 Surgery and Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 1.2.2 Chemotherapy and Targeted Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 1.3 High-Grade Astrocytomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 1.3.1 Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 1.3.2 Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 1.3.3 Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 1.4 Brainstem Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 1.4.1 Surgery and Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 1.4.2 Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 1.4.3 Targeted Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 2. Late Effects of Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 2.1 Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 2.1.1 Radiation Necrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 2.1.2 Necrotizing Leukoencephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 2.1.3 Cranial Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 2.1.4 Cognitive Disability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 2.1.5 Endocrine Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 2.1.6 Radiation-Induced Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 2.2 Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 2.2.1 Chronic Myelosuppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 2.2.2 Gonadal Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 2.2.3 Renal Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 2.2.4 Pulmonary Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 2.2.5 Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 2.2.6 Hearing Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 2.2.7 Cognitive Disability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 2.2.8 Chemotherapy-Induced Hematologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 2.3 Targeted Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

Abstract

Strategies for the treatment of childhood cancer have changed considerably during the last 50 years and have led to dramatic improvements in long-term survival. Despite these accomplishments, CNS tumors remain the leading cause of death in pediatric oncology. Astrocytic tumors form the most common histologic group among childhood brain tumors. They are a heterogeneous group that from a practical therapeutic point of view can be

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Burzynski

subdivided into low-grade astrocytomas (LGA), optic pathway gliomas (OPG), high-grade astrocytomas (HGA), and brainstem gliomas (BSG). This article focuses on the practical application of treatments that lead to long-term survival, improved quality of life, and reduced long-term complications. Improvement in therapy has led to better outcomes for patients with LGA and OPG. Careful follow-up without any treatment is indicated for a small percentage of patients diagnosed with LGA with an indolent course including children with neurofibromatosis type 1 (NF1). Surgery is the main recommended treatment for children with resectable LGA. Radiation therapy is generally recommended for children with progressive LGA, or after failure of chemotherapy, accomplishing tumor control at 10 years in over 60% of patients. Cytotoxic chemotherapy is usually reserved for children who have had treatment failure with surgery and radiation therapy. It is also offered for children who are too young to be treated with radiation or to defer or avoid radiotherapy. Carboplatin and vincristine achieve 5% complete and 28% partial responses but the use of vincristine is criticized due to poor penetration of the CNS. A regimen of tioguanine, procarbazine, mitolactol, lomustine, and vincristine is frequently administered as an alternative to carboplatin and vincristine in LGA. The introduction of temozolomide has allowed better responses, including a 24% complete response rate compared with 0â&#x20AC;&#x201C;5% complete response rates with the previous regimens. OPG are usually histologically LGA, and are treated with similar chemotherapy regimens. OPG is the most common type of brain tumor associated with NF1. Tumor growth in some of these patients is slow with no treatment recommended for an extended period of time. The prognosis for children with the remaining types of astrocytomas remains poor. Surgical resection is typically the first step in the treatment of HGA followed in older children by radiation therapy. The data regarding chemotherapy are mixed. Combination chemotherapy before or after radiation, including cisplatin, carmustine, cyclophosphamide, and vincristine or carboplatin, ifosfamide, cyclophosphamide, and etoposide has provided disappointing results. Clinical trials with temozolomide and agents directed against single targets have not shown substantially better results, but it is hoped that currently conducted studies will provide better outcomes. Diffuse intrinsic BSG are among the most difficult-to-treat brain tumors. Surgical treatment is not recommended for diffuse intrinsic BSG and standard radiation therapy is typically given in children aged >3 years. None of the numerous chemotherapy regimens, including temozolomide, has provided a significant response rate or an improvement in survival. It is expected that newer agents affecting multiple targets such as AEE-788 and antineoplastons, and combinations of single-targeted agents with chemotherapy will provide better results. Careful evaluation of histology, location of the tumor, patient age, and consideration of treatment-related morbidity play an important part in selecting between clinical observation, surgery, radiation, chemotherapy, or investigational agents. The goals of treatment for astrocytic tumors should extend well beyond objective responses and increased survival. Improvement of quality of life is an equally important objective of treatment. Radiation therapy and chemotherapy result in serious late toxicities.

Over the last 50 years, there has been dramatic progress in the treatment of childhood cancer. Long-term survival for all childhood malignancies has improved from <10% to 80%.[1] Despite these accomplishments, CNS tumors remain the leading cause of death in pediatric oncology.[2] Primary CNS tumors affect approximately 5500 children in the US each year and are the most common solid neoplasms in childhood.[3] Gliomas account for 56% of tumors in children aged <15 years and the most common histologic group is astrocytic tumors.[3] Astrocytomas are a heterogeneous group consisting of a number of histologic varieties.[4] From a practical therapeutic point of view, they can be subdivided into low-grade astrocytomas (LGA), optic pathway gliomas (OPG), high-grade astrocytomas (HGA), and brainstem gliomas (BSG). Progress has been made in the treatment of LGA and OPG, but there remains a great need to ďŁŠ 2006 Adis Data Information BV. All rights reserved.

improve the results of therapy for HGA and BSG.[5-7] Improved treatment outcomes for HGA including glioblastoma multiforme (GBM) with temozolomide in adult patients and the introduction of targeted agents raised hopes for more successful therapy of pediatric malignant brain tumors.[8-11] Results from clinical studies of temozolomide in childhood brain tumors have not been as good, but it is hoped that currently conducted larger clinical trials will provide better outcomes.[7,10,11] Targeted agents have shown interesting results in some clinical trials but in the majority, results fell short of expectations.[12] It is hoped that newer multi-targeted agents and combinations of single-targeted agents with chemotherapy will provide better results.[12] This article provides the latest information on the treatment of pediatric astrocytomas. The emphasis is on the practical application of the treatments. Readers are referred for further information Pediatr Drugs 2006; 8 (3)

Treatments for Astrocytic Tumors

to the numerous review articles that cover genetics, pathology, and the clinical and radiographic presentations of these tumors.[6,11-14] 1. Therapeutic Approaches to Different Types of Astrocytomas 1.1 Low-Grade Astrocytomas

LGA, which consist of grade 1 and 2 tumors, are the most common type of pediatric neoplasms within the category of glioma.[3] Of an entire group of 3793 children aged <15 years with primary brain tumors in the US, pilocytic astrocytoma was diagnosed in 24%.[3] In addition to pilocytic astrocytoma, grade 1 tumors include subependymal giant-cell astrocytomas, and grade 2 tumors are subdivided into diffuse astrocytomas (fibrillary, gemistocytic, and protoplasmic), pleomorphic xanthoastrocytomas, and mixed oligoastrocytomas.[6,15] The cerebellum is the most common location and accounts for 15–25% of all LGA. Published treatment data usually do not report results limited to LGA, but describe the therapy given to mixed small groups of adult and pediatric patients with tumors including other low-grade gliomas and newly diagnosed and recurrent tumors. Careful follow-up without any treatment is indicated for a small percentage of patients diagnosed with LGA with an indolent course, including children with neurofibromatosis type 1 (NF1).[16] The literature reports a sizable number of cases of spontaneous regressions of LGA.[17,18] Tumors causing aqueductal obstruction may require ventriculoperitoneal shunting or ventriculostomy; the majority of patients with low-grade tectal gliomas do not have progression for up to 10 years after such procedures.[19,20] 1.1.1 Surgery

Surgery is the main recommended treatment for children with resectable LGA. Shaw and Wisoff[18] compiled the results of five prospective clinical trials of low-grade gliomas in adults and children. A group of 660 pediatric patients was enrolled and evaluated based on the extent of surgical resection. Patients with gross total resection were observed, but those with subtotal resection or biopsy were either observed or administered radiation therapy.[18] The extent of resection was the main factor affecting overall survival; complete resection allowed long-term diseasefree survival in over 80% of children.[18,21] Patients with partial resection and marked residual disease usually have recurrence and tumor progression.[22] In such cases, ‘second-look’ surgery may be considered prior to radiation therapy and chemotherapy. 1.1.2 Radiation Therapy

Radiation therapy is generally recommended for children with progressive LGA, or after failure of chemotherapy, accomplishing tumor control at 10 years in over 60% of patients.[23] The diagnosis of LGA in a child creates a difficult clinical situation because of debilitating late toxicity of radiation therapy. Minimizing the dose  2006 Adis Data Information BV. All rights reserved.

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and field of radiation helps to allow normal growth and intellectual development in young children. Focal radiation fields covering the tumor volume visible on magnetic resonance imaging (MRI) [T2-weighted images] with a 2cm margin is usually recommended. Stereotactic radiotherapy improves the results and reduces toxicity, but hyperfractionated radiation therapy does not offer additional benefits.[24-26] 1.1.3 Chemotherapy

Cytotoxic chemotherapy is usually reserved for children who have had treatment failure with surgery and radiation therapy, or who are too young to be treated with radiation but it is also offered to a growing number of older children to defer or avoid radiotherapy.[6,27,28] Until approximately 20 years ago, LGA were seldom treated with chemotherapy. The initial regimens used dactinomycin, lomustine, and vincristine, and have been summarized in excellent reviews.[6,27,29,30] Selected recent regimens are summarized in table I. Carboplatin and vincristine achieve 5% complete response (CR) rates and 28% partial response (PR) rates, and vincristine and etoposide achieve 5% PR rates in patients with recurrent and newly diagnosed low-grade gliomas (mostly LGA).[36,37] Treatment with vinblastine for recurrent and refractory tumors has accomplished a 20% PR rate.[31,40] Tamoxifen and carboplatin in newly diagnosed and recurrent tumors allowed a 15% PR rate, but only 47% progression-free survival (PFS) at 3 years.[35] A regimen of tioguanine, procarbazine, mitolactol, lomustine, and vincristine first used in the treatment of hypothalamic gliomas is frequently administered as an alternative to carboplatin and vincristine in LGA.[38] The introduction of temozolomide allowed better responses, including 24% CR and 37% PR rates (in children and adults) in a phase II study.[33] Additional studies with temozolomide revealed a 10% (three patients) PR rate, but no CR, and 1year PFS was slightly more than 50%.[32] 1.1.4 Targeted Therapy

Clinical trials with agents affecting single targets are in progress and the preliminary results of multi-targeted therapy with the antineoplastons (ANP) A10 and AS2-1 have been reported.[39] In a small group of patients with progressive LGA, ANP accomplished a 60% CR rate, 10% PR rate, median survival of 7 years and 9 months, and maximum survival of more than 15 years.[39] 1.2 Optic Pathway Gliomas

OPG constitute approximately 6% of pediatric brain tumors.[41] They typically occur in children aged <12 years, and a majority of these tumors involve the chiasm and hypothalamus.[42-44] Histologically, these are low-grade gliomas. The type of treatment and prognosis varies from one patient to another. Chiasmatic and hypothalamic tumors create more difficulties including pronounced loss of vision and hypothalamic dysfunction than gliomas Pediatr Drugs 2006; 8 (3)

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Table I. Selected chemotherapy regimens for the treatment of low-grade astrocytoma in children Reference

Study

Tumor

Treatment

Efficacy

type

(no. of pts)

OS [%]

Bouffet et al.[31]

Pilot

Vinblastine (20)

Gururangan et al.[32]

Phase II

Temozolomide (32)a

Quinn et al.[33]

Phase II

Kuo et al.[34]

Phase II

Walter et al.[35] Packer et al.[36]

PR [% (no.)]

SD + MR [% (no.)]

PD [% (no.)] PFS (%)

0 (0)

20 (4)

60 (12)

20 (4)

100 (1y)

0 (0)

10 (3)

43 (13)

47 (14)

51 (1y)

Temozolomide (46)b

24 (11)

37 (17)

35 (16)

4 (2)

76 (1y)

Temozolomide (13)

0 (0)

23 (3)

46 (6)

31 (4)

Phase II

Tamoxifen, carboplatin (14)c

0 (0)

15 (2)

70 (9)

15 (2)

47 (3y)

Phase II

Carboplatin, vincristine (78)

5 (4)

28 (22)

60 (47)

7 (5)

86 (1y);

96 (1y)

69 (3y)

CR [% (no.)]

68 (3y) Pons et al.[37]

Phase II

Vincristine, etoposide (20)

0 (0)

5 (1)

70 (14)

25 (5)

Petronio et al.[38]

Phase II

Tioguanine, procarbazine,

0 (0)

60 (9)

13 (2)

27 (4)

60 (6)

10 (1)

30 (3)

0 (0)

mitolactol, lomustine, vincristine (15) Burzynski[39]

Phase IId

ANP (10)

100 (1y); 90 (3y);

90 (1y); 90 (3y)

MST = 93mo

Thirty evaluable pts.

Children and adults.

Thirteen evaluable pts.

Preliminary results.

survival; P = progressive tumor; PD = progressive disease; PFS = progression-free survival; PR = partial response; pts = patients; R = recurrent tumor; RP = recurrent and progressive tumor; SD = stable disease.

Burzynski

Pediatr Drugs 2006; 8 (3)

ANP = antineoplastons A10 and AS2-1; CR = complete response; MR = minor response; MST = median survival time; NR = newly diagnosed and recurrent tumor; OS = overall

Treatments for Astrocytic Tumors

of the optic nerve. Tumors that occur in children aged <1 year are typically larger and cause severe loss of vision and hypothalamic dysfunction while gliomas in older children carry a better prognosis. OPG is the most common type of brain tumor associated with NF1. In various series, 25–60% of the children diagnosed with this type of tumor had NF1.[45,46] Growth of OPG in some of these patients is slow with no treatment recommended for an extended period of time. Monitoring without therapeutic intervention is suggested for asymptomatic tumors. A biopsy is not required for hypothalamic and chiasmatic lesions in patients with typical MRI findings. Progressive visual deterioration may require surgery. Radiation and chemotherapy regimens are appropriate for recurrent and posterior OPG.[16,18,21,25,28,38] 1.2.1 Surgery and Radiation Therapy

These patients are typically not candidates for radical surgery, but when a substantial exophytic component is present, a >60% resection can be accomplished in very young children.[43] According to a report from a neurosurgical group, these tumors can remain stable after resection for a mean of 27 months.[47] Radiation therapy contributes to stabilization in most patients, but the chronic toxicity associated with such treatment precludes its use in young children.[48,49] 1.2.2 Chemotherapy and Targeted Therapy

Because of concerns about the long-term toxicity of radiation therapy, a number of chemotherapeutic regimens have been used in the treatment of OPG. The initial successful regimen included a combination of dactinomycin and vincristine in 24 children with a median age of 1.6 years.[50] PR was achieved in 12.5% of patients, stable disease (SD) in 50%, and progressive disease (PD) in 37.5%. The median survival was 4.3 years and 25% had a projected 70-month event-free survival. In another study, the treatment of 113 evaluable children (median age 3.7 years) with vincristine and carboplatin resulted in a 51% PR rate, 41% SD rate, and 8% PD rate.[51] Forty-two percent of children developed progression and median time to progression (MTP) was 22.5 months. New treatment regimens including ANP are under investigation.[52] 1.3 High-Grade Astrocytomas

Over 15% of all pediatric brain tumors are considered to be high-grade gliomas (WHO grade 3 and 4).[3,7] GBM (grade 4) is less common than anaplastic astrocytoma (grade 3; AA); in children aged <15 years, it constitutes only 2.8% of all CNS tumors.[3] The incidence of HGA is lower in very young children (3–11%) compared with older children.[53] The incidence of HGA differs depending on tumor location. AA and GBM constitute approximately 25% of all childhood cortical gliomas.[54] Cerebellar high 2006 Adis Data Information BV. All rights reserved.

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grade gliomas occur substantially less frequently (<5% of cerebellar gliomas).[55] 1.3.1 Surgery

Surgical resection is typically the first step in the treatment of HGA. The results of treatment of 131 children with GBM and AA confirm that >90% resection allows a statistically significant PFS.[56] PFS at 5 years for radical resections was 35% compared with 17% for a less aggressive procedure. Patients with AA had a PFS of 44% and patients with GBM had a PFS of 26% after radical surgery, compared with a PFS of 22% and 4%, respectively, with a more conservative procedure. Similar results have been obtained in additional studies.[57] 1.3.2 Radiation Therapy

Radiation therapy is usually not recommended in children aged <3 years because of unacceptable toxicity. The introduction of three-dimensional conformal therapy may allow successful treatment of such children, but clinical trials to study long-term adverse effects are required. Older children are usually treated after recovery from surgery with a total dose of radiation to the tumor, or the tumor bed, of between 54 and 60Gy in 1.8–2Gy fractions.[7] Hyperfractionated therapy and craniospinal radiation have not improved the outcomes,[58] and are usually not recommended. In the past, patients with disseminated disease were recommended to undergo craniospinal radiation, which is no longer the standard approach.[58] Stereotactic radiosurgery resulted in a 33% 3-year PFS in a small series of patients with newly diagnosed and recurrent high-grade gliomas, but requires further study.[59] Fewer than 25% of children with HGA achieve long-term survival after radiation therapy alone.[54,60] 1.3.3 Chemotherapy

Since the 1980s, a number of combination chemotherapy regimens have been used in the treatment of HGA. However, encouraging initial results with lomustine, vincristine, and prednisone, in combination with radiation therapy, have not been confirmed by subsequent studies.[61-63] Neoadjuvant chemotherapy with cisplatin, cytarabine, procarbazine, and topotecan did not show significant benefits.[64,65] Combination chemotherapy before or after radiation therapy, including cisplatin, carmustine, cyclophosphamide, and vincristine, or carboplatin, ifosfamide, cyclophosphamide and etoposide, and concurrent high-dose chemotherapy and radiation therapy with stem cell support have provided disappointing results.[66,67] A meta-analysis of the results of 27 clinical studies that accrued 576 children did not show significant benefits of chemotherapy.[68] Initial studies with temozolomide showed some responses.[11,69] A more recent report of a small series of 11 patients with recurrent malignant brain tumors (six GBM, two AA, one BSG, and one primitive neuroectodermal tumor) treated with temozolomide and etoposide has shown more encouraging results with one CR, seven PR, and an MTP of 8 months.[70] Another Pediatr Drugs 2006; 8 (3)

Seventeen evaluable pts. b

Fifty-seven evaluable pts.

RPS (10) Phase II Burzynski et al.[89]

RP (30) Phase II Burzynski et al.[88]

R (21)b Phase II Lashford et al.[10]

ANP = antineoplastons A10 and AS2-1; CR = complete response; MST = median survival time; N = newly diagnosed tumor; NA = not available; OS = overall survival; PD = progressive disease; PR = partial response; pts = patients; R = recurrent tumor; RP = recurrent and progressive tumor; RPS = recurrent and progressive tumors in children aged <4y; SD = stable disease.

30 (3) 40 (4) 0 (0) 30 (3) 26.3 60; 20 ANP

30 (9) 23 (7) 20 (6) 27 (8) 19.9

Temozolomide

Temozolomide, irinotecan 56 Multiinstitutional Broniscer et al.[86]

N (33)

Phase III

N (66a)

Cisplatin

ANP

46.7; 30

77.8 (14) 16.7 (3) 5.6 (1) 0 (0) 6.2 NA; NA

NA NA

44 (25) 31 (18) 2 (1)

NA 12 0; 0

MST (mo) OS (%) [2y; 5y] radiation therapy (Gy) (no. of pts)

chemotherapy

ANP

Efficacy Treatment Tumor type

Mandell et al.[78]

None of the numerous chemotherapeutic regimens, including temozolomide given before, with, and after radiation therapy has provided significant response rates or improvement in survival.[80-86] High-dose chemotherapy with autologous bone marrow transplantation has not produced better results.[87] Recurrent DBSG and tumors in small children carry an especially poor prognosis with no standard treatment available; temozolomide is also not effective in these patients (table II).[10] It is not expected that patients with recurrent DBSG will survive longer than 6 months, regardless of the therapy.[10]

Study type

1.4.2 Chemotherapy

Reference

Surgical treatment is not recommended for DBSG and standard radiation therapy of 54Gy in daily fractions of 1.8Gy through parallel opposed portals is typically given in children aged >3 years.[74,78,79] A number of hyperfractionation protocols have been tried without success.[78,80] Patients treated with standard irradiation have disappointing prognoses; only approximately 7% would survive 2 years with no survival expected over 5 years (table II).[78]

Table II. Treatment of diffuse, intrinsic brainstem glioma in children

1.4.1 Surgery and Radiation Therapy

CR [% (no.)]

Gliomas located in the brainstem affect approximately 690 children annually in the US.[3] Based on autopsy reports, the majority of patients have AA.[72] However, biopsies are performed only in some cases because of the difficult location, and are misleading because of sampling error. Typically, these tumors are classified based on MRI appearance into the following types: focal, dorsal, exophytic, cervicomedullary, and diffuse intrinsic BSG (DBSG).[72] DBSG is the most common (85% of cases) and most difficult to treat and is generally regarded as an HGA. DBSG is more aggressive in infants than in older children, and it is easier to manage in children with NF1.[73,74] Such children are frequently asymptomatic and have a stable tumor size for a longer time. Genetic abnormalities in DBSG have not been sufficiently studied.[75] Epidermal growth factor-receptor protein is detected in one-third of these patients and approximately 50% have a mutation of TP53 and loss of the PTEN tumor suppressor genes.[75-77] DBSG is among the most difficult-to-treat brain tumors; the remaining types of brainstem gliomas are treated in the same way as tumors in other parts of the brain with similar histopathologic diagnoses.

8.5

1.4 Brainstem Gliomas

7.1; 0

PR [% (no.)]

SD [% (no.)]

PD [% (no.)]

multi-institutional study of 31 children and young adults with newly diagnosed HGA and unfavorable LGA (48% GBM and 32% AA) treated with irinotecan followed by radiation therapy and temozolomide did not confirm the activity of temozolomide and irinotecan.[71] Despite numerous studies, the treatment of pediatric HGA remains suboptimal and the results are disappointing.

Burzynski

23 (13)

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Treatments for Astrocytic Tumors

1.4.3 Targeted Therapy

Single-targeted therapy has not yet been used in DBSG, but multi-targeted therapy with ANP has shown promising results.[12,88-91] In a group of 30 evaluable patients with recurrent and progressive DBSG, >40% of patients survived for more than 2 years and 30% more than 5 years. The responses included CR in 27%, PR in 20%, SD in 23%, and PD in 30%.[12,88] A small group of ten evaluable children aged <4 years diagnosed with DBSG was treated with ANP; the youngest was a 3-month-old infant.[89] The 2-year survival rate was 60%, 5-year survival was 20%, and the maximum survival was more than 7 years. CR occurred in 30%, SD in 40%, and PD in 30%.[89] The results are compiled in table II. 2. Late Effects of Therapy Interest in the research of late effects of radiation and chemotherapy has expanded in parallel with an improvement in efficacy and longer survival in children with brain tumors. 2.1 Radiation Therapy

Chronic toxicity of radiation affects the majority of children treated for brain tumors and in a significant percentage of cases leads to chronic disabilities and death. 2.1.1 Radiation Necrosis

In a series of 80 patients, Sheline et al.[92] determined that the interval from completion of radiation therapy to development of cerebral necrosis ranged from 4 months to 7.5 years. Recurrent tumors and late radiation necrosis share many similar clinical and MRI features. There is no effective treatment for delayed radiation necrosis; however, some patients have benefited from hyperbaric oxygen treatment. The incidence of radiation necrosis is related to the dosage of radiation and may occur in up to 7% of patients treated with hyperfractionated radiation.[93] Maintaining the dose of radiation for low-grade tumors to 54Gy in 30 fractions and for high-grade gliomas to 60Gy in 33 fractions may prevent radiation necrosis and subsequent death.[94] 2.1.2 Necrotizing Leukoencephalopathy

Necrotizing leukoencephalopathy was first described in children who received cranial irradiation and methotrexate.[95] Patients with this syndrome develop demyelinization, multifocal coagulation necrosis, and gliosis, and most have permanent neurologic deficits.[96,97] No known treatment exists for this condition, but it may reverse spontaneously in some cases. 2.1.3 Cranial Neuropathy

Optic neuropathy occurs in patients receiving high doses of radiation. This adverse effect was not reported in the study by Parson et al.,[98] in which 106 adult patients with head and neck tumors received <59Gy, but higher doses of radiation increase the incidence of optic neuropathy to 47%.[99] ďŁŠ 2006 Adis Data Information BV. All rights reserved.

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2.1.4 Cognitive Disability

Numerous studies have confirmed the deleterious effect of radiation on cognitive function.[100-102] The severity of impairment relates to the total dose of radiation, the fraction size, and the patientâ&#x20AC;&#x2122;s age. Children aged <4 years are especially vulnerable. Adults who received radiation therapy for brain tumors in childhood have greater difficulty finding employment.[103] 2.1.5 Endocrine Dysfunction

In various studies, 47â&#x20AC;&#x201C;65% of children treated with radiation for brain tumors had chronic growth hormone deficiency.[104-106] As a result, a high proportion of survivors have short stature.[107] Irradiation of the hypothalamic-pituitary axis can result in thyroid hormone and gonadotropin deficiency. In some studies, more than two-thirds of children developed postradiation thyroid dysfunction.[108] Gonadotropin deficiency leads to a lack or an interruption in pubertal development. The incidence of gonadotropin deficiency was as high as 11% in one study.[109] Children with endocrine dysfunction are evaluated and treated with hormone replacement. 2.1.6 Radiation-Induced Tumors

Radiation-induced tumors are distinct entities and include meningiomas, cranial sarcomas, and gliomas.[110] In a large series of children who had more than one malignancy, in approximately half of the patients, radiation therapy for the first malignancy was a possible etiologic factor for a second tumor. In approximately 25% of these patients, NF1 was felt to be a contributing factor.[111] Additional studies have supported an increased risk of a secondary malignancy in children after irradiation.[112,113] The British Childhood Cancer Research Group found a 5-fold increase in the risk of a secondary malignancy in a population of over 10 000 survivors of childhood malignancies.[114] 2.2 Chemotherapy

The use of chemotherapy as a primary treatment for astrocytoma, especially in very young children, has been justified by a reduction in radiation-induced brain damage.[115] Unfortunately, cytotoxic chemotherapy also contributes to a wide spectrum of chronic toxicities. 2.2.1 Chronic Myelosuppression

Nitrosoureas (carmustine and lomustine), cisplatin, and carboplatin may cause chronic myelosuppression that persists after discontinuation of chemotherapy.[116-118] Serious infection caused by leukopenia is the common fatal complication of carmustine treatment. Hemorrhage due to thrombocytopenia is less common, but cisplatin may cause significant anemia.[117] 2.2.2 Gonadal Dysfunction

Carmustine, lomustine, procarbazine, and cisplatin are known to cause gonadal dysfunction in girls and boys.[119-121] In prepubertal girls, primary ovarian dysfunction may improve and Pediatr Drugs 2006; 8 (3)

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Burzynski

ovarian function may return to normal after the cessation of treatment with carmustine.[122] Nitrosoureas contribute to a high incidence of oligospermia.[123] 2.2.3 Renal Insufficiency

Nitrosoureas and cisplatin may cause renal insufficiency.[124] Nephrotoxicity is proportional to the total dosage of chemotherapy. It may persist following the cessation of treatment, and lead to chronic renal failure requiring dialysis.[125,126] 2.2.4 Pulmonary Toxicity

An interstitial inflammatory process in the lungs causing decreased oxygen transfer was first reported in 1976 as a fatal complication of carmustine treatment.[127] Pneumonitis has been reported with procarbazine and vincristine.[128,129] These complications may respond to corticosteroid administration. 2.2.5 Neurotoxicity

Intracarotid administration of carmustine has been shown to cause ipsilateral visual loss in 25â&#x20AC;&#x201C;65% of patients.[130,131] Loss of vision may start several weeks after the treatment and progress to irreversible blindness. Leukoencephalopathy and increased incidences of seizures have been described in patients after high-dose carmustine.[132-134] Peripheral neuropathy is a well known adverse event associated with vincristine.[135] In some cases, cranial nerve dysfunction develops with diplopia, hoarseness, dysphagia, and facial nerve paralysis. Autonomic neuropathy with orthostatic hypotension and CNS symptoms including depression, confusion, and insomnia have also been reported.[136] Cisplatin may cause peripheral neuropathy that may progress to motor involvement.[137] The neuropathy may continue and worsen long after discontinuation of cisplatin.[138,139] 2.2.6 Hearing Loss

Treatment with cisplatin may result in sensory hearing loss.[140] It may start as tinnitus and progress to high-frequency hearing loss and deafness. Decreased hearing may worsen after discontinuation of the drug. Periodic audiograms may help to detect initial toxicity before occurrence of symptoms. 2.2.7 Cognitive Disability

Chemotherapy-induced decreased hearing (see section 2.2.6) may affect speech, normal cognitive development, and learning in children. Very young children have shown an abnormality in physical and psychologic development after pre-irradiation chemotherapy for brain tumors.[141] Neuropsychologic evaluation is recommended at the completion of chemotherapy and again 3â&#x20AC;&#x201C;5 years later for a young child. 2.2.8 Chemotherapy-Induced Hematologic Malignancies

Carmustine and lomustine have been reported to contribute to myelofibrosis, secondary myelodysplasia, and acute leukemia following treatment of gliomas.[142,143] The incidence of leukemia is ďŁŠ 2006 Adis Data Information BV. All rights reserved.

less frequent after treatment with procarbazine and cisplatin.[144,145] 2.3 Targeted Therapy

Therapy oriented against single targets has not yet been used in children for a sufficient period to determine latent effects. Based on the results in adult patients, the incidence of late toxicities is substantially lower than that for radiation and chemotherapy.[146] Multi-targeted ANP therapy is free from chronic toxicity in children and adults based on the results of numerous clinical studies involving 1652 adults and 335 children.[147] Long-term follow-up of children treated with ANP for astrocytomas revealed normal development, no cognitive or endocrine deficiencies, and normal fertility. A substantial number of these patients have been tumor free for >5 years and the follow-up period for some of these patients is >17 years. Data in the emerging literature on gene or protein micorarray analysis of tumors show these techniques to predict responses to targeted therapies and reduce toxicity with greater precision than is possible with clinical findings.[148] It is hoped that such an approach will provide individualized care for patients with brain tumors.[149] 3. Conclusion Astrocytomas form the most common histologic group among childhood brain tumors. Approaches to treatment have changed markedly during the last 50 years and have led to the following considerations. Patients with completely resected tumors usually do not require additional therapy, but should be followed up for possible recurrence. Children with NF1 should receive treatment only in cases of morbidity and clear progression. Radiation is the therapy of choice for newly diagnosed DBSG and as adjuvant treatment for children aged >3 years with HGA and progressive, recurrent, and unresectable LGA and OPG. Chemotherapy is the standard approach for younger children and even though it is less efficacious than radiation, it has a more acceptable toxicity profile. The use of vincristine, which is still administered, is open to criticism since published results suggest that vincristine does not penetrate the CNS and high concentrations in the cerebrospinal fluid are fatal.[150] Despite indisputable benefits from radiation and chemotherapy, approximately two-thirds of childhood cancer survivors experience at least one latent adverse effect and about 25% experience delayed toxicities that are severe or life threatening.[151,152] The goals of treatment for astrocytomas should extend well beyond objective responses and increased survival. Improvement of quality of life is an equally important objective of treatment. Radiation therapy and chemotherapy result in serious late toxicities in a significant number of children. Known late effects of Pediatr Drugs 2006; 8 (3)

Treatments for Astrocytic Tumors

radiation include radiation necrosis, necrotizing leukoencephalopathy, cranial neuropathy, cognitive disability, endocrine dysfunction, and radiation-induced tumors. Cytotoxic chemotherapy may cause chronic myelosupression, gonadal dysfunction, renal insufficiency, pulmonary toxicity, and hearing loss in addition to neurotoxicity, cognitive dysfunction, and secondary malignancies. Quality-of-life studies have been performed in patients with recurring malignant gliomas treated with brachytherapy, but quality-of-life data in patients receiving chemotherapy for astrocytoma are limited.[153,154] Limited applications of targeted therapy including ANP have contributed to significant responses, long-term survival, and a good quality of life with no chronic toxicities.[12] Genomic and molecular studies have revealed substantial differences between pediatric and adult brain tumors. TP53 tumor suppressor gene mutations occur in approximately 40% (50% in DBSG) of pediatric malignant gliomas and are associated with poor survival. p16 and retinoblastoma gene deletions are found in approximately 50% of tumors.[155] Mutations of PTEN and amplification of epidermal growth factor receptor are common in adult HGA, but are rare in pediatric tumors.[155] Successful treatment of astrocytomas in children requires targeting different mediators of neoplastic growth than those in adult patients. Agents affecting multiple targets currently in clinical trials such as AEE-788 may offer a better chance of successful treatment of pediatric astrocytomas. Advances in recent years in genomic and molecular research and a better understanding of the pathogenesis of astrocytomas will undoubtedly lead to better treatments in the near future. Acknowledgments No sources of funding were used to assist in the preparation of this review. Dr Burzynski is the President and Chairman of the Board of Directors of Burzynski Research Institute, Inc., which owns licenses for ANP in the US, Canada, and Mexico; and is a President of the Burzynski Clinic.

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Correspondence and offprints: Dr Stanislaw R. Burzynski, Burzynski Clinic, 9432 Old Katy Road, Houston, TX 77055, USA. E-mail: srb@burzynskiclinic.com

Pediatr Drugs 2006; 8 (3)