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Outcomes Research Program Focuses on Late Effects of Pediatric Cancer Therapies

Published on September 24, 2024 in Cornerstone Blog · Last updated 3 months ago
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Dr. Sogol Mostoufi-Moab is the Director of the new Pediatric Cancer Survivorship Outcomes Research Program.

Dr. Sogol Mostoufi-Moab is the Director of the new Pediatric Cancer Survivorship Outcomes Research Program.

More than 80% of children treated for cancer survive at least five years due to advances in therapies, but some can develop serious health problems as they grow older, known as late effects. Each child's experience is unique, depending on the type of cancer and type of treatments, such as chemotherapy, radiation, surgery, and immune therapy, and other factors.

For example, if a child has radiation to the abdomen, they can subsequently develop diabetes mellitus in young adulthood. For a child who has brain radiation, they may experience poor growth as a result of growth hormone deficiency.

A new Pediatric Cancer Survivorship Outcomes Research Program at Children's Hospital of Philadelphia is dedicated to improving long-term health and outcomes for childhood cancer survivors throughout their lifespan. Working together, researchers at CHOP and the University of Pennsylvania are searching for the cause of late-effect outcomes — which can include organ dysfunction, decreased fertility, impaired intellectual function, an overall diminished quality of life, and early death — and ways to prevent them.

"While clinicians and researchers focus on cure in cancer, cure alone is not enough," said Sogol Mostoufi-Moab, MD, MSCE, Program Director and an attending physician at CHOP. "We need to achieve cure while reducing late effects to improve quality of life in childhood cancer survivors."

Take for instance, Jill Ginsberg, MD, director of the Childhood Cancer Survivorship Program at CHOP, who has a robust research program on fertility preservation for cancer patients, as certain cancer therapies can affect a child's future reproductive health. By using the information from earlier observational studies, she is able to ask the right questions in terms of what is the mechanism that leads to decreased fertility.

"Mechanistic research studies are one of the hallmarks of what we do here at CHOP with well-established investigators," Dr. Mostoufi-Moab said.

The Program offers established CHOP and Penn investigators who are actively working in the area of survivorship and outcomes the opportunity to collaborate nationally and internationally, and it fosters the next generation of survivorship and outcomes researchers' careers.

"Investing in the infrastructure provides the opportunity to study outcomes on a large scale," Dr. Mostoufi-Moab said. "The Research Institute is poising the CHOP Pediatric Cancer Survivorship Outcomes Research Program to serve as that conduit for future researchers."

Discovering Primary and Secondary Prevention Strategies

As researchers better understand the mechanisms of why certain late effects occur, then through clinical trials they can search for ways to prevent that late effect from happening in the first place.

"That's called secondary prevention," Dr. Mostoufi-Moab said. "The patient has experienced the exposure through cancer treatment, but we're trying to at least prevent the late effect outcome of that specific exposure."

As an example, Dr. Mostoufi-Moab is conducting a clinical trial to test an intervention for declining muscle health after a young patient has a bone marrow transplant as part of their cancer treatment. Her team is looking at the use of exercise and a supplement called nicotinamide riboside that can increase the function of mitochondria — organelles that act as the powerhouse of skeletal muscle cells — to see if they can improve muscle health in these individuals.

Ultimately, the goal for survivorship and outcomes studies will be to achieve "primary prevention" of late effects. These clinical trials are designed to introduce interventions up front with the goal to prevent an outcome from occurring using more sophisticated understanding of patients' genotypes, as well as precision medicine at the time of cancer diagnosis.

(Adapted from Robinson and Bhatia)

(Adapted from Robinson and Bhatia)

"Critical research questions about primary and secondary prevention strategies in survivorship provide long-term opportunities to explore genomic and epigenomic predictors of risk, mechanistic studies, and interventional clinical trials," Dr. Mostoufi-Moab said. "This will, in turn, decrease the risk of developing specific adverse events, ideally by harnessing precision medicine approaches."

CHOP Helped to Establish Field of Survivorship and Outcomes

Anna Meadows, MD, led the way for survivorship studies of children with cancer.

Anna Meadows, MD, led the way for survivorship studies of children with cancer.

Pioneering pediatric oncologists Anna Meadows, MD; Audrey Evans, MD; and Giulio John D' Angio, MD, in the mid-1970s were the first to recognize treating children with cancer could cure them, but also could cause long-term health consequences.

As a fellow in pediatric oncology at CHOP, Dr. Meadows published the seminal paper "Late effects of cancer treatment: methods and techniques for detection," leading the way for survivorship studies of children with cancer.

Investigators were first interested in understanding and describing late effects. They showed that if you follow pediatric patients after a childhood cancer treatment over time, then there can be significant late effects that not only contribute to morbidity of these individuals, but also early mortality. Take for instance Hodgkin lymphoma, a curable tumor when treated with chemotherapy and chest radiation, according to Dr. Mostoufi-Moab. Unfortunately, some of these patients go on to experience serious heart-related conditions leading to early cardiovascular death after having chest radiation.

Using epidemiology concepts, an early goal of the survivorship and outcomes field was to better understand how to capture data describing long-term effects of cancer therapy in patients.

"With the help of large epidemiology studies, we have been able to first ask hypotheses- generating questions, lead observational studies, and subsequently focus on conducting mechanistic research studies to better understand how to prevent late effects of cancer therapy," Dr. Mostoufi-Moab said.

The Childhood Cancer Survivor Study (CCSS) was one of these earlier database opportunities. The initial cohort involved over 14,000 childhood cancer survivors diagnosed between 1970 and 1986 — more than half were CHOP patients. It also included siblings of survivors to serve as a comparison group. The study expanded to include survivors diagnosed between 1987 and 1999. CCSS data is an excellent resource to help investigate questions about the effects of therapy, interventions, and quality of life among childhood cancer survivors, Dr. Mostoufi-Moab said.