Tailoring chemoradiation therapy while minimizing anthracycline exposure produced strong survival results in stage IV favorable histology Wilms tumor (FHWT), according to new results from the Children’s Oncology Group AREN0533 study.
In the new regimen, patients whose isolated lung nodules completely respond to 6 weeks of vincristine/dactinomycin/doxorubicin (DD4A) therapy continue DD4A and forgo lung radiation therapy (RT), explained David B. Dix, MBChB, of British Columbia Children’s Hospital, Vancouver, B.C., and his associates. Incomplete responders and patients with loss of heterozygosity at chromosomes 1p/16q receive lung RT plus boosted chemotherapy consisting of DD4 plus four cycles of cyclophosphamide/etoposide (Regimen M).
Among 133 assessable complete responders who received the DD4A regimen and were followed for a median of 4.7 years, 4-year event-free survival (EFS) was 79.5% (95% confidence interval, 71%-88%) and 4-year overall survival (OS) was 96% (95% CI, 92%-100%), Dr. Dix and his associates wrote. The report was published in the Journal of Clinical Oncology.
Among 159 incomplete responders receiving Regimen M, 4-year EFS was 88.5% (95% CI, 82%-95%) and 4-year OS was 95% (95% CI, 91%-100%). Regimen M produced superior EFS and OS (P less than .001 for both comparisons) than the protocol used in the National Wilms Tumor Study (NWTS) 5 study, in which all patients with lung metastases received DD4A plus RT, regardless of lung nodule response. “These results provide a benchmark for future studies,” Dr. Dix and his associates concluded.
Most patients with FHWT have pulmonary metastases and historically have fared worse than peers with localized disease. Until now, patients have had two main treatment options. The Society of Pediatric Oncology (SIOP) protocol focuses on pre-nephrectomy DD4A and forgoes lung RT if chemotherapy or surgical resection achieves lung nodule CR. Patients in the most recently reported SIOP trial (93-01) received a high cumulative anthracycline dose of 350 mg/m2 and had 5-year EFS of 77% and 5-year OS of 87%. The second option – the NWTS protocol – more than halves the cumulative doxorubicin dose (150 mg/m2), but all patients undergo lung RT.
In contrast, the AREN0533 protocol involved cumulative doxorubicin doses of 150 mg/m2 for DD4A and 195 mg/m2 for Regimen M. Among complete responders, the expected event rate was 15% and the actual rate was 20% (P = .05). Among incomplete responders, observed and expected event rates were 25% and. 12%, respectively (P less than .001). The higher-than-expected event rates might stem from lower chemotherapy doses, but the SIOP study also did not include central image review and may have defined CR less stringently, Dr. Dix and his coinvestigators said.
They concluded that AREN0533 showed “excellent” survival results for patients with CR and that certain late risks of Regimen M – including an increased risk of leukemia from exposure to cyclophosphamide and etoposide – should be balanced against its superior 4-year EFS.