Systematic screening required to detect endocrine complications after childhood cancer
As childhood cancer cure rates have substantially improved, the rate of late-onset endocrine complications among childhood cancer survivors has risen, with an estimated 50% of survivors experiencing complications ranging from thyroid dysfunction to obesity or type 2 diabetes during their lifetime, according to recent analyses.
“Endocrine late effects are among the most commonly reported chronic conditions in childhood cancer survivors,” Wassim Chemaitilly, MD, of the division of endocrinology at St. Jude’s Children’s Research Hospital in Memphis, Tennessee, told Endocrine Today. “It is estimated that one out of two survivors will be diagnosed with at least one endocrine or reproductive complication during her or his lifetime.”
Since 1975, the 5-year survival rate for children diagnosed with cancer before age 20 years increased from just more than 50% to more than 80% in 2014, according to data from the National Cancer Institute. However, these patients remain at increased risk for developing a broad range of health conditions, including endocrinopathies, that can appear years or even decades after the completion of cancer treatments.
“More and more children now survive childhood cancer,” Robert Rapaport, MD, professor of pediatrics and chief of the division of pediatric endocrinology and diabetes at the Icahn School of Medicine at Mount Sinai, told Endocrine Today. When assessing risk, “there needs to be a distinction made between the underlying cancer treated, to see if it has any endocrine effects, and then see what treatment the patient received and see if that has any endocrine effects. There has been a huge body of literature that shows that both [the disease and the treatment] can have endocrine effects, and one cannot find them if one does not look for them.”
Cancer treatment, risk
In an analysis of endocrine abnormalities in aging survivors of childhood cancer published in the September issue of the Journal of Clinical Oncology, Sogol Mostoufi-Moab, MD, MSCE, assistant professor at the Perelman School of Medicine at the University of Pennsylvania, and colleagues assessed self-reported endocrine conditions in 14,290 5-year survivors from the Childhood Cancer Survivor Survey, comparing results with a nested case-control group of 4,031 healthy siblings. The likelihood of developing a specific endocrine disorder was stratified by 13 therapeutic exposures, including high-dose irradiation of the head, neck or pelvis, and exposure to high doses of alkylating agents. The researchers found that the cumulative incidence and prevalence of endocrine abnormalities increased across the lifespan for survivors (P < .01 for all), with the risk increasing depending on treatment.
Compared with survivors not exposed to high-risk therapies, those who were exposed to such therapies saw a higher risk for developing hypothyroidism (HR = 6.6; 95% CI, 5.6-7.8), hyperthyroidism (HR = 1.8; 95% CI, 1.2-2.8), thyroid nodules (HR = 6.3; 95% CI, 5.2-7.5), thyroid cancer (HR = 9.2; 95% CI, 6.2-13.7), growth hormone deficiency (HR = 5.3; 95% CI, 4.3-6.4), obesity (RR = 1.8; 95% CI, 1.7-2) and diabetes (RR = 1.9; 95% CI, 1.6-2.4).
However, even among survivors exposed to lower-risk therapies, thyroid disorders were more frequent when compared with healthy siblings, the researchers noted, with increased risk observed for hypothyroidism (HR = 2.2; 95% CI, 1.8-2.7), hyperthyroidism (HR = 2.4; 95% CI, 1.7-3.3), thyroid nodules (HR = 3.9; 95% CI, 2.9-5.4) and thyroid cancer (HR = 2.5; 95% CI, 1.2-5.3).
“Even childhood cancer survivors treated with non-high-risk therapies demonstrated an increased risk for certain endocrine outcomes compared with siblings, highlighting the need for long-term surveillance and individualized screening practices in childhood cancer survivors, even in the absence of high-risk treatment exposures,” Mostoufi-Moab and colleagues wrote.
In a summary of late-onset endocrine conditions observed in childhood cancer survivors published in the European Journal of Endocrinology, Chemaitilly and Laurie E. Cohen, MD, of the division of endocrinology at Boston Children’s Hospital and Harvard Medical School, noted that a systematic screening approach should facilitate the early diagnosis and treatment of endocrine conditions to improve health outcomes.
“[Our] overview highlights the need for a systematic approach where patients are screened at regular intervals, based on cancer- and treatment-related risk factors, for the different endocrine dysfunctions,” Chemaitilly said. “This approach allows patients to benefit from earlier diagnosis and treatment and, hence, may help improve their general health outcomes.”
In their analysis, Chemaitilly and Cohen outlined the prevalence and risk factors for common endocrine complications in childhood cancer survivors and cited best practices for diagnosis and management for each condition, including hypothalamic/pituitary axis dysfunction, GH deficiency, central precocious puberty, primary ovarian insufficiency, decreased bone mineral density, obesity and type 2 diabetes. Thyroid complications, including thyroid cancers, were cited as among the most common endocrine sequelae in the overall population of childhood cancer survivors, they noted.
“Thyroid function should be monitored on a regular basis, in my opinion, after treatment for any head and neck cancer in childhood or adolescence,” Laurence Kennedy, MD, FRCP, of the Cleveland Clinic, told Endocrine Today. In adolescent and adult survivors of childhood cancer, thyroid function should continue to be monitored, he added — and primary care physicians must be careful not to overlook a diagnosis.
“After diabetes, primary hypothyroidism is one of the most common endocrine conditions primary care physicians deal with, and they are used to measuring thyroid-stimulating hormone only,” Kennedy said. “For this population of patients, that is insufficient. Diagnoses of secondary hypothyroidism can and will be missed if there is a reliance only on TSH measurement. If you’re screening these young adults for possible development of endocrine deficiencies following treatment of childhood malignancies, you need to look at the free [thyroxine] level, not just the TSH.”
Chemaitilly and Cohen agreed, noting in their analysis that patients at risk for primary hypothyroidism after exposure to radiotherapy should be screened for the condition at least yearly (and more frequently in childhood) by measuring TSH and free T4 levels.
Screening modalities for thyroid cancer in at-risk patients remain controversial, they wrote.
“Some authors argue that these issues may outweigh the hypothetical benefits of an earlier diagnosis obtained via ultrasound when compared to what can be accomplished through a careful yearly examination of the neck by an experienced provider,” they wrote. “Others have favored using ultrasound and postulated that it will result in diagnosing the disease at a less advanced stage and, hence, decrease the need for invasive treatments.”
Importance of surveillance
For other endocrine complications, the type of surveillance for childhood cancer survivors depends on the age of the patient and the time since diagnosis and treatment, Kennedy said.
“In childhood, one of the most important things to monitor is linear growth, as height and growth velocity; these give clues as to whether growth hormone deficiency may be developing,” Kennedy said. “And there should be regular examination for signs of pubertal development. This can be even more important than measuring sex hormone levels, which can be difficult to interpret in early adolescence.”
Precocious puberty can sometimes mask GH deficiency in childhood cancer survivors, Rapaport said, recalling a female patient whose diagnosis of GH deficiency was initially overlooked.
“She was growing well because the puberty kept her growing,” Rapaport said. “By the time it came to the attention of a pediatric endocrinologist, her bones had fused, and she tested [GH]-deficient. The key to all of this is for people to consider that endocrine late-effects can happen.”
Bone health risks
Among long-term childhood cancer survivors, the prevalence of decreased BMD is estimated to be between 13% and 18%, with other bone health risks dependent on the type of cancer and specific therapies, according to Chemaitilly and Cohen. Children treated with hematopoietic stem cell transplantation, for example, tend to have a higher prevalence of severe BMD deficit in the 5 years after completion of therapy, whereas survivors of central nervous system tumors can experience decreased BMD due to treatment toxicity from glucocorticoid therapy.
In addition, up to 70% of children with leukemia present with disease-related skeletal abnormalities, such as fractures and severe BMD deficit (BMD z score –2) at the time of cancer diagnosis. In children with acute lymphoblastic leukemia, prolonged treatment with high-dose glucocorticoids may also lead to acute complications, including vertebral body compression fractures and avascular necrosis of the bone, Chemaitilly and Cohen wrote.The risk for osteoporosis in survivors treated with methotrexate, glucocorticoids and/or total-body irradiation was greater compared with survivors who were not exposed to these therapies (HR = 1.2; 95% CI, 1- 1.4), Mostoufi-Moab and colleagues wrote.
“This is a population of patients where you could make a case for much earlier screening with DXA for bone density,” Rapaport said.
Chemaitilly and Cohen noted that the interpretation of DXA results could potentially be confounded by pubertal delay or short stature.
“There are no specific management guidelines for low BMD in [childhood cancer survivors],” the researchers wrote. “Patients with hormonal deficiencies, including vitamin D deficiency, should be adequately treated, and individuals should be educated on nutritional sources of calcium, the benefits of regular physical activity and the deleterious effects of smoking/alcohol consumption.”
Obesity and type 2 diabetes
The risk for developing type 2 diabetes or obesity among childhood cancer survivors was higher among survivors of central nervous system tumors, particularly those with a history of hypothalamic/pituitary tumor or surgery, Chemaitilly and Cohen wrote.
Compared with healthy siblings, survivors treated with cranial irradiation with 18 Gy or greater had increased risk for developing obesity (RR = 1.4; 95% CI, 1.3-1.5), whereas those exposed to abdominal irradiation or total-body irradiation had increased risk for developing type 2 diabetes (RR = 2.7; 95% CI, 2.1-3.6), according to Mostoufi-Moab and colleagues. Survivors treated with cranial irradiation with 18 Gy or greater or abdominal irradiation or total-body irradiation had almost double the risk for obesity and type 2 diabetes, compared with survivors not exposed to such treatments, they noted.
Chemaitilly and Cohen noted that childhood cancer survivors should be screened every 6 to 12 months for overweight and obesity, with subsequent testing for CV risk factors following guidelines in place for the general population. Patients treated with total-body irradiation need to be screened for diabetes at least every 2 years, regardless of overweight or obesity status, the researchers wrote.
Transition to adult care
Diagnoses can be also missed, Rapaport said, during the time between late adolescence and adulthood, when patients typically transition from pediatric to adult care — when, for example, growth is no longer an indicator for GH deficiency.
“These patients need to be followed and transitioned from the pediatric to the adult endocrine care team carefully,” Rapaport said.
“My own experience would suggest that the time when things may not be picked up is during the time of transition between pediatric and adult care,” Kennedy said. “It makes sense to have good communication and collaboration between pediatricians and the adult endocrinologist. But for surveillance and screening, these patients aren’t likely to be referred to an endocrinology clinic for this, so it’s important for the family physicians and the internist to be made aware [of patient risk].”
Optimal care for childhood cancer survivors should be delivered in a multidisciplinary fashion, Rapaport said, dependent on the underlying condition the patient was treated for and the therapeutic modalities used to treat that condition. Potential endocrine effects may be cumulative or overlapping, depending on those factors.
“That’s why close collaboration with the team that treats them is very important,” Rapaport said. – by Regina Schaffer
- Chemaitilly W, Cohen LE. Eur J Endocrinol. 2017;doi:10.1530/EJE-17-0054.
- Mostoufi-Moab S, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.66.6545.
- National Cancer Institute at the NIH. Cancer in Children and Adolescents. Available at: www.cancer.gov/types/childhood-cancers/child-adolescent-cancers-fact-sheet. Accessed March 1, 2017.
- For more information:
- Wassim Chemaitilly, MD, can be reached at St. Jude’s Children’s Research Hospital, 262 Danny Thomas Place, MS 737, Memphis, TN 38105; email: firstname.lastname@example.org.
- Laurence Kennedy, MD, FRCP, can be reached at Cleveland Clinic Main Campus, 9500 Euclid Ave., Cleveland, OH 44195; email: email@example.com.
- Robert Rapaport, MD, can be reached at Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., New York, NY 10029; email: firstname.lastname@example.org.
Disclosure: Chemaitilly reports receiving consultant honoraria from Novo Nordisk and Pfizer. Kennedy reports receiving consultant and lecture fees from Pfizer, as well as sitting on an advisory board for Pfizer. Rapaport reports consulting for Ferring, Novo Nordisk and Sandoz. Cohen reports no relevant financial disclosures.