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.

Prognostic Factors for Wilms Tumor Recurrence: A Review of the Literature

“…The 2-year RFS reported for stage III FHWT patients registered in the NWTS-4 (91.1-95.3%) was comparable to stage I and II patients [38]. When adjusted for LOH 1p/16q (4-year RFS) and 1q gain (8-year RFS) in the subsequent NWTS-5 and AREN0532 and AREN0533 studies, relapse rates remained similar in all FHWT non-metastatic stages (Table 2) [29,42]. Similarly, in two UK studies with overlapping cohorts (UKW1-3 [46], and UKW2-3 and SIOP 2001 [47]), stage III was no longer of prognostic significance for recurrence when adjusted for copy number variations, including LOH 1p and/or 16q in both studies and 1q gain only in the latter (Table 3).…”

“…Effective use of LOH 1p/16q in clinical practice is therefore limited to small patient subsets. AREN0532 or AREN0533 have used LOH of 16q/1p as treatment stratification factor, and these studies, which included therapy intensification for patients with LOH 16q/1p, showed significantly better 4-year EFS rates compared to the preceding NWTS-5 study (Table 2) [42]. The prognostic significance of LOH of 1p and/or 16q will be further validated for SIOP patients in UMBRELLA [2].…”

“…In addition, patients received intensified treatment with increasing stage. However, from the NWTS-5 onwards, stage I and II FHWT COG patients have received the same therapy, resulting in comparable relapse rates [29,42]. This suggests that treatment stratification by LOH 1p/16q and 1q status overcomes the prognostic significance of capsular penetration and intravascular tumor extension in these stage II patients.…”

Reply to D.M. Green

“…1 cm (Figure A1A in our article). 2 The event-free survival and overall survival estimates were nearly identical, indicating that the excellent results were not restricted to patients with small lung nodules and that augmented therapy had a beneficial effect.…”

Identification of the potential novel biomarkers as susceptibility gene for Wilms tumor

“…This tumor is an embryonal childhood tumor of metanephric origin, as it is histologically similar to the early stages of nephrogenesis, and many of the genetic changes that support the disease occur in genes associated with fetal kidney genes [ 2 ]. With the development of modern multimodality therapy, favorable histology WT survival has been achieved in more than 90% [ 3 – 5 ]. Of course, the described above does not include patients with advanced disease, bilateral WT patients and patients with recurrence.…”