‘There needs to be urgency’ to address late endocrinopathies in childhood cancer survivors
For pediatric cancer survivors, the disease and its treatments place them at risk for subsequent health complications, many of which are endocrine related.
An estimated 40% to 50% of childhood cancer survivors will experience an endocrine disorder in their lifetime. The risk varies according to treatment received 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 HemOnc 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 likelihood the survivor will suffer from the consequences of these disorders.
“One of the ways to deal with this is to have a bridge between the acute part of therapy and the later survivorship experience,” Antal said, suggesting some patients undergo too long a period of surveillance after remission before referral is made for long-term follow-up.
But — with the 5-year childhood cancer rate exceeding 80%, and an estimated 420,000 childhood cancer survivors in the U.S. — this may not be so simple.
“At places like Weill Cornell and Memorial Sloan Kettering Cancer Center, there are resources for this survivorship experience,” he said. “In the community, it can be much different.”
HemOnc Today spoke with pediatric oncologists and endocrinologists about guideline recommendations to surveil patients and manage these conditions; which treatments and diseases put patients at risk; and whether educating patients, physicians and parents can mitigate the long-term consequences of cancer treatment.
With thousands of childhood cancer survivors in the U.S., and as many as half of them potentially at risk for treatment-related endocrine complications, it is imperative that clinicians are aware that this is an intensifying problem.
Two guidelines exist — the recently published Endocrine Society guidelines, and Children’s Oncology Group (COG) guidelines for late effects of cancer therapy that have existed for years.
The authors of both documents recommend regular or annual screening for everything from diabetes and hypothyroidism to growth disorders, pituitary hormone deficiencies, obesity and disorders of puberty.
The COG guidelines lay out the myriad complications that can occur.
For growth hormone deficiency, height and weight checks and pubertal stage evaluations should be routine, along with a wrist bone age X-ray if the survivor shows poor growth trends.
For disorders of puberty such as precocious puberty or, conversely, delayed or stalled pubertal development due to hypogonadism, clinicians are encouraged to monitor pubertal development in all children and check for follicle-stimulating hormone, luteinizing hormone and estradiol (girls) or testosterone (boys), or to conduct an X-ray for bone age as appropriate.
For thyroid dysfunction, clinical evaluation including height, weight and laboratory measurements of plasma-free T4 and thyroid-stimulating hormone (TSH) should be done at least annually or more frequently during times of rapid growth. To monitor for central adrenal insufficiency, a early morning (8 a.m.) serum cortisol is recommended.
The guidelines also recommend that hyperprolactinemia be monitored, if suspected, using a serum prolactin level, and that survivors with suspected hypopituitarism be referred to an endocrinologist. Additional recommendations for screening individuals at risk for diabetes, obesity, decreased bone density and other endocrinopathies are included in these guidelines.
“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 HemOnc 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 guidelines are comprehensives because they were 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 task force, a testicular task force, a hypothalamic/pituitary task force and an obesity/diabetes/bone mineral density task force,” she said in an interview. “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 guidelines — 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 who failed to adequately gain weight, should be monitored for impaired linear growth.
Survivors exposed to hypothalamic-pituitary axis radiation should be periodically assessed for deficiencies in growth hormone. 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 deficiency and adrenocorticotropic hormone deficiency.
Because the hypothalamic-pituitary axis is the main center that controls hormone production in the body, treatment of tumors located in this area 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, said in an interview.
“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/or 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 guidelines.
“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.”
That said, Sklar 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.”
Essentially, the guidelines promote spreading knowledge, according to Mostoufi-Moab.
“These guidelines contain basic information so that any clinician can feel comfortable that what they are looking at is in the literature,” she said. “That’s one very important role that the Endocrine Society guidelines play.”
Efforts are underway now to harmonize U.S. and international guidelines, Antal said.
“Experts in the U.S., Europe and Asia are looking to see how guidelines match or don’t match across countries and continents,” he said. “They are trying to understand how these groups look at data and abstracts around the world. It would be relevant to be able to create a list of guidelines that match on a macroscale to make sure they are useful across populations.”
Lack of screening, delayed diagnosis
Despite the availability of these guidelines, survivors are not being screened for these comorbidities at appropriate rates.
Failure to screen means failure to treat, and failure to treat means unchecked complications and unnecessary burden on the health care system, 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 [years], they are very subtle, or not noticeable at all.”
For Mostoufi-Moab, the simplest place to start is with awareness.
“On the oncology side, educating our patients is a huge responsibility,” she said. “Survivorship physicians play a huge, active role.”
Underdiagnosis of these disorders mainly stems from the fact that they 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.”
That said, Sklar emphasized that the diagnostic criteria for these endocrine events are mostly the same as those for the general population.
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.”
Additional diagnosis barriers exist that aren’t entirely understood, Chemaitilly added.
“For example, data from the St. Jude Lifetime Cohort have also shown high rates of untreated hypogonadism in adult survivors with potential repercussions on general health, such as decreased bone mineral density and impaired physical fitness,” Chemaitilly said. “Whether such delays are related to issues with access to specialized care, provider concerns regarding side effects of sex hormone replacement therapies or other factors remains to be seen.”
Access and referral issues are a bigger concern than misdiagnoses, according to Sklar.
“If we can find a way to get them referred to an endocrinologist in a timely fashion, they will get the appropriate diagnosis in most cases,” he said.
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 Cancer Outcomes and Survivorship at O’Neal Comprehensive Cancer Center University of Alabama, Birmingham.
“Brain tumors and acute lymphoblastic leukemia carry more risk than other pediatric cancers, because of the need to radiate the brain and spine,” Bhatia, who is also a HemOnc Today Editorial Board Member, said in an interview. “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 endocrinopathies.
Hodgkin lymphoma survivors had the greatest frequency, at 60.1%. Fifty-four percent of CNS tumor survivors developed an endocrine disorder, followed by 45.6% of leukemia survivors, 41.3% of sarcoma survivors, 29.7% of non-Hodgkin lymphoma survivors, 31.9% of neuroblastoma survivors, 28.5% of Wilms tumor survivors and 27.8% of bone cancer survivors.
“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 sixfold increased risk for premature ovarian insufficiency (RR = 6.3; 95% CI, 5-8), and men demonstrated higher prevalence of testosterone replacement following 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 risk 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, 1.6-2.4).
Importantly, regardless of treatment regimen, all survivors were more likely to be at risk for thyroid disorders and diabetes (P < .001 for all).
The thyroid gland is particularly vulnerable to long-term toxicity.
Inskip and colleagues investigated associations between radiation dose to the thyroid gland 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.
“Individuals with these exposures, especially those with tumor or surgery-related hypothalamic injury, may also experience excessive weight gain, or hypothalamic obesity and diabetes,” Chemaitilly said.
Impact on fertility
Cancer treatments also are widely known to place patients’ 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 males (n = 6,244) and females (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 males were less likely to sire a pregnancy (HR = 0.56; 95% CI, –0.49 to 0.63).
Multivariable models showed females were less likely to become pregnant following 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 males, siring a pregnancy appeared less likely following 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 (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 hoping to start a family, 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 groups 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.”
Dissemination of information
Early education of patients, parents and clinicians is critical to minimize the impact of late endocrine effects, according to Mostoufi-Moab.
“It’s important to address this immediately after treatment, when the patient is young,” Mostoufi-Moab said. “Likewise, as these children age into adulthood, the need to equally remain invested in their endocrine disorders should continue.”
The responsibility for having this conversation and dealing with these effects currently rests with oncology, Antal said.
“But you have to understand that pediatric endocrinology is underserved in much of the country,” he said. “Resources for survivorship care are also lacking.”
However, patient education may not be a solution to the problem, according to Sklar.
“These are complex issues,” he said. “You can tell the patient and their family to make sure to get yearly screening for pituitary problems, and 10 years later they end up in an adult endocrinologist’s office. But the endocrinologist might say, ‘You look normal; you’re fine.’ How would a patient know what to do next? It puts a huge burden on them.”
More comprehensive electronic medical records could help alert physicians that their patients may be at risk for endocrine effects, Antal added.
“Within institutions or health systems, yes, all the physicians who see a patient can see that the possibility of endocrine effects is there,” he said. “But, there isn’t as much crosstalk between systems. 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.
“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,” he added. “You have to know it’s there and go looking for it.”
This is where the guidelines come into play.
“Most physicians are aware that there are published guidelines from COG, and we are getting the word out on the Endocrine Society guidelines,” Mostoufi-Moab said. “When primary care or other adult providers learn that their adult patient is a pediatric cancer survivor, they can now access formal guidance.”
Sklar acknowledged that improved information and communication systems are helpful, but work remains.
“It’s a public health problem,” he said. “I don’t have a solution. I do think that it will never be adequately addressed by survivors. There needs to be other mechanisms in place that safeguard that they will get appropriate care across a lifespan.”
These issues go beyond endocrine effects.
“They are dealing with cardiovascular effects, blurred vision and hearing loss,” Sklar said. “These patients could be seeing a number of providers. Endocrine effects are just one part of that. As other late effects arise, they could become aware of the late endocrine effects, as well.”
Treatment and beyond
Attention to endocrine and other cancer effects has led to emphasis on treatment de-intensification.
“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. But, the reality is that it is impossible to forego late endocrine effects with chemotherapy and radiation in a young patients who is a vulnerable host.”
An example of an opportunity for therapy de-escalation is ALL.
“Not everyone with this disease should receive prophylactic cranial radiation,” Mostoufi-Moab said. “Otherwise, this results in many low-risk patients burdened with unnecessary long-term effects as a consequence of cranial radiation.”
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.”
Periodic, systematic assessment is the approach most likely to facilitate early treatment of endocrine effects, Chemaitilly said.
It’s also important to appreciate other potential sequelae, such as cardiac dysfunction and second cancers.
“Risk for other late effects, including second malignancies and cardiac late effects, needs to be taken into consideration 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
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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.
For more information:
Zoltan Antal, MD, can be reached at 505 E. 70th St., New York, NY 10021; email: firstname.lastname@example.org.
Smita Bhatia, MD, MPH, can be reached at 1600 7th Ave. S. Lowder 500, Birmingham, AL 35233; email: email@example.com.
Wassim Chemaitilly, MD, can be reached at 262 Danny Thomas Place MS 737, Memphis, TN 38105; email: firstname.lastname@example.org.
Lillian R. Meacham, MD, can be reached at 2015 Uppergate Drive NE, Atlanta, GA 30302; email: email@example.com.
Sogol Mostoufi-Moab, MD, MSCE, can be reached at 3401 Civic Center Blvd., Philadelphia, PA 19104; email: firstname.lastname@example.org.
Charles A. Sklar, MD, can be reached at 1275 York Ave., New York, N.Y., 10065; email: email@example.com.
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.