Please select the eligibility criteria that correspond to the clinical trial below.
Title: High Risk Neuroblastoma Study 1 of SIOP-Europe (SIOPEN)
Brief Summary: This is a randomized study of the European SIOP Neuroblastoma Group (SIOPEN) in high-risk neuroblastoma (stages 2, 3, 4 and 4s MYCN-amplified neuroblastoma, stage 4 MYCN non amplified \> 12 months at diagnosis).

The protocol consists of a rapid, dose intensive induction chemotherapy, peripheral blood stem cell harvest, attempted complete excision of the primary tumour, myeloablative therapy followed by peripheral blood stem cell rescue, radiotherapy to the site of the primary tumour and immunotherapy (R4 randomization - isotretinoin and ch14.18/CHO (Dinutuximab beta, Qarziba ®).), with or without s.c. aldesleukin (IL-2)). Patients diagnosed after the closure of R3 randomization will not be R4 randomized. For these patients the use of ch14.18/CHO antibody is recommended without scIL-2 as continuous infusion as standard of care outside of controlled trials. ch14.18/CHO received marketing authorization by EMA in May 2017 (Qarziba ®).

In the induction phase, all patients receive Rapid COJEC following the result of the R3 randomization which was closed on June 8th, 2017 after inclusion of 630 patients as planned.

Following induction treatment peripheral blood stem cell harvest (PBSCH) is performed and complete excision of the primary tumour will be attempted.

Patients with an inadequate metastatic response to allow BuMel MAT followed by PBSCR at the end of induction should receive 2 TVD (Topotecan, Vincristine, Doxorubicin) cycles.

After Rapid COJEC induction, localized patients will proceed to consolidation. Patients aged 12-18 months at diagnosis, with stage 4 neuroblastoma, no MYCN amplification and without segmental chromosomal alterations (SCAs) are thought to have a good prognosis and will stop treatment after induction therapy and surgery to the primary tumour.

Consolidation consists of BuMel MAT based on the results of the R1 randomization followed by peripheral blood stem cell rescue (PBSCR) and radiotherapy to the site of the primary tumour.

The R2 immunotherapy randomization using ch14.18/CHO as 8 hour infusion on 5 consecutive days ( total dose (100mg/m²) with or without aldesleukin (IL-2) alternated with isotretinoin (13-cis-RA) is closed.

The amended R4 immunotherapy randomization using ch14.18/CHO as continuous infusion (total dose 100mg/m² over 10 days) with or without aldesleukin (IL-2) alternated with isotretinoin (13-cis-RA) has accrued according to plan with results pending awaiting data maturity and DMC approval.


Options:
A: DISEASE CHARACTERISTICS: See General Eligibility Criteria

PATIENT CHARACTERISTICS: See General Eligibility Criteria
B: Inclusion Criteria:

* • Established diagnosis of neuroblastoma according to the International Neuroblastoma Staging System (INSS).

  * Age below 21 years.
  * High risk neuroblastoma defined as either:

    1. INSS stage 2, 3, 4, and 4s with MYCN amplification, or
    2. INSS stage 4 without MYCN amplification aged \> 12 months at diagnosis
  * Patients who have received no previous chemotherapy except for one cycle of etoposide and carboplatin (VP16/Carbo). In this situation patients will receive Rapid COJEC induction and the first Rapid COJEC cycle may be replaced by the first cycle VP16/Carbo (etoposide / carboplatin).
  * Written informed consent, including agreement of parents or legal guardian for minors, to enter a randomised study if the criteria for randomisation are met.
  * Tumour cell material available for determination of biological prognostic factors.
  * Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
  * Registration of all eligibility criteria with the data centre within 6 weeks from diagnosis.
  * Provisional follow up of 5 years.
  * National and local ethical committee approval.

Exclusion Criteria:

Any negative answer concerning the inclusion criteria of the study

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C: 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
D: DISEASE CHARACTERISTICS:

* Histologically confirmed newly diagnosed neuroblastoma OR ganglioneuroblastoma, and/or evidence of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites, meeting 1 of the following criteria:

  * Age greater than 18 months with stage IV disease, regardless of biologic factors
  * Age 12-18 months with stage IV disease meeting one of the following criteria:

    * Any unfavorable biologic feature (e.g., MYCN amplification, unfavorable pathology, and/or DNA index = 1)
    * Any biologic feature that is indeterminate, unsatisfactory, or unknown
* At least 1 year old with the following:

  * Stage IIa/IIb with MYCN amplification (\> 10) AND unfavorable pathology
  * Stage III with MYCN amplification (\> 10) OR unfavorable pathology
  * Stage I, II, or IVS with disease progression to stage IV without interval chemotherapy

    * No more than 3 weeks since progression
    * Must have been enrolled on protocol CCG-B973, COG-ANBL00B1, or POG-9047
* Less than 1 year old with the following:

  * Stage III, IV, or IVS disease with MYCN amplification (\> 10)
* Registration on protocol COG-ANBL00B1 required within 14 days of diagnosis

PATIENT CHARACTERISTICS:

Age:

* See Disease Characteristics
* 30 and under at time of diagnosis

Performance status:

* Not specified

Life expectancy:

* Not specified

Hematopoietic:

* Absolute neutrophil count ≥ 1,000/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Inadequate hematopoiesis secondary to bone marrow involvement with \> 10% tumor infiltration allowed

Hepatic:

* Bilirubin ≤ 1.5 mg/dL
* ALT ≤ 300 units/L

Renal:

* Creatinine ≤ 1.5 mg/dL
* Creatinine clearance or glomerular filtration rate ≥ 60 mL/min

Cardiovascular:

* ECG normal
* Ejection fraction ≥ 55% by echocardiogram or MUGA OR
* Fractional shortening ≥ 28% by echocardiogram

Other:

* Able to tolerate peripheral blood stem cell collection
* HIV negative
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception for at least 1 month prior to, during, and for 1 month after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* Not specified

Chemotherapy:

* See Disease Characteristics
* No more than 1 prior course of chemotherapy on the Intergroup low/intermediate risk neuroblastoma study (P9641, A3961)

Endocrine therapy:

* Not specified

Radiotherapy:

* Prior localized emergency radiotherapy to sites of life-threatening or function-threatening disease allowed

Surgery:

* Not specified

Other

* No other prior systemic therapy

Answer: B