Advances in cancer treatments during the past several decades have resulted in more children being cured of their cancer. That’s the good news. Unfortunately, some childhood cancer survivors face treatment-related health issues, including some that are life-threatening, years after their treatment ends.
This spring, an international research consortium focused on reducing health risks associated with radiation therapy for childhood cancers, published a series of evidence-based reviews in the International Journal of Radiation Oncology, Biology, Physics that may help physicians to develop equally effective but less toxic treatment plans for their patients.
UNC Lineberger’s Lawrence Marks, MD, helped lead this initiative and co-edited the special issue, which included 30 papers, reviews and editorials written by members of the Pediatric Normal Tissue Effects in the Clinic (PENTEC) team. Formed in 2012, PENTEC aims to develop a quantitative understanding of radiation therapy-related toxicities and late-stage health issues.
Marks also co-authored 11 of the papers. UNC Lineberger’s Dana Casey, MD, and Colette Shen, MD, PhD, each led one of the initiatives (secondary malignancies and ocular complications, respectively) and were first authors of two separate papers. UNC School of Medicine’s Shiva K. Das, PhD, was co-author of a paper investigating the risk of pulmonary complications associated with total body irradiation.
Global initiative outlines better, safer treatments
The PENTEC team includes physicians, physicists and epidemiologists from across the globe working collaboratively to review published research findings to help radiation oncologists plan better and safer treatments and guide them as they counsel patients and families. Specifically, the initiative aims to develop quantitative evidence-based dose/volume guidelines to inform treatment planning, describe relevant physics issues specific to pediatric radiotherapy, and propose dose-volume-outcome reporting standards to systematically inform future treatment guidelines.
Radiation therapy, alone and in combination with other treatments, is an effective approach for many childhood cancers, including brain cancer, kidney cancer, sarcoma and bone cancer. However, it also poses potential risks, such as damaging normal, healthy tissue next to the tumor.
“Treating children with radiation therapy can be particularly challenging. Their tissues are still developing and growing, and this makes them generally more susceptible to radiation injury than are adult or mature tissues,” said Marks, Sidney K. Simon Distinguished Professor of Oncology Research and former chair of radiation oncology at UNC School of Medicine.
“Also, since their bodies and organs are smaller, some of the technical limitations of radiation therapy delivery can be particularly important in children,” Marks said. “Even small increases in the treatment field size can result in meaningful increases in the fraction of normal organs irradiated.”
Treatment side effect arise in adulthood
The National Cancer Institute reports that 60% to 90% of childhood cancer survivors develop one or more chronic health issues in adulthood, and 20% to 80% will experience severe or life-threatening complications. Studies have shown that radiation therapy for childhood cancers can increase a child’s risk of various health issues in adulthood, including secondary cancer, heart- and lung-related complications, memory impairment and fertility issues.
Casey and her colleagues identified a significant radiation dose-response relationship for secondary cancers of the central nervous system and lungs and for sarcoma. “Our analysis suggests that more conformal radiation techniques that limit the high dose volume around the target might be a promising strategy for reducing the risk of secondary cancers following radiation therapy,” Casey said. “It is also important to consider other host- and treatment-related factors, including age and chemotherapy, when estimating the risk of secondary cancers after radiation.”
Eye- and vision-related health issues, specifically damage to the retina and optic nerve and the development of cataracts, are less studied late-stage complications from radiation therapy, but they can greatly affect a person’s quality of life, said Shen, who led the team investigating ocular toxicities. “Although radiation dose effects in the eye are inadequately studied in the pediatric population, we identified sufficient data to generate models that could be beneficial in determining the relationship between radiation therapy dose and the risk of long-term toxicities affecting vision,” Shen said.
Das was part of the team that studied the connection between whole-body radiation delivered in advance of stem cell transplantations and idiopathic pneumonitis syndrome, a serious, pneumonia-like condition. “Our review didn’t associate idiopathic pneumonitis syndrome with a specific total body irradiation factor,” Das said. “We developed a treatment model, but more research is needed to confirm this model and to understand how other factors, like chemotherapy and graft-versus-host disease, might affect the risk.”
Clever approaches overcome data challenges
Marks said the publication of the PENTEC findings is gratifying because some questioned whether it would be possible to provide guidelines and insights informed by peer-reviewed research.
“When we started this work, there was some skepticism whether there was enough published data to allow for a meaningful analysis, and whether we could effectively pool the data across publications,” Marks said. “Our colleagues, particularly in physics and statistics, designed some very clever ways to extract meaningful data from the published reports, including even some older reports.”
Analyzing data from older studies, where radiation doses and volumes were not accurately known, posed challenges for the researchers. They overcame these limitations by using modern tools to reconstruct the radiation doses and volumes used.
“This really was a huge team effort that took many years to complete,” Marks said.