Clinical Study

High-dose chemotherapy with autologous stem cell rescue for children with high risk and

recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors

Antonio Perez-Martınez, Alvaro Lassaletta, Marta Gonzalez-Vicent, Julian Sevilla, Miguel Angel Dıazand Luis MaderoDepartment of Pediatric Hematology and Oncology, Hospital Nino Jesus, Universidad Autonoma de Madrid, Spain

Key words: autologous peripheral blood progenitor cell transplantation, high-dose chemotherapy, high-risk braintumors, medulloblastoma, supratentorial primitive neuroectodermal tumors

Summary

Current treatment for high risk and recurrent medulloblastoma (MB) and supratentorial primitive neuroectodermaltumors (stPNET) has a very poor prognosis in children. High dose chemotherapy (HDCT) and autologous stem cellrescue have improved survival rates. We present 19 patients (thirteen classified in the high risk group and sixpatients with recurrent disease) that received HDCT and autologous stem cell rescue.In the high risk group [Med Pediatr Oncol 38 (2002) 83], all patients underwent neurosurgical debulking.

Standard chemotherapy was prescribed in 10 patients. Radiotherapy was given to 4 patients (all older than 4 yearsold). In the recurrence disease group [Childs Nerv Syst 15 (1999) 498], five patients underwent surgery. Radio-therapy was given to those who were not previously irradiated. The HDCT in twelve patients consisted of busulfan4mg/kg/day, orally over 4 days in 6-hourly divided doses and melphalan at a dose of 140mg/m2/day by intravenousinfusion over 5min on day )1. Three patients additionally received thiotepa 250mg/m2/day intravenously over2 days and four patients additionally received topotecan 2mg/m2/day over 5 days by intravenous infusion over30min. The other seven patients received busulfan and thiotepa at the same doses.Patient’s stem cells were mobilized with granulocyte colony-stimulating factor at a dose of 12 lg/kg twice daily

subcutaneously for four consecutive days. Cryopreserved peripheral blood progenitor cells were re-infused 48 h aftercompletion of chemotherapy. With a median follow-up of 34months (range 5–93) eight complete responses and onepartial response were observed. Three patients died of treatment-related toxicities (15%). The 2 year event-freesurvival was 37.67±14% in all patients and 57±15% for the high risk group.Therefore we conclude that HDCT may improve survival rates in patients with high risk/recurrent MB and

stPNET despite treatment toxicity.

Introduction

Recent advances in the treatment of cerebellar me-duloblastoma (MB) and supratentorial primitive neu-roectodermal tumors (stPNET) have extended 5-yearsurvival rates from 3 to more than 70% during the past50 years [1]. These improvements in survival rates haveresulted from a multi-modality approach includingsurgical resection, posterior fossa and craniospinalirradiation and chemotherapy for selected patients.However, some groups of patients as those with

recurrent disease or high-risk disease (children less than4 years and children with large residual tumors afterresection, brainstem infiltration, extraneural metastasisor leptomeningeal dissem- ination) have a poor survival[1,2]. Since 1986, investigators from different institutionshave used high-dose chemotherapy with autologousstem cell rescue (HDCT) in an attempt to improvesurvival in these groups of patients [1–8]. In this paperwe report our experience using HDCT in pediatric pa-tients with high-risk and recurrent MB and stPNETtumors.

Patients and methods

Patients

Between March 1995 and December 2002, 19 pediatricpatients with pathologic confirmation of MB or stPNETwere treated with HDCT. The patients were divided intotwo groups: those with high-risk and those with recur-rent tumors. Disease was staged as high-risk accordingto the following criteria: children less than 4 years,children with large post-surgical residual tumor volume,brainstem infiltration, extraneural metastasis or lepto-meningeal dissemination [9–11].Original treatment before HDCT in high-risk disease

consisted of surgical debulking with or without irradi-ation and standard chemotherapy.Maximal surgical resection of the tumor was attempted

in all patients. Radiation therapy dose was 50Gy over 6–7weeks in daily fractions of 200cGy (five fractions perweek) to the primary tumor and 35Gy to the craniospinalaxis. Only patients older than 4 years old were irradiated.Standard chemotherapy consisted in regimens of the

Journal of Neuro-Oncology (2005) 71: 33–38 � Springer 2005

French Society of Pediatric Oncology (SFOP) [12],International Society of Pediatric Oncology (SIOP) (6)and Children Cancer Group (CCG) [13].The main characteristics of the high-risk patients are

shown in Table 1.Patients with recurrent MB or stPNET were initially

treated with surgery, irradiation and standard chemo-therapy [14,15]. Treatment after recurrence consisted inmaximal surgical debulking with or without irradiation.The main characteristics of patients with disease

recurrence are shown in Table 2.Tumor staging at the time of the initial diagnosis was

performed according to the Chang system [9].Before HDCT, normal cardiac function (ejection

fraction >45% or shortening fraction >30% by echo-cardiogram), normal renal function (serum creatinineclearance >70ml/min/m2), normal liver function (AST<1.5 times normal) and bilirubin <1.5mg/dl), normalbone marrow function (hemoglobin >10 g/dl, WBCcount >3000/ll, absolute neutrophils count >1500 ll,and platelets >100,000mm3), and a Lansky score >70were required [16].

Transplant procedure

All patients had PBSCs mobilized with granulocytecolony-stimulating factor (G-CSF, Neupogen�, Amgen,Thousand Oaks, CA, USA) at a dose of 12 lg/kg twice

daily subcutaneously for four consecutive days beforestarting apheresis, as previously reported [17].Peripheral blood progenitor cells collection by large-

volume leukapheresis were performed on day +5 aftermobilization by a Cobe Spectra cell separator (CobeBCT, Lakewood, CO, USA).Each apheresis product was analyzed for CD34+ cell

content by flow cytometry using an Epics Elite flowcytometer (Coulter Corporation, Hialeah, Florida,USA). The final product containing 10% dimethylsulf-oxide (DMSO) was frozen using a computer-controlledfreezer and stored in liquid nitrogen at )196 �C.Conditioning regimen of 12 patients consisted of

busulfan 4mg/kg/day, orally over 4 days (from days)5 to)2) in 6-hourly divided doses and melphalan at a dose of140mg/m2/day by intravenous infusion over 5min on day)1. Three patients additionally received thiotepa 250mg/m2/day intravenously over 2 days (from days )3 to )2)and four patients additionally received topotecan 2mg/m2/day over 5 days by intravenous infusion over 30min(from days )11 to )7). The other seven patients receivedbusulfan and thiotepa at the same doses.On day 0, collected peripheral blood progenitor cells

were re-infused after rapid thawing at 37 �C.All patients received G-CSF intravenously (10 lg/kg/

day) starting on day +1 until an absolute neutrophilscount (ANC) >1 · 109/l was maintained for two con-secutive days. Version 2.0 of the National Cancer

Table 1. Characteristics of high-risk patients

Patient Sex Age (years) Diagnosis Surgery Radiotherapy Standard

chemotherapy

Status at ASCR

1 Male 2 MB Partial No No PD

2 Male 4 MB Total No No CR

3 Male 2 stPNET Total No SFOP CR

4 Female 2 stPNET Total No No PR

5 Female 14 MB Partial Yes CCG PR

6 Male 2 MB Total No SIOP CR

7 Male 1 MB Total No SIOP CR

8 Female 5 stPNET Total Yes SIOP CR

9 Female 9 MB Subtotal Yes SIOP CR

10 Female 2 MB Total No SFOP CR

11 Male 4 stPNET Partial No SFOP PR

12 Male 3 MB Total No SFOP CR

13 Male 5 MB Total Yes SIOP PD

Diagnosis: MB – medulloblastoma; stPNET – supratentorial primitive neuroectodermal tumors; Induction chemotherapy: SFOP – French

Society of Pediatric Oncology; SIOP – International Society of Pediatric Oncology; CCG – Children’s Cancer Group; CR – complete remission;

SD – stable disease; PR – partial remission; PD – progression disease; ASCR – autologous stem cell rescue.

Table 2. Characteristics of patients with recurrence disease

Patient Sex Age

(years)

Diagnosis Months from diagnosis

to recurrence

Surgery at

recurrence

Radiotherapy

at recurrence

Months from

recurrence to ASCR

Status at

transplantation

14 Male 12 MB 10 No No 1 PD

15 Male 14 MB 18 Total Yes 5 2�CR16 Female 6 MB 11 Total Yes 4 2�CR17 Female 15 MB 24 Partial No 2 PR

18 Male 5 stPNET 5 Total Yes 6 2�CR19 Male 15 MB 26 Partial No 1 PD

Diagnosis: MB – medulloblastoma; stPNET – supratentorial primitive neuroectodermal tumors; CR – complete remission; SD – stable disease;

PR – partial remission; PD – progression disease; ASCR – autologous stem cell rescue.

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Institute Common Toxicity Criteria was used to gradetoxicity [18].

Supportive care

After placement of a central venous line, patients wereadmitted to the hospital for HDCT and were nursedunder strict protective isolation in barrier nursing unitswith HEPA-filtered air. Infection prophylaxis was pro-vided with cotrimoxazole.Intravenous clonazepam was prescribed from the first

day of busulfan to the day of infusion in order to avoidbusulfan-related seizures.Platelet transfusions were administered to maintain a

platelet count higher than 2· 109/l and transfusions ofirradiated packed red blood cells were administered tomaintain a hematocrit concentration higher than 25%. Allblood-derived transfusions were irradiated prior to use.Empiric broad-spectrum antibiotic treatment was initiatedas soon as fever of >38 �C occurred. Amphotericin (1mg/kg/day) was added if fever and neutropenia continued for5 days after antibiotics were started. In addition, any pa-tient with a >10% weight loss from the time of startingtherapy received nutritional support using parenteralnutrition or nasogastric feeding.

Definitions

The high risk group was defined as age younger than4 years old, presence of more than 1.5 cm2 residual dis-ease as confirmed by postoperative gadolinium-enhanced MRI and T3b/T4 or M1-M4 in the Changstaging [9].Histological results or radiographic evidence were

required to define disease recurrence. The extent ofsurgical resection was defined as follows: a partialresection if reduction was greater than 10% but less than90% of the tumor mass; a subtotal resection if reductionwas greater than 90% of the tumor mass, but visibletumor remained; and a gross total resection if no tumorwas visible on postoperative MRI or CT scan.Neutrophil recovery was defined as the number of

days taken to achieve an ANC >0.5 · 109/l for threeconsecutive days without requiring transfusion.Standard radiographic criteria were used to determine

response. Complete response (CR) was defined ascomplete resolution of all lesions and no clinical pro-gression. Partial response (PR) was defined as a >50%reduction in the product of the maximum perpendiculardiameters of all lesions and no clinical progression.Stable disease (SD) was defined as <50% reduction and<25% increase in size with no clinical progression, andprogressive disease (PD) was defined as >25% increasein size.

Informed consent

Potential treatment risks and benefits, supportive careand therapeutic options were explained and discussed.Signed informed consent was obtained for each childfrom parents or legal guardians.

Statistical analysis

Data are expressed as the median and range. Event-freesurvival (EFS) was assessed from the date of HDCT tothe date of disease progression or death. Overall survivalwas assessed from the date of HDCT to death. Distri-butions of EFS were estimated using the method ofKaplan–Meier [19].

Results

Study population

Between March 1995 and December 2002, 19 children(12 boys and 7 girls) with a diagnosis of high-risk andrecurrent MB and stPNET were enrolled. The medianage at diagnosis was 4 years. Thirteen patients wereclassified as high-risk and 6 as patients with recurrentdisease.

High-risk patientsPatients assigned to the high-risk group were eight boysand five girls. The median age at diagnosis was 3 years(range 1–14). All patients had histologically documentedMB or stPNET.Complete surgical resection was achieved in nine pa-

tients and partial or subtotal resection was achieved infour patients. Only children older than 4 years of agewere irradiated (four patients). Standard chemotherapywas administered to seven patients (two SIOP95, oneCCG, four SEOP). At entry into HDCT, eight patientshad CR, three had PR and two had PD.Eight patients received as conditioning regimen

busulfan-melphalan, and five patients received busul-phan-thiotepa. Three patients of the busulfan-melpha-lan regimen additionally received thiotepa and anotherthree additionally received topotecan.

Patients with recurrent diseasePatients with recurrent disease were four boys and eightgirls. The median age at recurrence was 13 years (range5–15).At the time of relapse, all of them had radiographic

evidence of disease and five patients had histologicallydocumented recurrent MB or stPNET. The median timefrom initial diagnosis to relapse was 14.5months (range5–26). Original treatment consisted of surgery in allpatients (four received completed resection and twopartial resection), irradiation in three patients andstandard chemotherapy in four patients (three SIOP andone SEOP).After recurrence, five of the six patients received

additional surgical resection. Three of these patientsachieved complete neurosurgical resection and twopartial resection. Three previously non-irradiated pa-tients received radiotherapy. None of the six patientsreceived chemotherapy. The median time from relapseto HDCT was 3months (range 1–6). At entry intoHDCT, three patients had CR, one had PR, and twohad PD.

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Conditioning regimen was busulphan-melphalan infour patients, and busulphan-thiotepa in two patients.One patient of the busulphan-melphalan regimen, addi-tionally received topotecan.

Toxicity of HDCT and engraftment kinetics

Treatment-related mortality occurred in three patients,two from the high-risk group and one from the recurrentdisease group of patients. This was due to multi-organsystem failure in two patients and a systemic CMVinfection in the other patient.A median of 3.45 (0.6–42) · 106/kg peripheral blood

progenitor cells were re-infused on day 0. Hematologicalrecovery was achieved in 18 patients. The median timeto neutrophil count recovery was 9 days (7–12) and themedian time to platelet recovery was 13.5 days (8–60).One patient did not achieved platelet recovery.All patients experienced myelosuppression grade IV,

requiring a median of two packed red blood cells and twoplatelet transfusions and G-CSF treatment. All patientsdeveloped febrile neutropenic episodes and receivedtreatment with broad-spectrum antibiotics. Eight febrileepisodes during the neutropenia period were confirmedby clinical observation or positive culture: one patientdeveloped cutaneous vesicular eruption that resembledchickenpox and eight had catheter-related infection fromcoagulase-negative staphylococci.Grade IV gastrointestinal toxicity was seen in all pa-

tients. These patients required parenteral narcotics forpain control and intravenous alimentation was requiredin 15 children, with a median duration of 18 days.Four patients developed engrafment syndrome

requiring high-dose steroids to resolve it [20]. Two

patients developed veno-occlusive disease that were re-solved with supportive treatment. Two patients devel-oped grade IV CNS toxicity with seizures (busulphan-related seizures). One patient developed a secondaryneoplasm (fibrohistiocytoma of the jaw 6 years afterHDCT).The main characteristics of the toxicity and engraft-

ment kinetics are shown in Table 3.

Response to HDCT and survival

Tumor recurred in seven patients at a median of5months after HDCT (range 1–25months), three fromthe high-risk and four from the recurrent disease group.All of these patients died.Currently, nine patients are alive and event-free at a

median of 18months from HDCT (range 5–63months).Eight patients are tumor-free and one has partialremission. In the high-risk group, seven patients hadCR: five maintained the status at the time of trans-plantation and two (one PR and the other one PD)improved the pre-HDCT status and one patient PRmaintained disease status. Following HDCT only onepatient in the recurrent disease group had CR at14months follow-up.Among all patients, the 2-year Kaplan–Meier estimated

EFS rates was 37.67±14%. In high risk patients, the 2-year Kaplan–Meier estimates EFS rates was 57±15%.Only one patient in the recurrent disease group is alive andtumor-free (Figure 1).We did not find any difference between the Kaplan–

Meier estimated EFS in the medulloblastoma groupcompared with the stPNET group (P ¼ 0.485).

Table 3. Conditioning regimen, engraftment kinetic, toxicities, and outcome

Patient Conditioning CD34+/kg NR (days) PTR (days) Complications Outcome (+years

follow up)

1 BU-TI 42 · 106 7 15 Sepsis DTRM (0.33)

2 BU-TI 5.2 · 106 8 60 VOD/ES CR (5.3)

3 BU-TI 2.8 · 106 9 25 Seiz DOD (0.82)

4 BU-TI 8.06· 106 9 9 Sepsis/Seiz DOD (0.57)

5 BU-ME 3.84· 106 12 11 ES CR (2.8)

6 BU-TI-ME 16.6· 106 10 12 Sepsis DOD (2.96)

7 BU-TI-ME 24.8· 106 9 10 – CR (2.14)

8 BU-TI-ME 3.45· 106 11 19 ES/Sepsis CR (1.97)

9 BU-ME-TO 2.1 · 106 11 11 ES CR (1.97)

10 BU-ME-TO 3.27· 106 8 13 Chickenpox CR (1.97)

11 BU-ME-TO 2.4 · 106 10 8 – PR (1.86)

12 BU-ME 13.5· 106 11 14 Sepsis DTRM (0.66)

13 BU-TI 14.6· 106 7 15 Tumor 2� CR (7.91)

14 BU-TI 2.16· 106 10 – VOD DOD (0.99)

15 BU-TI 2.22· 106 9 9 Sepsis DOD (1.97)

16 BU-ME 0.6 · 106 11 15 Sepsis DOD (2.88)

17 BU-ME 1.26· 106 9 19 Sepsis DOD (2.88)

18 BU-ME 1.86· 106 9 10 – DTRM (3.37)

19 BU-ME-TO 7.3 · 106 10 14 ES CR (3.7)

NR – neutrophil recovery; PTR – platelet recovery; BU-TI-ME – busulfan-thiotepa-melphalan; BU-ME – busulfan-melphalan; BU-TO-ME –

busulfan-topotecan-melphalan; ES – engraftment syndrome; SEIZ – seizures; VCRI – venous catheter related infection; VOD – venoclusive

disease; CR – complete remission; PR – partial remission; DOD – died of disease; DTRM – died of transplant related toxicity.

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Discussion

Children under 4 years old, those with bulky residualtumor after surgery or disseminated central nervoussystem disease at diagnoses [9, 13], and children withrecurrent MB/stPNET have a dismal outcome withstandard or alternative treatments [1,2].HDCT with stem cell rescue appears to benefit pa-

tients with recurrent MB, especially those in whom tu-mor recurrence is detected and treated early. However,published experience with HDCT as first line of treat-ment for high-risk patients with newly diagnosed MB/stPNET is scanty, and it has not been systematicallystudied as it has been for patients with other solidtumors.We have not observed the reported favorable results

achieved with HDCT in patients with recurrent MB, butwe have observed that high-risk patients may benefitfrom this treatment. This observation has led us toeliminate the adverse consequences of radiation therapyin patients younger than 4 years old [2].Patient general condition and the status of the disease

before transplantation are prognostic factors for HDCT[5]. In our series, 5 of the 9 survivors (55%) were in CRbefore transplantation, vs. 3 of the 10 patients (33%) thatdied, indicating that patients in first remission beforetransplantation are more likely to benefit from high-dosetherapy.Bone marrow has been commonly used as the source

for hematopoietic stem cells. However, nowadays stem-cell collection from peripheral blood with previouslyadministered G-CSF is the most frequent employedsource [17], and has been the source in all of our cases.To date, the optimal conditioning regimen for pa-

tients with MB/stPNET has not yet been established. Abusulfan-based conditioning regimen may be effective inMB and stPNET treatment, as it has been reported inother solid tumors of childhood [7]. We used mainlybusulfan-melphalan regimens with the addition of analkylating agent or a topoisomerase II inhibitor. Withthese drugs we had similar toxicity than other studiesreported in the literature using different conditioningregimens [3].

Like other authors, we have found higher transplant-related toxicity and mortality in children with braintumors than in children with other solid tumors [2]. Thishigher mortality may be due to the status of disease attransplantation and to the intensity of previous treat-ments. A better selection of the patients (completeremission before transplantation, total resection…) canreduce the transplant related mortality.Overall disease-free survival was 37.67%±14% with

24months of median follow-up, but it was better for thehigh-risk group (57±15%). We achieved specially goodresults in children younger than 4 years old. Of the sevenchildren of this age, five are alive without sequelae, anddisease-free survival was 71.43±17% at a median fol-low-up of 21months.Although some authors consider stPNET to have a

worse prognosis than MB, we have not found anydifference.Although our study population is small, we believe

that high-dose chemotherapy may play a role as first linetherapy in high-risk children with MB and stPNET, andmay achieve long-term survival.

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Address for offprints: Dr. Luis Madero, Department of Pediatric

Hematology–Oncology Hospital Nino Jesus, Avda, Menendez Pelayo

65, 28009 Madrid, Spain; Tel.: +34-91-5035938; Fax: +34-91-5035902;

E-mail: lmadero.hnjs@salud.madrid.org

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