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.
- Compare the overall survival of patients treated with these regimens.
- 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.
- Correlate the activity of MIBG and whole-body radiation dose.
- 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).
- Arm II (experimental): Patients receive N8 chemotherapy comprising 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.
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.
Carl - Thiem - Klinkum Cottbus, Cottbus D-03048, Germany; Recruiting
D Mobius, MD, Phone: 49-355-462336
Charite University Hospital - Campus Virchow Klinikum, Berlin D-13353, Germany; Recruiting
Gunter Henze, Phone: 49-30-450-660-31
Children's Hospital, Cologne D-50924, Germany; Recruiting
Frank Berthold, MD, Phone: 49-221-478-4380, Email: frank.berthold@uk-koeln.de
Cnopf'sche Kinderklinik, Nuremberg 90419, Germany; Recruiting
W. Scheurlen, Phone: 49-911-334-002
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
Dr. von Haunersches Kinderspital der Universitaet Muenchen, Munich D-80337, Germany; Recruiting
Irene Schmid, MD, Phone: 49-89-5160-7978
Evangelisches Krankenhauus Bielfeld, Biefeld 33617, Germany; Recruiting
N. Jorch, MD, Phone: 49-52-177-278-050
Gemeinschaftskrankenhaus, Herdecke 58313, Germany; Recruiting
Christoph Tautz, MD, Phone: 49-2330-62-3914, Email: ctautz@yahoo.de
Helios Kliniken Wuppertal University Hospital, Wuppertal D-42283, Germany; Recruiting
K. Sinha, MD, Phone: 49-202-896-2441
Helios Klinikum Berlin, Berlin 13125, Germany; Recruiting
Lothar Schweigerer, MD, Phone: 49-30-9401-2345
Helios Klinikum Erfurt, Erfurt 99089, Germany; Recruiting
Axel Sauerbrey, MD, Phone: 49-361-781-3729, Email: asauerbrey@erfurt.helios-kliniken.de
Johannes Gutenberg University, Mainz D-55101, Germany; Recruiting
P. Gutjahr, MD, Phone: 49-6131-17-2112
Johanniter-Kinderklinik, St. Augustin 53757, Germany; Recruiting
Roswitha Dickerhoff, MD, Phone: 49-22-41-2491, Email: roswitha.dickerhoft@uni-bonn.de
Kinderklinik - Universitaetsklinikum Aachen, Aachen D-52074, Germany; Recruiting
R. Mertens, MD, PhD, Phone: 49-241-808-9902, Email: rmertens@ukaachen.de
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
Kinderklinik der Universitaet Bonn, Bonn D-53113, Germany; Recruiting
Udo Bode, MD, Phone: 49-228-2873-3215, Email: udo.bode@ukb.uni-bonn.de
Kinderklinik, Giessen D-35385, Germany; Recruiting
Alfred Reiter, MD, Phone: 49-641-994-3420
Kinderklink Siegen Deutsches Rotes Kreuz, Siegen D-57072, Germany; Recruiting
Rainer Burghard, MD, Phone: 49-271-2345-0, Email: rainer.burghard@drk-kinderklinik.de
Klinik St. Hedwig-Kinderklinik, Regensburg 93049, Germany; Recruiting
Ove Peters, Phone: 49-941-369-5404
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
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
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
Klinikum der J.W. Goethe Universitaet, Frankfurt D-60590, Germany; Recruiting
Thomas Klingebiel, MD, Phone: 49-69-6301-5094, Email: thomas.klingebiel@kgu.de
Klinikum Dortmund, Dortmund D-44137, Germany; Recruiting
Dominik T. Schneider, MD, Phone: 49-231-953-2-1670, Email: dominik.schneider@klinikumdo.de
Klinikum Duisburg, Duisburg D-47055, Germany; Recruiting
Ruef, MD, Phone: 49-203-733-2421
Klinikum Kassel, Kassel D-34125, Germany; Recruiting
Martina Rodehueser, MD, Phone: 49-561-980-3066
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
Klinikum Lippe - Detmold, Detmold D-32756, Germany; Recruiting
Klaus Wesseler, MD, Phone: 49-523-172-4511
Klinikum Minden, Minden D-32423, Germany; Recruiting
Bernhard Erdlenbruch, MD, Phone: 49-57-1801-4601, Email: bernhard.erdlenbruch@klinikum-minden.de
Klinikum Neubrandenburg, Neubrandenburg 17036, Germany; Recruiting
H. J. Feickert, MD, PhD, Phone: 49-395-775-2901, Email: feickerthj@dbk-nb.de
Klinikum Oldenburg, Oldenburg 26133, Germany; Recruiting
Hermann Mueller, MD, Phone: 49-441-403-2013, Email: mueller.hermann@klinikum-oldenburg.de
Krankenanstalt Mutterhaus der Borromaerinnen, Trier D-54290, Germany; Recruiting
Wolfgang Rauh, MD, Phone: 49-651-947-2654
Krankenhaus Muenchen Schwabing, Munich 80804, Germany; Recruiting
Stefan Burdach, MD, PhD, Phone: 49-89-3068-2352
Krankenhaus St. Elisabeth und St. Barbara, Halle D-06110, Germany; Recruiting
G. Guenther, MD, Phone: 49-345-482-50
Medizinische Hochschule Hannover, Hannover D-30625, Germany; Recruiting
Karl Welte, MD, Phone: 49-511-532-6710, Email: welte.karl.h@mh-hannover.de
Olgahospital, Stuttgart D-70176, Germany; Recruiting
Stefan Bielack, MD, Phone: 49-711-99-24-61, Email: st.bielack@olgahospital.de
St. Annastift Krankenhaus, Ludwigshafen 67065, Germany; Recruiting
Barbara Selle, MD, Phone: 49-621-5702-4449
Staedtisches Klinik - Kinderklinik, Mannheim D-68167, Germany; Recruiting
M. Duerken, Phone: 49-621-383-2243
Staedtisches Klinikum - Howedestrase, Braunschweig 38118, Germany; Recruiting
Wolfgang Eberl, MD, Phone: 49-531-595-1222, Email: w.eberl@kliniklum-braunschweig.de
Staedtisches Klinikum Karlsruhe gGmbH, Karlsruhe 76133, Germany; Recruiting
A. Leipold, Phone: 49-721-974-3311
Universitaets - Kinderklinik - Luebeck, Luebeck D-23538, Germany; Recruiting
Peter P. Bucsky, MD, Phone: 49-451-500-2956, Email: bucsky@paedia.ukl.mu-luebeck.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
Universitaets - Kinderklinik, Jena D-07745, Germany; Recruiting
Felix Zintl, MD, Phone: 49-3641-938-270
Universitaets - Kinderklinik, Erlangen 91054, Germany; Recruiting
W. Holter, MD, Phone: 49-9131-853-3118
Universitaets - Kinderklinik, Leipzig D-04317, Germany; Recruiting
U. Bierbach, MD, Phone: Not Available
Universitaetskinderklinik - Universitaetsklinikum Freiburg, Freiburg D-79106, Germany; Recruiting
Charlotte Niemeyer, MD, Phone: 49-761-270-4506, Email: charlotte.niemeyer@uniklinik-freiburg.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
Universitaetsklinikum des Saarlandes, Homburg 66421, Germany; Recruiting
Norbert Graf, Phone: 49-6841-162-4000
Universitaetsklinikum Duesseldorf, Duesseldorf D-40225, Germany; Recruiting
Arndt Borkhardt, Phone: 49-211-311-7990
Universitaetsklinikum Essen, Essen D-45147, Germany; Recruiting
Bernhard Kremens, MD, Phone: 49-201-723-2453
Universitaetsklinikum Giessen und Marburg GmbH - Marburg, Marburg D-35043, Germany; Recruiting
H. Christiansen, MD, Phone: 49-6421-286-2671
Universitaetsklinikum Goettingen, Goettingen D-37075, Germany; Recruiting
M. Lakomek, MD, Phone: 49-551-398-600
Universitaetsklinikum Halle, Halle D-06097, Germany; Recruiting
Dieter Koerholz, MD, Phone: 49-345-557-2387
Universitaetsklinikum Tuebingen, Tuebingen D-72076, Germany; Recruiting
Rupert Handgretinger, MD, Phone: 49-7071-298-2087
Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg, Magdeburg D-39120, Germany; Recruiting
P. Vorwerk, MD, Phone: 49-394-672-791
Universitats - Kinderklinik, Greiswald 17487, Germany; Recruiting
James F. Beck, MD, Phone: 49-383-486-6325, Email: beck@uni-greifswald.de
Universitatsklinikum Carl Gustav Carus, Dresden D-01307, Germany; Recruiting
M. Suttorp, MD, Phone: 49-351-458-0, Email: meinolf.suttorp@uniklinikum-dresden.de
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
University Medical Center Hamburg - Eppendorf, Hamburg D-20246, Germany; Recruiting
Rudolf Erttmann, MD, Phone: 49-40-4717-4270, Email: erttmann@uke.uni-hamburg.de
Vestische Kinderklinik, Datteln 45704, Germany; Recruiting
W. Andler, MD, Phone: 49-023-63-9750, Email: w.andler@kinderklinik-datteln.de
Kantonspital Aarau, Aarau CH-5001, Switzerland; Recruiting
R. Angst, Phone: 41-62-838-4906
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
Universitaets-Kinderspital beider Basel, Basel CH-4005, Switzerland; Recruiting
Thomas Kuhne, MD, Phone: 41-61-685-6565, Email: thomas.kuehne@ukbb.ch
University Children's Hospital, Zurich CH-8032, Switzerland; Recruiting
Felix Niggli, MD, Phone: 41-44-266-7823
