Roxanne Nelson, RN

May 14, 2015

CHICAGO — For children with a high-risk form of Wilms' tumor, the augmentation of standard therapy with additional agents can improve outcomes, according to two new studies.

The high-risk form of Wilms' tumor, a rare kidney cancer that mainly affects children younger than 5 years, can be identified by a specific biomarker. The biomarker — a tumor-specific combined loss of heterozygosity (LOH) on chromosomes 1p and 16q — is found in about 5% to 6% of children with Wilms' tumor. Of the 500 new cases of Wilms' tumor diagnosed each year in North America, about 25 to 30 children likely have this high-risk biomarker.

Results from the AREN0532 and AREN0533 studies demonstrate that in the subset of patients with the high-risk biomarker, outcomes are markedly better for patients with stage I or II disease when doxorubicin is added to standard therapy and for patients with stage III or IV disease when cyclophosphamide plus etoposide is added.

Four-year relapse-free survival rates were better with the augmented regimen than historic rates seen with standard therapy for patients with stage I or II disease (83.9% vs 74.9%) and for patients with stage III or IV disease (91.5% vs to 65.9%).

"Our conclusions are that augmentation of therapy for patients with favorable-histology Wilms' tumor and with LOH on chromosomes 1p and 16q can improve outcomes, particularly for patients with stage III and IV disease," said lead researcher David B. Dix, MD, from the British Columbia Children's Hospital in Vancouver, Canada. He was speaking at a press briefing held in advance of the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

"Augmentation of therapy can overcome a known adverse biomarker. This provides encouragement to search for other biomarkers of known prognostic significance and, ideally, that are found in a higher percentage of patients," he explained.

However, Dr Dix emphasized that the augmented regimen is appropriate only for the small subgroup of patients with the LOH biomarker. Intensification of upfront therapy for all patients is not an appropriate strategy to reduce relapse, he cautioned.

Research Shows Worse Outcomes

Previous research demonstrated that in patients with stage I or II disease treated with vincristine and dactinomycin, 4-year event-free survival was better in those without the biomarker than with it (91.2% vs 74.9%) (J Clin Oncol. 2005;23:7312-7321). The same was true for patients with stage III or IV disease treated with vincristine, dactinomycin, and doxorubicin plus radiotherapy (83.0% vs 65.9%)

Fewer Events, More Toxicity

In the AREN0532 and AREN0533 studies, Dr Dix and colleagues evaluated whether augmented therapy would improve event-free survival in 35 biomarker patients with stage I or II disease and 52 biomarker patients with stage III or IV disease.

Median follow up was 3.6 years.

There were fewer observed than expected events in stage I or II patients (6 vs 9) and in stage III or IV patients (4 vs 18).

"The toxicity in both of these trials was not unexpected, and it was manageable," Dr Dix reported. For stage I or II patients, there was no significant association between augmented therapy and short-term adverse effects. For stage III or IV patients, hematologic toxicity of grade 3 or higher affected 60% of patients.

The augmented regimen reduces the number of patients who would otherwise have to undergo very intensive relapse therapy, the researchers report. However, because it will likely be associated with some risk for reduced fertility, they recommend a clear discussion with families on the risks and benefits of augmented therapy.

It is important to understand that these studies would not have been possible without federal funding for cancer research, said ASCO President-Elect Julie M. Vose, MD, MBA, from the University of Nebraska Medical Center in Omaha.

"This is a rare cancer and there are not a lot of new and exciting drugs in this particular setting," she explained. "Without federal funding, we would have not been able to gather that information from all different cancer centers across North America."

It is also important to note that genetic testing was used to direct therapy in these studies, she pointed out.

Testing for the LOH biomarker is currently available at the Biopathology Center at Nationwide Children's Hospital in Columbus, Ohio, and at several other centers in North America.

"It's very encouraging that we're making progress even for kids with a rare, high-risk form of this disease. The ability to easily identify a small subset of patients with a poorer prognosis means these children can receive treatment that's right for them while decreasing side effects for lower-risk patients. And that means a better shot at surviving their cancer," Dr Vose said in a statement.

This study received funding from the National Institutes of Health.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract 10009. To be presented June 1, 2015.

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