Recurrent CNS Tumors Research Articles

A phase I study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors

The PI3K/Akt/mTOR signaling pathway is aberrantly activated in various pediatric tumors. We conducted a phase I study of the Akt inhibitor perifosine in patients with recurrent/refractory pediatric CNS and solid tumors. This was a standard 3+3 open-label dose-escalation study to assess pharmacokinetics, describe toxicities, and identify the MTD for single-agent perifosine. Five dose levels were investigated, ranging from 25 to 125 mg/m2/day for 28 days per cycle. Twenty-three patients (median age 10 years, range 4–18 years) with CNS tumors (DIPG [n = 3], high-grade glioma [n = 5], medulloblastoma [n = 2], ependymoma [n = 3]), neuroblastoma (n = 8), Wilms tumor (n = 1), and Ewing sarcoma (n = 1) were treated. Only one DLT occurred (grade 4 hyperuricemia at dose level 4). The most common grade 3 or 4 toxicity at least possibly related to perifosine was neutropenia (8.7%), with the remaining grade 3 or 4 toxicities (fatigue, hyperglycemia, fever, hyperuricemia, and catheter-related infection) occurring in one patient each. Pharmacokinetics was dose-saturable at doses above 50 mg/m2/day with significant inter-patient variability, consistent with findings reported in adult studies. One patient with DIPG (dose level 5) and 4 of 5 patients with high-grade glioma (dose levels 2 and 3) experienced stable disease for two months. Five subjects with neuroblastoma (dose levels 1 through 4) achieved stable disease which was prolonged (≥11 months) in three. No objective responses were noted. In conclusion, the use of perifosine was safe and feasible in patients with recurrent/refractory pediatric CNS and solid tumors. An MTD was not defined by the 5 dose levels investigated. Our RP2D is 50 mg/m2/day.

Phase 1 trial of p28 (NSC745104), a non-HDM2 mediated peptide inhibitor of p53 ubiquitination in children with recurrent or progressive CNS tumors: A final report from the Pediatric Brain Tumor Consortium.

10059 Background: Wild type and mutated TP53 are common in pediatric CNS tumors. p28 is a cell penetrating peptide that preferentially enters cancer cells and binds to wild type and mutant p53 prot...

TR-11 * A MOLECULAR BIOLOGY AND PHASE II STUDY OF IMETELSTAT (GRN163L) IN CHILDREN WITH RECURRENT OR REFRACTORY CENTRAL NERVOUS SYSTEM (CNS) MALIGNANCIES: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY

INTRODUCTION: Telomerase activation is critical in many cancers including CNS tumors making telomerase inhibition a potential therapeutic target. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of human telomerase and inhibits its enzymatic activity. METHODS: We conducted a molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-hour intravenous infusion at 285 mg/m2, 12-24 hours before surgery. Telomerase activity was evaluated by TRAP assay in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q 21-days) at 285mg/m2. Imetelstat pharmacokinetic and pharmacodynamics studies were performed during cycle 1. RESULTS: Of 2 evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95% compared to baseline archival tissue in one patient (HGG) and was inevaluable in one patient (medulloblastoma) due to tumor hemorrhage. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. The most common grade 3/4 toxicities included thrombocytopenia (32.5%), lymphopenia (17.5%), neutropenia (12.5%), ALT (7.5%) and AST (5%) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. The median number of courses in the phase II trial was 1 (range 1-3). No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. CONCLUSION: Imetelstat demonstrated intratumoral and PBMC target inhibition; however, the regimen proved too toxic in children with recurrent CNS tumors.

TR-03 * PHARMACOLOGICAL MODULATION OF BLOOD-BRAIN BARRIER: A NOVEL THERAPEUTIC APPROACH TO REFRACTORY CNS TUMORS

A key condition for the efficacy of chemotherapy is that it reaches the tumor mass at a therapeutic concentration. In CNS tumors this process is hampered by the blood brain barrier (BBB). Lately emerged that Multi Drug Resistance (MDR) phenomenon is explained through the cooperation of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), two “gatekeeper” efflux pumps working in tandem on the BBB, also present on plasma-membrane of certain brain tumors. Recently, we have demonstrated that morphine, ondansetron and dexamethasone can interfere with the permeability of BBB allowing doxorubicine accumulation within the rat brain, detected by LC-MS/MS mass spectrometry. All these drugs are substrates of P-gp and BCRP transporters. The aim of the current proposal is to understand the action mechanism of BBB “permeabilization” induced by morphine or other drugs and to exploit this method for the “treatment” of brain tumor in an animal model; i) Quantifying the level drugs that do not usually cross the BBB (mitoxantrone or melphalan) after morphine pre-treatment in a preclinical model. Verifying the cytotoxic effect of morphine plus doxorubicin (and other chemotherapeutic agents) treatment by using MTT and TUNEL analysis in glioblastoma cell lines; ii) Quantifying the level of drugs that do not usually cross the BBB after morphine pre-treatment in an artificial BBB through a monolayer of MDCKII cells over-expressing the human P-gp or BCRP; iii) Investigating the regulatory role of certain microRNA in MDR mechanism by RT-PCR and western blot analysis of P-gp, BCRP, miR-21, miR-27a and miR-451. Our preliminary results suggest that blocking efflux transporters by pretreatment with morphine, ondansetron or desamethasone is able to allow doxorubicin penetration inside the brain. These data will enable us to novel therapeutic approaches to refractory or recurrent CNS tumors in which molecules usually stopped by the BBB may have a therapeutic impact.

Re-irradiation of central nervous system tumors

Recurrence or progression of disease is a common occurrence for some CNS tumors and is an important therapeutic dilemma. Disease progression can lead to worsening of neurological symptoms, including potential neurologic death. Therefore, local control of brain tumors in previously irradiated patients is of critical importance clinically. This poses a therapeutic challenge for clinicians when considering re-irradiation in terms of efficacy and potential toxicity. Multiple re-irradiation strategies for the management of recurrent or progressive disease have been evaluated. This report reviews data for efficacy and safety of re-irradiation in managing recurrent or progressive CNS (brain and spine) tumors.

Antiangiogenic treatment of pediatric CNS tumors in Hungary with the Kieran schedule

In Hungary a new oral antiangiogenic treatment was introduced in cases of primary chemoresistant or recurrent pediatric CNS tumors, called Kieran schedule. The early results of this treatment were analyzed. From 2010 at Semmelweis University on individual decisions a daily combined per oral treatment was introduced in pediatric patients with recurrent or progressive CNS tumor (Kieran schedule: thalidomid, celecoxib, etoposid and cyclophosphamid). Efficacy of therapy was analyzed in terms of demographic data, histology, side effects and tolerability in a retrospective manner. From 2010 through 2013, twenty patients were treated with Kieran schedule (medulloblastoma: 3, ependymoma: 5, anaplastic astrocytoma: 2, GBM: 4, plexus choroideus carcinoma: 1, central primitive neuroectodermal tumor: 1, optic glioma: 2, brainstem tumor: 2). Median treatment time and median progression-free survival were 0.60 and 0.61 years, respectively. Based on the preliminary analysis of a limited cohort of patients, the therapy was efficient in those cases of medulloblastoma, ependymoma, high-grade and optic gliomas, where the expected survival time was more than 3 months at start of treatment. Side effects were slight myelosuppresion in terms of previous therapy, 16% transient ischemic attack (TIA)-like episodes. During therapy patients could live their everyday life. Kieran schedule was well-tolerable and efficient with good quality of life in certain cases of pediatric CNS tumors.

A phase I clinical trial of veliparib and temozolomide in children with recurrent central nervous system tumors: A Pediatric Brain Tumor Consortium report.

2036 Background: A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to: 1) estimate the maximum tolerated doses (MTD) or recommended phase II doses (RP2D) of veliparib and TMZ using the Continual Reassessment Method; 2) describe the toxicities of this regimen; and 3) evaluate plasma pharmacokinetics (PK) and peripheral blood mononuclear cell (PBMC) PARP inhibition after veliparib treatment. Methods: TMZ was given once daily and veliparib twice daily for 5 days, every 28 days. Five veliparib/TMZ dose levels were studied: 20/180; 15/180; 15/150; 20/135; and 25/135 mg/m2/dose, respectively. Baseline and serial veliparib PK samples were obtained on days 1 and 4. PBMC poly(ADP-ribose) (PAR) levels were also measured using an ELISA assay. A total of 12 subjects were enrolled at the RP2D. Results: Thirty-one patients (29 evaluable) with a median age of 7.0 years (range 1.3-19.8) were enrolled. Dose-limiting toxicities (DLT) included grade 4 neutropenia and thrombocytopenia at the 20/180 and 15/180 mg/m2/dose levels. Based on the toxicity profile, PKs and PBMC PAR results, the RP2D were veliparib, 25 mg/m2 BID, and TMZ, 135 mg/m2/day, for 5 days every 28 days. No objective responses were observed, although 4 subjects had SD > 6 months duration, including one patient each with glioblastoma multiforme, anaplastic ependymoma, pilocytic astrocytoma, and optic pathway glioma. At the veliparib RP2D, the PK parameters included: Cmax, 1.2 ± 0.7 µM; AUC0-12 hr, 1.53 ± 0.61 µg•hr/mL; and Cl/F, 173 ± ml/min/m2. PARP inhibition was observed in PBMC but did not correlate with veliparib dose levels. Conclusions: The combination of veliparib and TMZ was well tolerated in children with recurrent CNS tumors. Veliparib PK parameters at RP2D are similar to those in adults. PBMC PARP inhibition did not correlate with veliparib dose levels, perhaps due to the smaller number of patients at each dose level and the technical limitations of specimen collection/processing and the ELISA assay. A phase II trial of veliparib/TMZ in children with recurrent primary brain tumors is planned. Clinical trial information: NCT00946335.

Bevacizumab-Associated Osteonecrosis of the Wrist and Knee in Three Pediatric Patients With Recurrent CNS Tumors

Bevacizumab-Associated Osteonecrosis of the Wrist and Knee in Three Pediatric Patients With Recurrent CNS Tumors

Abstract 2364: Identification of therapy resistant pediatric brain tumor cells that have extraordinary survival and tumorigenic capabilities: The ultimate seed cells that drives the growth of autopsied tumor cells in mouse brains

Abstract Brain tumors are a leading cause of cancer related death in children. Little is known about the biology of recurrent or refractory pediatric CNS tumors, particularly those that are inoperable, such as hypothalamic or brainstem tumors. Since autopsy may be the only opportunity to obtain tumor tissue for inoperable or recurrent tumors, we have obtained postmortem tissue for the purpose of developing orthotopic xenografts. We hypothesized that a small fraction of tumor cells would survive the postmortem period of extreme hypoxia and starvation, maintain their tumorigenic capacity, leading to tumor formation in an appropriate in vivo microenvironment; and that these tumor cells may represent the ultimate seed cells that drive tumor recurrence and treatment failure. To identify this subpopulation of TREST cells, i.e. therapy resistant with extraordinary survival and tumorigenic capabilities, we collected 11 postmortem tumor samples, including 3 recurrent medulloblastomas (MBs),1 glioblastoma multiforme (GBM) and 7 diffuse intrinsic pontine glioma (DIPG), 5-72 hrs (mean 32 hrs) after the time of death. We examined tumor cell viability and their capacity of growth in vitro (neurospheres in serum-free medium and proliferation in FBS-based DMEM), analyzed the content of putative cancer stem cells, and determined their tumor forming capability in vivo in mouse brains. Our results showed that a small fraction (5-10%) of viable tumor cells exists in all the autopsied tumors, although most of them failed to proliferate in vitro. More importantly, we found that injection of unfractionated tumor cells into mouse brains resulted in the formation of xenograft tumors in 2 of 3 MBs (66.6%), 1/1 GBM and 5 of 7 DIPGs (71%). One of the medulloblastomas and the GBM model have been serially passaged in mouse brains 6 times, and two of the DIPGs in mouse brainstems 3 times. These tumors replicated the histopathological phenotypes of the corresponding patient tumors demonstrating diffuse invasion. Using a series of putative cancer stem cell markers (CD133, CD15, CD24/CD44, CD57 and CD117), we showed that CD133+ and CD15+ cells were enriched in the xenograft tumors. In conclusion, we have demonstrated that a small fraction of tumor cells, some of which expressed putative CSC markers, can survive a lengthy period of postmortem hypoxia/anoxia and starvation and maintain tumorigenic capabilities in mouse brains. Detailed analysis of these TREST cells, particularly with our unique panel of orthotopic xenograft mouse models, should provide novel insights about their biology and future development of new therapies specifically targeting the recurrent/late stage brain tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2364. doi:1538-7445.AM2012-2364

Phase I Trial of Lenalidomide in Pediatric Patients With Recurrent, Refractory, or Progressive Primary CNS Tumors: Pediatric Brain Tumor Consortium Study PBTC-018

A phase I trial of lenalidomide was performed in children with recurrent, refractory, or progressive primary CNS tumors to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile and pharmacokinetics. Lenalidomide was administered by mouth daily for 21 days, repeated every 28 days. The starting dose was 15 mg/m(2)/d orally, and the dose was escalated according to a modified continuous reassessment method. Correlative studies included pharmacokinetics obtained from consenting patients on course 1, day 1, and at steady-state (between days 7 and 21). Fifty-one patients (median age, 10 years; range, 2 to 21 years) were enrolled. Forty-four patients were evaluable for dose finding, and 49 patients were evaluable for toxicity. The primary toxicity was myelosuppression, but the MTD was not defined because doses up to 116 mg/m(2)/d were well-tolerated during the dose-finding period. Two objective responses were observed (one in thalamic juvenile pilocytic astrocytoma and one in optic pathway glioma) at dose levels of 88 and 116 mg/m(2)/d. Twenty-three patients, representing all dose levels, received ≥ six cycles of therapy. Pharmacokinetic analysis demonstrated that the lenalidomide area under the concentration-time curve from 0 to 24 hours and maximum plasma concentration increased with dosage over the range studied. Lenalidomide was tolerable in children with CNS tumors at doses of 116 mg/m(2)/d during the initial dose-finding period. The primary toxicity is myelosuppression. Antitumor activity, defined by both objective responses and long-term stable disease, was observed, primarily in patients with low-grade gliomas.

Detection of human herpesvirus-6 in adult central nervous system tumors: predominance of early and late viral antigens in glial tumors

The purpose is to determine the incidence of active and latent human herpesvirus-6 (HHV-6) infection in a large cohort of adult primary and recurrent CNS tumors. We screened a tissue microarray (TMA) containing more than 200 adult primary and recurrent CNS tumors with known clinical information for the presence of HHV-6 DNA by in situ hybridization (ISH) and protein by immunohistochemistry (IHC). One hundred six of 224 (47%) CNS tumors were positive for HHV-6 U57 Major Capsid Protein (MCP) gene by ISH compared to 0/25 non tumor control brain (P = 0.001). Fourteen of 30 (47%) tumors were HHV-6 MCP positive by nested PCR compared to 0/25 non-tumor brain controls (P = 0.001), revealing HHV-6 Variant A in 6 of 14 samples. HHV-6A/B early (p41) and late (gp116/64/54) antigens were detected by IHC in 66 of 277 (24%) (P = 0.003) and 84 of 282 (35%) (P = 0.002) tumors, respectively, suggesting active infection. HHV-6 p41 (P = 0.645) and gp116/64/54 (P = 0.198) antigen detection was independent of recurrent disease. Glial tumors were 3 times more positive by IHC compared to non glial tumors for both HHV-6 gp116/64/54 (P = 0.0002) and HHV-6 p41 (P = 0.004). Kaplan Meier survival analysis showed no effect of HHV-6 gp116/64/54 (P = 0.852) or HHV-6 p41 (P = 0.817) antigen detection on survival. HHV-6 early and late antigens are detected in adult primary and recurrent CNS tumors more frequently in glial tumors. We hypothesize that the glial-tropic features of HHV-6 may play an important modifying role in tumor biology that warrants further investigation.

Pilot trial of the rate of response, safety, and tolerability of temozolomide and oral VP-16 in patients with recurrent or treatment-induced malignant central nervous system tumors

Background The aim of this study was to determine the response and toxicity of patients with recurrent or treatment-induced brain tumors to TMZ and oral VP-16. Methods Eleven patients with recurrent or treatment-induced malignant CNS tumors, including treatment-induced PNET (in 1 patient), brainstem glioma (in 3 patients; 1 with treatment-induced, 2 with recurrence), recurrent anaplastic astrocytoma (in 3 patients), and recurrent glioblastoma (in 4 patients) were evaluated in a pilot study of TMZ and oral VP-16 chemotherapy. All patients received TMZ at 150 mg/m 2 per day on days 1 to 5 and oral VP-16 at 50 mg/m 2 per day on days 1 to 12. Cycles were repeated every 28 days. Results None experienced major acute toxicity related to TMZ and oral VP-16 during a total of 52 treatment courses. Five (45%) of 11 patients showed a PR to treatment. Among the 11 patients enrolled, 7 patients are alive with disease at a median of 9 months from time of study entry. The 6-month PFS is 45% (95% CI, 40%-74%). The histologic subtype of the tumor, its location, and its maximum response to chemotherapy did not have an impact on the duration of disease control. Conclusion This limited pilot study confirms the innocuousness and the activity of the combination of TMZ and oral VP-16 in recurrent malignant brain tumors. This promising activity warrants further investigation of this combination in larger phase II or III studies.

Phase I and Pharmacokinetic Study of the Oral Farnesyltransferase Inhibitor Lonafarnib Administered Twice Daily to Pediatric Patients With Advanced Central Nervous System Tumors Using a Modified Continuous Reassessment Method: A Pediatric Brain Tumor Consortium Study

A dose-escalation phase I and pharmacokinetic study of the farnesyltransferase inhibitor lonafarnib (SCH66336) was conducted in children with recurrent or progressive CNS tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs) and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in peripheral blood was also measured. Lonafarnib was administered orally twice daily at dose levels of 70, 90, 115, 150, and 200 mg/m2/dose bid. A modified continual reassessment method (CRM) was used to estimate the MTD based on actual dosages of lonafarnib administered and toxicities observed during the initial 4 weeks of treatment. Fifty-three children with progressive or recurrent brain tumors were enrolled, with a median age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or myelosuppression was observed in three of three patients at the 200 mg/m2/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m2/dose levels resulted in a recommended phase II dose of 115 mg/m2/dose. Significant diarrhea did not occur with prophylactic loperamide. Both radiographic response (one anaplastic astrocytoma) and stable disease (one medulloblastoma, two high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were noted, and seven patients remained on treatment for 1 year or longer. Although the estimated MTD by the CRM model was 98.5 mg/m2/dose, because of the relatively constant observed DLT rate at the lower four dose levels, the recommended phase II dose of lonafarnib is 115 mg/m2/dose administered twice daily by mouth with concurrent loperamide.

High-dose carmustine, thiotepa and etoposide followed by autologous bone marrow rescue for the treatment of high risk central nervous system tumors.

Forty-two patients (29 newly diagnosed) with high grade gliomas (n = 37), medulloblastoma (n = 2) or non-biopsied tumors (n = 3) with supratentorial (n = 24), brain stem (n = 11), posterior fossa (n = 5) or spinal (n = 2) location were eligible for this study with adequate organ function and no bone marrow tumor infiltration. Median patient age was 12.2 years (range, 0.7-46.8). A total of 600 mg/m2 BCNU, 900 mg/m2 thiotepa and 1500 or 750 mg/m2 etoposide (VP-16) was administered followed by autologous bone marrow reinfusion (ABMR). Twenty-one newly diagnosed patients received local irradiation (RT) post ABMR. Nine early deaths were observed (21%), as well as one secondary graft failure. Half of the patients aged 18 years or older experienced toxic deaths, whereas only 15% of patients younger than 18 years experienced toxic death (P = 0.05). Of 25 evaluable newly diagnosed patients, 20% achieved complete remission (CR) and 4% partial remission (PR), while 28% remained in continuing complete remission (CCR) and 44% remained with stable disease prior to RT. Of eight evaluable patients with recurrent disease, one achieved CR and two PR, while one remained in CCR and four with stable disease for 1 to 110.2 months. Overall survival was 36%, 24% and 17% at 1, 2 and 3 years following ABMR, with three newly diagnosed patients and one patient treated for recurrent disease being alive, without disease progression 64.4, 67.0, 86.3 and 110.2 months after ABMR, respectively. The combination of high-dose BCNU/ thiotepa/VP-16 has substantial toxicity but definite activity for high risk CNS tumors. Similar protocols with lower toxicity merit further evaluation in both newly diagnosed and recurrent CNS tumors.

High-dose thiotepa and etoposide-based regimens with autologous hematopoietic support for high-risk or recurrent CNS tumors in children and adults.

The prognosis in patients with primary brain tumors treated with surgery, radiotherapy and conventional chemotherapy remains poor. To improve outcome, combination high-dose chemotherapy (HDC) has been explored in children, but rarely in adults. This study was performed to determine the tolerability of three-drug combination high-dose thiotepa (T) and etoposide (E)-based regimens in pediatric and adult patients with high-risk or recurrent primary brain tumors. Thirty-one patients (13 children and 18 adults) with brain tumors were treated with high-dose chemotherapy: 19 with BCNU (B) and TE (BTE regimen), and 12 with carboplatin (C) and TE (CTE regimen). Patients received growth factors and hematopoietic support with marrow (n = 15), peripheral blood progenitor cells (PBPC) (n = 11) or both (n = 5). The 100 day toxic mortality rate was 3% (1/31). Grade III/IV toxicities included mucositis (58%), hepatitis (39%) and diarrhea (42%). Five patients had seizures and two had transient encephalopathy (23%). All patients had neutropenic fever and all pediatric patients required hyperalimentation. Median time to engraftment with absolute neutrophil count (ANC) >0.5 x 10(9)/l was 11 days (range 8-37 days). Time to ANC engraftment was significantly longer (P = 0.0001) in patients receiving marrow (median 14 days, range 10-37) than for PBPC (median 9.5 days, range 8-10). Platelet engraftment >50 x 10(9)/l was 24 days (range 14-53 days) in children. In adults, platelet engraftment >20 x 10(9)/l was 12 days (range 9-65 days). In 11 patients supported with PBPC, there was a significant inverse correlation between CD34+ dose and days to ANC (rho = -0.87, P = 0.009) and platelet engraftment (rho = -0.85, P = 0.005), with CD34+ dose predicting time to engraftment following HDC. Overall, 30% of evaluable patients (7/24) had a complete response (CR) (n = 3) or partial response (PR) (n = 4). Median time to tumor progression (TTP) was 7 months, with an overall median survival of 12 months. These TE-based BCNU or carboplatin three-drug combination HDC regimens are safe and tolerable with promising response rates in both children and older adults.

High-dose cyclophosphamide for poor-prognosis and recurrent pediatric brain tumors: a dose-escalation study.

To determine the maximum-tolerated dose (MTD) of cyclophosphamide (CTX) when administered over 2 consecutive days followed by hematopoetic stem-cell rescue given as two sequential courses to children with glioblastoma multiforme, poor-prognosis pontine gliomas, and other recurrent CNS tumors. Two identical doses of CTX were administered 24 hours apart to 14 children and followed by hematopoetic stem-cell rescue. This treatment was repeated immediately following hematologic recovery. The starting dose of CTX was 2.5 g/m2/d with increments of 0.5 g/m2/d. CTX pharmacokinetics and metabolism were measured during 22 courses of treatment. Toxicity and tumor response were recorded. There were two toxic deaths at the dose level of 4 g/m2/d. These were not clearly related to cardiac toxicity and may have been due to generalized capillary leak syndrome. Thus, the MTD of CTX was 3.5 g/m2/ d. There were six complete responses (CRs) (46%; (95% confidence interval [CI], 19% to 73%) and four partial responses (PRs) (31%; 95% CI, 6% to 56%), and one patient achieved stable disease. All children with intracranial primitive neuroectodermal tumors (PNETs) improved following CTX. The median duration of tumor response was 6 months (range, 4 to 29) and only one patient remains disease-free following CTX alone. Overall survival is 21% (95% CI, 13% to 29%) at a median follow-up time of 27 months (range, 12 to 34). The MTD of CTX when followed by hematopoetic stem-cell rescue is 3.5 g/m2 administered on each of 2 consecutive days. This treatment was tolerable in children with poor-prognosis brain tumors and produced complete responses in children with recurrent PNETs.

Pilot study of high-dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNS tumors. The Children's Cancer Group.

This study was designed to determine the toxicity, radiographic response rate, and outcome following high-dose thiotepa, etoposide, and autologous bone marrow rescue (ABMR) for young patients with recurrent malignant brain tumors. Eligibility criteria required adequate renal, hepatic, and pulmonary function, and no bone marrow infiltration. Thiotepa 300 mg/m2 and etoposide 500 mg/ m2 were infused on 3 consecutive days, and autologous bone marrow was infused 72 hours following chemotherapy. Forty-five patients with recurrent high-grade brain tumors, aged 8 months to 36 years (median, 8 years), were treated. Seven patients (16%) died of treatment-related toxicities within 56 days of marrow reinfusion. Delayed platelet engraftment occurred in 44% of patients who survived beyond day 56. Of 35 patients with radiographically measurable disease who survived at least 28 days following ABMR, there were two complete responses (CRs) and six partial responses (PRs), for an overall response (CRs plus PRs) rate of 23% (SE = 7%). Objective responses were observed in four of 14 assessable patients with high-grade glioma and in two of six with primitive neuroectodermal tumors (PNETs)/ medulloblastoma. Survival was significantly improved in patients treated with minimal residual disease (P < .0005). Five of 18 patients (28%) with high-grade gliomas remain free of disease at 39+, 44+, 49+, 52+, and 59+ months post-ABMR. The combination of high-dose thiotepa and etoposide has activity against a variety of recurrent childhood brain tumors. These results merit further evaluation in children and young adults with both recurrent and newly diagnosed high-grade brain tumors.

PCNU and recurrent childhood brain tumors.

PCNU, the latest nitrosourea analogue to be subjected to clinical trials, held promise as a superior chemotherapy agent for brain tumors because of more favorable biochemical and cytotoxic characteristics in laboratory studies. Thirty-nine children with a variety of recurrent primary CNS tumors, all of whom had evaluable disease, participated in a phase II PCNU trial. Their mean age was 9.7 (3-20) years. PCNU was administered as a 2 hour intravenous infusion in one of 2 dose schedules at 6-7 week intervals; 100-125 mg/m2 for minimally treated patients and 70-90 mg/m2 for heavily treated patients. Response was assessed after 2 courses of chemotherapy after attempting to taper the steroid dose. The overall objective response rate was 18% (7/39) for a mean of 5.9 months (2+ -12). Only partial responses were observed. Disease-specific responses rates were: brainstem glioma--18% (3/17); cerebral glioma--27% (3/12); ependymoma--1/1; and primitive neuroectodermal tumors--(0/9) including 5 medulloblastomas, 2 pineoblastomas and 3 cerebral primitive neuroectodermal tumors. Toxicity was primarily hematologic and clinically significant thrombocytopenia (less than 50,000 mm3) was encountered in 30/38 (79%) patient trials. Modest activity of PCNU in recurrent childhood gliomas is confirmed. Our response rates, using objective CT criteria, are somewhat lower than those reported for BCNU and CCNU. Because of comparable hematologic toxicity and efficacy, intravenous PCNU does not appear to offer a clinical advantage to existing nitrosoureas for children with recurrent brain tumors using a 2 hour intravenous infusion schedule.