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Feasibility and Response to Induction Chemotherapy Intensified With High-Dose Methotrexate for Young Children With Newly Diagnosed High-Risk Disseminated Medulloblastoma

From the Divisions of Pediatric Oncology; Neuroradiology; Neuropathology; and Pediatric Neurosurgery, New York University Medical Center, New York, NY.

Address reprint requests to Susan Chi, MD, Dana-Farber Cancer Institute, 44 Binney St, SW331, Boston, MA 02115; e-mail: susan_chi{at}dfci.harvard.edu

	ABSTRACT

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PURPOSE: To evaluate the feasibility of and response rate to an intensified induction chemotherapy regimen for young children with newly diagnosed high-risk or disseminated medulloblastomas.

PATIENTS AND METHODS: From January 1997 to March 2003, 21 patients with high-risk or disseminated medulloblastoma were enrolled. After maximal surgical resection, patients were treated with five cycles of vincristine (0.05 mg/kg/wk x three doses per cycle for three cycles), cisplatin (3.5 mg/kg per cycle), etoposide (4 mg/kg/d x 2 days per cycle), cyclophosphamide (65 mg/kg/d x 2 days per cycle) with mesna, and methotrexate (400 mg/kg per cycle) with leucovorin rescue. Following induction chemotherapy, eligible patients underwent a single myeloablative chemotherapy cycle with autologous stem-cell rescue.

RESULTS: Significant toxicities of this intensified regimen, including gastrointestinal and infectious toxicities, are described. Among the 21 patients enrolled, there were 17 complete responses (81%), two partial responses, one stable disease, and one progressive disease. The 3-year event-free survival and overall survival are 49% (95% CI, 27% to 72%) and 60% (95% CI, 36% to 84%), respectively.

CONCLUSION: This intensified induction chemotherapy regimen is feasible and tolerable. With the majority of patients with disseminated medulloblastoma having M2 or M3 disease at diagnosis, the encouraging high response rate of this intensified induction regimen suggests that such an addition of methotrexate should be explored in future studies.

	INTRODUCTION

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Young children with malignant brain tumors, particularly those who present with leptomeningeal dissemination, have poorer survival compared with older children. The latest Surveillance, Epidemiology and End Results (SEER) Program update on the survival of all children with medulloblastoma/primitive neuroectodermal tumor (PNET) confirms this pattern of poor survival rates in the youngest group of patients (younger than 3 years), with an overall survival (OS) rate of 39% at 5 years and median survival of 1.8 years.¹ Previous studies in large cooperative study groups consistently report this same trend, with collective survival rates ranging from 22% to 47%.^2-4 It is well established that the risks of radiation therapy in infants and young children outweigh the benefits of therapeutic response in terms of neurocognitive development⁵ and thus, surgery and chemotherapy have been the primary modes of treatment.

Strategies such as prolonged postoperative chemotherapy and intensified adjuvant chemotherapy have attempted to delay, minimize, and possibly, avoid the use of cranial irradiation and its long-term effects.^4,6,7 More recently, the encouraging results from trials that used myeloablative chemotherapy followed by autologous bone marrow transplantation in the setting of recurrence^8-10 have encouraged bringing such a strategy to the newly diagnosed young patient.

Since 1991, we have offered young children with malignant brain tumors an intensive chemotherapeutic regimen with the intent of avoiding irradiation. Previously published results with the first "Head Start" strategy were encouraging,¹¹ suggesting that a significant proportion of patients could achieve durable remission yet avoid irradiation and prolonged maintenance chemotherapy. The Head Start II chemotherapy trial began in 1997 in an attempt to improve on the previous induction regimen's response rate in patients with leptomeningeal dissemination.

As in the predecessor Head Start regimen, after diagnosis and clinical staging, patients received induction chemotherapy, consisting of five cycles of vincristine, cisplatin, high-dose cyclophosphamide, and etoposide. After these agents were administered, induction was intensified in Head Start II with high-dose methotrexate (400 mg/kg). We now present our experience with the cohort of patients with disseminated medulloblastoma who received this regimen, and examine the feasibility of such an intensified regimen, as well as the response rate and early outcomes.

	PATIENTS AND METHODS

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Eligibility
Children younger than 10 years at confirmatory diagnosis of malignant brain tumors were considered eligible for the Head Start II protocol. Patients with histologic diagnoses, including medulloblastoma, PNET, ependymoma, atypical teratoid/rhabdoid tumors, and choroid plexus carcinoma, were eligible for Regimens A or A2. Evidence of neuraxis or extraneural dissemination was required in order to be eligible for Regimen A2, the intensified regimen. Patients could not have previously received either irradiation or chemotherapy (excepting corticosteroids).

Between 1997 and 2003, 21 eligible patients with high-risk or disseminated medulloblastoma were treated at New York University (NYU) Medical Center or at one of the participating institutions: University of California San Francisco, San Francisco, CA; Connecticut Children's Medical Center, Hartford, CT; Maine Medical Center, Portland, ME; DeVos Children's Hospital, Grand Rapids, MI; Children's Hospital, Omaha, NE; Hackensack University Medical Center, Hackensack, NJ; Beth Israel Hospital North, New York, NY; New York-Presbyterian, New York, NY; State University of New York at Stony Brook, NY; State University of New York Upstate Medical University, Syracuse, NY; The Children's Hospital of Philadelphia, Philadelphia, PA; Penn State Children's Hospital, Hershey, PA; FLENI Neurological Institute, Buenos Aires, Argentina; The Children's Hospital at Westmead, Sydney, Australia; and BC Children's Hospital, Vancouver, Canada.

Children began induction chemotherapy within 42 days of their most recent definitive diagnostic surgical procedure. Patients had to have adequate hepatic (bilirubin < 1.5 mg/dL and transaminases < 2.5x the upper limits of normal) and renal (creatinine clearance > 60 mL/min/1.73 m²) function.

Surgery
All patients underwent maximal possible surgical resection consistent with preservation of neurologic function. The extent of surgical resection was defined as follows: biopsy, if surgical removal was less than 10% of the total tumor mass; partial resection, if surgical removal was greater than 10% but less than 50% of the total tumor mass; subtotal resection, if surgical removal was greater than 50% of the total tumor mass but visible tumor remained; and gross total resection, if no visible tumor remained on postoperative imaging studies.

Pathologic Review
Tumor pathology slides were centrally reviewed at NYU Medical Center and classified according to standard criteria.

Staging Criteria
Following surgical resection of tumor, all children had their disease evaluated, including brain magnetic resonance imaging (MRI) with gadolinium, total spine MRI with gadolinium, evaluation of CSF cytology, bone scan, and bone marrow biopsies (if bone scan was abnormal).

Metastatic disease was assessed using the Chang staging system: M0, no malignant cells identified in CSF and no evidence of dissemination of tumor beyond the primary site; M1, CSF cytology positive for tumor after day 14 following surgery or positive before initial surgery at diagnosis; M2, evidence of intracranial seeding on gadolinium-enhanced MRI scan; M3, evidence of tumor seeding down the spinal cord on gadolinium-enhanced MRI of the spine; M4, evidence of tumor dissemination beyond the neuraxis, eg, lymph nodes, bones, bone marrow, lungs, or liver.

Treatment Regimen
Induction chemotherapy consisted of cisplatin (3.5 mg/kg) on day 1; vincristine (0.05 mg/kg) on days 1, 8, and 15 of cycles 1 to 3 only (ie, nine total doses); etoposide (4 mg/kg/d) followed by cyclophosphamide (65 mg/kg/d) with mesna on days 2 and 3; methotrexate (400 mg/kg) was delivered on day 4 with leucovorin rescue until the methotrexate level was less than 0.1 µM. Granulocyte colony-stimulating factor (G-CSF) was administered subcutaneously 24 hours after completion of methotrexate infusion, and continued until neutrophil recovery. Five cycles were to be administered at 21-day intervals. Autologous peripheral blood stem-cell harvesting and cryopreservation was undertaken following the first or second cycle of induction chemotherapy. Chemotherapy was modified for grade 3 and 4 toxicities, in accord with the Children's Cancer Study Group Toxicity Rating Scale.

After induction chemotherapy was completed, repeat extent of disease evaluation was performed to determine if there were any sites of residual tumor. Patients with no evidence of residual tumor proceeded directly to consolidation with myeloablative chemotherapy. Patients with radiographic evidence of localized residual tumor were strongly considered for "second look" surgical intervention that would radically resect any residual viable tumor and minimize the patient's residual tumor burden. Any patient who showed radiographic evidence of tumor progression at any time during or after induction chemotherapy was not eligible to proceed with consolidation chemotherapy, and was considered off study.

Consolidation chemotherapy consisted of carboplatin 500 mg/m²/d on days –8 to –6 (with modification for creatinine clearance based on the pediatric Calvert formula to achieve an area under the curve of 7 mg/mL/min), thiotepa 300 mg/m²/d, and etoposide 250 mg/m²/d on days –5 to –3. Autologous peripheral blood stem-cells were infused on day 0, 72 hours after high-dose chemotherapy was completed. All patients received G-CSF 5 µg/kg/d starting 24 hours after stem-cell infusion.

Criteria for Radiation Therapy
Age and response determined eligibility for radiation therapy. Radiation therapy started following recovery from the consolidation phase. For patients older than 6 years or with evidence of residual disease at the completion of induction chemotherapy, radiation therapy was delivered to the craniospinal axis with focal boost to the tumor bed at a dose of 23.4 Gy. Patients younger than 6 years who had no evidence of disease at the completion of induction chemotherapy, or who were converted to complete response by "second look" surgical resection before starting consolidation chemotherapy, did not receive irradiation.

Supportive Care
Platelet counts were maintained above 10,000/mm³ and hemoglobin counts maintained above 8.0 g/dL with transfusions, as necessary, unless higher parameters were clinically indicated, ie, acute hemorrhage or respiratory distress. All blood products were irradiated. Febrile neutropenic patients were treated with broad-spectrum intravenous (IV) antibiotics and antifungal agents when appropriate. Patients received trimethoprim-sulfamethoxazole prophylaxis during induction chemotherapy, or an equivalent Pneumocystis carinii pneumonia prophylactic regimen.

Patient Monitoring/Toxicity Criteria
CBC and biochemical studies were to be obtained frequently throughout induction chemotherapy. The Children's Cancer Study Group Toxicity Rating Scale was used to grade toxicity. The site, measure, and grade for all grade 3 and 4 toxicities were reported.

At prescribed times during and following induction, the disease status of all patients was monitored with appropriate neurologic examinations, CSF cytologic examinations, and neuroimaging studies to assess the effect of induction chemotherapy on postoperative residual tumors. All neuroradiologic studies were centrally reviewed at the NYU Medical Center.

Criteria for response by CSF cytologic examination were defined as follows: complete response (CR), complete clearance of all malignant cell on cytospin analyses of lumbar or ventricular CSF; no response, incomplete clearance of malignant cells on cytospin analyses.

Criteria for response/relapse by neuroradiologic studies were defined as follows: CR, complete resolution of tumor on enhanced MRI scan; partial response (PR), a greater than 50% reduction in the product of the greatest tumor diameter and its perpendicular diameter as measured on an enhanced MRI scan; minor response, 25% to 50% reduction in the product of the greatest tumor diameter and its perpendicular diameter; stable disease, a less than 25% decrease in the product of the perpendicular diameters described; progressive disease, a greater than 25% increase in the tumor size, or appearance of tumor in a previously uninvolved area.

Informed Consent
Signed, informed consent was obtained for each child from parents or legal guardians. Potential risks and benefits, therapeutic alternatives such as conventional chemotherapy and irradiation, and supportive care issues were discussed. Protocols were approved by each local institutional review board.

Statistical Considerations
Kaplan-Meier analysis was used to estimate the distribution of event-free survival (EFS) and OS. OS was calculated from the date of diagnosis to date of last follow-up or date of death from any cause. EFS was calculated from the date of diagnosis to date of radiographic evidence of disease progression, as defined in Patient Monitoring/Toxicity Criteria. The cutoff for this analysis was May 2004.

	RESULTS

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Patient Demographics
Patient demographics are summarized in Table 1. Twenty-one patients with medulloblastoma and leptomeningeal dissemination were enrolled onto the Head Start II intensified induction chemotherapy, Regimen A2. The medical record for one patient was unassessable; the local institution provided only limited follow-up information. The median age of patients at diagnosis was 38 months (range, 7 to 119 months).

Responses and Outcomes
Of the 21 patients with disseminated medulloblastoma, 17 patients (81%) achieved CR, two patients achieved PR, one patient had stable disease, and one patient demonstrated progressive disease by the end of induction chemotherapy, for an objective response (CR + PR) rate of 91%. All patients went on to receive consolidation therapy with myeloablative chemotherapy followed by autologous stem-cell rescue.

To date, 10 patients have relapsed, of which eight have died from progressive disease. The sites of relapse include local (two patients), disseminated (three patients), local with dissemination (four patients), and unknown (one patient; limited follow-up data). The time-to-relapse rates ranged from 7 to 21 months postdiagnosis. Two patients are alive with disease. Eleven remaining patients are without evidence of disease.

Ten of the 21 patients have received radiation therapy to date, five received irradiation as part of their salvage therapy on relapse, three received irradiation as per protocol (older than 6 years at diagnosis), and two patients received irradiation at the investigators' preference (one patient aged 4 years at diagnosis; one patient with PR after induction). Six of the 11 patients who remain without evidence of disease have not received radiation therapy to date, four of these six were younger than 3 years at diagnosis.

The 3-year EFS and OS are 49% (95% CI, 27% to 72%) and 60% (95% CI, 36% to 84%), respectively (Fig 1), with mean follow-up of 40 and 48 months, respectively. The characteristics, responses, and outcomes are listed in Table 2.

View larger version (10K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival curves showing overall survival (OS) and event-free-survival (EFS) rates of 21 young children with disseminated medulloblastoma.

Hematopoeitic Toxicity
The mean number of platelet transfusions required per cycle was 3 (median, 3; range, 0 to 21). The mean number of packed RBC transfusions per cycle was 2 (median, 2; range, 0 to 22). As part of the supportive care guidelines, all patients received G-CSF.

The mean number of days spent in hospital per cycle, including days of chemotherapy administration, was 19 (range, 4 to 45). For several patients, the first two cycles of chemotherapy involved the same hospitalization.

Infection
There were 69 episodes (69% of assessable cycles delivered) of febrile neutropenia. Documented organisms included Staphylococcus aureus, Streptococcus viridans, Enterococcus, Escherichia coli and other gram-negative rod species, Bacillus species, Pseudomonas species, Klebsiella species, Clostridium difficile, respiratory syncytial virus, and fungus. One patient recovered from meningitis due to Staphylococcus epidermidis. Of note, while there were no toxic deaths among medulloblastoma patients, there were two toxic deaths among all the patients enrolled onto this intensified regimen (from S aureus meningitis and vancomycin-resistant Enterococcus sepsis), for a toxic mortality rate of 5.4% for this regimen.

Other Toxicities
Gastrointestinal toxicities were among other frequently reported toxicities. Several modifications in methotrexate administration were made because of grade 3/4 mucositis, requiring IV morphine sulfate. Severe nausea and vomiting, and transient elevations in liver transaminases were also observed. Two patients developed gastrointestinal bleeding; one of these patients required an embolization procedure to control bleeding.

Several patients demonstrated high-frequency hearing loss as documented by audiometric testing, and had their cisplatin dosages adjusted. One patient developed a facial droop after the first cycle of induction chemotherapy. Two patients had episodes of hemorrhagic cystitis and one patient exhibited evidence of Fanconi's syndrome. Three patients demonstrated evidence of venous thrombosis in the superior vena cava; each case was associated with indwelling venous access devices.

	DISCUSSION

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Intensification of chemotherapeutic regimens has been a strategy used to treat various pediatric cancers, including neuroblastoma,^12-14 osteosarcoma,¹⁵ and acute T-cell leukemia.¹⁶ We used high-dose methotrexate for intensification in this study because of data on the use of methotrexate as a single agent from several reports that suggest its clinical efficacy in pediatric brain tumors. Rosen et al,¹⁷ reported that methotrexate, administered at doses of 300 to 500 mg/kg with leucovorin rescue, resulted in favorable responses in five of seven patients with recurrent medulloblastoma. Allen et al,¹⁸ examined using 8 gm/m² of methotrexate in the neoadjuvant setting on a small number of patients with newly diagnosed high-risk brain tumors, and observed objective responses after single-agent IV administration.

Pharmacokinetic analyses of high-dose methotrexate IV infusions have previously been undertaken in children with acute leukemia^19,20 and in children with solid tumors.²¹ Borsi and Moe¹⁹ demonstrated that therapeutically effective concentrations can be achieved in the CSF at doses of 4 gm/m² and higher, and that this is a dose-dependent relationship. However, the highest treatment doses of methotrexate (18 to 25 gm/m²) did not necessarily achieve higher CSF levels. With interpatient variability taken into consideration, Borsi and Moe observed that every child who received 6 to 8 g/m² was able to achieve therapeutic levels in the CSF.

There are still some concerns about methotrexate toxicity, particularly in terms of neurocognitive development and the risk of leukoencephalopathy. Past studies of different cancer populations, including childhood leukemia and osteosarcoma patients, offer data about both the acute and long-term side effects of methotrexate. However, comparisons cannot be made because of the disparate methods of methotrexate administration as well as the different age groups treated. Neuropsychological examination of patients from Head Start I revealed that cognitive functioning was preserved in patients who were successfully treated without irradiation, specifically in the areas of overall intelligence, verbal and abstract visual reasoning, and academic testing.²² The present Head Start II study incorporates both baseline and follow-up neuropsychological testing; this testing is ongoing as of publication.

While craniospinal irradiation is an effective therapy for the treatment of leptomeningeal disease, standard doses of irradiation for leptomeningeal disease (3.6 Gy) result in unacceptable late sequelae in the youngest children. A survey from St Jude Children's Research Hospital reported on the neurodevelopmental outcome of 19 long-term survivors of infant medulloblastoma.²³ Walter et al reported that the rate of median intelligence quotient loss was at 3.9 points per year, and this rate had not yet plateaued at a median of 4.8 years postdiagnosis. A more recent study from St Jude highlighted this impact of radiation therapy, especially in the younger age group (younger than 8 years). This longitudinal examination of medulloblastoma patients confirmed the patients' intellectual decline over time, particularly in overall intelligence quotient, abstract thinking, and acquisition of new knowledge.²⁴ Head Start intends to avoid irradiation in the younger group (younger than 6 years of age) and reserves the use of irradiation for the older group. To date, six of the 11 medulloblastoma patients in this study who remain without evidence of disease have not received radiation therapy; four of these six were younger than 3 years at diagnosis.

The major limitations of this intensified regimen are its toxicities. Clearly, hospitalizations are prolonged with significant infectious risks and gastrointestinal toxicities. However, some toxicities may be mitigated with either different dose scheduling or with the addition of other supportive care methods. These efforts are being considered for the future Head Start III study.

As in the first Head Start protocol, the total length of our induction regimen remains short, with planned induction chemotherapy completion within 6 to 8 months from diagnosis. Despite the short intensive induction, all relapses were observed early, following induction chemotherapy, with patients' time to relapse ranging from 7 to 21 months postdiagnosis. Also, there was no association between Chang stage at diagnosis and risk of relapse, ie, relapses were observed in all M stages, M1-M3. As noted in the update of the Pediatric Oncology Group study of infants and very young children by Duffner et al, ² most relapses occurred in the first 6 months and none occurred after 2 years of therapy. This trend of early disease progression or relapses has been observed among other groups as well.^23,25

For chemotherapy regimens in young children with medulloblastoma and leptomeningeal spread at diagnosis, the CR and PR rates of our intensified induction regimen is the highest yet reported. Previous studies report induction response rates of 48% to 82%, including both CR and PR.^2,3,26,27 Recently, Kellie et al²⁸ reported on their experience with including methotrexate in the preirradiation chemotherapy regimen. What is notable in our study is the greater proportion of patients diagnosed with overt dissemination, ie, 17 of 21 patients with M2 or M3 disease. The high response rate of our induction regimen suggests that such an addition of high-dose methotrexate should be explored in the context of future studies.

Despite this impressive response rate, CR did not always translate into long-term disease control. Moreover, all the patients who did not achieve a CR by the end of intensive induction therapy (four patients) relapsed and died from progressive disease (three patients), or are alive with disease (one patient). This suggests that for patients with disseminated medulloblastoma who do not achieve a CR initially after intensive chemotherapy, high-dose chemotherapy with autologous stem-cell rescue and radiation therapy may not be adequate, and additional targeted therapies should be considered.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We are grateful to all the physicians, nurses, and clinical research assistants at the participating institutions in the United States, Argentina, Australia, and Canada for participating in and providing clinical information on patients enrolled onto this study.

	NOTES

 
Portions of this study were presented at the International Society of Pediatric Oncology (SIOP) in Porto, Portugal, September 2002, and at the 10th and 11th International Symposia on Pediatric Neuro-Oncology (ISPNO) in London, England, June 2002, and Boston, MA, June 2004.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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2. Duffner PK, Horowitz ME, Krischer JP, et al: The treatment of malignant brain tumors in infants and very young children: An update of the Pediatric Oncology Group experience. Neuro-oncol 1:152-161, 1999[CrossRef][Medline]

3. Kortmann RD, Kuhl J, Timmermann B, et al: Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: Results of the German prospective randomized trial HIT '91. Int J Radiat Oncol Biol Phys 46:269-279, 2000[CrossRef][Medline]

4. Zeltzer PM, Boyett JM, Finlay JL, et al: Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: Conclusions from the Children's Cancer Group 921 randomized phase III study. J Clin Oncol 17:832-845, 1999[Abstract/Free Full Text]

5. Silber JH, Radcliffe J, Peckham V, et al: Whole-brain irradiation and decline in intelligence: The influence of dose and age on IQ score. J Clin Oncol 10:1390-1396, 1992[Abstract/Free Full Text]

6. Lashford LS, Campbell RH, Gattamaneni HR, et al: An intensive multiagent chemotherapy regimen for brain tumours occurring in very young children. Arch Dis Child 74:219-223, 1996[Abstract]

7. Duffner PK, Horowitz ME, Krischer JP, et al: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328:1725-1731, 1993[Abstract/Free Full Text]

8. Gururangan S, Dunkel IJ, Goldman S, et al: Myeloablative chemotherapy with autologous bone marrow rescue in young children with recurrent malignant brain tumors. J Clin Oncol 16:2486-2493, 1998[Abstract]

9. Dupuis-Girod S, Hartmann O, Benhamou E, et al: Will high dose chemotherapy followed by autologous bone marrow transplantation supplant cranio-spinal irradiation in young children treated for medulloblastoma? J Neurooncol 27:87-98, 1996[CrossRef][Medline]

10. Finlay JL, Goldman S, Wong MC, et al: 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. J Clin Oncol 14:2495-2503, 1996[Abstract]

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24. Palmer SL, Goloubeva O, Reddick WE, et al: Patterns of intellectual development among survivors of pediatric medulloblastoma: A longitudinal analysis. J Clin Oncol 19:2302-2308, 2001[Abstract/Free Full Text]

25. Geyer JR, Zeltzer PM, Boyett JM, et al: Survival of infants with primitive neuroectodermal tumors or malignant ependymomas of the CNS treated with eight drugs in 1 day: A report from the Children's Cancer Group. J Clin Oncol 12:1607-1615, 1994[Abstract/Free Full Text]

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Submitted December 17, 2003; accepted September 24, 2004.

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