Childhood cancer survivors require lifelong vigilance for late endocrinopathies

An estimated 40% to 50% of childhood cancer survivors will experience an endocrine disorder in their lifetime. The risk varies according to cancer treatment and can persist for decades after diagnosis.

“When parents are signing consent forms, they grasp that chemotherapy and radiation can lead to these late effects, but the immediate needs of survival and cure for their children are obviously most important,” Zoltan Antal, MD, chief of pediatric endocrinology and associate professor of clinical pediatrics at Weill Cornell Medicine, and assistant attending pediatrician at NewYork-Presbyterian and Memorial Sloan Kettering Cancer Center, told Endocrine Today. “Many parents don’t internalize the concept that these late effects may happen, they are just hoping their child will live.”

Late effects — such as thyroid abnormalities, growth hormone deficiency, obesity, diabetes and gonadal dysfunction — can be managed effectively even if they go undiagnosed for years. However, the longer they go undiagnosed, the greater the consequences of these disorders.

Although guidelines for screening exist, many physicians are not aware that their patients may be at risk for endocrine effects, Antal said.

Photo by St. Jude Children’s Research Hospital. Printed with permission.

“When a patient moves, or sees a clinician in another system, those doctors might not see the notes from the oncologist recommending screening for endocrine effects,” Antal said. “In every health system, information is often compartmentalized, so to find information about late endocrine effects, you have to pull it out of these caves of information. You have to know it’s there and go looking for it.”

With the 5-year childhood cancer rate exceeding 80%, and an estimated 420,000 childhood cancer survivors in the U.S., it is imperative that clinicians are aware that this is an intensifying problem.

Available guidelines

The Endocrine Society and the Children’s Oncology Group (COG) have published guidelines for managing late effects of cancer therapy. Both documents recommend regular or annual screening for everything from diabetes and hypothyroidism to growth disorders, pituitary hormone deficiencies, obesity and puberty disorders.

The COG guideline lays out the myriad complications that can occur.

For GH deficiency, height and weight checks and pubertal stage evaluations should be routine, along with a wrist bone age X-ray if the child shows poor growth trends.

For disorders of puberty, such as precocious puberty or delayed or stalled pubertal development due to hypogonadism, clinicians are encouraged to monitor pubertal development in all children and check levels of follicle-stimulating hormone, luteinizing hormone and estradiol in girls or testosterone in boys or conduct an X-ray for bone age, as appropriate.

For thyroid dysfunction, height, weight and levels of plasma free thyroxine and thyroid-stimulating hormone should be assessed at least annually or more frequently during times of rapid growth. To monitor for central adrenal insufficiency, a yearly morning serum cortisol is recommended.

The guideline also recommends that hyperprolactinemia, if suspected, be monitored using a serum prolactin level, and that survivors with suspected hypopituitarism should be referred to an endocrinologist. Additional recommendations for screening individuals at risk for diabetes, obesity, decreased bone density and other endocrinopathies are included in the guideline.

“The COG guideline represents an exhaustive and comprehensive effort,” Sogol Mostoufi-Moab, MD, MSCE, a dual-certified pediatric oncologist and endocrinologist at Children’s Hospital of Philadelphia, and assistant professor of pediatrics at University of Pennsylvania, told Endocrine Today. “There has been an international effort to look at endocrine disorders as a result of cancer therapy. As we have more and more adult survivors of childhood cancer, the importance of these guidelines will be more evident.”

The guideline is comprehensive because it was created by distinct groups of specialists, according to Lillian R. Meacham, MD, Kathleen V. Amos children’s chair for cancer survivorship at Aflac Cancer Center/ Children’s Healthcare of Atlanta, and professor of pediatrics at Emory University.

“The endocrine portion of these guidelines was created through an ovarian taskforce, a testicular taskforce, a hypothalamic/pituitary taskforce and an obesity/diabetes/bone mineral density taskforce,” she told Endocrine Today. “Here you will find information on what types of cancer treatments place patients at risk, as well as recommendations for surveillance for detection of these late effects of cancer treatment.”

For the Endocrine Society guideline — published last year in The Journal of Clinical Endocrinology & Metabolism — Charles A. Sklar, MD, director of the long-term follow-up program and pediatric endocrinologist at Memorial Sloan Kettering Cancer Center, and professor of pediatrics at Weill Cornell Medicine, and colleagues first focused on childhood cancer survivors who had been exposed to cranial radiation therapy, craniospinal irradiation or total body irradiation. Those individuals, along with those with inadequate gain weight, should be monitored for impaired linear growth.

Survivors exposed to hypothalamic-pituitary axis radiation should be periodically assessed throughout life for GH deficiencies. A dose of at least 30 Gy should warrant subsequent screening for luteinizing hormone or follicle-stimulating hormone deficiency, along with lifelong annual screenings for TSH and adrenocorticotropic hormone deficiencies.

Treatment of tumors in the hypothalamic-pituitary axis may cause a multitude of disorders, according to Wassim Chemaitilly, MD, associate member and director of the division of endocrinology at St. Jude Children’s Research Hospital.

“Individuals with tumors located within or near this area of the brain, or whose management has required surgical procedures or radiotherapy involving this region, have a high risk for hypothalamic-pituitary dysfunction, which may result in either one or multiple pituitary hormone disorders, including growth hormone deficiency, precocious puberty, hypogonadism, hypothyroidism, adrenal insufficiency and diabetes insipidus,” he said.

Also, precocious puberty should be on the radar for children with a history of hydrocephalus or tumors developing in or near the hypothalamic region, according to the Endocrine Society guideline.

“The guidelines are confined just to one aspect of endocrine complications,” Sklar said. “It is important to understand that they are not meant to be broad spectrum guidelines for all endocrinopathies. It would have been impossible to cover all of these disorders in a single document.”

Sklar said he believes that such a document was long overdue.

“The COG guidelines, and those from the European International Consortium, were always aimed at the oncology or primary care communities,” he said. “These specifically target endocrinologists.”

Efforts are underway now to harmonize U.S. and international guidelines, Antal said.

Lack of screening, delayed diagnosis

Despite the availability of these guidelines, survivors are not being screened for these comorbidities at appropriate rates, the experts said.

Sklar offered one explanation for this trend.

“Radiation-induced late effects often take years, or even decades, to develop,” he said. “Often, when someone graduates from the pediatric world and enters the general adult population, their medical care is no longer specialized. They are not being seen by people who are familiar with these issues.”

Moreover, these disorders may be missed even with appropriate screening.

“Many doctors don’t know to screen for these disorders,” Sklar said. “When these patients develop growth hormone disorders or other pituitary effects at age 20 or 30, they are very subtle, or not noticeable at all.”

These disorders can occur at any time after treatment, Chemaitilly said.

“There is not, to our current state of knowledge, a time after which we can say that these issues will not occur,” he said. “It is important to emphasize to medical providers caring for these individuals that the risk for endocrine dysfunction may still be present even in long-term adult survivors of childhood cancers.”

The vagueness of symptoms also may hinder appropriate diagnosis.

“In a growing child, abnormal linear growth patterns — too rapid, too slow, crossing percentiles on the growth chart — should raise suspicion regarding growth, puberty and thyroid disorders,” Chemaitilly said. “Unfortunately, some of the symptoms of endocrine dysfunction — especially in adult survivors — are not as specific. Fatigue, difficulties with schoolwork and frequent illnesses may occur for a variety of reasons in a given individual but could, for example, be signs of thyroid disease or adrenal insufficiency.”

Tracing risk back to therapy

Understanding the most likely causes of endocrine effects is essential to ensure appropriate screening, according to Smita Bhatia, MD, MPH, Gay and Bew White endowed chair in pediatric oncology, vice chair for outcomes research in the department of pediatrics, and director of the Institute for Cancer Outcomes and Survivorship at University of Alabama, Birmingham Comprehensive Cancer Center.

“Brain tumors and acute lymphoblastic leukemia carry more risk than other pediatric cancers because of the need to radiate the brain and spine,” Bhatia told Endocrine Today. “Radiation is the primary culprit. Alkylating agent chemotherapy is associated with gonadal dysfunction.”

To better characterize endocrine effects in cancer survivors, Mostoufi-Moab and colleagues used the Childhood Cancer Survivor Study (CCSS) to evaluate data from 14,290 5-year survivors (46% female) and 4,031 of their siblings.

Results showed at least one endocrinopathy in 44% of the survivors, whereas 16.7% had at least two and 6.6% had three or more.

Hodgkin lymphoma survivors had the greatest frequency of endocrinopathy, at 60.1%. Among central nervous system (CNS) tumor survivors, 54% developed an endocrine disorder, followed by 45.6% of those with leukemia, 41.3% with sarcoma, 29.7% with non-Hodgkin lymphoma, 31.9% with neuroblastoma, 28.5% with Wilms tumor and 27.8% with bone cancer.

“Individuals with neck exposures to irradiation — such as craniospinal irradiation to treat central nervous system malignancies, chest or mediastinum or mantle radiotherapy for Hodgkin lymphoma — have a high risk for thyroid disorders, especially hypothyroidism and thyroid cancer,” Chemaitilly said.

Mostoufi-Moab and colleagues found that patients exposed to high-risk therapies — such as high-dose irradiation of the head, neck or pelvis — had a more than sixfold increased risk for primary hypothyroidism (HR = 6.6; 95% CI, 5.6-7.8), thyroid nodules (HR = 6.3; 95% CI, 5.2-7.5) and thyroid cancer (HR = 9.2; 95% CI, 6.2-13.7).

Women exposed to high-risk therapies had a sixfold increased risk for primary ovarian insufficiency (RR = 6.3; 95% CI, 5-8), and men demonstrated higher prevalence of testosterone replacement after treatment with 20 g/m² cyclophosphamide or 20 Gy testicular irradiation (RR = 10.8; 95% CI, 8.2-14.2).

Compared with their siblings, survivors also were at increased risks for 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-.4).

Importantly, regardless of treatment regimen, all survivors were at higher risks for thyroid disorders and diabetes (P < .001 for all).

Thyroid particularly vulnerable to long-term toxicity

Inskip and colleagues investigated associations between radiation dose to the thyroid and thyroid disorders in the hypothalamic-pituitary axis among 14,364 5-year survivors of childhood cancer.

Of the survivors — diagnosed between 1970 and 1986 — 1,193 developed hypothyroidism through 2009. Prevalence appeared highest among 5-year survivors of Hodgkin lymphoma (32.3%) and CNS tumors (17.7%).

Researchers observed a significant association between the incidence of hypothyroidism and radiation dose to the thyroid and pituitary areas, with a dose of 16 Gy or greater as a contributing factor. The radiation-related risk persisted for more than 25 years after treatment.

Hypothyroidism also was significantly associated with treatment with bleomycin (RR = 3.4; 95% CI, 1.6-7.3) and the alkylating agents cyclohexyl-chloroethyl-nitrosourea (RR = 3; 95% CI, 1.5-5.3) and cyclophosphamide (RR = 1.3; 95% CI, 1-1.8).

“Radiation of the hypothalamus can result in growth hormone, thyroid-stimulating hormone, gonadotropin and adrenocorticotropin deficiencies,” Meacham said. “Growth hormone deficiency can be seen after lower doses of radiation — 18 Gy — whereas other hormone deficiencies do not typically happen unless radiation doses exceed 30 Gy.”

Many cancer survivors also may be at risk for obesity and diabetes.

Meacham and colleagues investigated incidence of diabetes among 8,599 cancer survivors in the CCSS and 2,936 of their siblings. Diabetes occurred in 2.5% of the survivor cohort and 1.7% of siblings.

Adjusted analysis results showed that cancer survivorship carried a 1.8-fold greater risk (P < .001) for diabetes, with elevated diabetes risk associated with total body (OR = 12.6; P < .001), abdominal (OR = 3.4; P < .001) and cranial (OR = 1.6; P = .03) irradiation.

Use of alkylating agents (OR = 1.7; P < .01) and younger age at diagnosis (0-4 years; OR = 2.4; P < .01) also increased diabetes risk.

Impact on fertility

Cancer treatments also are widely known to place fertility at risk.

“Gonadal dysfunction is usually the result of direct radiation to the ovaries or testes, or radiation to the brain, or alkylating agent chemotherapy,” Bhatia said.

Using data from the CCSS, Green and colleagues evaluated the effect of treatment on fertility among men (n = 6,244) and women (n = 5,149) treated during childhood and adolescence.

Overall, female survivors appeared less likely than their siblings to ever be pregnant (RR = 0.81; 95% CI, 0.73-0.9) and men were less likely to sire a pregnancy (HR = 0.56; 95% CI, –0.49 to 0.63).

Multivariable models showed women were less likely to become pregnant after a hypothalamic/pituitary radiation dose of 30 Gy or higher (RR = 0.61; 95% CI, 0.44-0.83) or a uterine radiation dose greater than 5 Gy (5-10 Gy, RR = 0.56; 95% CI, 0.37-0.85; > 10 Gy, RR = 0.18; 95% CI, 0.13-0.26).

Among men, siring a pregnancy appeared less likely after radiation therapy of more than 7.5 Gy to the testes (HR = 0.12; 95% CI, –0.02 to 0.64), higher cumulative alkylating agent dose or treatment with cyclophosphamide (third tertile, HR = 0.42; 95% CI, –0.31 to 0.57) or procarbazine (Matulane, Leadiant Biosciences; second tertile, HR = 0.48; 95% CI, –0.26 to 0.87; third tertile, HR = 0.17; 95% CI, –0.07 to 0.41).

“Lack of puberty or premature gonadal insufficiency can result from female or male hormone deficiencies after chemotherapy that includes alkylating agents or radiation exposure of the ovaries or testes,” Meacham said. “Infertility can also occur after chemotherapy that includes alkylating agents or radiation exposure of the ovaries or testes.”

Although pediatric patients are likely years away from pregnancy, fertility is still a major concern.

“Fertility and hormonal function are high on the list of people’s concerns, and they may be impacted by both chemotherapy and radiation,” Antal said. “Nurses, the patient’s OB-GYN or fertility group can be part of helping patients with this very important and prevalent concern, even if they are not part of the oncology or endocrine team.”

Treatment and beyond

Attention to endocrine and other cancer effects has led to emphasis on treatment deintensification.

“Over time, oncologists are learning that tailoring treatment according to risk stratification is important,” Mostoufi-Moab said. “Something else to consider is that radiation doesn’t have to be included in every regimen.”

Data on late endocrine effects are essentially nonexistent or inconclusive for new, potentially less-toxic treatments, such as proton therapy, according to Mostoufi-Moab.

“We still need more follow-up time to determine if there are true reductions in incidence of cranial or pituitary disorders,” she said. “As for immunotherapy, many immune reactions to the endocrine glands are increasingly recognized as oncologists utilize more treatment regimens using the immune system.”

It is also important to appreciate other potential sequelae, such as cardiac dysfunction and second cancers.

“Awareness of risk for other late effects, including second malignancies and cardiac late effects, needs to be considered when managing endocrine disorders in pediatric cancer survivors,” Meacham said.

For Mostoufi-Moab, it all comes back to education.

“As a community of oncologists and endocrinologists, we need to come together,” she said. “The number of pediatric patients surviving into adulthood continues to increase, and there needs to be urgency to address endocrine late effects.” – by Rob Volansky

• For more information:
• Zoltan Antal, MD, can be reached at 505 E. 70th St., New York, NY 10021; email: zoa9003@med.cornell.edu.
• Smita Bhatia, MD, MPH, can be reached at 1600 Seventh Ave. S., Lowder Building, Suite 500, Birmingham, AL 35233; email: sbhatia@peds.uab.edu.
• Wassim Chemaitilly, MD, can be reached at 262 Danny Thomas Place MS 737, Memphis, TN 38105; email: wassim.chemaitilly@stjude.org.
• Lillian R. Meacham, MD, can be reached at 2015 Uppergate Drive NE, Atlanta, GA 30302; email: lillian.meacham@emory.edu.
• Sogol Mostoufi-Moab, MD, MSCE, can be reached at 3401 Civic Center Blvd., Philadelphia, PA 19104; email: moab@email.chop.edu.
• Charles A. Sklar, MD, can be reached at 1275 York Ave., New York, NY, 10065; email: sklarc@mskcc.org.

• References:
• Green DM, et al. J Clin Oncol. 2009;doi:10.1200/JCO.2008.20.1541.
• Green DM, et al. J Clin Oncol. 2010;doi:10.1200/JCO.2009.24.9037.
• Inskip PD, et al. Radiat Res. 2018;doi:10.1667/RR14888.1.
• Meacham LR, et al. Arch Intern Med. 2009;doi:10.1001/archinternmed.2009.209.
• Mostoufi-Moab S, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.66.6545.
• Sklar CH, et al. J Clin Endocrinol Metab. 2018;doi:10.1210/jc.2018-01175/5046572.

Disclosures: Sklar reports a consultant role with St. Jude Children’s Research Hospital. Antal, Bhatia, Chemaitilly, Meacham and Mostoufi-Moab report no relevant financial disclosures.