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Over the last four decades of the 20th century, the cure rates
for childhood cancer increased from less than 30% to almost
80%.1 Remarkably, most of the advances did not
occur from the discovery of new drugs; rather, they came from a better
understanding of the underlying biology of childhood cancers; from
improvements in the supportive care necessary for the delivery of
multimodality therapy; and from improvements in our understanding
and use of chemotherapy, radiotherapy, and surgery. The turn of
the century saw the introduction of molecularly targeted therapy,
heralded by the development of imatinib mesylate (Gleevec) for the
treatment of chronic myelogenous leukemia.2 Even as new
molecularly targeted therapies emerge, the success of cytotoxic
chemotherapy, coupled with the accumulating data of the potential
value of integrating molecularly targeted therapies with classic
cytotoxic drugs,3 suggests that the chemotherapeutic drugs
and radiotherapeutic modalities utilized today are likely to remain
the foundation of therapy for the foreseeable future. Advances in
radiation delivery have improved the therapeutic ratio in children,
enabling safer use of conformal radiation techniques that better
spare the developing normal tissues. An understanding of the principles
of therapy and management of the inherent toxicities of cancer therapy
are therefore important for pediatricians today.
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There are three fundamental principles of cancer
chemotherapy that are the cornerstone of successful treatment: (1)
combination chemotherapy, (2) dose intensity, and (3) adjuvant and
neoadjuvant chemotherapy.
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Systemic
treatment with chemotherapy works best when a combination of several agents
is used. This was first defined in a study conducted in the late
1950s in which children with acute lymphoblastic leukemia (ALL)
who were treated with concomitant administration of oral methotrexate
(MTX), an antifolate, and oral 6-mercaptopurine (6MP), a hypoxanthine
analog, had a significantly longer duration of remission than children
treated with these agents administered sequentially.4 The
principle of combining agents with different mechanisms of action,
especially those that are synergistic on a mechanistic basis, was
thus defined early in the development of successful childhood leukemia
therapy, and the combination of MTX and 6MP remains a cornerstone
of ALL therapy today.
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Most anticancer drugs have a steep dose-response curve, and small
increments in dose can significantly influence a drug’s
therapeutic efficacy. For many pediatric cancers, administration of
each chemotherapy agent at the maximum dose intensity, defined as
the amount of drug administered per unit of time (eg, mg/m2 per
week), correlates with an improved outcome.5 With a better
understanding of caring for the immunocompromised child, including
improved blood product support, administration of broad-spectrum
antibiotics for managing febrile neutropenia, and cytokine support
for myelosuppression, our ability to deliver chemotherapy at maximal
dose intensity has improved significantly.
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Chemotherapy is most successful when administered in the adjuvant setting—that
is, when there is no evidence of residual disease following ...