Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group project

Abstract

Purpose: Survival after neuroblastoma relapse is poor. Understanding the relationship between clinical and biologic features and outcome after relapse may help in selection of optimal therapy. Our aim was to determine which factors were significantly predictive of postrelapse overall survival (OS) in patients with recurrent neuroblastoma--particularly whether time from diagnosis to first relapse (TTFR) was a significant predictor of OS.

Patients and methods: Patients with first relapse/progression were identified in the International Neuroblastoma Risk Group (INRG) database. Time from study enrollment until first event and OS time starting from first event were calculated. Cox regression models were used to calculate the hazard ratio of increased death risk and perform survival tree regression. TTFR was tested in a multivariable Cox model with other factors.

Results: In the INRG database (N = 8,800), 2,266 patients experienced first progression/relapse. Median time to relapse was 13.2 months (range, 1 day to 11.4 years). Five-year OS from time of first event was 20% (SE, ± 1%). TTFR was statistically significantly associated with OS time in a nonlinear relationship; patients with TTFR of 36 months or longer had the lowest risk of death, followed by patients who relapsed in the period of 0 to less than 6 months or 18 to 36 months. Patients who relapsed between 6 and 18 months after diagnosis had the highest risk of death. TTFR, age, International Neuroblastoma Staging System stage, and MYCN copy number status were independently predictive of postrelapse OS in multivariable analysis.

Conclusion: Age, stage, MYCN status, and TTFR are significant prognostic factors for postrelapse survival and may help in the design of clinical trials evaluating novel agents.

Fig 1.

(A) Overall survival post relapse for 2,266 patients with neuroblastoma from the International Neuroblastoma Risk Group database. Median time to first relapse (TTFR) was 13.2 months (range, 1 day to 13.1 years). (B) Overall survival post relapse. TTFR less than 365 days from diagnosis (n = 1,012) versus TTFR 365 days or more from diagnosis (n = 1,254). Log-rank test P value is not valid because of violation of proportional hazards assumption, which can be seen in crossing of two curves.

Fig 2.

Relative risk (hazard ratio) of death for 6-month cohorts of time to first relapse in comparison with patients whose first relapse occurred more than 36 months from diagnosis. Patients whose first relapse occurred more than 36 months from diagnosis had a relative risk of death equal to 1. Blue bars are all patients (n = 2,266), and gold bars are the subset of stage 3 or 4 patients with MYCN amplified tumors (n = 504). SE bars are shown for relative risk of death for each cohort.

Fig 3.

Survival tree regression of overall survival post relapse. Modeling was performed with adjustment for time to first relapse. Within each subgroup box, the value of OS post relapse is presented as the 5-year point estimate (± SE). INSS, International Neuroblastoma Staging System; LDH, lactate dehydrogenase; OS, overall survival; TTFR, time to first relapse.