European Low and Intermediate Risk Neuroblastoma Protocol

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

Sex

All

Minimum age

90 Days

Maximum age

18 Years

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.

• BACKGROUNDBrodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, De Bernardi B, Evans AE, Favrot M, Hedborg F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993 Aug;11(8):1466-77. doi: 10.1200/JCO.1993.11.8.1466. PMID 8336186
• BACKGROUNDCohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, Faldum A, Hero B, Iehara T, Machin D, Mosseri V, Simon T, Garaventa A, Castel V, Matthay KK; INRG Task Force. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009 Jan 10;27(2):289-97. doi: 10.1200/JCO.2008.16.6785. Epub 2008 Dec 1. PMID 19047291
• BACKGROUNDDe Bernardi B, Gerrard M, Boni L, Rubie H, Canete A, Di Cataldo A, Castel V, Forjaz de Lacerda A, Ladenstein R, Ruud E, Brichard B, Couturier J, Ellershaw C, Munzer C, Bruzzi P, Michon J, Pearson AD. Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol. 2009 Mar 1;27(7):1034-40. doi: 10.1200/JCO.2008.17.5877. Epub 2009 Jan 26. PMID 19171711
• BACKGROUNDJanoueix-Lerosey I, Schleiermacher G, Michels E, Mosseri V, Ribeiro A, Lequin D, Vermeulen J, Couturier J, Peuchmaur M, Valent A, Plantaz D, Rubie H, Valteau-Couanet D, Thomas C, Combaret V, Rousseau R, Eggert A, Michon J, Speleman F, Delattre O. Overall genomic pattern is a predictor of outcome in neuroblastoma. J Clin Oncol. 2009 Mar 1;27(7):1026-33. doi: 10.1200/JCO.2008.16.0630. Epub 2009 Jan 26. PMID 19171713
• BACKGROUNDSchleiermacher G, Michon J, Huon I, d'Enghien CD, Klijanienko J, Brisse H, Ribeiro A, Mosseri V, Rubie H, Munzer C, Thomas C, Valteau-Couanet D, Auvrignon A, Plantaz D, Delattre O, Couturier J; Societe Francaise des Cancers de l'Enfant (SFCE). Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification. Br J Cancer. 2007 Jul 16;97(2):238-46. doi: 10.1038/sj.bjc.6603820. Epub 2007 Jun 19. PMID 17579628