1. Carlson, Robert H.

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Children with Wilms tumor who have favorable histology but loss of heterozygosity (LOH) at 1p and 16q benefitted from augmented chemotherapy in two studies from the Children's Oncology Group.

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In the AREN0532 and AREN0533 studies, chemotherapy regimens specifically tailored for patients with the LOH biomarker produced statistically significant improvements in progression-free survival, compared with historical controls.


The augmented regimen for early-stage disease added doxorubicin to the standard vincristine and actinomycin D regimen. For advanced disease, the standard vincristine-actinomycin D-doxorubicin plus radiotherapy regimen was augmented with four cycles of cyclophosphamide-etoposide.


The study's lead author, David B. Dix, MD, Clinical Investigator and Clinical Associate Professor at the University of British Columbia Children's Hospital, presented data from the studies on behalf of the Children's Oncology Group Renal Tumor Group in a teleconference for reporters in advance of the American Society Clinical Oncology Annual Meeting.

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"The prognosis for children with Wilms tumor, the most common renal tumor in pediatrics, has improved dramatically in the past few decades, and outcomes for treatment with chemotherapy for children with favorable histology is excellent for all stages," he said. But a significant number of patients with advanced stage disease relapse and have to be treated with much more intensive salvage chemotherapy.


Dix explained that intensification of upfront therapy for all patients is not an appropriate strategy to resolve this issue, as the side effects of treatment with favorable histology are fairly significant, especially for patients with advanced-stage disease.


"Therefore, we and other groups have looked for ways to identify high-risk disease at diagnosis and then tailor therapy based on the risk of relapse, to be able to escalate therapy for patients who are at increased risk for relapse, and de-escalate therapy for patients with better prognosis so we don't subject them unnecessarily to treatment related toxicities"


A previous large North American study, the National Wilms Tumor Study 5 (NWTS-5, which Dix said is affectionately known as "nitwits-5") showed four-year event-free survival for patients with stage 1 disease of 92 percent and four-year overall survival of 98 percent.


Among the 1,727 NWTS-5 patients with favorable-histology Wilms tumors, five percent had LOH at 1p and 16q, and that was associated with a significantly worse outcome.


Stage I/II patients with LOH at both loci had a four-year event-free survival rate of only 75 percent, compared with 92 percent for those with no LOH. And stage III/IV patients with LOH at both loci had a four-year event-free survival rate of only 66 percent, compared with 83 percent for those with no LOH.


Two Studies

COG's AREN0532 and AREN0533 studies, both funded by the National Cancer Institute, enrolled a total of 1,134 patients, and 87 were identified by microsatellite testing to have favorable-histology Wilms tumor with a combined LOH at 1p and 16q.


In AREN0532, 35 patients with stage I/II disease with LOH were treated with the same regimen as all patients in early stage in NWTS-5-vincristine and actinomycin D-with the addition of doxorubicin.


In AREN0533, 52 patients with stage III/IV disease with LOH received the NWTS-5 regimen for advanced disease-vincristine-actinomycin D-doxorubicin plus radiotherapy to sites of disease-with the addition of four cycles of cyclophosphamide-etoposide.


Four-year event-free survival for stage I/II patients with LOH in AREN0532 was 84 percent, which compared favorably with 75 percent in the NWTS-5 study, Dix said.


And four-year event-free survival for stage III/IV patients with LOH in AREN0533 was 92 percent, which compared very favorably with 66 percent in the NWTS-5 study.


Short-term toxicity on both studies was manageable, Dix said. The most common toxicity seen in patients with advanced disease was grade 3/4 hematological toxicity.


Summing up, Dix said that augmentation of therapy for Wilms tumor patients with favorable histology and with LOH 1p and 16q appears to improve outcomes, particularly for patients with advanced disease.


"These results provide encouragement to search for other biomarkers of prognostic significance-ideally present in a higher percentage of patients," he said.


He added that LOH 1p and 16q testing is now considered standard of care and available at the COG Biopathology Center and at several other centers across North America.