Risk-adapted therapy is a central concept in pediatric oncology phase
III clinical trials. Progress over the past five decades has resulted
in treatments that produce 5-year survival rates in excess of 90% for
some diagnoses, including Wilms tumor, Hodgkin lymphoma, and neuroblastoma occurring
in infants. However, some diagnoses continue to have very guarded
prognoses, including metastatic sarcomas of bone and soft tissues,
neuroblastoma occurring beyond infancy, and brain stem glioma or
supratentorial high-grade glioma. Even children with the same diagnosis
can have vastly different prognosis based on both clinical characteristics,
as well as on biologic characteristics of their cancers. As examples,
infants with disseminated neuroblastoma whose tumors have amplification
of the MYCN gene have long-term survival of less
than 30%, while similar infants with neuroblastoma whose tumors
have normal MYCN gene number have long-term survival
of greater than 90%. Likewise, children with acute lymphoblastic
leukemia (ALL) and favorable biological features (eg, a chromosomal
translocation involving the TEL and AML genes
or extra copies of multiple whole chromosomes) have quite favorable
outcome, while children with ALL and unfavorable biologic features
(eg, a chromosomal translocation involving the BCR and ABL genes)
have a much less favorable outcome. Clinical trials for children
who have cancers with favorable prognosis are tailored to their more
favorable outcome by evaluating modest modifications of standard
therapy that seek to reduce treatment-related sequelae while maintaining
favorable outcome. Conversely, clinical trials for children with
cancers associated with an unfavorable prognosis often evaluate
more aggressive treatment approaches or highly novel treatment strategies
that seek to improve survival rates above the currently unacceptable low
levels. All pediatric cancer clinical trials demand rigorous quality
assurance of eligibility, adherence to protocol-specified treatment
and evaluations, as well as validity of individual study subject
data, which are incorporated in the final study database. Fastidious
quality control guarantees the integrity of the science, which defines
the standard of care.