Description:
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
Title
- Brief Title: European Low and Intermediate Risk Neuroblastoma Protocol
- Official Title: European Low and Intermediate Risk Neuroblastoma Protocol
Clinical Trial IDs
- ORG STUDY ID:
LINES
- NCT ID:
NCT01728155
Conditions
- LOW AND INTERMEDIATE PAEDIATRIC NEUROBLASTOMA AND NEONATAL SUPRARENAL MASSES
Interventions
Drug | Synonyms | Arms |
---|
chemotherapy | | Group 10 |
Purpose
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
Trial Arms
Name | Type | Description | Interventions |
---|
Group1 | No Intervention | initial observation (chemotherapy is only given if there is subsequent progression) | |
Group 1: chemotherapy | Active Comparator | chemotherapy and surgery | |
Group 2 | Experimental | chemotherapy and surgery | |
Group 3 | Experimental | chemotherapy and surgery | |
Group 4 | No Intervention | Observation | |
Group 5 | Experimental | chemotherapy | |
Group 6 | Experimental | chemotherapy and surgery | |
Group 7 | Experimental | chemotherapy and surgery | |
Group 8 | Experimental | chemotherapy, surgery, radiotherapy and 13 cis-retinoic acid | |
Group 9 | Experimental | chemotherapy, surgery, radiotherapy and 13 cis-retinoic acid | |
Group 10 | Experimental | chemotherapy, surgery, | |
Eligibility 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.
Maximum Eligible Age: | 18 Years |
Minimum Eligible Age: | 90 Days |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Primary aim for Low Risk Neuroblastoma |
Time Frame: | 2 years |
Safety Issue: | |
Description: | 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%. |
Secondary Outcome Measures
Measure: | 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) |
Time Frame: | 2 year |
Safety Issue: | |
Description: | |
Measure: | 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) |
Time Frame: | 2 year |
Safety Issue: | |
Description: | |
Measure: | 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) |
Time Frame: | 2 year |
Safety Issue: | |
Description: | |
Measure: | To evaluate adherence to the protocol recommendations regarding LTS |
Time Frame: | 5 years |
Safety Issue: | |
Description: | |
Measure: | To reduce surgical morbidity by promoting strict adherence to Image Defined-Risk Factors (IDRFs) to determine surgical resectability |
Time Frame: | 5 year |
Safety Issue: | |
Description: | |
Measure: | 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). |
Time Frame: | 5 year |
Safety Issue: | |
Description: | |
Measure: | 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). |
Time Frame: | 3 year |
Safety Issue: | |
Description: | |
Measure: | 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) |
Time Frame: | 3 year |
Safety Issue: | |
Description: | |
Measure: | 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). |
Time Frame: | 3 year |
Safety Issue: | |
Description: | |
Measure: | 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). |
Time Frame: | 5 years |
Safety Issue: | |
Description: | |
Measure: | To manage infants with suprarenal masses discovered ante or neonatally with a uniform approach in Europe in a multicentre setting. |
Time Frame: | 5 years |
Safety Issue: | |
Description: | |
Measure: | 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. |
Time Frame: | 3 years |
Safety Issue: | |
Description: | |
Measure: | To determine the 3-year surgery-free survival in infants with suprarenal masses discovered ante or neonatally and managed conservatively (non initial surgery). |
Time Frame: | 3 years |
Safety Issue: | |
Description: | |
Measure: | To find out the natural history of perinatal suprarenal masses, according to the definitions set up for the study. |
Time Frame: | 5 years |
Safety Issue: | |
Description: | |
Measure: | 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). |
Time Frame: | 5 years |
Safety Issue: | |
Description: | |
Measure: | To collect tissue from those suprarenal masses excised in order to perform standard and investigational pathological and biological studies (INPC, MYCN, 1p, 11). |
Time Frame: | 5 years |
Safety Issue: | |
Description: | |
Measure: | To collect frozen plasma from all patients included in the study in order to perform research. |
Time Frame: | 5 years |
Safety Issue: | |
Description: | |
Details
Phase: | Phase 3 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Instituto de Investigacion Sanitaria La Fe |
Trial Keywords
- NEUROBLASTOMA, LOW RISK, INTERMEDIATE RISK
Last Updated
October 18, 2019