Outcome of children with neuroblastoma after progression or relapse. A retrospective study of the Italian neuroblastoma registry

doi:10.1016/j.ejca.2009.06.010

European Journal of Cancer

Volume 45, Issue 16, November 2009, Pages 2835-2842

https://doi.org/10.1016/j.ejca.2009.06.010 Get rights and content

Abstract

The Italian Neuroblastoma Registry was investigated to describe 781 children with neuroblastoma experiencing tumour recurrence (424 progressions and 357 relapses). Ten-year overall survival (OS) was 6.8% (95% confidence interval (CI) 4.3–10.0) after progression and 14.4% (95% CI 10.5–18.9) after relapse. For both circumstances, OS was better for age at diagnosis <18 months, less advanced International Neuroblastoma Staging System (INSS) stage, normal lactate dehydrogenase (LDH) serum level, normal MYCN gene status (P < 0.001) and a non-abdominal primary site (P = 0.034 for progression, and P = 0.004 for relapses). A local type of recurrence had a significantly better outcome only in case of relapse (P < 0.001). Probability of survival increased by era of diagnosis.

Survival of children with recurrent neuroblastoma is very poor. A small cohort of patients, mainly represented by children with stages 1 and 2 who underwent local recurrence or developed late relapse may still benefit from further conventional treatment. For the remaining larger proportion of patients, experimental therapies should be proposed.

Introduction

Neuroblastoma, the most common extracranial solid tumour of childhood, continues to have an unsatisfactory long-term prognosis. In fact, while approximately half of the patients have a localised tumour with high chance of cure, the remaining half present with disseminated disease and have a dismal outcome, except for infants.¹

Cure of children diagnosed with neuroblastoma mainly depends on achieving complete tumour remission.² Factors leading to tumour recurrence (progression or relapse) include inadequate therapy, inability to detect minimal residual disease and the actual incurability of some tumours by current therapeutic modalities. In case of recurrence, treatment is commonly decided on the basis of the type of recurrence, previously administered therapies, as well as on cost/benefit ratio. The literature provides scarce data on the features of recurrence, its treatment and evolution and eventual outcome. Although numerous phase I and phase II studies have evaluated salvage therapies in small cohorts of patients,3, 4, 5, 6 only one study analysed a large number of recurrences, although limited to patients with localised disease.⁷ More information on the features and on the clinical course of neuroblastoma patients failing front-line therapy would help clinicians to better tailor treatment strategies.

In this retrospective study we reviewed data from the Italian Neuroblastoma Registry (INBR) regarding children who experienced disease recurrence after being treated with the protocols of the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP).

Section snippets

Materials and methods

Inclusion criteria for this study were; diagnosis of neuroblastoma during childhood (0–14 years) between 1979 and 2004, registration in the INBR, treatment according to AIEOP8, 9, 10, 11 protocols and tumour recurrence. The INBR has been active since 1979 and includes patients with neuroblastoma diagnosed at the AIEOP centres. It has been estimated that more than 90% of the neuroblastomas expected each year in Italy are recruited through this network.¹² The INBR collects information on clinical

Results

Of 1924 children registered in the INBR between 1979 and 2004, a total of 781 (40.6%) developed tumour recurrence. There were 424 children with NB progression (54.3%) and 357 with tumour relapse (45.7%), and were eligible for this study. Table 1 reports the descriptive statistics of the original INBR cohort and of the 781 study patients.

Biological data were not available for all the patients. In particular, MYCN gene was not assayed in 969 (50.3%) patients mostly diagnosed before 1992.

Discussion

Our study reports the long-term outcome of the largest ever cohort of children with neuroblastoma registered in prospective protocols to undergo disease progression or relapse. Overall, the prognosis for these patients was poor with median survival time less than 1 year, and less than 10% of children surviving more than 10 years after recurrence.

Recurrences occurred more often in association with the following presenting features: age >17 months, disseminated disease, abdominal primary site,

Conflict of interest statement

None declared.

Acknowledgements

We thank Giovanni Erminio Papio and Barbara Galleni for data management and assistance in statistical analyses, and Ms. Valerie Perricone for revising the English text. We are also greatly indebted to the physicians and nurses who heartily participated in the clinical care of the children enrolled in these studies.

Research support: Supported in part by grants by the Italian Neuroblastoma Foundation (S.P. and D.D.) and the Italian Ministry of Health ‘Ricerca Finalizzata – Bando Oncologia 2006’.

References (27)

M. Schmidt et al.
The prognostic impact of functional imaging with (123)I-mIBG in patients with stage 4 neuroblastoma >1 year of age on a high-risk treatment protocol: results of the German Neuroblastoma Trial NB97
Eur J Cancer
(2008)
F. Berthold et al.
The recurrence patterns of stages I, II and III neuroblastoma: experience with 77 relapsing patients
Ann Oncol
(1996)
A. Garaventa et al.
Italian Cooperative Group for Neuroblastoma: localized unresectable neuroblastoma: results of treatment based on clinical prognostic factors
Ann Oncol
(2002)
B. De Bernardi et al.
Peripheral neuroblastic tumors
C.S. Alvarado et al.
Chemotherapy for patients with recurrent or refractory neuroblastoma: a POG Phase II study
J Pediatr Hematol Oncol
(1997)
H. Rubie et al.
Phase II study of temozolomide in relapsed or refractory high-risk neuroblastoma: a joint Société Française des Cancers de l’Enfant and United Kingdom Children Cancer Study Group–New Agents Group Study
J Clin Oncol
(2006)
R. Bagatell et al.
Phase I pharmacokinetic and pharmacodynamic study of 17-N-allylamino-17-demethoxygeldanamycin in pediatric patients with recurrent or refractory solid tumors: a pediatric oncology experimental therapeutics investigators consortium study
Clin Cancer Res
(2007)
R. Ladenstein et al.
Impact of megatherapy on survival after relapse from stage 4 neuroblastoma in patients over 1 year of age at diagnosis: a report from the European Group for Bone Marrow Transplantation
J Clin Oncol
(1993)
B. De Bernardi et al.
Localized resectable neuroblastoma: results of the second study of the Italian Cooperative Group for Neuroblastoma
J Clin Oncol
(1995)
B. De Bernardi et al.
Italian Co-Operative Group for Neuroblastoma: disseminated neuroblastoma in children older than one year at diagnosis: comparable results with three consecutive high-dose protocols adopted by the Italian Co-Operative Group for Neuroblastoma
J Clin Oncol
(2003)

M. Guglielmi et al.

Resection of primary tumor at diagnosis in stage IV-S neuroblastoma: does it affect the clinical course?

J Clin Oncol

(1996)

I. Baussano et al.

Expected number of childhood cancers in Italy from 2001 to 2015

Haematologica

(2007)

G.M. Brodeur et al.

International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma

J Clin Oncol

(1998)

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^☆: Presented in part at the XII Advances in Neuroblastoma Research Conference, Chiba, Japan, May 22–24, 2008.

View full text

Outcome of children with neuroblastoma after progression or relapse. A retrospective study of the Italian neuroblastoma registry☆

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Conflict of interest statement

Acknowledgements

Eur J Cancer

Ann Oncol

Ann Oncol

Peripheral neuroblastic tumors

Chemotherapy for patients with recurrent or refractory neuroblastoma: a POG Phase II study

J Pediatr Hematol Oncol

Phase II study of temozolomide in relapsed or refractory high-risk neuroblastoma: a joint Société Française des Cancers de l’Enfant and United Kingdom Children Cancer Study Group–New Agents Group Study

J Clin Oncol

Phase I pharmacokinetic and pharmacodynamic study of 17-N-allylamino-17-demethoxygeldanamycin in pediatric patients with recurrent or refractory solid tumors: a pediatric oncology experimental therapeutics investigators consortium study

Clin Cancer Res

Impact of megatherapy on survival after relapse from stage 4 neuroblastoma in patients over 1 year of age at diagnosis: a report from the European Group for Bone Marrow Transplantation

J Clin Oncol

Localized resectable neuroblastoma: results of the second study of the Italian Cooperative Group for Neuroblastoma

J Clin Oncol

Italian Co-Operative Group for Neuroblastoma: disseminated neuroblastoma in children older than one year at diagnosis: comparable results with three consecutive high-dose protocols adopted by the Italian Co-Operative Group for Neuroblastoma

J Clin Oncol

Resection of primary tumor at diagnosis in stage IV-S neuroblastoma: does it affect the clinical course?

J Clin Oncol

Expected number of childhood cancers in Italy from 2001 to 2015

Haematologica

International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma

J Clin Oncol