Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study

Abstract

PURPOSE We assessed the long-term outcome of patients enrolled on CCG-3891, a high-risk neuroblastoma study in which patients were randomly assigned to undergo autologous purged bone marrow transplantation (ABMT) or to receive chemotherapy, and subsequent treatment with 13-cis-retinoic acid (cis-RA). PATIENTS AND METHODS Patients received the same induction chemotherapy, with random assignment (N = 379) to consolidation with myeloablative chemotherapy, total-body irradiation, and ABMT versus three cycles of intensive chemotherapy. Patients who completed consolidation without disease progression were randomly assigned to receive no further therapy or cis-RA for 6 months. Results The event-free survival (EFS) for patients randomly assigned to ABMT was significantly higher than those randomly assigned to chemotherapy; the 5-year EFS (mean +/- SE) was 30% +/- 4% versus 19% +/- 3%, respectively (P = .04). The 5-year EFS (42% +/- 5% v 31% +/- 5%) from the time of second random assignment was higher for cis-RA than for no further therapy, though it was not significant. Overall survival (OS) was significantly higher for each random assignment by a test of the log(-log(.)) transformation of the survival estimates at 5 years (P < .01). The 5-year OS from the second random assignment of patients who underwent both random assignments and who were assigned to ABMT/cis-RA was 59% +/- 8%; for ABMT/no cis-RA, it was 41% +/- 8% [corrected]; for continuing chemotherapy/cis-RA, it was 38% +/- 7%; and for chemotherapy/no cis-RA, it was 36% +/- 7%.

Conclusion: Myeloablative therapy and autologous hematopoietic cell rescue result in significantly better 5-year EFS than nonmyeloablative chemo therapy; neither myeloablative therapy with [corrected] autologous hematopoietic cell rescue nor cis-RA given after consolidation therapy significantly improved OS.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

(A) Event-free survival (EFS) and overall survival (OS) for all patients (N = 539). (B) EFS and OS for patients with stage 4 disease (n = 466).

Fig 2.

(A) Event-free survival for patients randomly assigned to continuing chemotherapy (CC; n = 190) versus autologous bone marrow transplantation (BMT; n = 189). P = .0434. (B) Overall survival for patients randomly assigned to CC (n = 190) versus BMT (n = 189). P = .3917 by log-rank test; P < .0001 by test of the log(−log(.)) transformation of the survival estimates at 5 years.

Fig 3.

(A) Event-free survival for patients randomly assigned to 13-cis-retinoic acid (cis-RA) (n = 130) versus no cis-RA (n = 128). P = .1219. (B) Overall survival for patients randomly asigned to cis-RA (n = 130) versus no cis-RA (n = 128). P = .1946 by log-rank test; P = .0006 by test of the log(−log(.)) transformation of the survival estimates at 5 years.

Fig 4.

(A) Event-free survival for patients who participated in both the first and second random assignments (autologous bone marrow transplantation + 13-cis-retinoic acid [cis-RA] [n = 50] versus continuing chemotherapy (CC) + no cis-RA [n = 53]). P = .0038. (B) Overall survival for patients who participated in both the first and second random assignments (autologous bone marrow transportation + cis-RA versus CC + no cis-RA) P = .0540.