Augmenting therapy boosts event-free survival in high-risk Wilms tumor

Augmenting standard chemotherapy regimens with additional cytotoxic agents significantly boosted event-free survival rates in children with high-risk forms of Wilms tumor, particularly those with advanced-stage disease.

Adding doxorubicin to standard therapy with vincristine and dactinomycin in patients with stage I/II Wilms tumors carrying high-risk loss of heterozygosity mutations increased 4-year event-free survival (EFS) rates from 74.9% (with vincristine and dactinomycin chemotherapy alone), to 83.9.%

In patients with high-risk stage III/IV disease, adding four cycles of cyclophosphamide and etoposide to a standard regimen of vincristine, dactinomycin, doxorubicin and radiation improved 4-year EFS from 65.9% to 91.5%, reported Dr. David B. Dix of the British Columbia Children’s Hospital, Vancouver, B.C.

“Our committee is particularly encouraged by these results in that they clearly show evidence that augmentation of therapy can overcome a known adverse biomarker, and they also provide encouragement to search for other biomarkers of prognostic significance, ideally found in a higher percentage of patients,” he said at a briefing of studies to be presented at the 2015 annual meeting of the American Society of Clinical Oncology.

Dr. Julie M. Vose, ASCO president-elect, who comoderated the briefing but was not involved in the studies, said that the results show the importance of genetic testing to prevent overtreatment and rein in costs for low-risk patients, and to help improve treatment of high-risk patients with augmented therapies or additional treatment strategies.

The investigators focused on improving outcomes for children with favorable histology Wilms tumor who have loss of heterozygosity (LOH) mutations in chromosomal location 1p and 16q.

In the National Wilms Tumor Study 5, a multicenter North American cooperative trial, children with these mutations, who comprised 5% of the study population, had significantly worse outcomes. Among patients with stage I/II disease with LOH mutations at both chromosomal locations, the 4-year EFS in that trial was 74.9%, compared with 92% for patients with no LOH mutations. Among patients with stage III/IV disease, the respective 4-year EFS rates were 65.9% vs. 83%.

The investigators tested whether augmenting therapy would improve EFS for patients with favorable histology Wilms tumor with the combined LOH 1p and 16q mutations in two trials:

AREN0532 compared vincristine and dactinomycin with the same two drugs plus doxorubicin in patients with stage I/II disease.

AREN0533compared vincristine, dactinomycin, doxorubicin and radiation therapy with the same regimen plus four cycles of cyclophosphamide and etoposide in patients with stage III/IV disease.

In each trial, 4-year EFS rates were compared with those of the National Wilms Tumor Study 4. Median follow-up was 3.6 years.

The patients were generally able to tolerate the therapy well, Dr. Dix said. Short-term toxicities for patients with stage I/II disease were manageable, he noted.

Among patients with stage III/IV disease, the augmented regimen was associated with myelosuppression in 60% of patients, although this too was manageable, the investigators reported.

Dr. Dix and his colleagues noted that the augmented regimen for stage III/IV tumors may spare many patients from requiring even more intensive salvage therapy. They also acknowledged, however, that the augmented regimen is likely to cause reduced fertility in some patients, and urged clinicians to discuss the risks and benefits of augmented therapy with the patients’ families.

Testing for LOH 1p and 16q is available at the Children’s Oncology Group Biopathology Center at Nationwide Children’s Hospital in Columbus, Ohio, and at several other centers across North America, Dr. Dix noted.

Augmenting standard chemotherapy regimens with additional cytotoxic agents significantly boosted event-free survival rates in children with high-risk forms of Wilms tumor, particularly those with advanced-stage disease.

Adding doxorubicin to standard therapy with vincristine and dactinomycin in patients with stage I/II Wilms tumors carrying high-risk loss of heterozygosity mutations increased 4-year event-free survival (EFS) rates from 74.9% (with vincristine and dactinomycin chemotherapy alone), to 83.9.%

In patients with high-risk stage III/IV disease, adding four cycles of cyclophosphamide and etoposide to a standard regimen of vincristine, dactinomycin, doxorubicin and radiation improved 4-year EFS from 65.9% to 91.5%, reported Dr. David B. Dix of the British Columbia Children’s Hospital, Vancouver, B.C.

“Our committee is particularly encouraged by these results in that they clearly show evidence that augmentation of therapy can overcome a known adverse biomarker, and they also provide encouragement to search for other biomarkers of prognostic significance, ideally found in a higher percentage of patients,” he said at a briefing of studies to be presented at the 2015 annual meeting of the American Society of Clinical Oncology.

Dr. Julie M. Vose, ASCO president-elect, who comoderated the briefing but was not involved in the studies, said that the results show the importance of genetic testing to prevent overtreatment and rein in costs for low-risk patients, and to help improve treatment of high-risk patients with augmented therapies or additional treatment strategies.

The investigators focused on improving outcomes for children with favorable histology Wilms tumor who have loss of heterozygosity (LOH) mutations in chromosomal location 1p and 16q.

In the National Wilms Tumor Study 5, a multicenter North American cooperative trial, children with these mutations, who comprised 5% of the study population, had significantly worse outcomes. Among patients with stage I/II disease with LOH mutations at both chromosomal locations, the 4-year EFS in that trial was 74.9%, compared with 92% for patients with no LOH mutations. Among patients with stage III/IV disease, the respective 4-year EFS rates were 65.9% vs. 83%.

The investigators tested whether augmenting therapy would improve EFS for patients with favorable histology Wilms tumor with the combined LOH 1p and 16q mutations in two trials:

AREN0532 compared vincristine and dactinomycin with the same two drugs plus doxorubicin in patients with stage I/II disease.

AREN0533compared vincristine, dactinomycin, doxorubicin and radiation therapy with the same regimen plus four cycles of cyclophosphamide and etoposide in patients with stage III/IV disease.

In each trial, 4-year EFS rates were compared with those of the National Wilms Tumor Study 4. Median follow-up was 3.6 years.

The patients were generally able to tolerate the therapy well, Dr. Dix said. Short-term toxicities for patients with stage I/II disease were manageable, he noted.

Among patients with stage III/IV disease, the augmented regimen was associated with myelosuppression in 60% of patients, although this too was manageable, the investigators reported.

Dr. Dix and his colleagues noted that the augmented regimen for stage III/IV tumors may spare many patients from requiring even more intensive salvage therapy. They also acknowledged, however, that the augmented regimen is likely to cause reduced fertility in some patients, and urged clinicians to discuss the risks and benefits of augmented therapy with the patients’ families.

Testing for LOH 1p and 16q is available at the Children’s Oncology Group Biopathology Center at Nationwide Children’s Hospital in Columbus, Ohio, and at several other centers across North America, Dr. Dix noted.

Augmenting standard chemotherapy regimens with additional cytotoxic agents significantly boosted event-free survival rates in children with high-risk forms of Wilms tumor, particularly those with advanced-stage disease.

Adding doxorubicin to standard therapy with vincristine and dactinomycin in patients with stage I/II Wilms tumors carrying high-risk loss of heterozygosity mutations increased 4-year event-free survival (EFS) rates from 74.9% (with vincristine and dactinomycin chemotherapy alone), to 83.9.%

In patients with high-risk stage III/IV disease, adding four cycles of cyclophosphamide and etoposide to a standard regimen of vincristine, dactinomycin, doxorubicin and radiation improved 4-year EFS from 65.9% to 91.5%, reported Dr. David B. Dix of the British Columbia Children’s Hospital, Vancouver, B.C.

“Our committee is particularly encouraged by these results in that they clearly show evidence that augmentation of therapy can overcome a known adverse biomarker, and they also provide encouragement to search for other biomarkers of prognostic significance, ideally found in a higher percentage of patients,” he said at a briefing of studies to be presented at the 2015 annual meeting of the American Society of Clinical Oncology.

Dr. Julie M. Vose, ASCO president-elect, who comoderated the briefing but was not involved in the studies, said that the results show the importance of genetic testing to prevent overtreatment and rein in costs for low-risk patients, and to help improve treatment of high-risk patients with augmented therapies or additional treatment strategies.

The investigators focused on improving outcomes for children with favorable histology Wilms tumor who have loss of heterozygosity (LOH) mutations in chromosomal location 1p and 16q.

In the National Wilms Tumor Study 5, a multicenter North American cooperative trial, children with these mutations, who comprised 5% of the study population, had significantly worse outcomes. Among patients with stage I/II disease with LOH mutations at both chromosomal locations, the 4-year EFS in that trial was 74.9%, compared with 92% for patients with no LOH mutations. Among patients with stage III/IV disease, the respective 4-year EFS rates were 65.9% vs. 83%.

The investigators tested whether augmenting therapy would improve EFS for patients with favorable histology Wilms tumor with the combined LOH 1p and 16q mutations in two trials:

AREN0532 compared vincristine and dactinomycin with the same two drugs plus doxorubicin in patients with stage I/II disease.

AREN0533compared vincristine, dactinomycin, doxorubicin and radiation therapy with the same regimen plus four cycles of cyclophosphamide and etoposide in patients with stage III/IV disease.

In each trial, 4-year EFS rates were compared with those of the National Wilms Tumor Study 4. Median follow-up was 3.6 years.

The patients were generally able to tolerate the therapy well, Dr. Dix said. Short-term toxicities for patients with stage I/II disease were manageable, he noted.

Among patients with stage III/IV disease, the augmented regimen was associated with myelosuppression in 60% of patients, although this too was manageable, the investigators reported.

Dr. Dix and his colleagues noted that the augmented regimen for stage III/IV tumors may spare many patients from requiring even more intensive salvage therapy. They also acknowledged, however, that the augmented regimen is likely to cause reduced fertility in some patients, and urged clinicians to discuss the risks and benefits of augmented therapy with the patients’ families.

Testing for LOH 1p and 16q is available at the Children’s Oncology Group Biopathology Center at Nationwide Children’s Hospital in Columbus, Ohio, and at several other centers across North America, Dr. Dix noted.