Incidence, Survival, and Treatment of Localized and Metastatic Neuroblastoma in Germany 1979-2015

Abstract

Background: A comprehensive clinical long-term survey over the complete spectrum of neuroblatoma disease is lacking in the literature.

Objective: Our objective was to describe the incidence, risk profiles, therapies, and outcomes for the total cohort of German patients with neuroblastoma including all clinical stages and risk groups.

Methods: Epidemiological, clinical, and outcome data of neuroblastoma patients who participated in one of the six consecutive national trials between 1979 and 2015 were analyzed retrospectively.

Results: Of all German neuroblastoma patients known to the national childhood cancer registry, ninety seven percent enrolled in one of the trials. The absolute neuroblastoma rate has increased slightly, whereas the median age at diagnosis has decreased. Except for the screening period (1995-2000), the risk factors lactate dehydrogenase (LDH), ferritin, chromosome 1p, and the MYCN oncogene have remained largely constant, with the exception of an increase in MYCN amplification at stage 4 for those aged ≥18 months between trials NB97 (27%) and NB2004 (35%). The 10-year overall survival increased in patients with stage 1-3 neuroblastoma from 83 to 91%, for stage 4S from 80 to 85%, and for stage 4 aged ≥18 months from 2 to 38%. The fraction of patients in stages 1-3 who never received chemotherapy (neither for frontline nor at recurrence) increased from 35 to 60%. The proportion of macroscopically complete surgical resections of the primary tumor decreased for the total population as well as for patients with stage 4 aged ≥18 months. The impact of chemotherapy response on the outcome was trial dependent. The overall proportion of toxic death during the time of the protocol therapy was 6% for stage 4 patients aged ≥18 months and 2% for low-/intermediate-risk patients. The most frequently reported late sequelae in stage 4 patients aged ≥18 months were renal dysfunctions, hypothyroidism, major hearing impairment, and second malignancies.

Conclusion: The body of data for incidences, risk profiles, and survival rates from this survey of more than 37 years provides a useful perspective for future studies on neuroblastoma sub-cohorts.

Fig. 1

Incidence rates of neuroblastoma per million children in Germany 1980–2014 aged 0–14 years. Trend fitted 1986–2014, adjusted for population age distribution, German reunification, and screening trial

Fig. 2

Frequencies of achieved remission categories after induction chemotherapy in 1139 patients with stage 4 neuroblastoma aged ≥18 months by trial. CR complete remission, MR mixed response, PR partial remission, SD stable disease, VGPR very good partial remission

Fig. 3

Distribution of grades of surgical resection by trial in 1116 patients with stage 4 neuroblastoma aged ≥18 months by trial. complete macroscopic complete resection with and without microscopic residuals, incomplete macroscopic incomplete resection, biopsy only biopsy material obtained, no tumor resection. If more than one surgical intervention was performed, the best achieved result counted

Fig. 4

Patients without chemotherapy (not after initial diagnosis or after recurrence) (including intermediate-risk patients and children with recurrence therapy). Stages 1–3 (low and intermediate risk, n/N = 1130/2290) and 4S (n/N = 193/482)

Fig. 5

Kaplan–Meier estimates of a, b all patients with neuroblastoma (NB79–NB2004; n = 4463) by trial: a event-free survival, b overall survival; c, d stage 4 aged ≥18 months at diagnosis (NB79–NB2004; n = 1276) by trial: c event-free survival, d overall survival; e, f MYCN-amplified neuroblastoma by stage and age (NB90–NB2004; n = 586): e event-free survival, f overall survival. Log-rank tests, a–f p < 0.001

Fig. 6

Kaplan–Meier estimates of patients with neuroblastoma stage 4 aged ≥18 months (NB79–NB2004; n = 1139) by remission categories (a,c) and by grade of surgical resection (b,d): a event-free survival (log-rank test complete remission/very good partial remission vs. partial remission/mixed response/stable disease p = 0.002), c overall survival (log-rank test complete remission/very good partial remission vs. partial remission/mixed response/stable disease p = 0.021); stage 4 aged ≥18 months by best achieved grade of surgical resection (NB79–NB2004; n = 1116): b event-free survival (log-rank test biopsy vs. incomplete p < 0.001; incomplete vs. complete p = 0.807), d overall survival (log-rank test biopsy vs. incomplete p < 0.001; incomplete vs. complete p = 0.270). CR complete remission, MR mixed response, PR partial remission, SD stable disease, VGPR very good partial remission