Genetic Staging of Unresectable or Metastatic Neuroblastomain Infants: a Pediatric Oncology Group Study (original) (raw)

Journal Article

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Department of Hematology-Oncology, St. Jude Children's Research Hospital, and Department of Pediatrics, University of Tennessee

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Memphis

Correspondence to: Laura C. Bowman, M.D., Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794.

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Department of Pediatrics, University of Alabama

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Birmingham

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Moffitt Cancer Center and Research Institute, Cancer Control

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Tampa, FL

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Department of Pathology, East Carolina University

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Greenville, NC

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Children's Memorial Hospital and Department of Pediatrics, Northwestern University

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Chicago, IL

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Smith, Southwestern Medical Center and Department of Pediatric Surgery, University of Texas

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Dallas

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Department of Pediatrics, University of California

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San Diego

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Division of Oncology, Children's Hospital of Philadelphia

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PA

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Immunex Corporation

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Seattle, WA

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Department of Experimental Oncology and Department of Hematology-Oncology, St. Jude Children's Research Hospital, and Department of Pediatrics, University of Tennessee

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Received:

12 September 1996

Revision received:

23 December 1996

Accepted:

03 January 1997

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Laura C. Bowman, Robert P. Castleberry, Alan Cantor, Vijay Joshi, Susan L. Cohn, E. Ide Smith, Alice Yu, Garrett M. Brodeur, F. Ann Hayes, A. Thomas Look, Genetic Staging of Unresectable or Metastatic Neuroblastomain Infants: a Pediatric Oncology Group Study, JNCI: Journal of the National Cancer Institute, Volume 89, Issue 5, 5 March 1997, Pages 373–380, https://doi.org/10.1093/jnci/89.5.373
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Background: Current staging systems for unresectable or metastatic neuroblastoma do not reliably predict responses to chemotherapy in infants under 1 year of age. Previous studies have indicated that the DNA content, or ploidy, of malignant neuroblasts can discriminate between good and poor responders in this group of patients, but the clinical utility of ploidy assessment has remained in question. Purpose: We tested, in a prospective nonrandomized study, the hypothesis that neuroblast ploidy could be used as the sole guide for treatment selection in infants with unresectable or metastatic tumors and could differentiate between those who would respond to our previous standard regimen and those who would benefit from an immediate switch to another therapy. Methods: One hundred seventy-seven infants were enrolled in this trial. Five of these infants were subsequently excluded (two ineligible, two lacking ploidy information, and one protocol violation); therefore, 172 patients were included in the study. One hundred thirty infants with hyperdiploid tumors (DNA index > 1.0; better prognosis in retrospective studies) were treated with a well-tolerated regimen of cyclophosphamide (150 mg/m 2 per day orally or intravenously ondays 1–7) and doxorubicin (35 mg/m 2 intravenously on day 8). Forty-two infants with diploid tumors (DNA index = 1.0; worse prognosis in retrospective studies) received cisplatin (90 mg/m 2 intravenously on day 1) and teniposide (100 mg/m 2 intravenously on day 3) after an initial course of cyclophosphamideplus doxorubicin. Statistical end points were response and long-term survival. In addition, we assessed within each ploidy group (i.e., patients with hyperdiploid tumors and those with diploid tumors) the prognostic significance of NMYC gene copy number, tumor stage, and other variables commonly measured in this disease. Results: Of the 127 assessable infants with hyperdiploid tumors, 115 (91%) had complete responses—85 after receiving five courses of cyclophosphamide plus doxorubicin and 30 after receiving further therapy including cisplatin plus teniposide. The 3-year survival estimate for the entire hyperdiploid group was 94% (95% confidence interval [CI] = 89%–98%). Nineteen (46%) of 41 assessable infants with diploid tumors were complete responders. The overall 3-year survival estimate for this group was 55% (95% CI = 39%–70%). Prognostic factor analysis indicated that NMYC gene amplification and an elevated serum lactate dehydrogenase level were statistically significant markers of higher risk disease within the diploid group (two-sided P values of .005 and .003, respectively). Only NMYC was predictive in the hyperdiploidgroup ( P = .003). Conclusion: Use of a prognostic staging system based on tumor cell ploidy, augmented with the NMYC gene copy number and serum level of lactate dehydrogenase,would very likely improve the treatment of infants with unresectable or metastatic neuroblastoma. Patients with diploid tumors characterized by an amplified NMYC locus represent a particularly unfavorable risk group that may benefit from innovative new therapies. [JNatl Cancer Inst 1997;89:373–80]

Topic:

• diploidy
• infant
• genetics
• neoplasms
• pediatric oncology
• group trial

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