RATIONALE: Giving chemotherapy before an autologous stem cell transplant stops the growth of
tumor cells by stopping them from dividing or by killing them. It also prepares the
patient's bone marrow for the stem cell transplant. The stem cells are given to the patient
to replace the blood-forming cells that were destroyed by the chemotherapy. Giving
isotretinoin after transplant may kill any remaining tumor cells. It is not yet known which
combination chemotherapy regimen is more effective when given before a stem cell transplant
and isotretinoin in treating neuroblastoma.
PURPOSE: This randomized clinical trial is studying two different combination chemotherapy
regimens to compare how well they work when given before a stem cell transplant and
isotretinoin in treating young patients with high-risk neuroblastoma.
- Compare the event-free survival of pediatric patients with high-risk neuroblastoma
treated with standard induction chemotherapy vs topotecan hydrochloride-containing
induction chemotherapy followed by myeloablative autologous stem cell transplantation
and consolidation therapy with isotretinoin.
Secondary
- Compare early response (complete response, very good partial response, partial
response, mixed response, stable disease, and progression/relapse) after 2 courses of
standard vs experimental induction chemotherapy (or after 60 days if the second course
is not yet finished).
- Compare response to standard vs experimental induction chemotherapy before autologous
stem cell transplantation (or after 280 days if induction chemotherapy is not yet
finished).
- Compare the toxicity of standard vs experimental induction chemotherapy during courses
1 and 2 and the frequency of ≥ grade 3 toxicity during the last 6 courses of induction
chemotherapy.
- Compare the extent of initial surgery and best surgery (biopsy vs incomplete resection
vs macroscopic complete resection) and the frequency of complications related to
surgery (e. g., nephrectomy, bleeding, infection, or intestinal obstruction).
- Compare the acute and long-term side effects of external-beam radiotherapy.
- Collect and store tumor material in the tumor bank for future evaluation of other
molecular markers (MYCN and status of chromosome 1p and 11q) and prognostic significant
gene signatures.
OUTLINE: This is a multicenter study. Patients are stratified according to disease stage,
lactate dehydrogenase (LDH) status, MYCN status, and age at diagnosis (stage 4 disease; LDH
not elevated; any MYCN status; age at diagnosis 1-21 years vs stage 4 disease; LDH elevated;
any MYCN status; age at diagnosis ≥ 1 but < 2 years vs stage 4 disease; LDH elevated; any
MYCN status; age at diagnosis 2-21 years vs localized disease; MYCN amplification; age at
diagnosis ≥ 6 months)
- Induction chemotherapy: Patients are randomized to 1 of 2 induction chemotherapy arms.
continuously over 96 hours and etoposide phosphate IV continuously over 96 hours
on days 1-4 and vindesine IV over 1 hour on day 1. Patients also receive
filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 9 and
continuing until blood counts recover. Patients then receive N6 chemotherapy
comprising vincristine IV over 1 hour on days 1 and 8, dacarbazine IV over 1 hour
on days 1-5, ifosfamide IV continuously over 120 hours on days 1-5, and
doxorubicin hydrochloride IV over 4 hours on days 6 and 7. Patients also receive
G-CSF SC once daily beginning on day 10 and continuing until blood counts recover.
Treatment with N5 and N6 chemotherapy alternates every 21 days for 6 courses (N5
chemotherapy is given in courses 1, 3, and 5 and N6 chemotherapy is given in
courses 2, 4, and 6).
cyclophosphamide IV over 1 hour on days 1-7, topotecan hydrochloride IV
continuously over 168 hours on days 1-7, and etoposide phosphate IV over 1 hour on
days 8-10. Patients also receive G-CSF SC once daily beginning on day 12 and
continuing until blood counts recover. Treatment with N8 chemotherapy repeats
every 21 days for 2 courses. Patients then receive N5 chemotherapy alternating
with N6 chemotherapy as in arm I.
- Surgery: Patients may undergo secondary surgery after completion of 4 or 6 courses of
- Radiotherapy (131I-MIBG therapy and external-beam radiotherapy [EBRT]): Patients with
active residual primary tumor after the completion of induction chemotherapy undergo
^131I-MIBG therapy* prior to autologous stem cell transplantation (ASCT) and EBRT after
ASCT.
NOTE: *Patients with MIBG negative neuroblastoma at initial diagnosis will only receive
EBRT.
- Myeloablative ASCT: Patients receive melphalan IV over 30 minutes on days -8 to -5,
etoposide phosphate IV over 4 hours on day - 4, and carboplatin IV over 1 hour on days
- 4 to -2. Patients undergo reinfusion of CD34+ stem cells on day 0. Patients also
receive G-CSF SC or IV over 4 hours once daily beginning on day 2 and continuing until
blood counts recover.
- Consolidation therapy (isotretinoin)*: Beginning 30 days after ASCT, patients receive
oral isotretinoin once daily on days 1-14. Treatment repeats every 28 days for up to 6
courses. Beginning 3 months later, patients receive an additional 3 courses of
isotretinoin.
NOTE: *Isotretinoin must not be given concurrently with radiotherapy
After completion of study treatment, patients are followed every 6 weeks for 1 year, every 3
months for 4 years, and then every 6 months thereafter.
Minimum age: N/A.
Maximum age: 21 Years.
Gender(s): Both.
Kinderklinik - Universitaetsklinikum Aachen, Aachen D-52074, Germany; Recruiting
R. Mertens, MD, PhD, Phone: 49-241-808-9902, Email: rmertens@ukaachen.de
Klinikum Augsburg, Augsburg DOH-86156, Germany; Recruiting
Astrid Gnekow, Phone: 49-821-400-3603
Klinikum Bayreuth, Bayreuth D-95445, Germany; Recruiting
T. Rupprecht, Phone: 49-921-400-1400
Charite University Hospital - Campus Virchow Klinikum, Berlin D-13353, Germany; Recruiting
Gunter Henze, Phone: 49-30-450-660-31
Helios Klinikum Berlin, Berlin 13125, Germany; Recruiting
Lothar Schweigerer, MD, Phone: 49-30-9401-2345
Evangelisches Krankenhauus Bielfeld, Biefeld 33617, Germany; Recruiting
N. Jorch, MD, Phone: 49-52-177-278-050
Kinderklinik der Universitaet Bonn, Bonn D-53113, Germany; Recruiting
Udo Bode, MD, Phone: 49-228-2873-3215, Email: udo.bode@ukb.uni-bonn.de
Staedtisches Klinikum - Howedestrase, Braunschweig 38118, Germany; Recruiting
Wolfgang Eberl, MD, Phone: 49-531-595-1222, Email: w.eberl@kliniklum-braunschweig.de
Klinikum Bremen-Mitte, Bremen D-28205, Germany; Recruiting
Arnulf Pekrun, MD, PhD, Phone: 49-421-497-3656, Email: arnulf.pekrun@klinikum-bremen-mitte.de
Klinikum Chemnitz gGmbH, Chemnitz D-09116, Germany; Recruiting
Krause, MD, Phone: 49-371-3332-4124
Klinikum Coburg, Coburg 96450, Germany; Recruiting
Roland Frank, MD, Phone: 49-9561-22-5547
Children's Hospital, Cologne D-50924, Germany; Recruiting
Frank Berthold, MD, Phone: 49-221-478-4380, Email: frank.berthold@uk-koeln.de
Carl - Thiem - Klinkum Cottbus, Cottbus D-03048, Germany; Recruiting
D Mobius, MD, Phone: 49-355-462336
Vestische Kinderklinik, Datteln 45704, Germany; Recruiting
W. Andler, MD, Phone: 49-023-63-9750, Email: w.andler@kinderklinik-datteln.de
Klinikum Lippe - Detmold, Detmold D-32756, Germany; Recruiting
Klaus Wesseler, MD, Phone: 49-523-172-4511
Klinikum Dortmund, Dortmund D-44137, Germany; Recruiting
Dominik T. Schneider, MD, Phone: 49-231-953-2-1670, Email: dominik.schneider@klinikumdo.de
Universitatsklinikum Carl Gustav Carus, Dresden D-01307, Germany; Recruiting
M. Suttorp, MD, Phone: 49-351-458-0, Email: meinolf.suttorp@uniklinikum-dresden.de
Universitaetsklinikum Duesseldorf, Duesseldorf D-40225, Germany; Recruiting
Arndt Borkhardt, Phone: 49-211-311-7990
Klinikum Duisburg, Duisburg D-47055, Germany; Recruiting
Ruef, MD, Phone: 49-203-733-2421
Helios Klinikum Erfurt, Erfurt 99089, Germany; Recruiting
Axel Sauerbrey, MD, Phone: 49-361-781-3729, Email: asauerbrey@erfurt.helios-kliniken.de
Universitaets - Kinderklinik, Erlangen 91054, Germany; Recruiting
W. Holter, MD, Phone: 49-9131-853-3118
Universitaetsklinikum Essen, Essen D-45147, Germany; Recruiting
Bernhard Kremens, MD, Phone: 49-201-723-2453
Klinikum der J.W. Goethe Universitaet, Frankfurt D-60590, Germany; Recruiting
Thomas Klingebiel, MD, Phone: 49-69-6301-5094, Email: thomas.klingebiel@kgu.de
Universitaetskinderklinik - Universitaetsklinikum Freiburg, Freiburg D-79106, Germany; Recruiting
Charlotte Niemeyer, MD, Phone: 49-761-270-4506, Email: charlotte.niemeyer@uniklinik-freiburg.de
Kinderklinik, Giessen D-35385, Germany; Recruiting
Alfred Reiter, MD, Phone: 49-641-994-3420
Universitaetsklinikum Goettingen, Goettingen D-37075, Germany; Recruiting
M. Lakomek, MD, Phone: 49-551-398-600
Universitats - Kinderklinik, Greiswald 17487, Germany; Recruiting
James F. Beck, MD, Phone: 49-383-486-6325, Email: beck@uni-greifswald.de
Krankenhaus St. Elisabeth und St. Barbara, Halle D-06110, Germany; Recruiting
G. Guenther, MD, Phone: 49-345-482-50
Universitaetsklinikum Halle, Halle D-06097, Germany; Recruiting
Dieter Koerholz, MD, Phone: 49-345-557-2387
University Medical Center Hamburg - Eppendorf, Hamburg D-20246, Germany; Recruiting
Rudolf Erttmann, MD, Phone: 49-40-4717-4270, Email: erttmann@uke.uni-hamburg.de
Medizinische Hochschule Hannover, Hannover D-30625, Germany; Recruiting
Karl Welte, MD, Phone: 49-511-532-6710, Email: welte.karl.h@mh-hannover.de
Universitaets-Kinderklinik Heidelberg, Heidelberg D-69120, Germany; Recruiting
Andreas E. Kulozik, MD, PhD, Phone: 49-6221-564-555, Email: andreas.kulozik@med.uni-heidelberg.de
Gemeinschaftskrankenhaus, Herdecke 58313, Germany; Recruiting
Christoph Tautz, MD, Phone: 49-2330-62-3914, Email: ctautz@yahoo.de
Universitaetsklinikum des Saarlandes, Homburg 66421, Germany; Recruiting
Norbert Graf, Phone: 49-6841-162-4000
Universitaets - Kinderklinik, Jena D-07745, Germany; Recruiting
Felix Zintl, MD, Phone: 49-3641-938-270
Staedtisches Klinikum Karlsruhe gGmbH, Karlsruhe 76133, Germany; Recruiting
A. Leipold, Phone: 49-721-974-3311
Klinikum Kassel, Kassel D-34125, Germany; Recruiting
Martina Rodehueser, MD, Phone: 49-561-980-3066
University Hospital Schleswig-Holstein - Kiel Campus, Kiel D-24105, Germany; Recruiting
A. Claviez, MD, Phone: 49-431-597-1622, Email: a.claviez@pediatrics.uni-kiel.de
Klinikum Kemperhof Koblenz, Koblenz D-56065, Germany; Recruiting
M. Rister, MD, Phone: 49-261-499-2602
Klinikum Krefeld GmbH, Krefeld D-47805, Germany; Recruiting
S. Volpel, MD, Phone: 49-2151-32-2375
St. Annastift Krankenhaus, Ludwigshafen 67065, Germany; Recruiting
Barbara Selle, MD, Phone: 49-621-5702-4449
Universitaets - Kinderklinik - Luebeck, Luebeck D-23538, Germany; Recruiting
Peter P. Bucsky, MD, Phone: 49-451-500-2956, Email: bucsky@paedia.ukl.mu-luebeck.de
Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg, Magdeburg D-39120, Germany; Recruiting
P. Vorwerk, MD, Phone: 49-394-672-791
Johannes Gutenberg University, Mainz D-55101, Germany; Recruiting
P. Gutjahr, MD, Phone: 49-6131-17-2112
Staedtisches Klinik - Kinderklinik, Mannheim D-68167, Germany; Recruiting
M. Duerken, Phone: 49-621-383-2243
Universitaetsklinikum Giessen und Marburg GmbH - Marburg, Marburg D-35043, Germany; Recruiting
H. Christiansen, MD, Phone: 49-6421-286-2671
Klinikum Minden, Minden D-32423, Germany; Recruiting
Bernhard Erdlenbruch, MD, Phone: 49-57-1801-4601, Email: bernhard.erdlenbruch@klinikum-minden.de
Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster, Muenster D-48149, Germany; Recruiting
Heribert F. Juergens, MD, Phone: 49-251-834-7742, Email: jurgh@uni-muenster.de
Dr. von Haunersches Kinderspital der Universitaet Muenchen, Munich D-80337, Germany; Recruiting
Irene Schmid, MD, Phone: 49-89-5160-7978
Krankenhaus Muenchen Schwabing, Munich 80804, Germany; Recruiting
Stefan Burdach, MD, PhD, Phone: 49-89-3068-2352
Klinikum Neubrandenburg, Neubrandenburg 17036, Germany; Recruiting
H. J. Feickert, MD, PhD, Phone: 49-395-775-2901, Email: feickerthj@dbk-nb.de
Cnopf'sche Kinderklinik, Nuremberg 90419, Germany; Recruiting
W. Scheurlen, Phone: 49-911-334-002
Klinikum Oldenburg, Oldenburg 26133, Germany; Recruiting
Hermann Mueller, MD, Phone: 49-441-403-2013, Email: mueller.hermann@klinikum-oldenburg.de
Klinik St. Hedwig-Kinderklinik, Regensburg 93049, Germany; Recruiting
Ove Peters, Phone: 49-941-369-5404
Kinderklinik - Universitaetsklinikum Rostock, Rostock D-18057, Germany; Recruiting
Carl Friedrich Classen, MD, PD, Phone: 49-381-494-0, Email: carl-friedrich.classen@med.uni-rostock.de
Kinderklink Siegen Deutsches Rotes Kreuz, Siegen D-57072, Germany; Recruiting
Rainer Burghard, MD, Phone: 49-271-2345-0, Email: rainer.burghard@drk-kinderklinik.de
Johanniter-Kinderklinik, St. Augustin 53757, Germany; Recruiting
Roswitha Dickerhoff, MD, Phone: 49-22-41-2491, Email: roswitha.dickerhoft@uni-bonn.de
Olgahospital, Stuttgart D-70176, Germany; Recruiting
Stefan Bielack, MD, Phone: 49-711-99-24-61, Email: st.bielack@olgahospital.de
Krankenanstalt Mutterhaus der Borromaerinnen, Trier D-54290, Germany; Recruiting
Wolfgang Rauh, MD, Phone: 49-651-947-2654
Universitaetsklinikum Tuebingen, Tuebingen D-72076, Germany; Recruiting
Rupert Handgretinger, MD, Phone: 49-7071-298-2087
Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm, Ulm D-89075, Germany; Recruiting
Klaus M. Debatin, MD, Phone: 49-731-5002-7790, Email: klaus-michael.debatin@medizin.uni-ulm.de
Universitaets - Kinderklinik Wuerzburg, Wuerzburg D-97080, Germany; Recruiting
P. G. Schlegel, MD, Phone: 49-931-201-27-831, Email: schlegel@mail.uni-wuerzburg.de
Helios Kliniken Wuppertal University Hospital, Wuppertal D-42283, Germany; Recruiting
K. Sinha, MD, Phone: 49-202-896-2441
Kantonsspital Aarau, Aarau CH-5001, Switzerland; Recruiting
R. Angst, Phone: 41-62-838-4906
Universitaets-Kinderspital beider Basel, Basel CH-4005, Switzerland; Recruiting
Thomas Kuhne, MD, Phone: 41-61-685-6565, Email: thomas.kuehne@ukbb.ch
Kinderspital Luzern, Lucerne 16 CH-6000, Switzerland; Recruiting
U. Caflisch, MD, Phone: 41-41-205-11-11
Ostschweizer Kinderspital, St. Gallen CH-9006, Switzerland; Recruiting
Jeanette Greiner, MD, Phone: 41-71-243-13-60, Email: jeanette.greiner@kispisg.ch
University Children's Hospital, Zurich CH-8032, Switzerland; Recruiting
Felix Niggli, MD, Phone: 41-44-266-7823