European Low and Intermediate Risk Neuroblastoma Protocol

Instituto de Investigacion Sanitaria La Fe

Status and phase: Completed; Phase 3

Conditions: LOW AND INTERMEDIATE PAEDIATRIC NEUROBLASTOMA AND NEONATAL SUPRARENAL MASSES

Treatments: Drug: chemotherapy

Study type: Interventional

Funder types: Other

Identifiers

NCT01728155

LINES

Details and patient eligibility

About

The European study, LINES 2009 (Low and Intermediate Risk Neuroblastoma European Study), groups together in a single protocol the treatment of all patients with "non high risk" neuroblastoma (NB), with stratification into two groups: low risk and intermediate risk. These two separate cohorts are included in one single protocol to enable patient data from these two groups to be entered into a common database, as the current prognostic classifications determining treatment may evolve further with subsequent more detailed molecular analysis of the tumours.

1. LOW RISK STUDY

The Low Risk Study is proposed in order to:

• minimise the amount of treatment (chemotherapy and surgery) for all appropriate low risk patients, who in previous studies have been shown to have an excellent long-term outcome (as in the SIOPEN 99.1-2 infant neuroblastoma studies where the overall survival was greater than 97%(H. Rubie, JCO).

• improve the EFS and maintain the OS (overall survival) in L2 and Ms patients with a SCA(Segmental Cromosomal Aberration) genomic profile tumour (presence of any segmental chromosomal change (SCA)) by electively treating these patients with chemotherapy despite the absence of symptoms.

  2. INTERMEDIATE RISK STUDY

The Intermediate Risk Study is proposed in order to:

• reduce the amount of chemotherapy for differentiating histology INRG (International Neuroblastoma Risk Group) stage L2 NB and ganglioneuroblastoma nodular patients who in previous SIOPEN study have been shown to have an excellent long-term outcome;
• increase the amount of treatment (radiotherapy and 13-cis-RA (13-cis-Retinoic Acid) for poorly differentiated or undifferentiated histology INRG stage L2 NB or ganglioneuroblastoma nodular patients in order to improve the EFS registered in the previous SIOPEN study;
• improve the EFS (Event Free Survival) of MYCN (V-Myc myelocytomatosis viral related oncogene, NB derived ,avian )amplified INSS (International NB Staging System) stage 1 NB patients with the introduction of adjuvant treatment;
• maintain the very good results obtained in previous SIOPEN study for INRG stage M infants with a moderate treatment.

NEONATAL SUPRARENAL MASSES

The incidence of suprarenal tumours/masses has increased in the last decade due to the expanded use of prenatal ultrasonography in routine obstetric care and in the neonatal and early infancy care. The differential diagnosis of these masses ranges from benign (adrenal haemorrhage) to malignant processes (neuroblastoma, adrenal carcinoma). Knowledge on perinatal suprarenal masses, although based on a relatively large literature, is scattered amongst studies on very few cases with no methodical approach and often short follow up. Therefore, the optimal management of these masses has not been clearly defined. Neuroblastoma at this age is an intriguing entity with a very good prognosis in most cases. The SIOPEN Group, based on their results in the first multicenter European Trial for infants with neuroblastoma (INES) and the world-wide experience provided in the literature, is launching this European surveillance study (Multi-centre, non-blinded, one armed prospective trial) for these masses. Treatment: Observation

Full description

1. LOW RISK STUDY

The low risk group of patients includes NB patients without MYCN amplification with or without life threatening symptoms in the following clinical situations:

• Children aged ≤ 18 months with localised neuroblastoma associated with image defined risk factors precluding upfront surgery (stage INRG L2).

• Children aged ≤ 12 months with disseminated neuroblastoma without bone, pleura, lung or CNS (Central Nervous System) disease (stage INRG Ms)

  2. INTERMEDIATE RISK STUDY

The intermediate risk group of patients includes NB patients in the following clinical situations:

• Children aged >18 months with localised neuroblastoma without MYCN amplification, associated with image defined risk factors precluding upfront surgery (stage INRG L2).
• Children aged ≤12 months with disseminated neuroblastoma involving bone, pleura, lung and/or CNS (stage INRG M), without MYCN amplification.
• Children with localised resected NB (stage INSS I) with MYCN amplification. NEONATAL SUPRARENAL MASSES

The incidence of suprarenal tumours/masses has increased in the last decade due to the expanded use of prenatal ultrasonography in routine obstetric care and in the neonatal and early infancy care. The differential diagnosis of these masses ranges from benign (adrenal haemorrhage) to malignant processes (neuroblastoma, adrenal carcinoma). Knowledge on perinatal suprarenal masses, although based on a relatively large literature, is scattered amongst studies on very few cases with no methodical approach and often short follow up. Therefore, the optimal management of these masses has not been clearly defined. Neuroblastoma at this age is an intriguing entity with a very good prognosis in most cases. The SIOPEN Group, based on their results in the first multicenter European Trial for infants with neuroblastoma (INES) and the world-wide experience provided in the literature, is launching this European surveillance study (Multi-centre, non-blinded, one armed prospective trial) for these masses. Treatment: Observation

Enrollment: 685 patients

Sex: All

Ages: 90 days to 18 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

1. LOW RISK STUDY

   Inclusion criteria for the whole low risk group:

   • informed consent and follow-up warranted; group assignment completed within 6 weeks from diagnosis; no prior chemotherapy or radiotherapy
   • Biopsy proven neuroblastoma
   • Tumour genomic profile obtained in a NRL according to guidelines
   • MYCN non-amplified

   Exclusion criteria for the whole low risk group:

   * Diagnosis of ganglioneuroma or ganglioneuroblastoma intermixed INRG Stage L2

   Inclusion criteria:

   *age ≤ 18 months

   Exclusion criteria:

   • any metastatic site
   • MYCN amplification
   • age > 18 months INRG Stage Ms

   Inclusion criteria:

   * age ≤ 12 months

   Exclusion criteria:

   • bone, pleura/lung and/or CNS metastasis
   • MYCN amplification
   • age > 12 months

2. INTERMEDIATE RISK STUDY

   Inclusion criteria for the whole intermediate risk group:

   • informed consent and follow-up warranted; group assignment completed within 6 weeks from diagnosis; no prior chemotherapy or radiotherapy
   • Tumour material available for biological studies according to guidelines
   • Biopsy proven neuroblastoma confirmed in a National Reference Laboratory (NRL)

   Exclusion criteria for the whole intermediate risk group:

   * Diagnosis of ganglioneuroma or ganglioneuroblastoma intermixed

   INRG Stage L1 and INSS stage 1:

   Inclusion criteria:

   * MYCN amplified

   Exclusion criteria:

   • MYCN non-amplified
   • INSS stages 2, 3, 4, 4s

   INRG Stage L2:

   Inclusion criteria:

   • Histology: differentiating, poorly differentiated, undifferentiated neuroblastoma or ganglioneuroblastoma nodular
   • MYCN non-amplified
   • age >18 months

   Exclusion criteria:

   • neuroblastoma NOS
   • MYCN amplification.
   • age ≤ 18 months

   INRG Stage M:

   Inclusion criteria:

   • Any histology
   • MYCN non-amplified
   • age ≤ 12 months

   Exclusion criteria:

   • MYCN amplification
   • age > 12 months

3. NEONATAL SUPRARENAL MASSES

Inclusion criteria:

• Age less than or equal to 90 days when the suprarenal mass is discovered.
• Suprarenal mass detected by ultrasound and/or MRI. The suprarenal mass may be cystic and/or solid, but IT CANNOT REACH THE MIDLINE AND should MEASURE ≤ 5 CM AT THE LARGEST DIAMETER.
• No regional involvement: MRI scan does not show evidence of positive ipsi/contralateral lymph nodes or other spread outside the suprarenal gland.
• No metastatic involvement.
• Frozen plasma available.
• Informed consent.
• Availability to do the adequate follow-up

Exclusion criteria:

• Age older than 90 days.
• Suprarenal mass bigger than 5 cm.
• Regional involvement.
• Metastatic involvement.
• Inability to undertake mandatory diagnostic studies (biological markers, US, MRI, MIBG).
• Follow-up not guaranteed by parents/guardians.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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685 participants in 11 patient groups

Group1

No Intervention group

Description:

initial observation (chemotherapy is only given if there is subsequent progression)

Group 1: chemotherapy

Active Comparator group

Description:

chemotherapy and surgery

Treatment:

Drug: chemotherapy

Group 2

Experimental group

Description:

chemotherapy and surgery

Treatment:

Drug: chemotherapy

Group 3

Experimental group

Description:

chemotherapy and surgery

Treatment:

Drug: chemotherapy

Group 4

No Intervention group

Description:

Observation

Group 5

Experimental group

Description:

chemotherapy

Treatment:

Drug: chemotherapy

Group 6

Experimental group

Description:

chemotherapy and surgery

Treatment:

Drug: chemotherapy

Group 7

Experimental group

Description:

chemotherapy and surgery

Treatment:

Drug: chemotherapy

Group 8

Experimental group

Description:

chemotherapy, surgery, radiotherapy and 13 cis-retinoic acid

Treatment:

Drug: chemotherapy

Group 9

Experimental group

Description:

chemotherapy, surgery, radiotherapy and 13 cis-retinoic acid

Treatment:

Drug: chemotherapy

Group 10

Experimental group

Description:

chemotherapy, surgery,

Treatment:

Drug: chemotherapy