Alkylating agents
Busulfan
Cisplatin
Cyclophosphamide
Ifosfamide
Mechlorethamine
Melphalan
Nitrosureas
BCNU (carmustine)
CCNU (lomustine)
Procarbazine
Thiotepa
Primary factors associated with late endocrine complications are as follows:
1.
Radiotherapy: the involved field, cumulative dose, and the greater duration of exposure
2.
Chemotherapy: type and dose
3.
Surgery: degree and number of surgeries
These are treatment and not disease specific. Therefore, knowledge of current and past therapies is critical in understanding their risk and for selection of the appropriate diagnostic evaluations required to screen for those risks. Treatment exposures can be modified by a number of factors:
1.
Age: In some cases, younger age is protective, whereas in other cases, younger age is associated with increased endocrine dysfunction.
2.
Gender: For unclear reasons, females are at slightly higher risk for many of these endocrine disorders.
3.
Genetics: hereditary predisposition.
4.
Social: health and lifestyle practices, e.g., smoking, alcohol, and obesity.
26.2 Disorders of the Hypothalamic–Pituitary Axis
Childhood cancer survivors are at risk for multiple pituitary hormone deficiencies (Table 26.2) .
Table 26.2
Therapy-related complications affecting the hypothalamic–pituitary axis
Complication | Therapy-related risks | Relationship to time, dose, and available cumulative incidence data |
|---|---|---|
GH deficiency | Surgery | Immediate effect |
Radiation to the hypothalamic–pituitary region | Doses > 30Gy: effect by 5 years after exposure. Cumulative evidence ~ 90 % over 4 years | |
Doses 18–24 Gy: effect only > 10 years after exposure | ||
Precocious puberty | Radiation to the hypothalamic–pituitary region | Doses > 18 Gy |
Increased risk for girls < 5 years with incidence 10–20 % | ||
Hypogonadotropic hypogonadism | Radiation to the hypothalamic–pituitary region | Doses > 30 Gy |
Incidence 10–20 % with doses > 50 Gy | ||
ACTH deficiency | Surgery | Immediate effect |
Radiation to the hypothalamic–pituitary region | Doses > 30 Gy: possible cumulative incidence 38 % over 4 years | |
Glucocorticoids | Effect dose and duration dependent | |
TSH deficiency | Radiation to the hypothalamic–pituitary region | Doses > 30 Gy |
Cumulative incidence 23 % over 4 years with doses > 40 Gy |
1.
Growth Hormone Deficiency (GHD)
a.
Impaired linear growth resulting in adult short stature occurs frequently, particularly in individuals treated before puberty .
b.
Results from the direct insult to pituitary somatotropes due to tumor expansion in the pituitary gland, surgical resection, or cranial radiotherapy.
c.
The most common anterior pituitary deficit to develop after cranial radiotherapy.
d.
GHD following irradiation of the hypothalamic–pituitary region occurs in a time- and dose-dependent fashion, i.e., greater risk is associated with higher doses of radiation (> 30 Gy) and longer interval from treatment.
e.
Radiation-induced GHD is usually permanent.
i.
Patients should be retested after the completion of linear growth before considering treatment with growth hormone (GH) through adulthood.
f.
Diagnosis requires failing of at least one of the two stimulation tests, e.g., insulin tolerance and glucagon stimulation tests.
g.
Safety of GH therapy
i.
No increased risk of primary tumor recurrence in patients treated with GH (primarily brain tumor survivors).
ii.
Treatment with GH may slightly increase the risk of a secondary solid tumor, such as meningiomas.
h.
Benefits of GH therapy
i.
Positive effects on quality of life.
ii.
Modest improvements in metabolic parameters, e.g., body composition, lipids, and cardiovascular risk markers .
2.
Disorders of Luteinizing Hormone/Follicle-Stimulating Hormone
a.
Central precocious puberty (CPP)
Cranial irradiation at both lower doses (18–35 Gy) and higher doses (> 35 Gy) is associated with the development of CPP by disrupting inhibitory cortical influences .
i.
Risk factors following cranial irradiation
Female sex
Young age at treatment (i.e., before puberty)
Body mass index (BMI) > 30 kg/m2
ii.
Risk factors for early menarche
Radiation before the age of 5 years
Radiation with doses > 50 Gy
iii.
Definition
In girls, the onset of sustained breast development < 8 years of age
In boys, testicular volume that is inappropriately small for a given stage of puberty
iv.
Assessment
Skeletal maturation assessed using the standard bone age (X-ray examination of the left wrist and hand) to estimate the individual’s skeletal age.
Advancement of the bone age > 2 standard deviations for chronological age is consistent with CPP.
In girls, uterine growth on pelvic ultrasound is a sign of estrogen stimulation.
Gonadotropin secretion is best assessed using the gonadotropin-releasing hormone (GnRH) or GnRH agonist stimulation tests. Ample luteinizing hormone (LH) response, greater than the follicle-stimulating hormone (FSH) response, indicates a pubertal pattern.
Plasma estradiol levels in girls and testosterone levels in boys are important indicators of pubertal development.
v.
Treatment
Delaying the progression of puberty by using long-acting formulations of GnRH agonists stabilizes the advancement of bone age and improves statural outcome.
b.
Hypogonadotropic hypogonadism
i.
Deficits of LH and FSH secretion following cranial irradiation occur less often than GHD, and generally only occur following doses to the sellar region, from 30 to 40 Gy .
ii.
Late menarche (onset of menstrual cycles > 16 years of age) is associated with doses of radiation > 50 Gy, treatment after 10 years of age, and the diagnosis of medulloblastoma.
iii.
In female acute lymphoblastic leukemia (ALL) survivors, “subtle” defects of gonadotropin secretion following radiation doses in the 18–24 Gy range have been described.
c.
Adrenocorticotropic hormone (ACTH) deficiency
i.
Apart from transient ACTH deficiency resulting from chronic suppression due to the prolonged use of high doses of glucocorticoids, ACTH deficiency is relatively uncommon.
ii.
May be observed either as a result of direct tumoral impingement on the hypothalamic–pituitary axis and surgery in that region, or following high-dose (> 30 Gy) radiation.
d.
Thyroid-stimulating hormone (TSH) deficiency
i.
TSH deficiency is rare following cranial irradiation, but has been reported following doses > 30 Gy.
ii.
In contrast, doses < 30 Gy does not induce central hypothyroidism .
26.3 Disorders of the Thyroid Gland
Thyroid dysfunction is among the most frequent endocrine complications in childhood cancer survivors (Table 26.3).
Table 26.3
Therapy-related complications relating to the thyroid
Complication | Therapy-related risks | Relationship to time, dose, and available cumulative incidence data |
|---|---|---|
Hypothyroidism | Radiation to the neck | Hodgkin’s lymphoma survivors: cumulative incidence 28 %, reaches 50 % with doses > 45 Gy over 20 years |
Hyperthyroidism | Radiation to the neck | Doses > 35 Gy, cumulative incidence 5 % over 25 years |
Autoimmune disease | Hematopoietic stem cell transplantation | By transfer of abnormal clones of B or T cells from donor to host |
Cancer | Radiation to the neck | Doses > 20 Gy: cumulative incidence 18 % Patients treated < 10 years of age higher risk Median latency > 20 years |
1.
Therapy-induced primary hypothyroidism
a.
The most frequently observed thyroid disorder following radiation exposure of the gland to the following types of radiation:
i.
Neck/mantle irradiation for Hodgkin’s lymphoma
ii.
Craniospinal irradiation for brain tumors
iii.
Total body irradiation (TBI) for cytoreduction before hematopoietic stem cell transplantation (HSCT)
b.
Risk factors for developing hypothyroidism
i.
Total dose of radiation to the thyroid
ii.
Increased duration of exposure
iii.
Female gender
iv.
Caucasian race
v.
Age > 15 years
2.
Therapy-induced primary hyperthyroidism
a.
Occurs less frequently than primary hypothyroidism , and is diagnosed most often following external beam radiation to the neck for Hodgkin’s lymphoma.
b.
A risk factor is exposure to radiation doses > 35 Gy to the thyroid.
c.
In ALL survivors, the cumulative incidence of primary hyperthyroidism was 0.6 %, which is much lower than the incidence of primary hypothyroidism but still higher than the incidence of hyperthyroidism observed in a sibling control population.
3.
Autoimmune thyroid disease
a.
May occur in allogeneic HSCT recipients by the adoptive transfer of abnormal clones of T or B cells from donor to recipient.
b.
Hypothyroidism with or without a preceding hyperthyroid phase may be observed in subjects with positive thyroglobulin autoantibody.
c.
Hyperthyroidism with positive TSH receptor autoantibodies has also been reported following allogeneic HSCT.
4.
Thyroid neoplasms
a.
Risk factors
i.
Exposure of the thyroid to either direct or scatter radiation.
ii.
Children < 10 years of age treated with radiation doses in the range of 20–29 Gy.
iii.
Survivors of Hodgkin’s lymphoma (majority of cancers are differentiated carcinomas, i.e., papillary and follicular).
b.
The association between thyroid irradiation and thyroid neoplasms is linear at low doses of radiation. With doses > 30 Gy, neoplasms are less likely to develop and tend to have a more indolent natural history.
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