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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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Combination Therapy

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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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Dose Intensity

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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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Adjuvant Therapy

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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 local therapy with ...

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