When chemotherapy agents are used to treat cancer, they are most effective when administered in combination. The development of drug combinations evolved from the pioneering work by medical oncologists in the 1950s and 1960s. For example, clinical studies led by Frei and Freireich demonstrated that dramatic improvements in the treatment of childhood leukemia could be achieved through the use of increasing numbers of drugs (1,2). Specifically, response rates in the range of 40% and no cures with methotrexate alone increased to >95% complete response and 35% cure rates with the inclusion of 6-mercaptopurine, prednisone, and vincristine into the treatment regimen. Eventually, cure rates increased to 75% to 80% with the inclusion of asparaginase, daunorubicin, and cytarabine. The principle

underlying this approach was to administer combinations of chemotherapeutic drugs with nonoverlapping toxicities in full doses as early as possible in the disease (3).