European Low and Intermediate Risk Neuroblastoma Protocol

Study Overview
=================
Brief Summary
-----------------
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

Detailed 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

Official Title
-----------------
European Low and Intermediate Risk Neuroblastoma Protocol

Conditions
-----------------
LOW AND INTERMEDIATE PAEDIATRIC NEUROBLASTOMA AND NEONATAL SUPRARENAL MASSES

Intervention / Treatment
-----------------
* Drug: chemotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
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 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 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.

Ages Eligible for Study
-----------------
Minimum Age: 90 Days
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Group1<br>initial observation (chemotherapy is only given if there is subsequent progression) | |
| Active Comparator: Group 1: chemotherapy<br>chemotherapy and surgery | Drug: chemotherapy<br> <br> |
| Experimental: Group 2<br>chemotherapy and surgery | Drug: chemotherapy<br> <br> |
| Experimental: Group 3<br>chemotherapy and surgery | Drug: chemotherapy<br> <br> |
| No Intervention: Group 4<br>Observation | |
| Experimental: Group 5<br>chemotherapy | Drug: chemotherapy<br> <br> |
| Experimental: Group 6<br>chemotherapy and surgery | Drug: chemotherapy<br> <br> |
| Experimental: Group 7<br>chemotherapy and surgery | Drug: chemotherapy<br> <br> |
| Experimental: Group 8<br>chemotherapy, surgery, radiotherapy and 13 cis-retinoic acid | Drug: chemotherapy<br> <br> |
| Experimental: Group 9<br>chemotherapy, surgery, radiotherapy and 13 cis-retinoic acid | Drug: chemotherapy<br> <br> |
| Experimental: Group 10<br>chemotherapy, surgery, | Drug: chemotherapy<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary aim for Low Risk Neuroblastoma | To demonstrate through a randomisation between observation and chemotherapy that you can safely reduce treatment in a subgroup of L2 low risk patients (those without life threatening symptoms (LTS) and without any segmental chromosomal changes (SCA), i.e. study group 1) by giving less treatment than has been given historically while maintaining an excellent OS of 100%. | 2 years | 
| Primary aim for Intermediate Risk Neuroblastoma | To improve the EFS to 70% with an OS of 90% of INRG stage L2 patients over the age of 18 months, with poorly differentiated or undifferentiated tumour histology (INPC criteria), by the addition of radiotherapy and 13-cis RA compared to historical conventional treatment (study group 8). | 2 years | 
| Primary Aim for Neonatal Suprarenal Masses | To maintain a 3-year event free survival over 80% with a non-operative therapeutic approach (serial monitoring, surgery if warranted) in infants with a localised suprarenal mass discovered ante or neonatally. | 3 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To maintain a 2 year EFS of at least 90% and an OS of at least 95% in L2 patients with LTS without SCA (study group 2) |  | 2 year | 
| To maintain the 2 year EFS of 85% and an OS of at least 98% in Ms patients without SCA (study groups 4 and 5) |  | 2 year | 
| To improve the 2 year EFS to at least 90% and maintain the OS of close to 100% in L2 patients with SCA (Study Group 3) and improve the 2 year EFS to over 70% in Ms patients with SCA (study group 6) |  | 2 year | 
| To evaluate adherence to the protocol recommendations regarding LTS |  | 5 years | 
| To reduce surgical morbidity by promoting strict adherence to Image Defined-Risk Factors (IDRFs) to determine surgical resectability |  | 5 year | 
| To define the long term follow-up and natural history of the Stage L2 non-resected masses that have remained IDRF positive at the end of treatment (study groups 1-3). |  | 5 year | 
| To confirm in a larger patient cohort the excellent OS of 95% in stage M neuroblastoma without MYCN amplification, less than 12 months of age, when treated with moderate therapy (study group 10). |  | 3 year | 
| Maintain the results of 3yr-EFS of 90% and 3yr-OS of 100% in stage L2 patients over the age of 18 months, with differentiating neuroblastoma or differentiating ganglioneuroblastoma nodular, despite a treatment reduction (group7) |  | 3 year | 
| To improve the 3 year EFS to at least 50% and the 3 year OS to 80% in INSS stage I patients with MYCN amplified neuroblastoma by the addition of adjuvant treatment (study group 9). |  | 3 year | 
| To evaluate the impact of the tumour genomic profile on patient outcome, in order to consider its role in the treatment stratification of these intermediate risk patients (all study groups). |  | 5 years | 
| To manage infants with suprarenal masses discovered ante or neonatally with a uniform approach in Europe in a multicentre setting. |  | 5 years | 
| To maintain an excellent overall survival with a non-operative therapeutic approach (serial monitoring, surgery if warranted) in infants with a localised suprarenal mass discovered ante or neonatally. |  | 3 years | 
| To determine the 3-year surgery-free survival in infants with suprarenal masses discovered ante or neonatally and managed conservatively (non initial surgery). |  | 3 years | 
| To find out the natural history of perinatal suprarenal masses, according to the definitions set up for the study. |  | 5 years | 
| To study the kinetics of regression in those suspected suprarenal neuroblastomas in infants with suprarenal masses discovered ante or neonatally and managed conservatively (non initial surgery). |  | 5 years | 
| To collect tissue from those suprarenal masses excised in order to perform standard and investigational pathological and biological studies (INPC, MYCN, 1p, 11). |  | 5 years | 
| To collect frozen plasma from all patients included in the study in order to perform research. |  | 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NEUROBLASTOMA, LOW RISK, INTERMEDIATE RISK