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illustration of cancer cells attacking kidneys

Renal cell carcinoma study shows excellent short-term outcomes without adjuvant therapy

illustration of cancer cells attacking kidneys

Researchers found that patients with localized pediatric renal cell carcinoma have excellent short-term outcomes without adjuvant therapy.

Although renal cell carcinoma (RCC) is the second most common kidney cancer diagnosed in children and adolescents, guidance regarding its clinical management has been confined to retrospective case series, which were limited by reporting bias, varied treatment approaches and a lack of central pathology review to confirm the diagnosis.

Research conducted by the Children’s Oncology Group (COG) and led by Jeffrey Dome, M.D., Ph.D., vice president of the Center for Cancer and Blood Disorders at Children’s National Hospital, found that patients with localized pediatric RCC have excellent short-term outcomes without adjuvant therapy with 4-year overall survival estimates of 96% for patients with stage I disease, 100% for patients with stage II disease and 88% for patients with stage III disease.

“The results of this study provide important practical insights into the management of pediatric RCC,” said Dr. Dome. “Oncologists now have validation that a surgery-only approach is appropriate management for the majority of children and adolescents with RCC.”

Jeffrey Dome

“The results of this study provide important practical insights into the management of pediatric RCC,” said Jeffrey Dome, M.D., Ph.D.

The excellent survival in patients with stage III disease held up even in those with tumor involvement of regional lymph nodes, a finding that differs from adult RCC. However, patients with metastatic disease (stage IV), had a 4-year overall survival estimate of only 29%, demonstrating the need to find active treatments for this group. Outcomes varied according to tumor histological subtype. Nearly all recurrences occurred in patients with the translocation histology and renal medullary carcinoma; recurrences were rare in other subtypes.

A follow-up study called AREN1721 is now open in the Children’s Oncology Group and adult cancer cooperative groups that participate in the National Clinical Trials Network. This study involves a comparison of two treatment regimens for metastatic or unresectable “translocation” renal cell carcinoma, the most common subtype of renal cell carcinoma in children, adolescents and young adults. The treatment regimens will include nivolumab, a PD1 immune checkpoint inhibitor, with or without axitinib, a tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR).

Jeffrey Dome

Treating Wilms Tumor with vincristine and irinotecan

Jeffrey Dome

“The study was impactful because it established the activity of vincristine/irinotecan against Wilms tumor. Based on these findings, this chemotherapy combination will be applied more broadly in the treatment of Wilms tumor,” says study leader Jeffrey S. Dome, M.D, Ph.D.

Wilms tumor, the most common kidney cancer of childhood, may be classified into different subtypes based on its appearance under the microscope. The “favorable histology” subtype is associated with an excellent survival rate of approximately 90%, whereas the “diffuse anaplastic” subtype is associated with survival rates of only 55% for patients with stage II-IV disease.

The Children’s Oncology Group AREN0321 study, led by Jeffrey S. Dome, M.D, Ph.D., vice president of the Center for Cancer and Blood Disorders at Children’s National Hospital, tested the anti-tumor activity of the chemotherapy combination vincristine and irinotecan in patients with metastatic diffuse anaplastic Wilms tumor.

The study also evaluated whether a new treatment regimen containing carboplatin in addition to the currently used agents (vincristine, doxorubicin, cyclophosphamide and etoposide) would improve patient outcomes. The results, published in the March 5th issue of the Journal of Clinical Oncology, showed that the vincristine/irinotecan combination is highly active. Out of the group, 78% of patients who received this combination had an objective tumor response.

The study also demonstrated that additional chemotherapy drugs can reduce the rate of relapse, but it is likely that we have reached the limit of what children can tolerate. “Future gains will likely be made by using agents with novel mechanisms of action, such as immunotherapy and new drugs that target the molecular abnormalities of Wilms tumor cells,” says Dr. Dome.

Moreover, the additional chemotherapy agents improved cancer-free survival rates to levels unprecedented for diffuse anaplastic Wilms tumor. However, the decrease in relapse rate came at the cost of increased toxicity.

“The study was impactful because it established the activity of vincristine/irinotecan against Wilms tumor. Based on these findings, this chemotherapy combination will be applied more broadly in the treatment of Wilms tumor,” Dr. Dome added.

Chromosomes

Precision medicine for Wilms tumor patients

Chromosomes

Previously, researchers discovered that loss of heterozygosity (LOH) on chromosomes 1 and 16 is associated with a significantly increased risk of relapse of Wilms tumor.

About 650 children are diagnosed each year in the U.S. with Wilms tumor, the most common pediatric kidney cancer. The vast majority of patients respond well to the current standard of care involving a combination of surgery, chemotherapy and radiation. However, approximately 20% of patients with “favorable histology” Wilms tumor experience recurrence.

Previously, researchers discovered that loss of heterozygosity (LOH) on chromosomes 1 and 16 is associated with a significantly increased risk of relapse. A research team in the Children’s Oncology Group (COG), led by Jeffrey Dome, M.D., Ph.D., vice president of the Center for Cancer and Blood Disorders at Children’s National Hospital, sought to determine whether an augmented chemotherapy regimen can overcome the negative effect of LOH.

More than 2,500 patients with Wilms tumor were enrolled in the biology and classification study over a 7–year period. Tumor tissue was tested for LOH and patients with LOH at both chromosomes 1 and 16 received more intensive chemotherapy regimens compared to the standard approach. The results showed that the increased treatment provided a statistically significant benefit in the 4-year event-free survival, with trends toward improved overall survival. For low-stage disease (stage I-II), the four-year event-free survival was 87.3%, compared to a historical rate of 68.8%. Similarly, for advanced stage disease (stage III/IV) four-year event-free survival was 90.2%, compared with 61.3% historically.

Although the new regimens involved additional chemotherapy agents compared to the standard regimens, the short-term toxicities were expected and manageable. There is an increased risk of long-term toxicity including infertility and second malignancies, which requires careful discussion with families. Future studies will seek to mitigate these risks with newer chemotherapy agents.

By better understanding which patients might benefit from more intensive treatment regimens through precision medicine, doctors can tailor therapy according to the risk of relapse, Dr. Dome says.

“This study represents a significant milestone in the treatment of Wilms tumor because it is the first to demonstrate that patient outcome can be improved using a molecular biomarker to guide treatment,” he explains. “We have entered the age of precision medicine for Wilms tumor.”

cancer-patient-Sully-Shields

New approach improves pediatric kidney cancer outcomes

cancer-patient-Sully-Shields

Wilms tumor, also known as nephroblastoma, is the most common pediatric kidney cancer, typically seen in children ages three to four. Compared to patients with unilateral Wilms tumors, children with bilateral Wilms tumors (BWT) have poorer event-free survival (EFS) and are at higher risk for later effects such as renal failure. The treatment of BWT is challenging because it involves surgical removal of the cancer, while preserving as much healthy kidney tissue as possible to avoid the need for an organ transplant.

A new Children’s Oncology Group (COG) study published in the September issue of the Annals of Surgery demonstrated an exciting new approach to treating children diagnosed with BWT that significantly improved EFS and overall survival (OS) rates after four years when compared to historical rates. Jeffrey Dome, M.D., Ph.D., Vice President of the Center for Cancer and Blood Disorders at Children’s National Health System, was co-senior author of this first-ever, multi-institutional prospective study of children with BWT.

Historically, patients with BWT have had poor outcomes, especially if they have tumors with unfavorable histology. In this study, Dr. Dome and 18 other clinical researchers followed a new treatment approach consisting of three chemotherapy drugs before surgery rather than the standard two drug regimen, surgical removal of cancerous tissue within 12 weeks of diagnosis, and postoperative chemotherapy that was adjusted based on histology.

The study found that preoperative chemotherapy expedited surgical treatment, with 84 percent of patients having surgery within 12 weeks of diagnosis. The new treatment approach also vastly improved EFS and OS rates for patients participating in the study. The four-year EFS rate was 82.1 percent, compared to 56 percent on the predecessor National Wilms Tumor Study-5 (NWTS-5) study. The four-year OS rate was 94.9 percent, compared to 80.8 percent on NWTS-5.

“I am very encouraged by these results, which I believe will serve as a benchmark for future studies and lead to additional treatment improvements, giving more children the chance to overcome this diagnosis while sparing kidney tissue,” says Dr. Dome.

A total of 189 patients at children’s hospitals, universities and cancer centers in the United States and Canada participated in this study. These patients will continue to be followed for 10 years to track kidney failure rates. This study was funded by grants from the National Institutes of Health to the Children’s Oncology Group.