Radiation Avoidable in Some Wilms Tumor Patients With Lung Metastases

Jeffrey S. Dome, MD, PhD

A novel risk stratification and treatment approach led to enhanced clinical outcomes overall, as well as the successful omission of radiotherapy (RT) for some patients with stage IV favorable histology Wilms tumor and pulmonary metastases, according to findings from the COG AREN0533 published in the Journal of Clinical Oncology.

In AREN0533, 297 patients with isolated pulmonary nodules received either immediate nephrectomy (n = 188) or preoperative chemotherapy (n = 109). Patients were treated with vincristine/dactinomycin/doxorubicin for the first 6 weeks of therapy, and those who had complete response (CR) with no viable tumor cells continued receiving DD4A without lung RT.

Patients with partial response, stable disease, or combined loss of heterozygosity (LOH) at 1p and 16q were treated with DD4A plus cyclophosphamide and etoposide (Regimen M) and lung RT.

Overall, 133 patients had CR and 159 had incomplete response (IR). Twelve patients with IR had stable disease, while the rest had partial response.

At a median follow-up of 4.72 years, 124 patients without LOH had CR and received DD4A without RT. Estimated 4-year event-free survival (EFS) was 79.5% (95% CI, 71.2-87.8) and overall survival (OS) was 96.1% (95% CI, 92.1-100). However, investigators observed more EFS events than expected (20.2% vs 15%; one-sided P = .052).

“Patients with isolated lung metastases and lung nodule CR after 6 weeks of therapy had excellent OS when treated initially without lung RT in the setting of low cumulative doxorubicin exposure,” corresponding author Jeffrey S. Dome, MD, PhD, Center for Cancer and Blood Disorders, Children’s National Health System, and colleagues wrote.

“The treatment approach avoided initial lung RT in approximately 40% of patients, which is a clinically significant advance because lung RT is a contributing factor to congestive heart failure, pulmonary fibrosis, and breast cancer in Wilms tumor survivors,” added Dome et al.

For the 131 patients without LOH who had IR and received Regimen M and lung RT, 4-year estimated EFS was 88.5% (95% CI, 81.8-95.3) and 4-year estimated OS was 95.4% (95% CI, 90.9-99.8). The expected EFS events exceeded what was observed (25% vs. 12.2%; one-sided P <.001).

Overall for the AREN0533 population, the 4-year EFS was 85.4% (95% CI, 80.5-90.2) and 4-year OS was 95.6% (95% CI, 92.8-98.4). In comparison, EFS was 72.5% (95% CI, 66.9-78.1; P <.001) and OS was 84% (95% CI, 79.4-88.6; P <.001) in the predecessor NWTS-5 study.

For local stage III tumors, patients who underwent nephrectomy at diagnosis received flank/abdominal RT by week 2. Patients who received preoperative chemotherapy received RT by week 7. For patients who required lung RT, investigators delivered radiation at week 7 after assessment of response.

Most patients (n = 237) were stage III, 50 were stage II, and 10 were stage I. The median patient age was 50 months (range, 6.8-350.4).

Four-year EFS was 80% (95% CI, 51.4-100) for patients with stage I disease, 90% (95% CI, 80.0-100) for stage II, and 85% (95% CI, 79.0-90.2) for stage III. Four-year OS was 100%, 94%, and 95.8%, respectively.

Eighteen patients had pulmonary metastases only and LOH at 1p and 16q—8 of whom had lung nodule CR and 10 had IR. All 18 received Regimen M and lung RT, and estimated 4-year EFS and OS was 100%.

Investigators conducted a posthoc analysis of the prognostic significance of tumor 1q gain in 212 patients with isolated pulmonary metastases and available tumor DNA. The 4-year EFS was significantly worse for patients with a lung nodule CR with 1q gain. The data also showed a trend toward worse OS.

Twenty-four patients without LOH and with lung nodule CR who received DD4A without RT experienced relapse and 1 had a second malignancy, acute myelogenous leukemia. From enrollment in the trial to first relapse, the median time was 0.81 years (range, 0.38-3.11). Twenty-two patients relapsed in the lung only while 1 patient relapsed in the liver and lung (n = 1), and 1 relapsed in the abdomen.

Fourteen patients without LOH who had IR and received Regimen M and lung RT relapsed. One had a second malignancy, parotid mucoepidermoid carcinoma, and 1 died from an unknown cause. The median time to first relapse was 0.88 years (range, 0.70-1.50). Nine patients relapsed in the lung only, 3 relapsed in the abdomen and tumor bed, and 1 each relapsed in the lung and abdomen and the brain.

Twelve patients reported 22 adverse events (AEs)—8 in the DD4A group and 14 in the Regimen M group. One patient in the DD4A group died due to surgical complications within the first 6 weeks, and 1 patient receiving Regimen M died of undetermined cause. Investigators found that the rate of grade ≥3 nonhematologic AEs was low in the Regimen M group, the most common being infections and infestations (14.1%) and hypokalemia (5.4%).

Dix DB, Seibel NL, Chi YY, et al. Treatment of stage IV favorable histology Wilms tumor with lung metastases: a report from the Children’s Oncology Group AREN0533 study [published online April 16, 2018]. J Clin Oncol. doi: 10.1200/JCO.2017.77.1931.