Augmentation of Therapy for Combined Loss of Heterozygosity 1p and 16q in Favorable Histology Wilms Tumor: A Children's Oncology Group AREN0532 and AREN0533 Study Report

Abstract

Purpose: In National Wilms Tumor Study 5 (NWTS-5), tumor-specific combined loss of heterozygosity of chromosomes 1p and 16q (LOH1p/16q) was associated with adverse outcomes in patients with favorable histology Wilms tumor. The AREN0533/AREN0532 studies assessed whether augmenting therapy improved event-free survival (EFS) for these patients. Patients with stage I/II disease received regimen DD4A (vincristine, dactinomycin and doxorubicin) but no radiation therapy. Patients with stage III/IV disease received regimen M (vincristine, dactinomycin, and doxorubicin alternating with cyclophosphamide and etoposide) and radiation therapy.

Methods: Patients were enrolled through the AREN03B2 Biology study between October 2006 and October 2013; all underwent central review of pathology, surgical reports, and imaging. Tumors were evaluated for LOH1p/16q by microsatellite testing. EFS and overall survival were compared using the log-rank test between NWTS-5 and current studies.

Results: LOH1p/16q was detected in 49 of 1,147 evaluable patients with stage I/II disease (4.27%) enrolled in AREN03B2; 32 enrolled in AREN0532. LOH1p/16q was detected in 82 of 1,364 evaluable patients with stage III/IV disease (6.01%) in AREN03B2; 51 enrolled in AREN0533. Median follow-up for 83 eligible patients enrolled in AREN0532/0533 was 5.73 years (range, 2.84 to 9.63 years). The 4-year EFS for patients with stage I/II and stage III/IV disease with LOH1p/16 was 87.3% (95% CI, 75.1% to 99.5%) and 90.2% (95% CI, 81.8% to 98.6%), respectively. These results are improved compared with the NWTS-5 updated 4-year EFS of 68.8% for patients with stage I/II disease (P = .042), and 61.3% for patients with stage III/IV disease (P = .001), with trends toward improved 4-year overall survival. The most common grade 3 or higher nonhematologic toxicities with regimen M were febrile neutropenia (39.2%) and infections (21.6%).

Conclusion: Augmentation of therapy improved EFS for patients with favorable histology Wilms tumor and LOH1p/16q compared with the historical NWTS-5 comparison group, with an expected toxicity profile.

Trial registration: ClinicalTrials.gov NCT00352534 NCT00379340.

Figures

FIG 1.

Treatment protocols used in the AREN0532 and AREN0533 studies. Regimen DD4A: vincristine, dactinomycin, and doxorubicin with no radiation therapy (RT); regimen M: vincristine, dactinomycin, and doxorubicin alternating with cyclophosphamide and etoposide with RT. A: dactinomycin 0.023 mg/kg/dose IV × 1 for infants 2/dose IV × 5 days for children ≥ 1 year. D: doxorubicin 1.5 mg/kg/dose IV × 1 for infants < 1 year; 45 mg/m2/dose IV × 1 for children ≥ 1 year. D*: doxorubicin 1 mg/kg/dose IV × 1 for infants < 1 year; 30 mg/m2/dose IV × 1 for children ≥ 1 year. E: etoposide 3.3 mg/kg/dose IV × 5 days for infants < 1 year; 100 mg/m2/dose IV × 5 days for children ≥ 1 year. V: vincristine: 0.025 mg/kg/dose intravenously (IV) × 1 for infants < 1 year; 0.05 mg/kg/dose IV × 1 for children ≥ 1 year to 2.99 years; 1.5 mg/m2/dose IV × 1 for children ≥ 3 years (maximum dose: 2 mg). V*: vincristine: 0.034 mg/kg/dose IV × 1 for infants < 1 year; 0.067 mg/kg/dose IV × 1 for children ≥ 1 year to 2.99 years; 2 mg/m2/dose IV × 1 for children ≥ 3 years (maximum dose: 2 mg). RT: for local stage III tumors, 10.8 Gy flank radiation was used, with a 10.8 Gy boost for gross residual disease after surgery. Patients with preoperative tumor rupture, cytology-positive ascites, or diffuse peritoneal seeding were treated with whole-abdomen RT to a dose of 10.5 Gy. Patients with lung metastases received whole lung RT to a dose of 12 Gy in 1.5 Gy fractions (reduced to 10.5 Gy for patients < 12 months old). FHWT, favorable histology Wilms tumor; NWTS-5, National Wilms Tumor Study 5.

FIG 2.

Consort diagram of patients with combined loss of heterozygosity of chromosomes 1p and 16q (LOH1p/16q). FHWT, favorable histology Wilms tumor; LOH, loss of heterozygosity; NWTS-5, National Wilms Tumor Study 5; regimen DD4A, vincristine, dactinomycin, and doxorubicin with no radiation therapy; regimen EE4A, vincristine and dactinomycin; regimen M: vincristine, dactinomycin, and doxorubicin alternating with cyclophosphamide and etoposide with radiation therapy.

FIG 3.

(A) Event-free survival for patients with stage I/II disease with combined loss of heterozygosity of chromosomes 1p and 16q treated in AREN0532 compared with National Wilms Tumor Study 5 (NWTS-5). (B) Overall survival for patients with stage I/II disease with combined loss of heterozygosity of chromosomes 1p and 16q treated in AREN0532 compared with NWTS-5.

FIG 4.

(A) Event-free survival for patients with stage III/IV disease with combined loss of heterozygosity of chromosomes 1p and 16q treated in AREN0533 compared with National Wilms Tumor Study 5 (NWTS-5). (B) Overall survival for patients with stage III/IV disease with combined loss of heterozygosity of chromosomes 1p and 16q treated in AREN0533 compared with NWTS-5.

FIG A1.

(A) Event-free survival for AREN0533 lung metastases only by size of nodule. (B) Overall survival for AREN0533 lung metastases only by size of nodule.

FIG A2.

(A) and (B) Event-free survival for AREN0533 lung metastases only, treated with DD4A and a complete response after induction, by loss of heterozygosity (LOH) of 1p and 16q. (C) and (D) Event-free survival for AREN0533 lung metastases only, treated with Regimen M and an incomplete response after induction, by loss of heterozygosity (LOH) of 1p and 16q.