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Clinical Outcome and Biological Predictors of Relapse After Nephrectomy Only for Very Low-risk Wilms Tumor: A Report From Children's Oncology Group AREN0532

Fernandez, Conrad V. MD, FRCPC; Perlman, Elizabeth J. MD; Mullen, Elizabeth A. MD; Chi, Yueh-Yun PhD; Hamilton, Thomas E. MD; Gow, Kenneth W. MD; Ferrer, Fernando A. MD; Barnhart, Douglas C. MD, MSPH; Ehrlich, Peter F. MD, MSc; Khanna, Geetika MD; Kalapurakal, John A. MD, FACR; Bocking, Tina BN, RN; Huff, Vicky PhD; Tian, Jing MS; Geller, James I. MD; Grundy, Paul E. MD; Anderson, James R. PhD; Dome, Jeffrey S. MD, PhD; Shamberger, Robert C. MD

doi: 10.1097/SLA.0000000000001716
Original Articles

Objective: To determine if observation alone after nephrectomy in very low-risk Wilms tumor (defined as stage I favorable histology Wilms tumors with nephrectomy weight <550g and age at diagnosis <2 years) results in satisfactory event-free survival and overall survival, and to correlate relapse with biomarkers.

Patients and Methods: The AREN0532 study enrolled patients with very low-risk Wilms tumor confirmed by central review of pathology, diagnostic imaging, and surgical reports. After nephrectomy, patients were followed without adjuvant chemotherapy. Evaluable tumors were analyzed for WT1mutation, 1p and 16q copy loss, 1q copy gain, and 11p15 imprinting. The study was powered to detect a reduction in 4-year EFS from 87% to 75% and overall survival from 95% to 88%.

Results: A total of 116 eligible patients enrolled with a median follow up of 80 months (range: 5–97 months). Twelve patients relapsed. Estimated 4-year event-free survival was 89.7% (95% confidence interval 84.1–95.2%) and overall survival was 100%. First sites of relapse were lung (n = 5), tumor bed (n = 4), and abdomen (n = 2), with one metachronous tumor in the contralateral kidney (n = 1) at a median time of 4.3 months for those who relapsed (range 2.3–44 months). The presence of intralobar (P = 0.46) or perilobar rests (P = 1.0) were not associated with relapse (P = 0.16). 1q gain, 1p and 16q loss, and WT1 mutation status were not associated with relapse. 11p15 methylation status was associated relapse (20% relapse with loss of heterozygosity, 25% with loss of imprinting, and 3.3% relapse with retention of the normal imprinting (P = 0.011)).

Conclusions: Most patients meeting very low-risk criteria can be safely managed by nephrectomy alone with resultant reduced exposure to chemotherapy. Expansion of an observation alone strategy for low-risk Wilms tumor incorporating both clinical features and biomarkers should be considered.

*IWK Health Center, Dalhousie University, Halifax, Nova Scotia, Canada

Ann and Robert H. Lurie Children's Hospital, Chicago, IL

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA

§Department of Biostatistics, University of Florida, Gainesville, FL

Boston Children's Hospital, Boston, MA

||Division of General and Thoracic Surgery, Seattle Children's Hospital, Seattle, WA

**Connecticut Children's Medical Center, Hartford, CT

††Primary Children's Hospital, Salt Lake City, UT

‡‡University of Michigan, Ann Arbor, MI

§§Washington University School of Medicine in St. Louis, St. Louis, MO

¶¶Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL

||||Anderson Cancer Center, Houston, TX

***Children's Oncology Group Data Center, University of Florida, Gainesville, FL

†††Cincinnati Children's Hospital Medical Center, Cincinnati, OH

‡‡‡Alberta Health Services, Edmonton, Alberta, Canada

§§§Merck Research Laboratories – Oncology, North Wales, PA

¶¶¶Children's National Medical Center, District of Columbia, WA.

Reprints: Conrad V. Fernandez, MD, FRCPC, Department of Pediatrics, IWK Health Center, 5850/5980 University Ave, PO Box 9700, Halifax NS B3K 6R8 Canada. E-mail: conrad.fernandez@iwk.nshealth.ca.

Funding: The study is supported by grants U10CA180886, U10CA180899, U10CA098543, U10CA098413, and U24CA114766 from the National Cancer Institute, National Institutes of Health (NIH), to support the Children's Oncology Group (COG). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Clinical Trials.gov identifier: NCT00352534.

E. J. P. received R21 grant money from the NIH relevant to this study.

E. A. M., C. V. F., and J. A. K. received support for travel to meetings relevant to this study from the U10 grants cited above administered through the COG. J. A. K. has a grant pending in application from COG.

Y. Y. C., J. T., P. E. G., J. R. A., and J. S. D.'s institution received grant money relevant to this study from the U10 grants cited above administered through the COG. J. R. A. is currently employed at Merck but the manuscript was completed before this employment. J. S. D. holds a patent with St. Jude's Research Hospital for the invention of telomerase antibody for which he receives royalties.

Disclosure: Presented in part at the 2015 American Society of Clinical Oncology annual meeting, Chicago, IL, May 31, 2015.

The authors declare no conflicts of interest.

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