Pediatr Blood Cancer 2012;58:334–343 REVIEW Lessons From the Past: Opportunities to Improve Childhood Cancer Survivor Care Through Outcomes Investigations of Historical Therapeutic Approaches for Pediatric Hematological Malignancies

Progress in therapy for pediatric hematological malignancies over the last five decades has resulted in remarkable gains in survival for children afflicted by these diseases. Five year survival exceeds 85% for children with acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL) and has reached 60% for those with acute myeloid leukemia (AML) [1]. This success resulted from discoveries that stimulated changes in therapeutic approaches over the last five decades. Increased understanding of cancer biology led to the improved diagnosis, risk assessment, disease monitoring, and treatment, as well as the discovery of therapeutic targets for drug development. More precise, non-invasive imaging technology facilitated nonsurgical staging for children with HL. Appreciation of both acute and late modality-specific toxicities motivated investigations to elucidate the pathophysiology and risk factors for treatmentrelated morbidity and mortality. The results of these studies have played a critical role in the evolution of pediatric cancer treatment approaches and informed risk counseling and health screening recommendations of long-term survivors. Contemporary therapy for the majority of pediatric malignancies is risk-adapted, based on a variety of clinical, biological, and genetic factors, and more recently, also on early treatment response. While novel biological and molecularly targeted agents are the subjects of ongoing research, cytotoxic chemotherapy, and irradiation continue to be used for the treatment of the majority of children diagnosed with cancer. Evaluation of late health outcomes of survivors treated with these modifications is important to characterize their subsequent health. However, one may debate how relevant the study of late effects of historical therapeutic approaches is to the design and evaluation of contemporary treatment protocols and follow-up of present-day survivors. Using data from representative pediatric cancer trials, this review will address this issue by: (1) summarizing major trends in the evolution of treatment of pediatric hematological malignancies since 1960; (2) identifying treatment-specific exposures in historic cohorts from the four decades before 2000 that have relevance to clinical trials in the past decade; and (3) determining the extent to which the study of retrospective cohorts of long-term survivors can be used to inform the anticipated risks of late effects in patients under active treatment.