Application of stem cell transplant for brain tumors

Abstract:  Brain tumors are the second most common malignancy in children and the most common solid tumor. The majority of children are treated with surgery alone or in combination with radiation and/or chemotherapy. Recently investigators have used high dose chemotherapy with autologous stem cell rescue (ASCR) in patients with malignant brain tumors. This approach has been most successful in chemosensitive tumors including medulloblastoma, supratentorial primitive neuroectodermal tumors (SPNET) and central nervous system germ cell tumors (CNS GCT). In addition, the use of high dose chemotherapy has enabled the reduction and in many cases elimination of radiation therapy to very young children. To date there have been no prospective randomized studies comparing high dose chemotherapy and ASCR with conventional therapy. Radiation therapy is often not an option for patients with recurrent disease and conventional dose chemotherapy rarely if ever results in long-term survival. Unfortunately, the majority of studies using conventional therapy in order to delay irradiation in young children newly diagnosed with malignant brain tumors have been unsuccessful. Although the numbers are small, preliminary data suggest that not only is survival but also quality of life is superior with the use of high dose chemotherapy. Future studies will most likely include the use of new agents as part of the cytoreduction. In addition, through the use of peripheral blood stem cells and improvements in supportive care, multiple courses of high dose chemotherapy can be administered. High dose chemotherapy with ASCR is a foundation upon which many different types of therapies can be built. Several possibilities include the use of anti-angiogenesis agents, monoclonal antibodies and biologic response modifiers.     

Outcome for children <4 years of age with malignant central nervous system tumors treated with high-dose chemotherapy and autologous stem cell rescue

BACKGROUND: Children <4 years of age (yo) with malignant central nervous system (CNS) tumors have a dismal prognosis. In an attempt to delay or obviate radiation therapy (XRT) and improve outcome, our institution has treated children <4 yo with newly diagnosed malignant CNS tumors with high-dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) followed by selective XRT. PROCEDURE: Fifteen children (age 4-38 months) with malignant CNS tumors have completed treatment with HDC/ASCR. All patients received three cycles of induction chemotherapy (cisplatin 3.5 mg/kg- day 0, cyclophosphamide 60 mg/kg- day 1 and 2, etoposide 2.5 mg/kg- day 0-2, vincristine 0.05 mg/kg, day 0, 7, 14) followed by three cycles of HDC (carboplatin 17 mg/kg and thiotepa 6 mg/kg, day 0 and 1) with ASCR. Histology included five medulloblastomas, four primitive neuroectodermal tumors (PNET), five malignant gliomas, and one ependymoma. Outcome and treatment toxicities were evaluated by retrospective chart review. RESULTS: Median follow-up time of the 15 patients is 22 months (range 8-82 months). The 1- and 2-year progression-free survival (PFS) is 86.1% and 52.2% and overall survival (OS) 91.6% and 72.1%, respectively. Ten patients are alive and disease free 3-77 months (median 18 months) after having completed HDC/ASCR, thereoff five received XRT. Toxicity was primarily myelosuppression. There was no treatment mortality. CONCLUSIONS: We are encouraged by the outcome of 15 children <4 yo with malignant CNS tumors treated with tandem cycles of HDC and ASCR at our institution. The treatment regimen is relatively well tolerated.     

Differential responsiveness among "high risk" pediatric brain tumors in a pilot study of dose-intensive induction chemotherapy

BACKGROUND: These factors have been predictive for progressive disease on therapy (PDOT) among pediatric brain tumors: >1.5 cm(2) unresectable tumor, glioblastoma, supratentorial primitive neuroectodermal tumor, and metastatic medulloblastoma (MBL). This pilot study sought to correlate cytoreductive response with progression free survival. PROCEDURES: Four courses of cisplatinum, cyclophosphamide, etoposide, and vincristine preceded hyperfractionated radiotherapy (RT). Maintenance chemotherapy consisted of eight cycles of carboplatin, etoposide, and vincristine. Biopsy specimens were immunohistochemically studied for labeling index, hypoxia, and multidrug resistance proteins. RESULTS: Twenty newly diagnosed patients [nine primitive neuroectodermal tumors/MBL, one choroid plexus carcinoma, eight malignant gliomas, and two anaplastic ependymomas] were treated. Ten patients, who required neuraxis irradiation, constituted the "PNET" group. These demonstrated five complete and one partial response (PR), with an estimated median progression free survival of 44 months and median survival in excess of 53 months. Patients treated with involved field irradiation were designated the "Glioma" group. Induction chemotherapy produced partial and minor responses (MRs) among 5/10. Their estimated median progression free survival was 6.9 months (P = 0.035 relative to the PNET) with a median survival of 10.7 months (P = 0.04). Age, labeling index, the presence of hypoxia, and Pgp/MDR1 expression failed to discriminate between the two groups. CONCLUSIONS: This induction regimen produced a cytoreductive response in 6/10 and achieved a significant improvement in progression free survival among 7/10 in the PNET group. Unfortunately, responses among Glioma patients did not translate into durable control. Expression of the biologic factors was similar between both groups and did not correlate with diagnosis or response.     

CNS primitive neuroectodermal tumors of childhood

Primitive neuroectodermal tumors ( PNET ) of the central nervous system in children are rare, highly malignant, cystic, and sometimes calcific, and hemorrhagic tumors sharply demarcated from adjacent brain. Microscopically they consist of small predominantly undifferentiated dark cells with neuronal, glial, and mesenchymal elements. We have recently diagnosed and treated five children with PNET . We will review their case histories as well as summarize the previous 133 reported cases with reference to presenting complaints, tumor location, neurodiagnostic studies, and the retrospective results of four treatment programs: 1) surgery alone; 2) surgery and radiation therapy; 3) surgery, radiation therapy, and chemotherapy at time of recurrence; and 4) surgery, radiation therapy, and chemotherapy at onset.     

Pediatric neuro-oncology: Controversies in current therapy

Current Phase III clinical trials for the treatment of malignant central nervous system (CNS) tumors of childhood are reviewed. Combination neurosurgical, radiation treatment and chemotherapy have improved both the quality and duration of life for the affected children. Controversy exists regarding the appropriate adjunctive chemotherapy for newly diagnosed CNS neoplasms but this is being prospectively studied in controlled trials. Major dilemmas persist regarding the management of low-grade gliomas and recurrent CNS neoplasms. Preliminary data on possibly favourable protocols are cited. Future directions for clinical and basic laboratory investigation are also briefly reviewed.     

Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas

Seventeen patients less than or equal to 20 years of age with newly diagnosed (n = 10) or recurrent (n = 7) malignant gliomas (anaplastic astrocytoma and glioblastoma multiforme) were treated with cyclophosphamide in association with hematopoietic cytokines (GM-CSF or G-CSF). Cyclophosphamide was given at a dose of 2 g/m² daily for 2 days at 4-week intervals. Toxicity consisted of grade IV neutropenia and thrombocytopenia in 95% and 48% of cycles, respectively. There were no cyclophosphamide-related cardiac, pulmonary, or urothelial toxicities observed. Four of 10 patients with newly diagnosed disease demonstrated responses (three complete and one partial responses; one CR was only of 2 months duration). None of the seven patients with recurrent tumors demonstrated a response. We conclude that high-dose cyclophosphamide warrants further evaluation in children with newly diagnosed malignant glioma. Med. Pediatr. Oncol. 30:75–80, 1998. © 1998 Wiley-Liss, Inc.     

Activity of postoperative carboplatin,etoposide, and high-dose methotrexate in pediatric CNS embryonal tumors: results of a phase II study in newly diagnosed children

BACKGROUND: Chemotherapy is used as an alternative to irradiation or to minimize the irradiation exposure among infants with medulloblastoma or other CNS embryonal tumors. Adjuvant chemotherapy is commonly used in older children with high-risk medulloblastoma to improve survival or to allow a reduction in the craniospinal irradiation dose in standard-risk patients. However, optimal multimodality therapy, including the precise role of chemotherapy, has not been defined for these groups of patients. The objective of the present study is to assess the efficacy and toxicity of four postoperative courses of carboplatin, etoposide, and high-dose methotrexate in newly diagnosed children with medulloblastoma or other CNS embryonal tumors. PROCEDURE: Twenty-eight children, aged from 0.3 to 15.9 years (median, 6.2 years) with post-operative measurable residual CNS embryonal tumors were enrolled, comprising medulloblastoma (n = 19), supratentorial PNET (n = 7), and pineoblastoma (n = 2). Post-operative chemotherapy comprised carboplatin 350 mg/m(2) and etoposide 100 mg/m(2) on Days 1 & 2, and methotrexate 8 g/m(2) on Day 3, repeated at 21-28-day intervals for a total of four courses. Therapy following completion of the initial Phase II study was influenced by patient age and investigator preference. RESULTS: The combined complete response rate (CR, 7/19) and partial response rate (PR, 7/19) was 74% in patients with medulloblastoma, 89% for patients with PNET/pineoblastoma (CR, 2/9 and PR, 6/9), and for all patients it was 79%. Patients aged < 3 years at diagnosis had a combined PR and CR rate of 71% compared to 81% in patients aged > 3 years. Treatment was well tolerated although myelosuppression and thrombocytopenia were common. CONCLUSIONS: The combination of carboplatin, etoposide, and high-dose methotrexate is highly active in pediatric patients with CNS embryonal tumors.     

Temozolomide and oral VP-16 for children and young adults with recurrent or treatment-induced malignant gliomas

BACKGROUND: Children and young adults with recurrent or treatment-induced malignant gliomas have limited responses to temozolomide or oral VP-16 when either is administered as a single agent. We postulated that a combination of these two drugs for patients with recurrent or treatment-induced malignant gliomas might result in better and more prolonged responses. A retrospective analysis was performed on patients treated with the combination of temozolomide and VP-16. PROCEDURE: Eleven patients with recurrent or treatment-induced malignant gliomas were treated with varying combinations of temozolomide (150-210 mg/m2/d for 5 days) and oral VP-16 (50 mg/m2/d for 4-12 days). Responses were assessed by MRI scan, and data on clinical course and toxicity were retrospectively obtained from the medical record. RESULTS: The median age of the 11 patients was 17 years (range 5-23 years). Diagnoses included recurrent brain stem glioma (2), recurrent anaplastic astrocytoma (2), and glioblastoma (7) (3 treatment-induced, 2 malignant transformations of lower grade tumors, 1 recurrence, and 1 second tumor arising 10 months after diagnosis of medulloblastoma). All 11 patients had received radiotherapy (including 4 who received craniospinal radiation), and 7 had prior chemotherapy. Nine patients were treated at first recurrence, two at second recurrence. One patient had a complete response (CR), six had partial responses (PR), and four had progressive disease (PD). The median progression-free survival for the seven responding patients was 6 months (range 4-15+ months). There was one grade 4 neutropenia, but no other grade 3 or 4 toxicities. CONCLUSIONS: These data suggest there is activity of temozolomide in combination with oral VP-16 for children and young adults with recurrent malignant gliomas.     

CENTRAL NERVOUS SYSTEM (CNS) TUMORS IN THE FIRST SIX MONTHS OF LIFE: The Childrens Hospital Los Angeles Experience, 1979–2005

Background: The authors report the experience at the Children's Hospital Los Angeles with brain tumors diagnosed before 6 months of age, describing the characteristics of the patients, their tumors, treatment strategies, and prognostic factors. Methods: Thirty-three children who were identified between 1979 and 2005 were included. Twelve were female (36%). There were 11 gliomas, 9 choroid plexus tumors, 8 medulloblastomas and supratentorial primitive neuroectodermal tumors (PNET), 2 atypical teratoid/rhabdoid tumors (ATRT), and 1 each of ependymoma, craniopharyngioma, and immature teratoma. Locations of primary tumors included 21 supratentorial (64%) and 7 posterior fossa, and 5 tumors involved both compartments. The treatment strategies included 5 patients with biopsy only, 18 less than gross total resections (<GTRx), and 9 GTRx. Fourteen children (42%) received chemotherapy. Three patients (9%) received irradiation, 1 at initial diagnosis and 2 at relapse. Nine patients (27%) demonstrated metastases, 6 at diagnosis and 3 at relapse. Results: The Kaplan Meier analysis of event-free survival (EFS) and overall survival (OS) for all patients is 21 ± 9% and 35 ± 9% at 5 years. For the glioma patients, the 4-year OS is 48 ± 17%, while the 5-year OS for the medulloblastoma/PNET/ATRT patients is 12 ± 11% (p = .39). The 5-year OS for children achieving a GTRx is 64 ± 21% and for those with <GTRx is 27 ± 10% (p = .08).     

Tamoxifen and carboplatin for children with low-grade gliomas: a pilot study at St. Jude Children's Research Hospital

PURPOSE: The authors conducted a single-arm, prospective study using tamoxifen and carboplatin for the treatment of children with progressive or symptomatic low-grade gliomas. PATIENTS AND METHODS: Fourteen children with consecutively diagnosed cases of low-grade glioma were enrolled in this Study; all patients were younger than 14 years. One patient was excluded after induction chemotherapy because of the diagnosis of a nonmalignant condition. Patients were treated with daily tamoxifen (20 mg/m2 administered twice per day) in addition to targeted, monthly intravenous carboplatin at an area under the curve (AUC) exposure of 6.5 mg/mL x minute for 1 year or until they had clinical or radiologic evidence of disease progression. RESULTS: The median age at diagnosis was 5.3 years, the median age at initiation of chemotherapy was 8.3 years. Eight patients had tumors of the hypothalamus/optic pathway, two patients had thalamic tumors, and one patient each had tumors in the temporal lobe, tectum, and brain stem. Tumor histologic findings included fibrillary astrocytoma (n = 2), juvenile pilocytic astrocytoma (n = 6), and oligodendroglioma (n = 1). The best response to therapy was a partial response in two patients, stable disease in nine patients, and progressive disease in two patients. The overall survival at 3 years is 69%. The 3-year progression-free survival is 47%. Tamoxifen and carboplatin chemotherapy did not result in a significant number of objective responses in children with low-grade gliomas. The progression-free survival is similar to that of other published series. Nonmyelosuppressive agents such as tamoxifen deserve additional evaluation in the treatment of children with low-grade gliomas.     

CLINICAL AND RADIOGRAPHIC RESPONSE IN THREE CHILDREN WITH RECURRENT MALIGNANT CEREBRAL TUMORS WITH HIGH-DOSE TAMOXIFEN

The purpose of this study was to deliver tamoxifen as antiangiogenic therapy to children with recurrent progressive malignant brain tumors. Tamoxifen was administered orally in very high dosage to one child as monotherapy and to two children in combination with oral etoposide and dexamethasone. One boy was diagnosed with high-grade astrocytoma in the brain stem, one girl with anaplastic ependymoma of the fourth ventricule, and one girl with high-grade astrocytoma in the midbrain. Conventional treatment with multiple surgeries, first- and second-line chemotherapy, and external beam therapy had failed. Tumor reduction was seen in radiographic images together with clinical improvement in 2 children, and clinical and radiographic halting of tumor progression was demonstrated in the patient with anaplastic ependymoma. None of the patients developed complications from the treatment. Follow up of the patients ranged from 15 to 30 months with a mean of 17 months. These encouraging preliminary results suggest a potential for this type of therapy. More studies are needed to start clinical trials and prove that angiostatic activity may contribute to the therapeutic effect of antiestrogens in estrogen receptor-negative tumors.     

Successful mobilization,harvest and transplant of peripheral blood stem cells using AMD3100 and G‐CSF following high dose craniospinal irradiation for medulloblastoma in a young child

Contemporary protocols for the treatment of malignant brain tumors such as medulloblastoma (MB) in children, often involve craniospinal irradiation (CSI) at diagnosis followed by serial courses of high dose chemotherapy and autologous hematopoietic stem cell support. Patients often require several pheresis procedures in order to collect sufficient stem cells for this type of treatment, particularly if they have already had CSI. We describe the successful mobilization, collection and subsequent transplant of a 7‐year‐old female with medulloblastoma after recent CSI using granulocyte colony stimulating factor (G‐CSF) and the CXCR4 antagonist AMD3100 after a failed previous mobilization attempt using G‐CSF alone. Pediatr Blood Cancer 2010;54:613–615. © 2009 Wiley‐Liss, Inc.     

Medulloblastome, primitiv neuroektodermale Tumoren und Ependymome

Medulloblastoma, primitive neuroectodermal tumor (PNET), and ependymoma are the most frequent malignant brain tumors of childhood. Since the 1980s, multimodal therapy optimization trials of the German Society of Pediatric Oncology and Hematology (GPOH) have led to improved survival rates. Within the current primary treatment trial HIT 2000, modern strategies for radiotherapy and chemotherapy are evaluated according to histology, staging, and age after maximal safe tumor resection. Young children with desmoplastic medulloblastoma receive chemotherapy alone, and the aim for young children with classic medulloblastoma and PNET is for chemotherapy to delay radiotherapy. Intensified treatment concepts are evaluated in metastatic disease. In ependymoma, the extent of resection and local radiotherapy are most important. Prolonging survival while preserving a good quality of life is the aim of the trial HIT-REZ 2005 for children with relapsed medulloblastoma, PNET, or ependymoma; it includes the evaluation of new drugs and treatment modalities (temozolomide, intraventricular etoposide). Central tumor banking and improved treatment stratification by prognostic molecular markers are planned for future trials.     

Chemotherapy of brain tumors in childhood. Review of the literature and pilot protocol

The evaluation of 29 phase II studies demonstrate a complete, partial, and unequivocal response (CR + PR/UR) in 36% of 739 reported patients. A response rate of 55% has been reached in studies with initial neoadjuvant chemotherapy. Regarding different histologic types chemotherapy produced response rates of 56% in PNETs (primitive neuroectodermale tumors), 49% in medulloblastomas, 32% in ependymomas, 31% in brain stem gliomas, and 30% in astrocytomas/glioblastomas. Concerning a variety of cytotoxic drugs the following response rates have been observed: 59% with cyclophosphamide (monotherapy + combinations), 52% with MOPP/COPP, 48% with "8 in 1", 46% with BCNU/CCNU combinations, 42% with procarbazine combinations, 32% with cisplatin (22% with monotherapy; 64% with combinations), and 24% with AZQ (monotherapy + combinations). Because of the poor outcome of children with malignant brain tumors, and concerning the present evaluation as well as few phase III studies the brain tumor study group of the german society of pediatric oncology (GPO) created a pilot multidrug regimen including procarbazine (or 5-fluorouracil), ifosfamide + VP 16, hd methotrexate, and cisplatin + cytosinarabinoside. We observed one unequivocal response and one stable disease in two children after one course of this regimen without complications.     

High dosage methotrexate in combination with "8 in 1" in therapy of pediatric grade III/IV brain tumors]

20 patients with malignant brain tumors in childhood were treated according to a regimen which included initial surgery, preradiation chemotherapy and subsequent irradiation. The chemotherapy consisted of alternating cycles of high-dose methotrexate (12 g/m2) and "8 drugs in 1 day" (Bleyer, 1983). Each cycle was to be given up to six times, as tolerated. The diagnoses were medulloblastoma in 10 cases, astrocytoma in 5 cases, ependymoma and PNET in 2 patients each, and malignant mesenchymoma in 1 case. 15 patients were previously untreated, 5 patients experienced relapse after a different first line therapy and a longer time interval. 8 patients are in continuous complete remission for 13 to 54 months. The toxicity upon the bone marrow, the kidney and the inner ear was tolerable. Long lasting emesis contributed a marked problem to the patients but did not cause abbreviation of the therapy. The neurotoxicity was notably mild. Three episodes of generalized seizures were seen without subsequent sequelae, four cases of peripheral neuropathy were attributable to vincristine. A leukoencephalopathy was neither detected on clinical grounds nor on neuroradiological imaging. Therapy related deaths were not seen. We conclude that the combination of HD-MTX and "8 in 1" markedly contributes to the intensification of the chemotherapy for malignant brain tumors in childhood. In the setting as preradiation chemotherapy the toxicity is tolerable.     

Management of childhood lymphomas—Hodgkin's disease and non-Hodgkin's lymphomas

Hodgkin's disease can be cured in greater than 70% of the children diagnosed. Overall 5-year survival rates now approach 90% and approximotely 80% for 10-year survival. Combination chemotherapy along with irradiation has decreased the relapse rate in all stages of Hodgkin's disease. Intensive chemotherapy and irradiation therapy is associated with long-term complications including development of second malignant tumors. Optimum therapy is the minimum therapy associated with uncomplicated care. In 80 to 90% of children with non-Hodgkin's lymphoma the disease is widerspread when obvious clinically at diagnosis, and the first site of relapse is commonly the bone marrow or central nervous system (CNS). Combined chemotherapy, irradiation and CNS prophylaxis has resulted in 50% to 80% 3-year, disease-free survival. Patients with mediast'nal or extensive intrabdominal disease have a poor prognosis.     

Children's Oncology Group's 2013 blueprint for research: Central nervous system tumors

In the US, approximately 2,500 children are diagnosed annually with brain tumors. Their survival ranges from >90% to <10%. For children with medulloblastoma, the most common malignant brain tumor, 5‐year survival ranges from >80% (standard‐risk) to 60% (high‐risk). For those with high‐grade gliomas (HGGs) including diffuse intrinsic pontine gliomas, 5‐year survival remains <10%. Sixty‐five percent patients with ependymoma are cured after surgery and radiation therapy depending on the degree of resection and histopathology of the tumor. Phase II trials for brain tumors will investigate agents that act on cMET, PDGFRA, or EZH2 in HGG, DIPG, or medulloblastoma, respectively. Phase III trials will explore risk‐based therapy stratification guided by molecular and clinical traits of children with medulloblastoma or ependymoma. Pediatr Blood Cancer 2013; 60: 1022–1026. © 2012 Wiley Periodicals, Inc.     

The role of myeloablative chemotherapy with autologous hematopoietic cell rescue in central nervous system germ cell tumors

This review of the experience of high dose chemotherapy in patients with recurrent or refractory intracranial germ cell tumor confirms that sustained tumor control can be achieved with this modality both in germinoma and non‐germinomatous germ cell tumors. Data from cooperative groups in Europe and North America suggest that the success rate is higher among patients with recurrent germinoma. The role of adjuvant radiation in that context remains unclear. These promising results have led some cooperative groups to incorporate in their protocols a high dose chemotherapy component for newly diagnosed patients with high‐risk features or poor response to initial chemotherapy. Pediatr Blood Cancer 2010;54:644–646. © 2010 Wiley‐Liss, Inc.     

Favorable response of intraommaya topotecan for leptomeningeal metastasis of neuroblastoma after intravenous route failure

A 3-year-old male, diagnosed with stage 4 neuroblastoma, developed recurrent leptomeningeal metastasis after multi-modality treatment including multi-agent chemotherapy, surgery, high dose chemotherapy plus stem cell rescue, cis-retinoic acid and intravenous (IV) topotecan. He then received intraommaya (IO) topotecan three times weekly (maximum dose; 0.4 mg). A complete response was achieved by a resolution of malignant cells in cerebrospinal fluid and resolution leptomeningeal enhancement by brain MRI. Treatment toxicities included low-grade fever and minimal headache. The duration of treatment response from IO topotecan was 18 weeks. The survival time from CNS recurrence in this patient was 13 months. We suggest IO topotecan be considered for neoplastic meningitis of tumors with known sensitivity to topotecan.