Growth Hormone Not Linked to Later Tumors in Cancer Survivors

Becky McCall

May 13, 2014

WROCŁAW, Poland — Childhood cancer survivors with growth-hormone (GH) deficiency after surgery or radiotherapy who receive GH replacement do not have a higher risk for subsequent tumors of the central nervous system (CNS), such as meningioma or glioma, according to new epidemiological data.

Giving an overview of the whole topic at the European Congress of Endocrinology (ECE) 2014, Roger Abs, MD, recently retired, former head of the department of endocrinology,University Hospital of Antwerp, Belgium, explained that GH deficiency is common among pediatric cancer survivors who received radiation exposure to the hypothalamus and/or pituitary.

Concern has been raised about GH treatment having a causal role in recurrence or second malignancies, and there have been reports of higher rates of second malignancies in cancer survivors treated with GH.

Dr. Abs focused particularly on new results from the Childhood Cancer Survivor Study (CCSS), which show that, after researchers controlled for cranial irradiation, there is no increased risk for the development of meningioma and glioma — the 2 most commonly occurring CNS tumors — or for any other malignancy of the CNS in patients in this database who received GH replacement.

Hence, he concluded that GH replacement is justified in such patients, whose quality of life is often poor but is greatly improved by GH.

Commenting, Richard Ross, MD, FRCP, professor of endocrinology, University of Sheffield, United Kingdom, agreed that there is little evidence to suggest that GH replacement induces secondary malignancies.

"Dr. Abs is recommending that growth-hormone–deficient cancer survivors receive growth hormone irrespective of radiotherapy. This supports current practice."

Andrew Toogood, MD, consultant endocrinologist from University Hospitals Birmingham NHS Foundation Trust, United Kingdom, concurs. The data support the use and safety of growth hormone in adults treated for brain tumors during childhood, he said.

He added that the decision to start GH therapy is taken in consultation with the patient and the patient's oncologist. "As a pragmatic approach, I wait for 2 years following the completion of treatment before commencing growth hormone to avoid the period when [risk of] relapse of the primary lesion is greatest," he noted.

"The key is that these patients need to be managed in a specialist center by an endocrinologist with experience in the field who works closely with colleagues in oncology. There does need to be continued vigilance, as the current follow-up is relatively short, and someone may be on growth hormone for many years," Dr. Toogood stressed.

No Increase in Subsequent CNS Tumors in Survivors on GH

Dr. Abs explained that radiotherapy to treat childhood cancers can result in GH deficiency: for example, hypothalamic irradiation for CNS tumors (30–60 Gy) is associated with a 5% to 100% chance of GH deficiency, while those who receive cranial irradiation for acute lymphoblastic leukemia or non-Hodgkin's lymphoma (18–24 Gy) have a 25% to 50% chance of GH deficiency.

These patients often receive GH-replacement therapy, but this decision is often viewed as controversial.

"Our concern is that the incidence of childhood cancer survivors is increasing and now one in 500 young adults is a cancer survivor, so the number of patients treated with growth hormone will increase, too. Clear guidelines regarding follow-up are needed," Dr. Abs said.

He added that these latest data will help inform the understanding of the risk factors involved in the development of subsequent tumors in this particular group of patients.

The results he reported at ECE relate to 12,098 childhood cancers survivors in CCSS; the data were also published online February 25 in the Journal of Clinical Endocrinology and Metabolism by Briana Patterson, MD, from Emory University/Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Georgia, and colleagues.

Among cancer survivors treated with growth hormone, 16/338 (4.7%) developed subsequent tumors of the CNS, including 10 with meningiomas and 6 with gliomas. By comparison, among cancer survivors not treated with growth hormone, 203/11,760 (1.7%) developed subsequent tumors of the CNS, including 138 with meningiomas, 49 with gliomas, and 16 with other CNS tumors.

The adjusted rate ratios for development of subsequent meningioma and glioma between those treated vs untreated with growth hormone were 0.8 (P = 0.61) for meningioma and 1.9 (P = 0.21) for glioma.

"There is no increase in occurrence in meningioma nor in glioma in patients who received growth-hormone–replacement therapy," concluded Dr. Abs.

He added that data from 2 other sources also support this assertion: analysis of Lilly's United States–based HypoCCS database and early unpublished data from the Pfizer KIMS database.

Radiation More Likely to Be the Culprit in Subsequent Tumors

Dr. Abs also reported the cumulative incidence of glioma and meningioma since primary cancer diagnosis in the CCSS study. With respect to gliomas, there was a progressive increase in subsequent tumors up to 20 years' postdiagnosis, after which no further increase was found.

"This was not the case for meningiomas, where there was a progressive increase even after 30 to 35 years," he observed.

However, he emphasized, "There was no difference seen in patients who were irradiated and received growth hormone vs those irradiated but who did not receive growth hormone."

Indeed, Dr. Patterson told Medscape Medical News by e-mail, it appears more likely that radiation plays a role in future cancers.

"While growth hormone treatment was not associated with increased rates of the subsequent tumors, radiation therapy was strongly associated with their occurrence and was associated in a dose-dependent manner, so the higher the dose, then the higher the rate of tumors," she noted.

Management of Patients on Growth Hormone

Dr. Abs stressed also that cancer survivors taking growth hormone should be closely monitored, because if a subsequent tumor is discovered, the issue then becomes how to manage it.

"The growth hormone might not have induced the tumor but [may] promote its evolution due to the presence of growth hormone and [insulinlike growth factor 1] IGF-1 receptors on tumor cells. In these cases, it might be best to stop treatment even if quality of life then suffers."

Dr. Toogood said he manages patients on growth hormone by titrating the hormone against the impact it has on the patient's quality of life, aiming for the lowest effective dose while keeping the IGF-1 level within the age-appropriate normal range.

He does not undertake additional imaging for this patient group but advises a low threshold for scanning in the event of symptoms developing.

"Relapse of the primary lesion or development of secondary neoplasia is a complex situation, which needs careful management. Growth hormone is contraindicated in a patient with active malignancy as per license.

"If a patient is found to have active malignancy, then I recommend that growth hormone is discontinued in the first instance to determine the effect on quality of life. If the patient reports a significant deterioration in quality of life, then after discussion we decide whether to reinstate the GH at the lowest possible dose to achieve the greatest benefit."

But if the lesion is benign and a period of observation is undertaken, for example with meningioma, "I usually continue the growth hormone at the lowest effective dose," he concluded.

Dr. Abs is a member of the KIMS scientific committee (Pfizer International Metabolic Database). Dr. Ross has declared a patent on a fusion protein compromising growth hormone and growth-hormone receptor. Dr. Patterson has participated in Pfizer, Novo Nordisk, Genentech, and Lilly GH postmarketing safety studies. Dr. Toogood has reported no relevant financial relationships.

European Congress of Endocrinology 2014. May 6, 2014; Wrocław, Poland. Abstract S21.3.

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