Clinical trial NCT00017225: Chemotherapy and Radiation Therapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Neuroblastoma
Official title: Neuroblastoma Study Phase II Study of Various Therapies in Patients With Neuroblastoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Neuroblastoma
Keywords: localized resectable neuroblastoma
regional neuroblastoma
disseminated neuroblastoma
stage 4S neuroblastoma
recurrent neuroblastoma
localized unresectable neuroblastoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-01-27
Sex: ALL
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy or radiation therapy used to kill tumor cells. Combining these therapies may kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of combining chemotherapy and radiation therapy with or without peripheral stem cell transplantation in treating patients who have neuroblastoma.

Detailed description: OBJECTIVES:

* Determine the frequency of spontaneous remission in pediatric patients with localized neuroblastoma.
* Determine the course of regression in patients with spontaneous remission.
* Determine the event-free survival rate of patients with high-risk neuroblastoma treated with maintenance chemotherapy OR consolidation chemotherapy followed by autologous stem cell rescue.
* Determine if a correlation exists between long-term overall survival and catecholamine response in these high-risk patients.
* Determine if a correlation exists between cytotoxic and conditioning chemotherapies, in terms of bone marrow toxicity, in these high-risk patients.

OUTLINE: This is a multicenter study. Patients are stratified according to risk (low vs standard vs high).

* Observation stratum (low risk): Patients undergo surgical biopsy followed by observation for 6-12 months. Patients may also undergo second-look surgery. Patients with tumor regression receive no further therapy. Patients with disease progression or no tumor regression receive standard-risk chemotherapy as in the standard-risk stratum.
* Standard-risk stratum: Patients undergo surgical biopsy. Patients at least 6 months of age receive 1 course of chemotherapy comprising cisplatin IV and etoposide IV continuously on days 1-4 and vindesine IV over 1 hour on day 1. Patients then receive 1 course of chemotherapy comprising vincristine IV over 1 hour on days 1 and 8, dacarbazine IV over 1 hour on days 1-5, ifosfamide IV continuously on days 1-5, and doxorubicin IV over 4 hours on days 6 and 7.

Patients under 6 months of age receive doxorubicin IV over 30 minutes and vincristine IV on days 1, 3, and 5 and cyclophosphamide IV over 5 minutes on days 1-7. Treatment repeats every 3 weeks for 2 courses in the absence of unacceptable toxicity.

After chemotherapy, patients may undergo second-look surgery followed by 2 additional courses of chemotherapy as above. Patients with complete response or very good partial response receive no further therapy. Patients with partial response, minimal response, no response, or progressive disease undergo local radiotherapy daily 5 days a week for approximately 6 weeks. Patients with no response after radiotherapy may then receive therapy as in the high-risk stratum.

* High-risk stratum: Patients undergo surgical biopsy. Patients at least 6 months of age receive induction chemotherapy comprising cisplatin, etoposide, and vindesine as in the standard-risk stratum combined with filgrastim (G-CSF) subcutaneously (SC) daily beginning on day 8 and continuing until blood counts recover. Patients also receive alternating courses of vincristine, dacarbazine, ifosfamide, and doxorubicin as in the standard-risk stratum combined with G-CSF SC daily beginning on day 9 and continuing until blood counts recover. Treatment repeats every 3 weeks for up to 6 courses in the absence of unacceptable toxicity.

Patients under 6 months of age receive 2 courses of induction chemotherapy as in the standard-risk stratum followed by 4 courses of alternating chemotherapy as above.

Patients may also undergo second-look surgery.

Patients then receive consolidation chemotherapy comprising melphalan IV over 30 minutes on days -8 to -5, etoposide IV over 4 hours on day -4, and carboplatin IV over 1 hour on days -4 to -2. Patients undergo autologous stem cell transplantation (ASCT) on day 0. Patients also receive G-CSF SC or IV over 2 hours daily beginning on day 0. Patients may then undergo radiotherapy daily 5 days a week for 6 weeks.

Patients who were diagnosed less than 1 year ago and who do not demonstrate MYCN amplication receive maintenance chemotherapy comprising oral cyclophosphamide on days 1-8 (instead of consolidation chemotherapy and ASCT as above). Treatment repeats every 3 weeks for 4 courses.

Beginning 4-6 weeks after transplantation or 4 weeks after initiation of the last course of maintenance chemotherapy, all patients receive consolidation therapy with oral tretinoin 3 times daily on days 1-14. Treatment repeats every 28 days for 6 courses followed by a 3-month rest. Patients then receive 3 additional courses.

Patients are followed at 6 weeks, every 3 months for 5 years, and then every 6 months thereafter.

PROJECTED ACCRUAL: Approximately 130 patients (50 in high-risk stratum, 15 in standard-risk stratum, and 65 in observation stratum) will be accrued for this study within 1 year.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed neuroblastoma
* Observation stratum:

  * MYCN gene not amplified
  * Infants with stage I-IVS disease OR
  * Over 1 year of age and stage I or II resectable disease
* Standard-risk stratum:

  * MYCN gene not amplified
  * Infants with serious symptoms and stage II-IVS disease OR
  * Over 1 year of age with stage II or III unresectable disease
* High-risk stratum:

  * Stage IV disease OR
  * Stage I-IVS MYCN gene-amplified disease

PATIENT CHARACTERISTICS:

Age:

* 20 and under

Performance status:

* Not specified

Life expectancy:

* Not specified

Hematopoietic:

* Not specified

Hepatic:

* Not specified

Renal:

* No kidney insufficiency

Cardiovascular:

* No cardiac insufficiency

Other:

* Not pregnant
* Fertile patients must use effective contraception
* No other serious illness

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* Not specified

Chemotherapy:

* No prior chemotherapy within 6 months after diagnosis

Endocrine therapy:

* Not specified

Radiotherapy:

* Not specified

Surgery:

* Not specified

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Urologische Klinik - Universitaetsklinikum Aachen
city: Augsburg
country: Germany
facility: Kinderkrankenhaus Josefinum
city: Augsburg
country: Germany
facility: Zentralklinikum Augsburg
city: Bad Mergentheim
country: Germany
facility: Caritaskrankenhaus
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth
city: Berlin
country: Germany
facility: Helios Klinikum Berlin
city: Berlin
country: Germany
facility: Charite - Campus Virchow Klinikum
city: Biefeld
country: Germany
facility: Krankenanstalten Gilead
city: Bonn
country: Germany
facility: Kinderklinik der Universitaet-Bonn
city: Braunschweig
country: Germany
facility: Stadt Klinikum - Howedestrase
city: Bremen
country: Germany
facility: Zentralkrankenhaus
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz GMBH
city: Coburg
country: Germany
facility: Klinikum Coburg
city: Cologne
country: Germany
facility: Medizinische Universitaetsklinik I
city: Cottbus
country: Germany
facility: Carl - Thiem - Klinkum Cottbus
city: Datteln
country: Germany
facility: Vestische Kinderklinik
city: Detmold
country: Germany
facility: Klinikum Lippe - Detmold
city: Dortmund
country: Germany
facility: Stadt. Kliniken
city: Dresden
country: Germany
facility: Stadt. KH Dresden - Neustadt
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carl Carus
city: Duesseldorf
country: Germany
facility: Universitaetsklinik Duesseldorf
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt GmbH
city: Erlangen
country: Germany
facility: Universitaets - Kinderklinik
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe Universitaet
city: Freiburg
country: Germany
facility: Universitaetskinderklinik - Universitaetsklinikum Freiburg
city: Gelsenkirchen
country: Germany
facility: Stadt. Kinderklinik
city: Giessen
country: Germany
facility: Kinderklinik
city: Goettingen
country: Germany
facility: Universitaetsklinikum Goettingen
city: Greiswald
country: Germany
facility: Universitats - Kinderklinik
city: Gummersbach
country: Germany
facility: Kreiskrankenhaus Gummersbach GMBH
city: Halle
country: Germany
facility: St. Barbara Krankenhaus
city: Halle
country: Germany
facility: Martin Luther Universitaet
city: Hamburg
country: Germany
facility: Altonaer Kinderkrankenhaus
city: Hamburg
country: Germany
facility: Universitaets-Krankenhaus Eppendorf
city: Hamm
country: Germany
facility: Evangelische Krankenhaus Hamm
city: Hannover
country: Germany
facility: Kinderkrankenhaus auf der Bult
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitaets-Kinderklinik Heidelberg
city: Herdecke
country: Germany
facility: Gemeinschaftskrankenhaus
city: Homburg
country: Germany
facility: Universitatsklinik Homburg
city: Homburg
country: Germany
facility: Marien Hospital
city: Iserlohn
country: Germany
facility: Praxis am Evangelischen Krankenhaus Bethanien
city: Jena
country: Germany
facility: Universitaets - Kinderklinik
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum GmbH
city: Karlsruhe
country: Germany
facility: Stadt. Kinderklinik
city: Kassel
country: Germany
facility: Kinderkrankenhaus
city: Kassel
country: Germany
facility: Klinikum Kassel
city: Kiel
country: Germany
facility: Staedtische Krankenhaus Kiel
city: Kiel
country: Germany
facility: University Hospital Schleswig-Holstein - Kiel Campus
city: Koblenz
country: Germany
facility: Stadt. Krankenhaus Kemperhof
city: Koln - Riehl
country: Germany
facility: Staedtisches Kinderkrankenhaus
city: Konstanz
country: Germany
facility: Klinik Konstanz
city: Krefeld
country: Germany
facility: Klinikum Krefeld GmbH
city: Leipzig
country: Germany
facility: Universitaets - Kinderklinik
city: Leipzig
country: Germany
facility: Universitaets Klinik fuer Kinderchirurgie
city: Lubeck
country: Germany
facility: Universitaets - Kinderklinik - Luebeck
city: Ludwigshafen
country: Germany
facility: St. Annastift Krankenhaus
city: Magdeburg
country: Germany
facility: Universitatsklinikum der MA
city: Mainz
country: Germany
facility: Johannes Gutenberg University
city: Mannheim
country: Germany
facility: Stadt. Klinik - Kinderklinik
city: Marburg
country: Germany
facility: Universitaets - Kinderklinik
city: Minden
country: Germany
facility: Klinikum Minden
city: Muenster
country: Germany
facility: Klinik und Poliklinik fuer Kinderheilkunde - Universitaetsklinikum Muenster
city: Munich
country: Germany
facility: Universitaets - Kinderpoliklinik
city: Munich
country: Germany
facility: Kinderklinik d. TU / Schwabing
city: Munich
country: Germany
facility: Staedtisches Krankenhaus Muenchen - Harlaching
city: Munich
country: Germany
facility: Kinderklinik
city: Neunkirchen
country: Germany
facility: Kinderklinik Kohlhof
city: Nuernberg
country: Germany
facility: Cnopfche Kinderklinik
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Osnabruck
country: Germany
facility: Kindershospital
city: Regensburg
country: Germany
facility: Krankenhaus D Barmherzigen Brueder
city: Rosenheim
country: Germany
facility: Staedtische Klinikum-Kinderklinik
city: Rostock
country: Germany
facility: Kinderklinik - Universitaetsklinikum Rostock
city: Saarbrucken
country: Germany
facility: Saarbrucker Winterbergkliniken
city: Schwabisch Hall
country: Germany
facility: Diakone - Krankenhaus
city: Schwerin
country: Germany
facility: Klinikum Schwerin
city: Schwienfurt
country: Germany
facility: Leopoldina - Krankenhaus
city: Siegen
country: Germany
facility: Deutsches Rotes Kreuz
city: St. Augustin
country: Germany
facility: Johanniter-Kinderklinik
city: Stuttgart
country: Germany
facility: Olgahospital
city: Trier
country: Germany
facility: Mutterhaus der Borromaerinnen
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Ulm
country: Germany
facility: Universitaet Ulm
city: Vechta
country: Germany
facility: St. Marien Hospital
city: Wilhelmshaven
country: Germany
facility: Reinhard - Nieter - Krankenhaus
city: Wuerzburg
country: Germany
facility: Universitaets - Kinderklinik Wuerzburg
city: Wuppertal
country: Germany
facility: Helios Klinikum Wuppertal
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Basel
country: Switzerland
facility: University Children's Hospital
city: Locarno
country: Switzerland
facility: Ospedale "la Carita", Locarno
city: Luzerne 16
country: Switzerland
facility: Kinderspital Luzerne
city: Zurich
country: Switzerland
facility: University Children's Hospital
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Frank Berthold, MD
role: STUDY_CHAIR
References:
citation: Krams M, Hero B, Berthold F, Parwaresch R, Harms D, Rudolph P. Proliferation marker KI-S5 discriminates between favorable and adverse prognosis in advanced stages of neuroblastoma with and without MYCN amplification. Cancer. 2002 Feb 1;94(3):854-61.
citation: Simon T, Hero B, Dupuis W, Selle B, Berthold F. The incidence of hearing impairment after successful treatment of neuroblastoma. Klin Padiatr. 2002 Jul-Aug;214(4):149-52. doi: 10.1055/s-2002-33179.
citation: Spitz R, Hero B, Westermann F, Ernestus K, Schwab M, Berthold F. Fluorescence in situ hybridization analyses of chromosome band 1p36 in neuroblastoma detect two classes of alterations. Genes Chromosomes Cancer. 2002 Jul;34(3):299-305. doi: 10.1002/gcc.10070.
citation: Hero B, Simon T, Spitz R, Ernestus K, Gnekow AK, Scheel-Walter HG, Schwabe D, Schilling FH, Benz-Bohm G, Berthold F. Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol. 2008 Mar 20;26(9):1504-10. doi: 10.1200/JCO.2007.12.3349.
citation: Simon T, Hero B, Benz-Bohm G, von Schweinitz D, Berthold F. Review of image defined risk factors in localized neuroblastoma patients: Results of the GPOH NB97 trial. Pediatr Blood Cancer. 2008 May;50(5):965-9. doi: 10.1002/pbc.21343.
citation: Berthold F, Hero B, Kremens B, Handgretinger R, Henze G, Schilling FH, Schrappe M, Simon T, Spix C. Long-term results and risk profiles of patients in five consecutive trials (1979-1997) with stage 4 neuroblastoma over 1 year of age. Cancer Lett. 2003 Jul 18;197(1-2):11-7. doi: 10.1016/s0304-3835(03)00076-4.
citation: Spitz R, Hero B, Ernestus K, Berthold F. Deletions in chromosome arms 3p and 11q are new prognostic markers in localized and 4s neuroblastoma. Clin Cancer Res. 2003 Jan;9(1):52-8.
citation: Spitz R, Hero B, Ernestus K, Berthold F. FISH analyses for alterations in chromosomes 1, 2, 3, and 11 define high-risk groups in neuroblastoma. Med Pediatr Oncol. 2003 Jul;41(1):30-5. doi: 10.1002/mpo.10313.
citation: Spitz R, Hero B, Ernestus K, Berthold F. Gain of distal chromosome arm 17q is not associated with poor prognosis in neuroblastoma. Clin Cancer Res. 2003 Oct 15;9(13):4835-40.
citation: von Schweinitz D, Hero B, Berthold F. The impact of surgical radicality on outcome in childhood neuroblastoma. Eur J Pediatr Surg. 2002 Dec;12(6):402-9. doi: 10.1055/s-2002-36952.
citation: Simon T, Hero B, Bongartz R, Schmidt M, Muller RP, Berthold F. Intensified external-beam radiation therapy improves the outcome of stage 4 neuroblastoma in children > 1 year with residual local disease. Strahlenther Onkol. 2006 Jul;182(7):389-94. doi: 10.1007/s00066-006-1498-8.
citation: Kremens B, Hero B, Esser J, Weinel P, Filger-Brillinger J, Fleischhack G, Graf N, Gruttner HP, Niemeyer C, Schulz A, Wickmann L, Berthold F. Ocular symptoms in children treated with human-mouse chimeric anti-GD2 mAb ch14.18 for neuroblastoma. Cancer Immunol Immunother. 2002 Apr;51(2):107-10. doi: 10.1007/s00262-001-0259-x. Epub 2002 Feb 1.
citation: Decarolis B, Simon T, Krug B, Leuschner I, Vokuhl C, Kaatsch P, von Schweinitz D, Klingebiel T, Mueller I, Schweigerer L, Berthold F, Hero B. Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed. BMC Cancer. 2016 Jul 27;16:542. doi: 10.1186/s12885-016-2513-9.