Factors associated with recurrence and survival length following relapse in patients with neuroblastoma

Nermine O Basta, Gail C Halliday, Guy Makin, Jillian Birch, Richard Feltbower, Nick Bown, Martin Elliott, Lucas Moreno, Giuseppe Barone, Andrew Dj Pearson, Peter W James, Deborah A Tweddle, Richard Jq McNally, Nermine O Basta, Gail C Halliday, Guy Makin, Jillian Birch, Richard Feltbower, Nick Bown, Martin Elliott, Lucas Moreno, Giuseppe Barone, Andrew Dj Pearson, Peter W James, Deborah A Tweddle, Richard Jq McNally

Abstract

Background: Despite therapeutic advances, survival following relapse for neuroblastoma patients remains poor. We investigated clinical and biological factors associated with length of progression-free and overall survival following relapse in UK neuroblastoma patients.

Methods: All cases of relapsed neuroblastoma, diagnosed during 1990-2010, were identified from four Paediatric Oncology principal treatment centres. Kaplan-Meier and Cox regression analyses were used to calculate post-relapse overall survival (PROS), post-relapse progression-free survival (PRPFS) between relapse and further progression, and to investigate influencing factors.

Results: One hundred eighty-nine cases were identified from case notes, 159 (84.0%) high risk and 17 (9.0%), unresectable, MYCN non-amplified (non-MNA) intermediate risk (IR). For high-risk patients diagnosed >2000, median PROS was 8.4 months (interquartile range (IQR)=3.0-17.4) and median PRPFS was 4.7 months (IQR=2.1-7.1). For IR, unresectable non-MNA patients, median PROS was 11.8 months (IQR 9.0-51.6) and 5-year PROS was 24% (95% CI 7-45%). MYCN amplified (MNA) disease and bone marrow metastases at diagnosis were independently associated with worse PROS for high-risk cases. Eighty percent of high-risk relapses occurred within 2 years of diagnosis compared with 50% of unresectable non-MNA IR disease.

Conclusions: Patients with relapsed HR neuroblastomas should be treatment stratified according to MYCN status and PRPFS should be the primary endpoint in early phase clinical trials. The failure to salvage the majority of IR neuroblastoma is concerning, supporting investigation of intensification of upfront treatment regimens in this group to determine whether their use would diminish likelihood of relapse.

Conflict of interest statement

Dr Lucas Moreno discloses the following activities: consultancy/advisory board participation for Novartis, AstraZeneca, RocheGenentech, Mundipharma and Bayer. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flow diagram showing number of cases included in the study.
Figure 2
Figure 2
Kaplan–Meier graphs for post-relapse overall survival time for the high-risk group (N=159). (A) Post relapse overall survival (PROS) time. Median PROS time for high-risk cases was 4.5 months (IQR=1.9–11.4). Five-year PROS for high-risk cases was 7.4% (95% CI 4.0–12.1%). (B) Post-relapse overall survival by year of diagnosis. Median PROS time was 2.9 months (IQR 1.4–6.9) for cases diagnosed ⩽2000 vs 8.4 months (IQR 3.0–17.4) for cases diagnosed >2000 (P<0.001). Five-year PROS for high-risk cases diagnosed ⩽2000 was 2.4% (95% CI 0.5–7.7%) vs 12.7% (95% CI 6.4–21.2%) for cases diagnosed >2000. (C) PROS by MYCN status. Median PROS time was 2.9 months (95% CI 2.0–4.3) for MYCN amplified vs 8.5 months for MYCN non-amplified (95% CI 5.9–11.1; P<0.001). Five-year PROS for MYCN non-amplified cases was 9.0% (95% CI 3.7–17.2%) vs 4.1% (95% CI 0.8–12.3%) for MYCN amplified cases. (D) PROS for cases diagnosed ⩽2000 by MYCN status. For cases diagnosed ⩽2000, the median PROS for MYCN amplified disease was 1.5 months (95% CI 0.9–2.7) vs 5.1 months (95% CI 2.9–7.9) for MYCN non-amplified cases (P<0.001). Five year PROS for MYCN non-amplified was 3.6% (95% CI 0.3–15.4%) vs 0% for MYCN amplified cases. (E) PROS for cases diagnosed >2000 by MYCN status. For cases diagnosed >2000, the median PROS for MYCN amplified disease was 4.3 months (95% CI 2.9–6.6) vs 10.9 months (95% CI 6.3–14.4) for MYCN non-amplified (P=0.02). Five-year PROS for MYCN non-amplified cases was 12.8% (95% CI 4.7–25.2%) vs 7.7% (95% CI 1.3–21.7%) for MYCN amplified cases.
Figure 3
Figure 3
Flow diagram showing treatments that high-risk patients received at first relapse and its outcome. Abbreviations: PROS = post-relapse overall survival; IQR = interquartile range; PRPFS = post-relapse progression-free survival.

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