Intensified Chemotherapy Extends EFS for Children With Wilms Tumor

Author(s):

Treatment with an intensified chemotherapy regimen was associated with improvements in event-free survival for children with favorable histology Wilms tumor with loss of heterozygosity in chromosomes 1p and 16q.

David Dix, MD

Treatment with an intensified chemotherapy regimen was associated with improvements in event-free survival (EFS) for children with favorable histology Wilms tumor (FHWT) with loss of heterozygosity (LOH) in chromosomes 1p and 16q, according to a combined analysis of the AREN0532 and AREN0533 studies presented in advance of the 2015 ASCO Annual Meeting.

"Our committee is particularly encouraged by these results, in that they clearly show evidences that augmentation of therapy can overcome a known adverse biomarker," lead author David B. Dix, MD, a physician at the British Columbia Children’s Hospital in Vancouver, Canada, said during a presentation of the results. "These findings provide encouragement to search for other biomarkers of prognostic significance, ideally found in a higher percentage of patients."

LOH in both 1p and 16q, which occurs in approximately 5% of patients with FHWT, is associated with a significantly worse prognosis, according to findings from the large NWTS-5 study. Patients with these alterations have significantly lower EFS compared with those with no LOH or only a single alteration, prompting the exploration of a more aggressive treatment strategy.

The goal of the combined AREN0532 and 0533 studies was to assess whether intensive therapy could improve outcomes for patients with poor prognosis FHWT. A descriptive statistical analysis was used to compare findings from the analysis with those observed in the NWTS-5 trial.

In NWTS-5, 1727 patients were treated with standard therapy: vincristine plus actinomycin (EE4A) for patients with stage I/II disease and vincristine, actinomycin, and doxorubicin (DD4A) plus radiotherapy for stage III/IV tumors. In the combined studies, 1134 patients with FHWT were enrolled with FHWT.

For those with dual 1p/16q LOH (n = 87), the treatment was intensified. Patients with stage I/II disease (n = 35) were treated with DD4A and those with stage III/IV FHWT (n = 52) received DD4A with 4 cycles of cyclophosphamide and etoposide plus radiation therapy (Regimen M).

After a median follow-up of 3.6 years (0.1-8.1 years), the 4-year EFS in patients with stage I/II disease was 83.9% with intensive treatment compared with 75% in NWTS-5. In those with stage III/IV disease, the 4-year EFS was 91.5% with Regimen M compared with 66% for those treated with standard DD4A plus radiotherapy.

Patients with stage I/II FHWT did not experience a significant increase in adverse events with the DD4A regimen. Hematological adverse events were reported in 60% of patients treated with Regimen M, primarily myelosuppression. While less intensive than commonly utilize salvage therapies for FHWT following relapse, Regimen M could be associated with a long-term impact on fertility.

"The toxicity on both of these trials was not unexpected and certainly was manageable," Dix said.

In addition to assessing LOH in 1p/16q, AREN0533 examined outcomes based on response to initial therapy. In an analysis of the study presented at the 2014 ASCO Annual Meeting, patients with stage IV FHWT with lung metastases who experienced an incomplete response to DD4A plus radiation therapy demonstrated superior EFS when treated with Regimen M.

In 163 patients who met the criteria for this analysis, the estimated 3-year EFS was 88% with Regimen M compared with 74.5% with DD4A plus radiation. The estimated 3-year OS rate was 92% compared with 86%, with Regimen M and standard therapy, respectively.

“It’s very encouraging that we’re making progress for kids with a rare, high-risk form of this disease," ASCO president-elect Julie M. Vose, MD, MBA, said in a statement about the results. "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."

References

Dix DB, Fernandez CV, Chi Y-Y, et al. Augmentation of therapy for favorable histology Wilms Tumor with combined loss of heterozygosity of chromosomes 1p and 16q: A report from the Children’s Oncology Group studies AREN0532 and AREN0533. J Clin Oncol. 2015;(suppl; abstr 10009).
Dix DB, Gratias EJ, Seibel N, et al. Treatment of stage IV favorable histology Wilms tumor with incomplete lung metastasis response after chemotherapy: A report from Children’s Oncology Group study AREN0533. J Clin Oncol. 2014;32:5s (suppl; abstr 10001).