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Endocrine consequences of childhood cancer: Long-term follow-up is key
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Advances in cancer therapy and treatment have resulted in increased survival rates for children with cancer — nearly 80% of children diagnosed with cancer are alive at least five years after diagnosis, according to the National Cancer Institute. However, significant survival benefits are also associated with short- and long-term morbidity later in life, and many of these are consequences of disturbances in the endocrine system.
Data published in the January issue of Cancer, Epidemiology, Biomarkers and Prevention indicated that childhood cancer survivors appear to be predisposed to obesity, diabetes, dyslipidemia and hypertension. Meacham and colleagues studied 8,599 childhood cancer survivors who had lived at least five years after pediatric cancer diagnosis and 2,936 healthy siblings enrolled in the Childhood Cancer Survivor Study. Cancer survivors were 70% more likely than their siblings to be diagnosed with diabetes, 60% more likely to take a cholesterol-lowering medication and nearly 90% as likely to take a blood pressure-lowering medicine.
Long-term survivors of childhood cancer may also be at risk for growth and pubertal disorders as a consequence of hypothalamic-pituitary dysfunction; gonadal deficiency and failure; thyroid deficiency and damage; and metabolic bone disorders, among others.
“The problem is that unless you are in a particular setting, these patients are encountered infrequently, which can lead to problems because many are not familiar with the endocrine risks of childhood cancer and do not understand the implications of the cancer treatments,” Charles A. Sklar, MD, of Memorial Sloan-Kettering Cancer Center, told HemOnc Today. “This often results in the patients’ problems being unrecognized and undiagnosed for long periods of time.
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Photo by: Memorial Sloan-Kettering Cancer Center |
“Educating both pediatric and, more importantly, adult providers who see survivors of childhood cancer as they grow older is critically important,” Sklar said.
HemOnc Today interviewed several experts about specific endocrine consequences of childhood cancer, effects of treatment and the need for long-term follow-up.
Childhood Cancer Survivor Study
The Childhood Cancer Survivor Study, a retrospective cohort study of 14,000 childhood cancer survivors diagnosed between 1970 and 1986 and 4,000 sibling controls, is the largest study of the long-term health of childhood cancer survivors.
Researchers who have studied the Childhood Cancer Survivor Study data thus far have identified a number of potential late effects of cancer, including a high prevalence of chronic complications, premature menopause, stroke and second cancers.
“We are finding risk factors in cancer survivors in their early 30s that we would not think would be present until they are older,” Lillian R. Meacham, MD, medical director of the Cancer Survivor Program of the Aflac Cancer Center and professor of pediatrics at Emory University, said in an interview. Meacham participated in the study that indicated childhood cancer survivors in the Childhood Cancer Survivor Study were predisposed to obesity, diabetes, dyslipidemia and other chronic conditions.
“Complications of childhood cancer are usually progressive,” Nursen Gurtunca, MD,
fellow in the department of pediatric endocrinology at Children’s Hospital of Pittsburgh, told HemOnc Today. “Patients may not have any complications during initial screening, and if they are growing normally, they may fall off the radar, but many of these endocrine complications can appear many years later.”
In a 2006 analysis published in The New England Journal of Medicine, Kevin C. Oeffinger, MD, Sklar and colleagues at Memorial Sloan-Kettering Cancer Center reported that 62% of children in the Childhood Cancer Survivor Study reported one chronic complication at least five years after diagnosis, 24% reported three complications and 28% reported a severe or life-threatening complication. The cumulative incidence of complications reached 70% 30 years after treatment of the cancer.
Another 2006 analysis, published in the Journal of the National Cancer Institute, revealed an increased risk for premature menopause in childhood cancer survivors. Sklar and colleagues assessed 2,819 survivors of childhood cancer aged 18 years and older and 1,065 female siblings. Premature menopause occurred in 126 childhood cancer survivors compared with 33 siblings. Of these, 60 survivors (48%) and 31 siblings (94%) had surgically induced menopause (RR=0.8; 95% CI, 0.52-1.23; median age of occurrence, 37 years). Researchers noted no significant difference in premature menopause as a result of surgery between cancer survivors and siblings. However, survivors had a higher cumulative incidence of nonsurgical premature menopause by age 40 years, compared with siblings (8% vs. 0.8%; RR=13.21; 95% CI, 3.26-53.51).
Consequences of cancer treatment
The long-term effects of childhood cancer are treatment-specific, according to Sklar.
“Whether or not there is going to be a particular endocrine problem is entirely dependent on the treatment received — not the diagnosis,” he said.
According to Sklar, it is common for many to be unfamiliar with the implications of cancer treatments on long-term endocrine function.
“The first time you see a patient in your office, unless you know exactly what their treatment consisted of, it is impossible to advise them and do appropriate testing unless you have this information — and often you do not — which creates a huge problem,” he said.
“If a patient who does not seem to have an obvious clinical problem is referred to the endocrinologist for an endocrine problem, the fact that the patient received a particular dose of radiation to the pituitary is important,” Sklar said.
Individual therapeutic agents may have a different toxicity profile, and various doses of radiation or chemotherapeutic agents may result in endocrine complications.
In the aforementioned Childhood Cancer Survivor Study published in the Journal of the National Cancer Institute, chemotherapy treatment for childhood cancer was associated with an increased risk for premature menopause in those who had significant exposure to alkylating agents. Childhood cancer survivors who received both radiation and alkylating drugs had a cumulative incidence of premature menopause of nearly 30%.
Another example is the results of a 2009 study published in the Journal of Clinical Endocrinology & Metabolism indicating that men who were childhood cancer survivors and had brain surgery or were treated with chemotherapy or testicular radiation had the highest prevalence for hypogonadism.
Patrik Romerius, MD, resident physician at the Pediatric Clinic of Lund University Hospital in Sweden, and colleagues assessed 151 boys who were childhood cancer survivors treated from 1970 to 2002 (aged 18 to 45 years in 2004) and compared them with 141 healthy fertile men. They reported that the overall risk for hypogonadism was higher in the childhood cancer survivor cohort when compared with fertile men (OR=6.7; 95% CI, 2.7-17).
“The whole issue of hypogonadism as a consequence of cancer treatment has been overlooked — more focus has been placed on the issue of fertility,” Romerius told HemOnc Today.
“It is perhaps not surprising that childhood cancer survivors do have an increased risk for hypogonadism. The effect may be both on the hypothalamus and pituitary, with brain surgery or irradiation, but also directly on the testes, with surgery, cytotoxic drugs and irradiation,” Romerius said.
Gurtunca provided several other examples of the consequences of cancer treatment. “Other endocranial tumors, after surgical resection or especially high doses of radiation therapy, may also lead to pituitary deficiencies. In terms of chemotherapy, high-dose alkylating chemotherapy for leukemia patients, for example, may result in endocrine complications such as gonadal dysfunction.”
Mark A. Sperling, MD, professor of the department of pediatrics at University of Pittsburgh, Children’s Hospital of Pittsburgh, said another common problem related to treatment may be hypothyroidism with elevated thyroid- stimulating hormone if the patient has received radiation to the back of the head. Another could be low thyroid-stimulating hormone or low thyroxine if the patient had the area of the hypothalamus that provides thyroid-stimulating hormone damaged.
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“The most important thing for any provider who is seeing a childhood cancer survivor is to obtain information about his or her specific treatment and its associated health risks,” Melissa M. Hudson, MD, director of the cancer survivorship division and co-leader of the Cancer Prevention and Control Program at St. Jude’s Children Research Hospital, said in an interview.
“We say that the best care is risk-based care, in which the provider considers all pertinent factors related to that survivor’s cancer history; for example, the patient’s age at diagnosis and the specific type of treatment, including surgery, chemotherapy, radiation therapy or even transfusions or transplants. These are all important because each is associated with a specific risk,” Hudson said.
Sex-specific complications
Some long-term complications associated with cancer treatment pose greater risks for complications for specific sexes. Based on the specific complication, girls or boys may have a greater risk.
Although Hudson said sex-specific differences in complications do not necessarily affect follow-up care, it is important to be aware that there may be greater differences in risk between boys and girls and men and women. For example, girls appear to be at higher risk for neurocognitive dysfunction after cancer treatment that affects the central nervous system. Conversely, the sperm cells of boys are more sensitive to the effects of alkylating agent chemotherapy than the egg follicles of girls.
“A young girl is more likely to maintain normal ovarian and germ cell function after non-transplant doses of alkylating agent chemotherapy, whereas boys have a significant risk for having germ cell failure,” Hudson said.
The most dramatic risk, she said, is related to the risk for breast cancer.
“Girls treated with chest radiation have a marked increased risk for breast cancer that warrants breast cancer surveillance at a much younger age, whereas boys treated with comparable therapy do not show this excess risk,” Hudson said.
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Recent data published in the Journal of Clinical Oncology on the Childhood Cancer Survivor Study indicate that male cancer survivors are less likely to sire a pregnancy five or more years after diagnosis when compared with their healthy siblings (HR=0.56; 95% CI, 0.49-0.63). When researchers further adjusted for marital status, race/ethnicity and education, the likelihood for ever siring a pregnancy increased (HR=0.91; 95% CI, 0.73-1.14) for survivors who did not have an alkylating agent (dose score of 0), did not have hypothalamic/pituitary radiation (dose of 0 Gy) and did not have testes radiation (dose of 0 Gy).
Follow-up care
All of the experts whom HemOnc Today interviewed agreed that long-term follow-up care is the most important task for the physician.
“Most pediatric cancer centers have survivors that are being ‘primed’ to know their cancer histories and to share details with their local providers,” Hudson said. “We want these providers to understand that they need to have a summary of a survivor’s cancer treatment history to anticipate health risks and guide appropriate health screening. If a survivor does not come in with this health information, contact the treating pediatric oncologist or cancer center to obtain medical records.”
Kirsten K. Ness, PhD, assistant member of the department of epidemiology and cancer control at St. Jude Children’s Research Hospital, said physicians who care for adult survivors of childhood cancer should follow the Children’s Oncology Group long-term follow-up guidelines (sidebar).
The Children’s Oncology Group guidelines were developed by a panel of experts who care for childhood cancer survivors on a daily basis. The guidelines provide more than 140 recommendations for the screening and management of long-term effects of cancer treatment. According to the guideline authors, “the screening recommendations are suitable for asymptomatic survivors of childhood, adolescent or young adult cancer presenting for routine exposure-based medical follow-up.”
Gurtunca told HemOnc Today that one major barrier of follow-up treatment is that the problems that occur after patients have completed their treatment seem minor compared with what they experienced with cancer.
“For example, a young girl who has stopped menstruating may not be worried about it after all that she went through with her cancer,” Gurtunca said. “This creates a barrier for follow-up with other specialists, which means the long-term follow-up may not be as good as it should be.”
Sperling said from an endocrine perspective, it is important to monitor childhood cancer survivors for thyroid disorders, growth and growth hormone deficiency, precocious puberty and pubertal delay.
“In particular, a normal growth velocity does not rule out an endocrine problem,” Sperling said. “For example, irradiation of the hypothalamus may cause growth hormone deficiency and, simultaneously, precocious puberty, two opposing effects on growth, which cancel out and mislead the physician into thinking all is well.
“Hence, careful physical examination of children who had cranial irradiation should be performed at each visit to rule out precocious puberty, even when there is no pubertal ‘growth spurt,’” he added.
Moving forward
As changes have been made in cancer treatment during the past 50 years, Hudson said “progress has been made in reducing the health risks for childhood cancer survivors. We rarely see severe life-threatening effects of the heart, lung or liver because we have made adjustments in these therapies, not wanting to trade one life-threatening disease for another.
“In many cases, we are seeing an acceleration of the diseases associated with aging or earlier onset of some conditions that are common in an aging population,” Hudson said.
The problem with subclinical injuries remains as “consequences are detected, as other adverse effects are added to the mix, as the patients’ age or those associated with bad health habits.”
More data for the Childhood Cancer Survivor Study should be compiled in the coming years. In 2007, researchers for the study began recruiting a second set of participants: 14,000 adults treated for cancer as children between 1987 and 1999. Until that expanded cohort has been recruited and followed for five years, data are based on survivors who were treated before 1986.
“Childhood cancer survivors definitely need to come to an endocrine clinic with experience in managing children who have had tumors of any kind,” Sperling said.
“Educating both pediatric and, more importantly, adult providers who see these patients as they grow older is critically important, and there is a huge lack of appreciation for a lot of the issues these patients face,” Sklar said. – by Jennifer Southall
What steps do you take when seeing a patient who is a childhood
cancer survivor?
For more information:
- Green DM. J Clin Oncol. 2010;28:332-339.
- Meacham L. Cancer Epidemiol Biomarkers Prev. 2010;19:170-181.
- Romerius P. J Clin Endocrinol Metab. 2009;94: 4180-4186.
- Sklar C. J Natl Cancer Inst. 2006;13:890-896.