Improving the outcome for children with cancer: Development of targeted new agents

Abstract

The outcome for children with cancer has improved significantly over the past 60 years, with greater than 80% of patients today becoming 5-year survivors. Despite this progress, cancer remains the leading cause of death from disease in children in the United States, and significant short-term and long-term treatment toxicities continue to impact the majority of children with cancer. The development of targeted new agents offers the prospect of potentially more effective and less toxic treatment for children. More than a decade since imatinib mesylate was introduced into the treatment of children with Philadelphia chromosome-positive acute lymphoblastic leukemia, transforming its outcome, a range of targeted agents has undergone study in pediatric cancer patients. Early lessons learned from these studies include a better understanding of the adverse event profile of these drugs in children, the challenge of developing pediatric-specific formulations, and the continued reliance on successful development for adult cancer indications on pediatric drug development. The collaborative research infrastructure for children with cancer in the United States is well positioned to advance novel treatments into clinical investigations for a spectrum of rare and ultra-rare childhood cancers. A greater investment of resources in target discovery and validation can help drive much needed development of new, more effective treatments for children with cancer.

Keywords: Children's Oncology Group; acute lymphoblastic leukemia; pediatric oncology/hematology; research infrastructure.

FIGURE 1

Approximate 5-Year Survival for Children Treated in 1960 (red bars) Versus Children Treated in the Year 2000 (blue bars). (A) Over the past 50 plus years, significant improvements in outcome have been made in a range of childhood cancers; (B) whereas, for certain cancers, despite intensification of treatment, progress has been more limited or has not been realized.

FIGURE 2

Trends in ALL Survival. Steady improvement in the outcome of children with acute lymphoblastic leukemia was observed from the late 1960s through the 1990s. This improvement in outcome continues today.

FIGURE 3

Highest Grade of Toxicity Experienced by Children Undergoing Treatment for Rhabdomyosarcoma. More than 80% of children with high-risk cancers experience severe, life-threatening, or fatal toxicity at some point during their treatment (data from: Crist W, Gehan EA, Ragab AH, et al. The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol. 1995;13:610–630).

FIGURE 4

Annual Accrual to Children’s Oncology Group Clinical Trials by Disease Area. For most childhood cancers, the only time accrual is limiting is when there is no open study, as occurred for non-Hodgkin lymphoma (NHL). ALL indicates acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CNS, central nervous system; NBL, neuroblastoma; STS, soft tissue sarcoma.

FIGURE 5

Long-Term Outcome of Children Treated on Children’s Oncology Group (COG) Study AALL0031. The study incorporated imatinib mesylate into a high-risk chemotherapeutic regimen for children with Philadelphia chromosome-positive acute lymphoblastic leukemia relative to historic controls who did not receive this targeted new drug (data from: Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a Children’s Oncology Group study. J Clin Oncol. 2009;27:5175–5181; Schultz KR, Carroll A, Heerema NA, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s Oncology Group study AALL0031. Leukemia. 2014;28:1467–1471; and personal communication, Steven Hunger, MD).