Abstract
Simple SummaryNeuroblastoma, the most common extracranial malignancy of childhood, shows a highly variable course of disease ranging from spontaneous regression or maturation into a benign tumor to an aggressive and intractable cancer in up to 60% of patients. To adapt treatment intensity, risk staging at diagnosis is of utmost importance. The A-NB94 trial was the first in Austria to stratify therapy intensity according to tumor staging, patient’s age, and MYCN amplification status, the latter being a biologic marker turning otherwise low-risk tumors into high-risk disease. Recent publications showed a prognostic impact of various genomic features including segmental chromosomal aberrations (SCAs). We retrospectively investigated the relevance of SCAs within this risk-adapted treatment strategy. The A-NB94 approach resulted in an excellent long-term survival for the majority of patients with acceptable long-term morbidity. An age- and stage-dependent frequency of SCAs was confirmed and SCAs should always be considered in future treatment decision making processes.We evaluated long-term outcome and genomic profiles in the Austrian Neuroblastoma Trial A-NB94 which applied a risk-adapted strategy of treatment (RAST) using stage, age and MYCN amplification (MNA) status for stratification. RAST ranged from surgery only to intensity-adjusted chemotherapy, single or multiple courses of high-dose chemotherapy (HDT) followed by autologous stem cell rescue depending on response to induction chemotherapy, and irradiation to the primary tumor site. Segmental chromosomal alterations (SCAs) were investigated retrospectively using multi- and pan-genomic techniques. The A-NB94 trial enrolled 163 patients. Patients with localized disease had an excellent ten-year (10y) event free survival (EFS) and overall survival (OS) of 99 ± 1% and 93 ± 2% whilst it was 80 ± 13% and 90 ± 9% for infants with stage 4S and for infants with stage 4 non-MNA disease both 83 ± 15%. Stage 4 patients either >12 months or ≤12 months but with MNA had a 10y-EFS and OS of 45 ± 8% and 47 ± 8%, respectively. SCAs were present in increasing frequencies according to stage and age: in 29% of localized tumors but in 92% of stage 4 tumors (p < 0.001), and in 39% of patients ≤ 12 months but in 63% of patients > 12 months (p < 0.001). RAST successfully reduced chemotherapy exposure in low- and intermediate-risk patients with excellent long-term results while the outcome of high-risk disease met contemporary trials.
Highlights
Neuroblastoma is the most common extracranial malignancy of childhood and originates from the sympathetic nervous system
Between June 1994 and March 2006, a total of 163 patients were enrolled to the ANB94 trial (Table 2) with most patients (n = 153) treated in five major Austrian centers
We found four infants harboring heterogeneous MNA (hetMNA); one of them was only recognized in a later tumor sample and this patient was treated according to the original result as per MYCN amplification (MNA) protocol
Summary
Neuroblastoma is the most common extracranial malignancy of childhood and originates from the sympathetic nervous system. It shows a highly heterogeneous behavior ranging from spontaneous regression or maturation into a benign ganglioneuroma to an aggressive and intractable disease. MNA, a strong biologic marker associated with rapid tumor growth [4,5], transforms otherwise favorable risk profiles of infants [6,7] and children with localized resectable [8,9] or unresectable [10] disease into high-risk [11]. Metastatic disease in children older than 18 months constitutes per se an unfavorable risk group regardless of MYCN status [12]. A recent study highlights the importance of viewing it separately from the MNA profile and its unfavorable risk implication, prognostication and therapy allocation are still unsolved issues [14,15]
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