More than 98% of adult survivors of childhood cancer in a large clinically evaluated cohort had a chronic health condition, including a substantial number of previously undiagnosed problems that are more likely to occur in an older population. “These findings underscore the importance of ongoing health monitoring for adults who survive childhood cancer,” the investigators concluded in a study published in JAMA.¹

The surprising finding of the study was not that survivors were experiencing problems, but that the conditions were so varied “across a spectrum of systems,” said the study’s lead author, Melissa Hudson, MD, in one of the media reports of the study.² Dr. Hudson is Director of the Cancer Survivorship Division and Co-Leader of the Cancer Prevention and Control Program at St. Jude Children’s Research Hospital in Memphis.

In an interview with The ASCO Post, she added, “It’s not just the conditions across many systems, but the spectrum of severity. At very young ages, many of the patients were showing subclinical or undiagnosed abnormalities that may become more clinically significant as they age. These findings emphasize the importance of survivors adhering to regular medical checkups with health-care providers who are informed about the health risks predisposed by treatment for childhood cancer.”

Accelerated Aging Process

Late effects research has shown that adults who were treated for childhood cancers with cytotoxic approaches had organ system problems more likely to be found in older populations, according to Dr. Hudson. “Some of the functional measures and outcomes that we observed are more typical of individuals who are 60 years of age or older.”

The median age of the 1,713 study participants, however, was 32 years old, with just 3.1% or 53 patients between the ages of 50 and 66 at recruitment and most in their 20s and 30s. All the study patients had been treated for childhood cancer at St. Jude and were enrolled in the St. Jude Lifetime Cohort Study (SJLIFE). The median time from diagnosis was 25 years, with a range of 10 to 47 years.

All participants completed health questionnaires that provided self-reported outcomes and information about their quality of life and health perceptions and health habits. “This is really important information, because we are going to able to understand how health habits have contributed to or modified the risk of these chronic health conditions,” Dr. Hudson explained. The standard laboratory assessment included blood counts, chemistries, and a battery of hormonal function tests, “to improve our understanding about the impact of aging on their endocrine and reproductive organs,” she said.

Strength, balance, stamina, and other measures of neuromuscular function were evaluated at the St. Jude human performance lab, run by study coauthor Kirsten K. Ness, PT, PhD, Associate Member of the St. Jude Faculty, and the results were compared with norms to assess risk for falls or other morbidities. Patients were also assessed for cognitive function.

Systematic exposure-based medical assessments looked at late effect associated with specific treatments. The clinical evaluations were consistent with the risk-based screening and surveillance recommended by the Children’s Oncology Group (COG)³ but were expanded for this study. All patients also provided biologic specimens for genetic testing “that will help understand potential genetic factors that are contributing to their outcomes,” Dr. Hudson added.

Abnormal Pulmonary Function Ranks Highest

Leading the list of adverse health outcomes was abnormal pulmonary function, with a crude prevalence rate of 65.2%. Other high rates were 62.1% for hearing loss, 62% for endocrine or reproductive disorders, 56.4% for cardiac conditions, and 48% for neurocognitive impairment. Lower rates were 13% for liver dysfunction, 9.6% for skeletal problems, 5% for kidney dysfunction, and 3% for abnormalities involving hematopoietic function.

In many cases, the adverse health outcomes were subclinical and were first diagnosed as part of the SJLIFE evaluation. For example, 35.7% of those with abnormal lung function and 46.5% of those with cardiac abnormalities were identified during the SJLIFE evaluation, underscoring the need for ongoing health monitoring.

The study linked adverse outcomes to specific cancer treatments. The highest prevalence of abnormal lung function occurred among those who received lung radiation (74.4%, 95% confidence interval [CI] = 69.1%–79.2%), the authors reported, followed by those treated with bleomycin (73.3%, 95% CI = 61.9%–82.9%) and thoracotomy (53.2%, 95% CI = 44.1%–62.0%). Heart valve abnormalities were found in 56.7% (95% CI = 52.2%–61.1%) of survivors exposed to cardiac-directed radiation.

Second Neoplasms

A total of 335 solid and 13 hematologic neoplasms occurred among 272 of the survivors. Second neoplasms include a spectrum of low-grade or benign conditions, like nonmelanoma skin cancer or meningioma, to high-grade invasive malignancies.  Survivors with low-grade or indolent subsequent neoplasms may later develop invasive neoplasms. Therefore, it is important for survivors and their providers to be aware if their cancer history or treatment warrants early initiation of screening for common adult-onset cancers. 

For example, women treated with chest radiation for cancer during childhood have a markedly increased risk of breast cancer.  Because of this risk, breast cancer surveillance is recommended to begin at a much younger age (8 years after radiation or at age 25, whichever occurs last) than that recommended for women in the general population.

Forty-four of the cancers were identified by the health evaluations conducted as part of the study. “The subsequent malignancies identified through imaging were all breast cancers, but the majority of the other cancers were detected on physical examination,” Dr. Hudson reported. “Typically, atypical skin lesions or palpable masses. So never underestimate the importance of a thorough physical examination.”

Quality-of-life Issues

In the conclusion of the study report, the investigators pointed out that clinically focused monitoring is important not only “for conditions that have significant morbidity if not detected and treated early, such as second malignancies and heart disease, [but also] for those that if remediated can improve quality of life, such as hearing loss and vision deficits.”

Dr. Hudson said, “We pay a lot of attention to those issues when patients are in the pediatric age range because it is so important for their progress in school and in achieving vocational and educational goals. I think we are appreciating that there is further decline in those systems as the patients are aging.” She noted that survivors themselves may not be aware of this further decline, and it may not be “on the radar for providers.”

Some survivors undergoing evaluation “showed cognitive deficits by formal testing that are commonly observed after cancer therapies affecting the central nervous system.  Many had not appreciated these abnormalities were a consequence of their previous cancer treatment,” Dr. Hudson said. “This lack of awareness may affect a survivor’s access to appropriate testing and remedial services that may improve their quality of life.” The most frequent deficits among survivors exposed to central nervous system treatments were in mathematics (29.2%), memory (25.4%), and processing speed (24.4%).

Changes in Therapy

As associations between specific treatments and long-term effects become better known, efforts have been made to reduce use of harmful treatments. “This has been among the changes that have been made to improve pediatric cancer treatments over the past 30 or 40 years,” Dr. Hudson said. It took years of following pediatric patients to understand some of the delayed effects of treatment, “like understanding the impact of cranial radiation on growth hormone, understanding the impact of radiation anywhere on the risk of subsequent malignancy development, particularly solid tumors, or understanding the impact of chest radiation on heart disease,” Dr. Hudson explained.

“One of the major changes in childhood leukemia therapy,” pioneered at St. Jude, was to stop using cranial radiotherapy, “which was the mainstay of controlling or treating and preventing central nervous system leukemia in the old days,” Dr. Hudson said.

Greater use of targeted treatments could also potentially reduce adverse outcomes for survivors, but these agents are relatively new, with little information on long-term follow-up. “Right now most of the information that’s available is more about acute toxicity. So we still have research to do to define long-term outcomes after these treatments,” Dr. Hudson said. “We can’t assume long-term survivors are safe. They need to be monitored as well, and we want to be sure that there are no other secondary effects that were not anticipated.”

Another aim of the study is to characterize the risk in different patients, “so we can stratify the frequency and intensity of follow-up and screening based on the risk contributed not only by cancer treatment, but also by genetic factors, health habits, and other comorbid health conditions,” she said.

Creating Greater Awareness

“Pediatric oncologists are very aware that many of our treatments predispose to these long-term health issues or late effects,” Dr. Hudson said. Medical oncologists are becoming increasingly aware as long-term survival has improved significantly for adult-onset cancers.

“It’s not practical to expect community providers to be experts in the health risks associated with pediatric cancer since survivors may be relatively uncommon in most practices.  We disseminate information about cancer treatment–related health risks to community providers through the survivor at point of care,” Dr. Hudson said. “We want them to be aware that when they are seeing these survivors—especially survivors who have very complicated health histories, with relapses, or having had a bone marrow transplant or intensive multimodality therapy—they really need to consider all of those exposures during childhood and how that may impact their health long-term.”

She continued, “We want providers to understand that the toxicity profile varies based on the specific chemotherapeutic agent or radiation treatment field.  To anticipate health risks for a given patient, one needs to consider the age at treatment and doses and combinations of agents and modalities used to cure the cancer. In particular, it is pertinent to consider the organs in the radiation treatment field and the impact of treatment on organ function as the survivor is aging.”

As Dr. Hudson said in the The Wall Street Journal,⁴ “Doctors may not be thinking about a heart-valve disorder in someone in his 30s, but if you had radiation to your chest at 10, this is something to think about.” ■

Disclosure: Dr. Hudson reported no potential conflicts of interest.

References

1. Hudson MM, Ness KK, Gurney JG, et al: Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309:2371-2381, 2013.

2. Charlier T: Most survivors of childhood cancers suffer chronic health problems, St. Jude study finds. Commercial Appeal. June 11, 2013.

3. Children’s Oncology Group Long-term Follow-up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers, version 3.0. Available at http://www.survivorshipguidelines.org. Accessed July 5, 2013.

4. Marcus AD: Childhood cancer’s health woes persist for years. Wall Street Journal. June 11, 2013.