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INTRODUCTION

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In the past four decades, the cure rate for childhood cancer has increased to nearly 85%. A growing understanding of the biology of childhood cancer coupled with advances in systemic cytotoxic chemotherapy; local control measures, including radiotherapy and surgery; and improvements in supportive care have made this achievement possible. Today, there are nearly 400,000 survivors of childhood cancer in the United States, many of whom have significant late effects of therapy. Understanding the principles of therapy and the inherent acute and long-term toxicities of cancer therapy is important for pediatricians and all healthcare providers who are caring for increasing numbers of childhood cancer survivors.

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The fundamental principle of curative therapy for children and adolescents with cancer is eradication of malignant cells and their precursors by tailoring treatment plans to incorporate surgery, radiation, and systemic chemotherapy, as required for specific cancer types and subtypes. The majority of pediatric cancers are best managed with a multidisciplinary approach in which local control with surgery or radiotherapy is used in combination with chemotherapy. Risk-stratified, multimodality therapy is based on a variety of factors including patient age and gender, site of disease, extent of disease (localized or disseminated, or extent of extramedullary involvement), histology, molecular characteristics of the cancer cells, and response to therapy. For many children and adolescents with solid tumors, complete surgical resection is a critical component of therapy. The established cornerstones of successful treatment with chemotherapy and radiation are (1) combination therapy, (2) dose intensity, and (3) adjuvant and neoadjuvant therapy. Anticancer drugs that inhibit the molecular signaling pathways in malignant cells and drugs that overcome cancer’s ability to evade immune response may provide a new foundation to improve outcome for children and adolescents with cancer.

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Combination Therapy

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Systemic chemotherapy generally combines several cytotoxic drugs that have synergistic mechanisms of action and nonoverlapping toxicity. This was defined early in the development of successful childhood leukemia therapy with the combination of methotrexate (MTX) and 6-mercaptopurine (6MP), a cornerstone of acute lymphoblastic leukemia (ALL) therapy today. Systemic chemotherapy can be administered prior to or following local control of solid tumors and may be administered concurrently or sequentially with radiation therapy in children or adolescents with leukemia or solid tumors.

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Dose Intensity

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Most cytotoxic 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. Better supportive care for immune-compromised children has improved our ability to deliver therapy at maximal dose intensity without stem cell rescue. Cytotoxic chemotherapy regimens are frequently administered intravenously every 2 to 3 weeks to permit normal tissues time to recover from the acute side effects.

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Preparative chemotherapy regimens for bone ...

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