July 2015, Special ASCO Edition
Genetic Abnormality Pinpointed for Intensive Therapy in Wilms Tumor
In children with favorable-risk 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 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 showed that 4-year event-free survival (EFS) was boosted in patients with stage I/II disease harboring LOH 1p, 16q, 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 for high-risk patients at diagnosis [LOH 1p, 16q], 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.
COG AREN0532/AREN0533 enrolled 1134 patients; AREN0532 included patients with stage I/II disease, and AREN0533 enrolled patients with stage III/IV disease. In AREN0532, 35 patients had favorable histology stage I/II Wilms tumor and LOH 1p, 16q; in AREN0533, 52 had favorable histology stage III/IV Wilms tumor and LOH 1p, 16q.
Different augmented regimens were used in the studies. For patients with stage I/II disease, regimen DD4a (vincristine, dactinomycin, and doxorubicin) was used. Patients with stage III/IV disease received regimen M (vincristine, dactinomycin, and doxorubicin alternating with 4 cycles of cyclophosphamide/etoposide, plus radiotherapy).
Previous studies have shown that patients with stage I/II disease and LOH who received standard therapy (vincristine/dactinomycin) had a 4-year EFS rate of 74.9%, and patients with stage III/IV disease and LOH who received standard therapy (vincristine and dactinomycin plus doxorubicin and radiotherapy) had a 4-year EFS rate of 65.9%.
The median follow-up was 3.6 years. By augmenting the regimens and targeting them to patients with high-risk Wilms tumor (favorable histology, but LOH 1p, 16q), the 4-year EFS rate increased from 74.9% in patients with stage I/II disease (in a previous study on standard therapy) to 83.9% in the present study; the 4-year EFS rate increased from 65.9% in a previous study on standard therapy to 91.5% for patients with stage III/IV disease with augmented therapy.
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/II disease had improved outcomes, but the benefit was less pronounced as a result of the small study sample.
Both augmented regimens were generally well tolerated. In patients with stage III/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 of the Division of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha.
Dear Colleague, Each year, we look forward to the American Society of Clinical Oncology (ASCO) Annual Meeting where the oncology community gathers to review the past year and discuss the lessons and successes that will impact the lives of patients. The value in gathering is not only in sharing what [ Read More ]
Prevention of common skin cancers and precancers is possible by taking an inexpensive, widely available oral pill twice a day. The pill, a vitamin B3 supplement called nicotinamide, cut the rate of new squamous and basal cell skin cancers by 23% compared with placebo after 1 year. Nicotinamide also reduced [ Read More ]