New Drug Development for Children with Cancer

Since the introduction of chemotherapy more than 50 years ago, the prognosis of childhood cancer has improved dramatically, with overall 5-year survival rates approaching 80%. Despite these advances, several childhood cancers still have unacceptably low cure rates, and even when treatment is successful, the acute and long-term morbidity of current therapy can be substantial. Over the past decade, progress in our ability to improve the outcome for children with cancer has slowed significantly. We are, however, entering an era with the potential to understand the molecular basis of all childhood cancers in a timeframe previously unimaginable. At a national level, however, our cancer clinical trials infrastructure faces a number of challenges, most notably the ability to move new ideas forward towards successful clinical trials in a timely manner. Our clinical trial resources will need to be primarily focused on diseases with poor to moderate outcome where there is a clear rationale to investigate a relevant targeted new agent. Coupled to this challenge will be to design trials that can clearly isolate the effect of a new agent under study. The most significant near term change may well be in the design of phase II trials, with incorporation of randomized designs needing to be increasingly utilized. Academic centers, government, industry and patient advocates must work together towards a common goal of leveraging discoveries into improved outcomes for all children with cancer. Since the introduction of chemotherapy for the treatment of childhood leukemia more than 50 years ago, (1) the prognosis of childhood cancer has improved dramatically. The 5-year survival rate for childhood cancers, many of which were uniformly fatal in the pre-chemotherapy era, was 80% for all forms of childhood cancer diagnosed between 1996 and 2004. (2) This improvement in survival is a result of the incorporation of anticancer drugs into treatment regimens that previously relied only on surgery or radiotherapy for the primary tumor. The multimodality approach, which integrates surgery and radiotherapy to control local disease with chemotherapy to eradicate systemic disease, has become the standard approach to treating most childhood cancers. Despite these advances, several childhood cancers still have unacceptably low cure rates, (3) and even when treatment is successful, the acute and long-term morbidity of current therapy can be substantial. (4,5) As detailed in recent report based on data from the Surveillance, Epidemiology and End Results (SEER) Program, over the past decade progress in our ability to improve the outcome, as measured by the overall mortality rate, has slowed substantially for children with cancer, most notably for children with solid tumors. (6) Over the past 35+ years, the overarching strategic approach for most childhood cancer treatment, intensification of therapy, is no longer yielding meaningful improvement in survival. As is well known to pediatric oncologists, children who receive standard dose-intensive chemotherapy have greater than an 80% chance of having at least one drug-related toxicity that is severe, life threatening or fatal over the course of their treatment, (7) and the late effects of cancer treatment, including permanent organ and tissue damage, hormonal and reproductive dysfunction and second cancers, are of special concern. Perhaps more startling is a recent report that, relative to the general population, the overall life expectancy for survivors of childhood cancer is shortened by 10 years. (8) Thus the development of new anticancer drugs must be a priority for childhood cancer basic, translational and clinical researchers.