Lessons from the past: Opportunities to improve childhood cancer survivor care through outcomes investigations of historical therapeutic approaches for pediatric hematological malignancies

Abstract

Investigations of long-term outcomes have been instrumental in designing safer and more effective contemporary therapies for pediatric hematological malignancies. Despite the significant therapeutic changes that have occurred over the last five decades, therapy modifications largely represent refinements of treatment protocols using agents and modalities that have been available for more than 30 years. This review summarizes major trends in the evolution of treatment of pediatric hematological malignancies since 1960 to support the relevance of the study of late effects of historical therapeutic approaches to the design and evaluation of contemporary treatment protocols and the follow-up of present-day survivors.

Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study

“…Whereas contemporary protocols aim to restrict or eliminate gonadotoxic treatment exposures, alkylating agents are a critical component of therapy for many haematological and solid paediatric malignancies and are likely to remain so, in the immediate future, considering the excellent outcomes achieved with current regimens and the challenges associated with integrating novel, potentially less toxic, agents into first-line therapies. 48,49 Thus, our findings have clinical relevance to the counselling and management of children and adolescents who need alkylating agent chemotherapy to achieve long-term disease-free survival. Additional investigation is needed to address the effect of alkylating agent exposure to define exposure-specific risks related to fertility, the role of genetic factors that modulate the sensitivity of an individual's germinal epithelium to alkylating agents, and interventions to optimise access to and participation in age-appropriate methods of gamete preservation.…”

Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions

“…For example, in the aforementioned 1975 proceedings, Gilladoga and colleagues 16 recommended maximum cumulative anthracycline doses of 500 and 600 mg/m 2 in children treated with or without cardiac radiation, respectively. Subsequently, newer protocols have sought to balance the benefits of treatment with the risk of anthracycline-related cardiomyopathy by testing lower cumulative doses 18 and alternative dosing schedules and methods of administration, 19,20 as well as by adding potentially cardioprotective agents. [21][22][23] Similarly, to reduce the risk of cardiac disease and second malignant neoplasms (eg, breast cancer), the use, dose, and volume of radiation to the heart has decreased substantially in frontline trials for children with hematological and low-stage, biologically favorable solid malignancies.…”

“…Most pediatric cancer protocols still rely on cytotoxic chemotherapy and radiation, with few integrating new biological and molecularly targeted agents. 18 Research establishing dose-related toxicity profiles for specific chemotherapeutic agents (eg, anthracyclines; alkylating agents) and radiation has guided their risk-adapted use in current protocols. The universal objective of all pediatric cancer trials is to prescribe treatments at cumulative doses that balance cancer control with preserved health and function of normal tissues.…”

A Systematic Review of Selected Musculoskeletal Late Effects in Survivors of Childhood Cancer

“…There has been a gradual refinement in therapeutic approaches to reduce late effects (31, 115) and several studies included in this review were instrumental in this process. Identification of adverse musculoskeletal effects after asymmetric and high-dose radiation among children treated for Wilms tumor led to the use of symmetric administration and lowering of radiation dose and restriction of radiation to only those with advanced stage tumor (31).…”