Treatment of Stage IV Favorable Histology Wilms Tumor With Lung Metastases: A Report From the Children's Oncology Group AREN0533 Study

David B Dix, Nita L Seibel, Yueh-Yun Chi, Geetika Khanna, Eric Gratias, James R Anderson, Elizabeth A Mullen, James I Geller, John A Kalapurakal, Arnold C Paulino, Elizabeth J Perlman, Peter F Ehrlich, Marcio Malogolowkin, Julie M Gastier-Foster, Elizabeth Wagner, Paul E Grundy, Conrad V Fernandez, Jeffrey S Dome, David B Dix, Nita L Seibel, Yueh-Yun Chi, Geetika Khanna, Eric Gratias, James R Anderson, Elizabeth A Mullen, James I Geller, John A Kalapurakal, Arnold C Paulino, Elizabeth J Perlman, Peter F Ehrlich, Marcio Malogolowkin, Julie M Gastier-Foster, Elizabeth Wagner, Paul E Grundy, Conrad V Fernandez, Jeffrey S Dome

Abstract

Purpose The National Wilms Tumor Study (NWTS) treatment of favorable histology Wilms tumor with lung metastases was vincristine/dactinomycin/doxorubicin (DD4A) and lung radiation therapy (RT). The AREN0533 study applied a new risk stratification and treatment strategy to improve event-free survival (EFS) while reducing exposure to lung RT. Methods Patients with favorable histology Wilms tumor and isolated lung metastases showing complete lung nodule response (CR) after 6 weeks of DD4A continued receiving chemotherapy without lung RT. Patients with incomplete response (IR) or loss of heterozygosity at chromosomes 1p/16q received lung RT and four cycles of cyclophosphamide/etoposide in addition to DD4A drugs (Regimen M). AREN0533 was designed to preserve a 4-year EFS of 85% for lung nodule CR and improve 4-year EFS from 75% to 85% for lung nodule IR. Results Among 292 assessable patients, 133 had CR and 159 had IR. For patients with CR, 4-year EFS and overall survival (OS) estimates were 79.5% (95% CI, 71.2% to 87.8%) and 96.1% (95% CI, 92.1% to 100%), respectively. Expected versus observed event rates were 15% and 20.2% ( P = .052), respectively. For patients with IR, 4-year EFS and OS estimates were 88.5% (95% CI, 81.8% to 95.3%) and 95.4% (95% CI, 90.9% to 99.8%), respectively. Expected versus observed event rates were 25% and 12.2% ( P < .001), respectively. Overall, 4-year EFS and OS were 85.4% (95% CI, 80.5% to 90.2%) and 95.6% (95% CI, 92.8% to 98.4%) compared with 72.5% (95% CI, 66.9% to 78.1%; P < .001) and 84.0% (95% CI, 79.4% to 88.6%; P < .001), respectively, in the predecessor NWTS-5 study. Conclusion Excellent OS was achieved after omission of primary lung RT in patients with lung nodule CR, although there were more events than expected. EFS was significantly improved, with excellent OS, in patients with lung nodule IR using four cycles of cyclophosphamide/etoposide in addition to DD4A drugs. The overall AREN0533 treatment strategy yielded EFS and OS estimates that were superior to previous studies.

Trial registration: ClinicalTrials.gov NCT00379340.

Figures

Fig 1.
Fig 1.
Treatment regimens used in AREN0533. V: vincristine: 0.025 mg/kg/dose intravenously (IV) × 1 for infants 2/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). A: dactinomycin 0.023 mg/kg/dose IV × 1 for infants < 1 year; 0.045 mg/kg/dose IV × 1 for children ≥ 1 year (maximum dose: 2.3 mg). 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. C: cyclophosphamide 14.7 mg/kg/dose IV × 5 days for infants < 1 year; 440 mg/m2/dose IV × 5 days 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. Radiation therapy (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 incomplete lung nodule response received whole-lung RT to a dose of 12 Gy in 1.5 Gy fractions (reduced to 10.5 Gy for patients < 12 months). DD4A, vincristine/dactinomycin/doxorubicin; M, four cycles of cyclophosphamide/etoposide in addition to DD4A drugs.
Fig 2.
Fig 2.
CONSORT diagram of patients with pulmonary nodules without other metastatic sites included in the AREN0533 study. (*) Twelve patients with lung nodule incomplete response (IR) came off therapy before starting lung radiation therapy (RT) and four cycles of cyclophosphamide/etoposide in addition to vincristine/dactinomycin/doxorubicin (DD4A) drugs (Regimen M) for the following reasons: patient was subsequently found to have anaplasia on delayed nephrectomy (n = 1), physician determined it was in the patient's best interest (n = 4), progressive disease (n = 2), or refusal of additional protocol therapy by patient/parent/guardian (n = 7). An additional two patients received DD4A therapy against protocol guidelines. (**) One patient with lung nodule complete response (CR) came off therapy because the physician thought it was in the patient’s best interest. FHWT, favorable histology Wilms tumor; LOH, loss of heterozygosity.
Fig 3.
Fig 3.
Event-free survival (EFS) and overall survival (OS) for patients with lung nodule complete response who completed treatment with vincristine/dactinomycin/doxorubicin without lung radiation therapy.
Fig 4.
Fig 4.
Event-free survival (EFS) and overall survival (OS) for patients with incomplete lung nodule response without loss of heterozygosity who completed treatment with lung radiation therapy and four cycles of cyclophosphamide/etoposide in addition to vincristine/dactinomycin/doxorubicin.
Fig 5.
Fig 5.
(A) Event-free survival (EFS) and (B) overall survival (OS) for patients with isolated pulmonary metastases in AREN0533 compared with NWTS-5.

Source: PubMed

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