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.

• Authors: David B Dix, Conrad V Fernandez, Yueh-Yun Chi, Elizabeth A Mullen, James I Geller, Eric J Gratias, Geetika Khanna, John A Kalapurakal, Elizabeth J Perlman, Nita L Seibel, Peter F Ehrlich, Marcio Malogolowkin, James Anderson, Julie Gastier-Foster, Robert C Shamberger, Yeonil Kim, Paul E Grundy, Jeffrey S Dome, AREN0532 and AREN0533 study committees
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 37 Issue 30 Pg. 2769-2777 (10 20 2019) ISSN: 1527-7755 [Electronic] United States
• PMID: 31449468 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor

Topics

• Adolescent
• Adult
• Biomarkers, Tumor (genetics)
• Chromosomes, Human, Pair 1 (genetics)
• Female
• Humans
• Kidney Neoplasms (genetics, therapy)
• Loss of Heterozygosity
• Male
• Progression-Free Survival
• Prospective Studies
• Retrospective Studies
• Wilms Tumor (genetics, therapy)
• Young Adult