August 2015 Vol 8, Special Issue: Payers' Perspectives in Oncology - Personalized Medicine
Phoebe Starr

In children who are at risk for Wilms tumor, the presence of a rare genetic abnormality identifies children who can have a survival benefit from the augmentation or intensification of therapy. The abnormality—loss of heterozygosity (LOH) on chromosomes 1p and 16q (LOH 1p/16q)—is associated with worse prognosis in children with Wilms tumor.

Two phase 3 Children’s Oncology Group (COG) studies, presented at ASCO 2015, showed that 4-year event-free survival (EFS) was boosted in patients with stage I/II disease and the LOH 1p/16q biomarker, and even more so in patients with stage III/IV disease.

“We are encouraged that augmentation of therapy can overcome a known adverse biomarker,” said lead investigator David B. Dix, MBChB, Division of Oncology/Hematology/Blood and Marrow Transplant, British Columbia Children’s Hospital, Vancouver, Canada.

“Intensification of therapy up front is not advisable for all patients with Wilms tumor. It has significant side effects. But we have identified a biomarker [LOH 1p/16q] for high-risk patients at diagnosis, and in these patients, intensification of therapy improves outcomes.”

Approximately 500 new cases of Wilms tumor are diagnosed annually in North America, and 5% to 7% of these cases have LOH 1p/16q.

The studies (COG AREN0532 and AREN0533) enrolled 1134 patients; AREN0532 included patients with stage I or II disease, and AREN0533 enrolled patients with stage III or IV disease. One study had 35 patients with favorable histology stage I or II Wilms tumor and LOH 1p/16q, and the second study had 52 patients with favorable histology stage III or IV Wilms tumor and LOH 1p/16q.

Different augmented regimens were used in both studies. For patients with stage I or II disease, regimen DD4a (vincristine [Oncovin], dactinomycin [Cosmegen], and doxorubicin [Adriamycin]) was used. Patients with stage III or IV disease received regimen M (vincristine, dactinomycin, and doxorubicin, alternating with 4 cycles of cyclophosphamide [Cytoxan]/etoposide [Toposar], plus radiotherapy). The median follow-up was 3.6 years.

Previous studies have shown that patients with stage I or II disease and LOH who received standard therapy (ie, vincristine/dactinomycin) had a 4-year EFS rate of 74.9%, and patients with stage III or IV disease and LOH who received standard therapy (ie, vincristine and dactinomycin plus doxorubicin and radiotherapy) had a 4-year EFS rate of 65.9%.

By augmenting the regimens and targeting them to patients with high-risk Wilms tumor (favorable histology, but with LOH 1p/16q), the 4-year EFS rate increased from 74.9% in patients with stage I or II disease (in a previous study using standard therapy) to 83.9% in the present study; the 4-year EFS rate increased from 65.9% in a previous study using standard therapy to 91.5% for patients with stage III or IV disease with augmented therapy.

Dr Dix said that the most marked benefit was observed in patients with advanced disease and LOH 1p/16q. The smaller number of patients with stage I or II disease had improved outcomes, but the benefit is less pronounced as a result of the small study sample.

Both augmented regimens were generally well-tolerated. In patients with stage III or IV disease, regimen M led to myelosuppression in 60% of patients; regimen M also carries the risk for future infertility. The trade-off is a reduced chance of relapse and having to undergo even more intensive therapy. Testing for LOH 1p/16q is the standard of care for COG trials.

Both studies were funded by the National Institutes of Health. “It would not be possible to do this study without federally funded research. The goal of this study is to use genetic testing to escalate therapy in high-risk patients and de-escalate it in low-risk patients,” said ASCO President-Elect Julie M. Vose, MD, MBA, Chief, Division of Oncology/Hematology, University of Nebraska Medical Center, Omaha.

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