A test measuring the status of DNA multiplication in tumor cells (ploidy), along with other known predictors of treatment response, could provide guidance in selecting chemotherapy for infants with neuroblastoma, the most common childhood cancer, according to a study reported in the March 5th Journal of the National Cancer Institute.
Laura C. Bowman, md, St. Jude Children's Research Hospital, Memphis, Tennessee, and coauthors of the study report explain that existing systems for staging infants under 1 year of age with inoperable or metastatic neuroblastoma have been inadequate for predicting response to chemotherapy. Their earlier studies had suggested that the DNA content (or ploidy) of the malignant neuroblast cells might be a predictor of treatment response. Based on those results, the researchers conducted a prospective, nonrandomized study of 172 infants with nonresectable or metastatic neuroblastoma to determine whether neuroblast ploidy could be used to guide treatment choice and to differentiate between those who would respond to standard therapy and those requiring an immediate switch to an alternative chemotherapy regimen. The authors note that a delay in initiating alternative chemotherapy when standard therapy is ineffective is associated with a worse outcome.
Of the infants in the study whose tumor cell ploidy status could be assessed, 127 had hyperdiploid tumors, while 41 had diploid tumors. Ploidy status was assessed after all of the children received one initial cycle of cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) plus doxorubicin(Drug information on doxorubicin) (a well-tolerated standard therapy). Those with diploid tumors were then switched to cisplatin(Drug information on cisplatin) (Platinol) followed by teniposide(Drug information on teniposide) (Vumon), since earlier studies suggested that diploid tumors responded less well to standard therapy. Infants with hyperdiploid tumors received successive cycles of cyclophosphamide and doxorubicin; if any of these children showed evidence of disease progression, however, they were switched to the alternative chemotherapy.
The researchers also assessed other prognostic factors commonly measured in patients with neuroblastoma, such as NMYC gene copy number, serum lactate dehydrogenase, and tumor stage. After treatment, the children were followed for a median of 5.6 years.
Study Results
Of the 127 infants with hyperdiploid tumors, 115 (91%) had complete responses (defined as more than 90% regression of tumor at the primary site and complete regression of all metastatic disease, including bone lesions). The 3-year survival estimate for this group was 94%. Among the infants with diploid tumors, 19 (46%) of the 41 assessable children had complete responses, and the overall 3-year survival estimate was 55%. The researchers also found that amplified NMYC gene (ie, extra copies of this gene) and elevated serum lactate dehydrogenase were statistically significant markers of higher-risk disease in the diploid group.
On the basis of these results, the authors believe that tumor cell ploidy is a major determinant of treatment response variation in neuroblastoma and that a prognostic staging system based on ploidy and augmented with NMYC gene copy number and serum lactate dehydrogenase level would likely improve treatment selection for infants with inoperable or metastatic disease. The high-risk group defined by diploid tumors with amplified NMYC, they suggest, may particularly benefit from innovative new therapies.
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