Detailed Description:
PRIMARY OBJECTIVES:
I. To prospectively analyze the factors that are currently used for risk-group assignment
(v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog [MYCN] copy number
by fluorescent in situ hybridization [FISH], deoxyribonucleic acid [DNA] content by flow
cytometry, and tumor histology using the International Neuroblastoma Pathologic
Classification System) in neuroblastoma tumors at the time of diagnosis.
II. To maintain a reference bank containing clinically and genetically characterized frozen
tumor tissue, tumor DNA and ribonucleic acid (RNA), histology slides and paraffin blocks,
neuroblastoma-derived cell lines, patient serum and paired normal DNA obtained at the time of
diagnosis, at the time of second-look surgery and at the time of relapse for future research
studies.
III. To prospectively analyze 1p, 11q, 14q and 17q allelic status, MYCN copy number by
quantitative polymerase chain reaction (PCR); and the expression pattern of
neurotrophin-related genes in diagnostic neuroblastoma tumors, and assay for the presence of
rare tumor cells in biological specimens by reverse transcription (RT)-PCR; these biological
variables will be analyzed for independent clinical significance compared to MYCN
amplification, International Neuroblastoma Staging System (INSS) stage, age, ploidy, and
histologic variables in predicting either response to treatment or outcome.
IV. To build a database of the known biologic prognostic factors for patients on therapeutic
studies.
V. To serve as a Registry for neuroblastoma patients whose tumors demonstrate clinical and
genetic features defined as ?Low Risk? for treatment failure in the absence of adjuvant
therapy.
SECONDARY OBJECTIVES:
I. To prospectively analyze the concordance between detection of MYCN amplification in tumor
samples and quantitative detection of MYCN DNA in serum, and to analyze the prognostic
significance of MYCN amplification as detected in serum samples.
II. To build a database that includes information regarding the presentation and natural
history of neuroblastoma-associated health problems including but not limited to opsoclonus
myoclonus ataxia (OMA) and/or spinal cord compression.
OUTLINE:
Patients undergo collection of blood, tissue, and bone marrow samples for analysis via
RT-PCR, quantitative PCR, flow cytometry, and FISH.
After completion of study, patients are followed up periodically.
Inclusion Criteria:
- All newly diagnosed patients with suspected neuroblastoma, suspected
ganglioneuroblastoma, or suspected ganglioneuroma/maturing subtype seen at Children's
Oncology Group (COG) institutions are eligible for this study
- There will be no penalty under any circumstances for enrollment of a patient
whose definitive institutional diagnosis, or central review diagnosis, is found
to be a tumor other than neuroblastoma, ganglioneuroblastoma, or ganglioneuroma/
maturing subtype
- Patients may not have received chemotherapy prior to enrollment on ANBL00B1 and
procurement of study-related tissues with the following exception:
- Patients that in the opinion of the treating physician are too ill to undergo
pre-treatment tissue biopsy and require EMERGENT chemotherapy may be enrolled on
ANBL00B1; documentation of the emergent nature of therapy initiation is required
- It is required that a good faith effort (documented by specimen tracking) be made to
submit a neuroblastoma sample (tumor, metastasis, and/or tumor-involved bone marrow)
of sufficient quality for MYCN analysis in the Neuroblastoma Reference Laboratory in
order for any newly diagnosed patient to be enrolled on ANBL00B1; this should be
obtained prior to initiation of therapy
- Exceptions
- In rare cases, patients may be deemed too ill to undergo pre-treatment tissue
biopsy and require EMERGENT therapy; the following eligibility guidelines apply
to these cases:
- For presumed INSS stage 4S patients: Efforts to submit tumor tissue (e.g.,
primary tumor, skin nodule, or metastatic site) within 96 hours of EMERGENT
therapy initiation should be made; however, if the child is deemed too
unstable for such a procedure they may still be enrolled as long as
pre-treatment peripheral blood and serum have been submitted
- For all other INSS stages: tumor tissue should be obtained as soon as
possible within 96 hours of EMERGENT therapy initiation; patients without
tumor tissues submitted within this time-frame are not eligible for
enrollment
- Note: it may not be possible to obtain all necessary tumor biomarkers
for therapy stratification in such cases; if a patient enrolled on
ANBL00B1 undergoes an additional diagnostic procedure within 96 hours
of initiating therapy, additional tumor specimens may be submitted to
obtain biomarkers used for risk classification; the decision to perform
such procedures, and/or submit these specimens, is to be made by the
managing clinicians and should reflect the clinical need to know the
status of such biomarkers
- Patients enrolled on ANBL1232 in Group A (either A1 or A2) will not have a
tumor biopsy or resection upfront; tumor tissue submission is therefore not
required for these patients to enroll on ANBL00B1; a peripheral blood and
serum sample is the only specimen required to be submitted for this group of
patients; should they undergo a biopsy or resection at a later date tumor
can be submitted for biomarker testing at this time
- All patients and/or their parents or legal guardians must sign a written informed
consent
- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
Exclusion Criteria:
- Patients with relapsed neuroblastoma who were not enrolled on ANBL00B1 at original
diagnosis are NOT eligible; samples should be submitted as part of the ABTR04B1
protocol
Primary outcome:
1. Factors currently used for risk-group assignment (DNA content, MYCN copy number, and tumor histology) (Time Frame - Up to 3 years):
Life tables, Kaplan-Meier survival curves, log-rank tests, and Cox regression will be used to explore the relationship of laboratory variables to outcome.
2. Prevalence of 1p, 11q, 14q, and 17q allelic status (Time Frame - Up to 3 years):
These biological variables will be analyzed for independent clinical significance compared to MYCN amplification, INSS stage, age, ploidy, and histologic variables in predicting either response to treatment or outcome.
3. MYCN copy number by quantitative PCR (Time Frame - Up to 3 years):
These biological variables will be analyzed for independent clinical significance compared to MYCN amplification, INSS stage, age, ploidy, and histologic variables in predicting either response to treatment or outcome.
4. Expression pattern of neurotrophin-related genes in diagnostic neuroblastoma tumors (Time Frame - Up to 3 years):
These biological variables will be analyzed for independent clinical significance compared to MYCN amplification, INSS stage, age, ploidy, and histologic variables in predicting either response to treatment or outcome.
5. Presence of rare tumor cells in biological specimens by RT-PCR (Time Frame - Up to 3 years):
These biological variables will be analyzed for independent clinical significance compared to MYCN amplification, INSS stage, age, ploidy, and histologic variables in predicting either response to treatment or outcome.
6. Database of the known biologic prognostic factors for patients on therapeutic studies (Time Frame - Up to 3 years):
During the testing for treatment effect in Phase III trials, the biologic prognostic factors may be needed for adjustment in the Cox regression model-building process.
Secondary outcome:
1. MYCN status per tumor (Time Frame - Up to 3 years):
Cross tabulations of MYCN status per tumor versus MYCN status per blood will be generated, the percentage concordant and the percentage discordant will be calculated, and receiver operating characteristic (ROC) analyses will be performed. Kaplan-Meier curves of MYCN status per blood will be generated, and a logrank test comparison performed. The prognostic ability of MYCN status per tumor versus MYCN status per blood will be tested in a multivariable Cox model.
2. MYCN status per blood (Time Frame - Up to 3 years):
Cross tabulations of MYCN status per tumor versus MYCN status per blood will be generated, the percentage concordant and the percentage discordant will be calculated, and ROC analyses will be performed. Kaplan-Meier curves of MYCN status per blood will be generated, and a logrank test comparison performed. The prognostic ability of MYCN status per tumor versus MYCN status per blood will be tested in a multivariable Cox model.
3. Incidence of OMA (Time Frame - Up to 3 years):
Descriptive analysis will be performed.
4. Incidence of spinal cord compression (Time Frame - Up to 3 years):
Descriptive analysis will be performed.
5. Presentation with multifocal primary tumors (Time Frame - Up to 3 years):
Descriptive analysis will be performed.
- Cytology Specimen Collection Procedure (Cytologic Sampling):
Correlative studies - Laboratory Biomarker Analysis:
Correlative studies
Quelle: ClinicalTrials.gov
