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Dose Intensity of Chemotherapy for Childhood Cancers

Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA

Correspondence: Malcolm Smith, M.D., Ph.D., Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Room 741, EPN, Bethesda, MD 20892, USA. Telephone: 301-496-2522; Fax: 301-402-0557; e-mail: smithm{at}dct.nci.nih.gov

Since the formulation of the "dose-intensity" concept of anticancer therapy in the mid-1980s, the concept that "more is better" has gained general acceptance among pediatric oncologists. However, recently published clinical trials results for adults with breast cancer, germ-cell tumors, and ovarian cancer raise questions about the value of dose intensification in improving outcome. Given the differences in sensitivity between pediatric and adult tumors to cytotoxic agents, the results from these adult trials suggest a need for caution but do not suggest that evaluations of dose intensity for pediatric tumors are unwarranted (especially for a tumor such as Ewing’s sarcoma, which is especially sensitive to alkylating agents).

Since dose-intensive therapies have significant short- and long-term costs for the patient, it is important to obtain reliable data concerning possible benefits of this strategy. Toward this end, NCI-sponsored randomized clinical trials evaluating the role of dose intensification have been initiated for several tumors of children (including neuroblastoma, germ-cell tumors, Ewing’s sarcoma, and brain tumors in infants). These trials should be completed and reported in the next two to three years, and they may make unique contributions in defining the benefits and limitations of dose intensity as a cancer treatment strategy.

In the long term, however, the utility of dose intensification is limited for children with cancer because of the inherent toxicities associated with its application. Identification of agents that more specifically target tumor cells is essential. Fortunately, pediatric tumor cells do have unique biological characteristics that may be susceptible to targeting for therapeutic benefit.

Key Words. Drug dose-response relationship • Ewing’s sarcoma • Rhabdomyosarcoma • Neuroblastoma • Alkylating agents • Acute lymphocytic leukemia • Child • Infant