Medical assessment of adverse health outcomes in Dutch childhood cancer survivors; a nationwide project; SKION LATER Q2008 onderzoek:
Growth hormone deficiency in children, after treatment for childhood cancer

Advances in diagnosis and treatment of childhood cancer over the last decades
have dramatically increased long-term survival. As a result, the numbers of
childhood cancer survivors (CCS) are growing and it has become increasingly
clear that the former disease and its treatment can significantly impair
long-term health. The need for long-term follow-up is uniformly recognized.
Research focusing on identification and characterization of high-risk
populations is an essential foundation on which to build evidence-based
recommendations for long-term follow-up. Furthermore, research focusing on more
accurate screening tests and effective interventions is needed to reduce excess
morbidity and mortality in CCS. The SKION LATER Q2008 - growth hormone study
phocuses on growth hormone deficiency in CCS .
After cranial radiation therapy for childhood cancer, endocrine deficienties
are frequently seen. Damage to the hypothalamic-pituitary axis is time and dose
dependent. The incidence of problems increases in time. For both the
hypothalamus and the pituitary gland, the dose per fraction that is
administered is of importance next to the total administered dose. Younger
patients are more vulnerable than older patients.
The hypothalamus is more radiosensitive than the pituitary gland; damage can be
expected after 40-50 Gy, and after higher doses also the pituitary gland may be
damaged. However, also at doses < 40 Gy hypopituitarism may be present due to
hypothalamic dysfunction.
Of the production of the pituitary hormones, the synthesis of GH will be
affected first, mostly followed by LH & FSH, ACTH, and TSH. Next to a GH
deficiency, also GH neurosecretory dysfunction has been described to occur,
characterized by a normal GH peak in the stimulation test but a decreased
spontaneous 24-hour GH-secretion.
Growth retardation after treatment with chemotherapy has also been described.
The glucocorticoids are one of the best known drugs to cause growth retardation
and are frequently administered to children during cancer treatment, as
anti-emetic or as part of the cytotoxic regimen. Reduced growth velocity in
children treated with multiple cytotoxic drugs is common, and it is likely that
the effects of underlying disease and the different drugs interact or act
additively. The exact influence of chemotherapy on the GH axis is unknown.
The diagnosis of growth hormone deficiency is difficult as there is no golden
standard. The diagnosis is always made with the combination of presenting
symptoms; short stature with delayed bone-age, low IGF-1 with low IGF-BP3, in
absence of other endocrine deficiencies and other diseases such as kidney or
liver disease. In this case GH-stimulation tests are performed twice. In case
of a maximum peak of GH < 20 mE/L, GH deficiency is made more likely.

• To assess the prevalence of short stature, in combination with an aberrant
IGF-1 in combination with IGF-BP3 in the entire cohort of childhood cancer
survivors and the therapy related risk factors.
• To assess the distribution of IGF-1 and IGF-BP3 in the entire cohort of
childhood cancer survivors.

This study with cross sectional design will consist of a history and physical
exam, and a venapuncture. For half of the population, these tests will be part
of regular patient follow up as defined by the guidelines for screening for
late toxicity in CCS. Data will be collected anonymously in a central database.

Half of the survivors (n=200) will have the outpatient visit, and venapuncture
as part of their regular follow up based on screening guidelines for CCS. For
the CCS treated with chemotherapy, the visit at the outpatient clinic is part
of the regular follow up based on screening guidelines for CCS, but the
venapuncture is done as part of the study (15 minutes) . There are no risks for
the study participants.