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Cancer survivors at increased risk for endocrine diseases

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June 29, 2018

Mette Vestergaard Jensen

Adolescent and young adult cancer survivors had a higher than expected rate of hospital contact for endocrine diseases, including thyroid disease, testicular dysfunction and diabetes, according to a Danish population-based study.

Adolescent and young adult cancer survivors — defined as those who had a cancer diagnosis when aged 15 to 39 years — differ from younger and older patients with cancer in terms of biology, epidemiology and clinical outcomes. This population also is at risk for long-term morbidity associated with their cancer or cancer treatment.

“As survival rates from cancer have improved dramatically over the last decades, there is a need to explore the long-term consequences,” Mette Vestergaard Jensen, MD, research scholar at the Danish Cancer Society Research Center, told HemOnc Today. “Most data on the long-term sequelae in cancer survivors at a young age are derived from studies of childhood cancer survivors. Survivors of cancer in adolescence and young adulthood, their relatives and the treating clinicians also require information on the long-term outcomes of treatment.”

Few studies have explored the long-term effects of cancer and its treatment in this population, according to Jensen.

Jensen and colleagues followed 32,548 adolescent and young-adult 1-year cancer survivors (43.1% male) from the Danish Patient Registry for a median of 10 years (range, 0-34). For a control cohort, the investigators also assessed 188,728 cancer-free participants (43.8% male) for a mean of 15 years (range, 0-34).

Exclusion criteria included an endocrine disease diagnosed before the cancer, chromosome abnormalities, congenital endocrine malformations and pituitary tumors.

Overall, 6.5% of cancer survivors had at least one hospital contact for an endocrine disease, whereas researchers expected a hospitalization rate of 3.8% (rate ratio [RR] = 1.73; 95% CI, 1.65-1.81).

Male survivors appeared to be at a higher risk for an endocrine disease than female survivors (RR = 2.41; 95% CI, 2.23-2.61 vs. RR = 1.46; 95% CI, 1.38-1.55).

Researchers observed the highest RRs among cancer survivors for testicular hypofunction (75.12; 95% CI, 45.99-122.7), ovarian hypofunction (14.65; 95%CI, 8.29-25.86) and pituitary hypofunction (11.14; 95% CI, 8.09-15.34).

When evaluated as the proportion of absolute excess risks, the leading reasons for hospital contacts included thyroid disease (38%), testicular dysfunction (17.1%) and diabetes (14.4%).

Survivors of leukemia had the highest risk for any endocrine disease (RR = 3.97; 95% CI, 3.1-5.09), followed by survivors of Hodgkin lymphoma (RR = 3.06; 95% CI, 2.62-3.57) and survivors of brain cancer (RR = 3.03; 95% CI, 2.53-3.64).

Hodgkin lymphoma survivors had the highest risk for hypothyroidism (absolute excess risk, 362 per 100,000 person-years; 95% CI, 280-443).

“Our study does not reveal the mechanisms behind this association, but we already know that radiation therapy causes tissue damage to the radiated area,” Jensen told HemOnc Today. “That explains for instance why Hodgkin lymphoma survivors are at high risk for thyroid diseases. Previous studies have also shown an association between certain types of chemotherapy and testicular damage.”

When researchers stratified the survivors by period of treatment, those diagnosed with cancer from 1990 to 2009 had 48% higher risk for hospital contact for endocrine disease (RR = 2.13; 95% CI, 2-2.26) compared with those diagnosed from 1975 to 1989 (RR 1.44; 95% CI, 1.35-1.54).

Also, multivariate analyses showed risk for any endocrine disorder decreased with increasing age at cancer diagnosis (age 35-39 years vs. 15-19 years; HR = 0.55; 95% CI, 0.43-0.71).

“Our study provides new, accurate and detailed information about these survivors and important clinical information on how the risks for such late effects are modified by patient factors. This knowledge can help clinicians and patients with the highest risk to be more aware of symptoms so that endocrine diseases can be diagnosed early,” Jensen told HemOnc Today. “Thus, patients will receive the right treatment earlier and hopefully prevent more severe sequelae.”

Photo of Marjerrison, Stacey 2018
Stacey Marjerrison
Photo of Ronnie Barr
Ronald D. Barr

Stacey Marjerrison, MD, MSc, and Ronald D. Barr, MB, ChB, MD, of McMaster University, addressed limitations of the study — which included surveillance bias, limited information on cancer stage and treatment, and lack of information on less severe endocrine diseases not requiring hospital contact — in an accompanying editorial.

“[Although] the choice to limit the definition of endocrinopathy to one that required contact with a hospital was only mentioned briefly by the authors in the limitations section, it is an important area for discussion with regard to methodology,” they wrote. “As conditions such as hypothyroidism and type 2 diabetes mellitus are commonly seen by primary care providers, many additional cases likely were diagnosed outside the hospital setting and, thus, the reported prevalence of these late effects in this study is likely to be a significant underestimate of the actual risk.”

Marjerrison and Barr also discussed survivorship care programs specifically for adolescent and young adult cancer survivors.

These programs may be “deemed impossible because of financial constraints and the need for oncologists to focus on their active oncology practices,” they wrote.

However, there are several program models that have been implemented. Studies have shown these programs are feasible and can save overall health costs by addressing and potentially mitigating the severity of late effects through detection and management, according to Marjerrison and Barr.

“Given the prevalence of these [endocrine late effects] and other late effects, survivorship care for this group is a critical imperative that must be addressed by health systems,” they wrote. “Experience from pediatric oncology can inform the development of these programs, and there are adolescent and young adult-specific models that are both feasible and demonstrably successful in meeting the considerable needs of this underserved population of cancer survivors.” – by Cassie Homer

Disclosures: The authors, Marjerrison and Barr report no relevant financial disclosures.

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Jensen and colleagues report on hospital-based encounters for endocrine complications in a national cohort of individuals who have survived for at least 1 year following a malignancy diagnosed when they were adolescents or young adults (AYA) aged 15 to 39 years. Researchers abstracted data pertaining to health care used spanning 3 decades (1976-2009) from Danish Healthcare Registries on 32,548 survivors and 188,728 age and sex-matched controls who did not experience cancer as an AYA.

The results of this study showed that survivors of AYA cancers followed for a median 10 years were significantly more likely to seek care for endocrine complications compared with controls (RR = 1.73; 95% CI, 1.65-1.81). The risk was highest for gonadal hypofunction, hypothalamic-pituitary deficits, hypoparathyroidism and hypothyroidism. Looking at the risk for a given endocrine disease by cancer site, survivors of brain cancers had the highest risk for hypothalamic-pituitary deficits, leukemia survivors had the highest risk for gonadal hypofunction, and Hodgkin lymphoma survivors had the highest risk for hypothyroidism.

This study is unique in its focus on the AYA population, as previous reports have primarily been on cohorts of childhood or adult cancer survivors. The findings are, however, confirmatory of previous work in this field showing known associations between endocrine late effects and the irradiation of endocrine organs, as well as gonadotoxic treatments such as alkylating agents.

Clinician awareness of cancer therapies that increase the risk for endocrine disorders and adherence to evidence-based risk-stratified surveillance for endocrine late effects, such as those proposed by the Children’s Oncology Group, provide cancer survivors with a higher chance of benefiting from timely diagnosis and therapy, which may improve their overall state of health.

Wassim Chemaitilly, MD, and Melissa Hudson, MD

St. Jude Children’s Research Hospital

Disclosure: Chemaitilly and Hudson report no relevant financial disclosures.