Clinical trials have played a central role in converting many
of the once fatal childhood cancers into conditions in which the
vast majority of children with these diagnoses can be cured. For
example, much of the progress in improving survival rates for children
with acute lymphoblastic leukemia (ALL) can be attributed to the
conduct of sequential phase III clinical trials in which more effective
treatment approaches for children with ALL were reliably identified
and carried forward as the standard of care that replaced less effective
therapies. The end result of these series of clinical trials conducted
over more than four decades has been the identification of treatments
that produce much higher 5-year survival rates than those previously
achieved (Fig. 446-1).
Five-year relative survival rates for children (<
15 years) with acute lymphoblastic leukemia.
Pediatric oncologists continue to feel that it is generally appropriate to
offer families the opportunity to participate in clinical trials,
because even the best currently available treatments are not optimal
for many childhood cancers. For many cancers, a substantial proportion
of children do not achieve long-term survival with current standard
treatments. Furthermore, many treatment approaches cause short-
and long-term treatment-related sequelae that reduce quality of
life and survivorship. Although participation in clinical trials
cannot provide guaranteed benefit to individual study subjects,
the conduct of well-designed clinical trials addressing critical
questions of therapy, most often linked to correlative biologic
studies, remains the path forward for identifying more effective
and less toxic treatments for children with cancer.
The general ethical principles that apply to research involving
children are especially important in the pediatric oncology setting,
given the vulnerability of children with these life-threatening
diseases. Subpart D of the Code of Federal Regulations represents
the regulatory embodiment of these principles, and institutional
review boards are responsible for ensuring adherence to these principles.
As cancer therapies evaluated in the research setting inherently
involve greater than a minor increase over minimal risk, participation
by children in cancer treatment clinical trials must offer the prospect
of direct benefit as prescribed by 45 CFR 46.405 (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).
The risks associated with clinical trial participation must be justified
by the anticipated benefit, and the relation of benefit to risk
must be at least as favorable as current treatment alternatives
for the population being studied.
Phase I clinical trials for children with cancer are a key step
in the introduction of new treatment approaches into the pediatric
setting.1 The standard approach to these “first
in children” clinical trials of novel anticancer agents
requires previously defining the toxicity profile of the agent and
establishing a recommended phase II dose for the agent in adult
cancer patients. This adult experience allows the initial pediatric
phase I study, conducted in children with resistant or refractory
diseases, to begin at a dose near the adult recommended phase ...