Chemotherapy and Radiation Therapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Neuroblastoma

NCT ID: NCT00017225

Last Updated: 2013-08-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 1997-05-31
• Study Completion Date: 2002-02-28

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.

Conditions

Neuroblastoma

Keywords

localized resectable neuroblastoma; regional neuroblastoma; disseminated neuroblastoma; stage 4S neuroblastoma; recurrent neuroblastoma; localized unresectable neuroblastoma

Study Design

• Primary Study Purpose: TREATMENT

Interventions

filgrastim

Intervention Type: BIOLOGICAL

carboplatin

Intervention Type: DRUG

cisplatin

Intervention Type: DRUG

cyclophosphamide

Intervention Type: DRUG

dacarbazine

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

etoposide

Intervention Type: DRUG

ifosfamide

Intervention Type: DRUG

melphalan

Intervention Type: DRUG

tretinoin

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

vindesine

Intervention Type: DRUG

autologous bone marrow transplantation

Intervention Type: PROCEDURE

conventional surgery

Intervention Type: PROCEDURE

peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Eligibility Criteria

Inclusion 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

• Maximum Eligible Age: 20 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

German Society for Pediatric Oncology and Hematology GPOH gGmbH

OTHER

Sponsor Role: lead

Principal Investigators

Frank Berthold, MD

Role: STUDY_CHAIR

Children's Hospital Medical Center, Cincinnati

Locations

Urologische Klinik - Universitaetsklinikum Aachen

Aachen, , Germany

Kinderkrankenhaus Josefinum

Augsburg, , Germany

Zentralklinikum Augsburg

Augsburg, , Germany

Caritaskrankenhaus

Bad Mergentheim, , Germany

Klinikum Bayreuth

Bayreuth, , Germany

Helios Klinikum Berlin

Berlin, , Germany

Charite - Campus Virchow Klinikum

Berlin, , Germany

Krankenanstalten Gilead

Biefeld, , Germany

Kinderklinik der Universitaet-Bonn

Bonn, , Germany

Stadt Klinikum - Howedestrase

Braunschweig, , Germany

Zentralkrankenhaus

Bremen, , Germany

Klinikum Chemnitz GMBH

Chemnitz, , Germany

Klinikum Coburg

Coburg, , Germany

Medizinische Universitaetsklinik I

Cologne, , Germany

Carl - Thiem - Klinkum Cottbus

Cottbus, , Germany

Vestische Kinderklinik

Datteln, , Germany

Klinikum Lippe - Detmold

Detmold, , Germany

Stadt. Kliniken

Dortmund, , Germany

Stadt. KH Dresden - Neustadt

Dresden, , Germany

Universitatsklinikum Carl Gustav Carl Carus

Dresden, , Germany

Universitaetsklinik Duesseldorf

Düsseldorf, , Germany

Helios Klinikum Erfurt GmbH

Erfurt, , Germany

Universitaets - Kinderklinik

Erlangen, , Germany

Universitaetsklinikum Essen

Essen, , Germany

Klinikum der J.W. Goethe Universitaet

Frankfurt, , Germany

Universitaetskinderklinik - Universitaetsklinikum Freiburg

Freiburg im Breisgau, , Germany

Stadt. Kinderklinik

Gelsenkirchen, , Germany

Kinderklinik

Giessen, , Germany

Universitaetsklinikum Goettingen

Göttingen, , Germany

Universitats - Kinderklinik

Greiswald, , Germany

Kreiskrankenhaus Gummersbach GMBH

Gummersbach, , Germany

St. Barbara Krankenhaus

Halle, , Germany

Martin Luther Universitaet

Halle, , Germany

Altonaer Kinderkrankenhaus

Hamburg, , Germany

Universitaets-Krankenhaus Eppendorf

Hamburg, , Germany

Evangelische Krankenhaus Hamm

Hamm, , Germany

Kinderkrankenhaus auf der Bult

Hanover, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Universitaets-Kinderklinik Heidelberg

Heidelberg, , Germany

Gemeinschaftskrankenhaus

Herdecke, , Germany

Universitatsklinik Homburg

Homburg, , Germany

Marien Hospital

Homburg, , Germany

Praxis am Evangelischen Krankenhaus Bethanien

Iserlohn, , Germany

Universitaets - Kinderklinik

Jena, , Germany

Westpfalz-Klinikum GmbH

Kaiserslautern, , Germany

Stadt. Kinderklinik

Karlsruhe, , Germany

Kinderkrankenhaus

Kassel, , Germany

Klinikum Kassel

Kassel, , Germany

Staedtische Krankenhaus Kiel

Kiel, , Germany

University Hospital Schleswig-Holstein - Kiel Campus

Kiel, , Germany

Stadt. Krankenhaus Kemperhof

Koblenz, , Germany

Staedtisches Kinderkrankenhaus

Koln - Riehl, , Germany

Klinik Konstanz

Konstanz, , Germany

Klinikum Krefeld GmbH

Krefeld, , Germany

Universitaets - Kinderklinik

Leipzig, , Germany

Universitaets Klinik fuer Kinderchirurgie

Leipzig, , Germany

St. Annastift Krankenhaus

Ludwigshafen, , Germany

Universitaets - Kinderklinik - Luebeck

Lübeck, , Germany

Universitatsklinikum der MA

Magdeburg, , Germany

Johannes Gutenberg University

Mainz, , Germany

Stadt. Klinik - Kinderklinik

Mannheim, , Germany

Universitaets - Kinderklinik

Marburg, , Germany

Klinikum Minden

Minden, , Germany

Universitaets - Kinderpoliklinik

Munich, , Germany

Kinderklinik d. TU / Schwabing

Munich, , Germany

Staedtisches Krankenhaus Muenchen - Harlaching

Munich, , Germany

Kinderklinik

Munich, , Germany

Klinik und Poliklinik fuer Kinderheilkunde - Universitaetsklinikum Muenster

Münster, , Germany

Kinderklinik Kohlhof

Neunkirchen, , Germany

Cnopfche Kinderklinik

Nuremberg, , Germany

Klinikum Oldenburg

Oldenburg, , Germany

Kindershospital

Osnabrück, , Germany

Krankenhaus D Barmherzigen Brueder

Regensburg, , Germany

Staedtische Klinikum-Kinderklinik

Rosenheim, , Germany

Kinderklinik - Universitaetsklinikum Rostock

Rostock, , Germany

Saarbrucker Winterbergkliniken

Saarbrücken, , Germany

Johanniter-Kinderklinik

Sankt Augustin, , Germany

Diakone - Krankenhaus

Schwäbisch Hall, , Germany

Klinikum Schwerin

Schwerin, , Germany

Leopoldina - Krankenhaus

Schwienfurt, , Germany

Deutsches Rotes Kreuz

Siegen, , Germany

Olgahospital

Stuttgart, , Germany

Mutterhaus der Borromaerinnen

Trier, , Germany

Universitaetsklinikum Tuebingen

Tübingen, , Germany

Universitaet Ulm

Ulm, , Germany

St. Marien Hospital

Vechta, , Germany

Reinhard - Nieter - Krankenhaus

Wilhelmshaven, , Germany

Helios Klinikum Wuppertal

Wuppertal, , Germany

Universitaets - Kinderklinik Wuerzburg

Würzburg, , Germany

Academisch Ziekenhuis Maastricht

Maastricht, , Netherlands

University Children's Hospital

Basel, , Switzerland

Ospedale "la Carita", Locarno

Locarno, , Switzerland

Kinderspital Luzerne

Luzerne 16, , Switzerland

University Children's Hospital

Zurich, , Switzerland

Countries

Germany; Netherlands; Switzerland

References

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.

Reference Type: BACKGROUND

PMID: 11857322 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12165893 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12007190 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18349403 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17914735 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12880954 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12538451 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12764740 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 14581355 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12548494 (View on PubMed)

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.

Reference Type: RESULT

PMID: 16826357 (View on PubMed)

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.

Reference Type: RESULT

PMID: 11904735 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27465021 (View on PubMed)

Other Identifiers

CDR0000068664

Identifier Type: REGISTRY

Identifier Source: secondary_id

EU-20102

Identifier Type: -

Identifier Source: secondary_id

GER-GPOH-NB97

Identifier Type: -

Identifier Source: secondary_id

GPOH-GERMANY-NB97

Identifier Type: -

Identifier Source: org_study_id