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 (Cytoxan, Neosar) plus doxorubicin (a well-tolerated
standard therapy). Those with diploid tumors were then switched to cisplatin
(Platinol) followed by 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.
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.