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Chapter 93 Late Complications of Hematologic Diseases and Their Therapies 1499

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was 44% by 25 years after therapy; the risk for developing thyroid childhood ranges from 29% to 39%, with increased risk at higher
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cancer was 1.7% (15.6 times the expected risk). Most cases of overt doses and longer time from treatment, and may predispose adult
hypothyroidism after HCT result from primary hypothyroidism survivors of childhood ALL, particularly females, to abdominal
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caused by radiation injury. The incidence of hypothyroidism after obesity and metabolic syndrome. Yearly monitoring of BMI is
HCT depends on the type of myeloablative conditioning regimen, recommended for all survivors.
ranging from 10% to over 50% after fractionated TBI, to as high as
90% after exposure to single-dose TBI. 16,96
Thyroid nodules are common in patients treated with neck radia- Gonadal Dysfunction
tion for HL, but the majority of these do not undergo malignant
transformation. 97,98 In a study of 647 children treated for HL, 67 Treatment-related gonadal dysfunction has been well documented in
developed thyroid nodules during or after therapy (median time male and female patients after therapy for hematologic malignancies
between diagnosis of HL and thyroid nodule was 10.5 years, with a and there is a reasonable body of research that provides a basis for
range of 0.2–24.8 years). All but one of these patients had received counseling patients regarding the long-term gonadal effects of radia-
neck radiation as part of their therapy, with a median dose to the tion and chemotherapy.
thyroid of 35 Gy. Seven (10%) of the 67 nodules were malignant. 97 Radiation effects on the ovary are age and dose dependent. It has
Monitoring for survivors at risk for thyroid complications should been estimated that there is a 50% depletion in oocytes after exposure
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include yearly thyroid examination as well as yearly measurement of of the ovaries to 2 Gy. Amenorrhea develops in approximately 68%
free thyroxine and thyroid-stimulating hormone. 82 of prepubescent females treated for HL with ovarian doses of
12–15 Gy, whereas 100% of adult females older than 40 years of age
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will sustain irreversible ovarian failure after doses of 4–7 Gy. Spinal
Growth irradiation for the treatment of childhood leukemia appears to result
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in clinically significant ovarian damage in some survivors, and
Poor linear growth and short adult stature are common complications cranial irradiation in young girls is associated with an increased risk
after successful treatment of hematologic malignancies in childhood. for premature puberty. 122
The adverse impact of central nervous system (CNS) irradiation on The effects of radiation on testicular function, including germ cell
adult final height among childhood leukemia patients has been well number and Leydig cell function, have been investigated. Reduced
documented, with final heights below the fifth percentile in 10% to sperm production has been observed after testicular doses of 1–6 Gy
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15% of survivors. 99–102 The effects of cranial irradiation appear to be and follows a dose-dependent pattern. Azoospermia has been
related to age and sex, with females and children younger than 8 years reported among HL patients with calculated testicular irradiation
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at the time of therapy being more susceptible. 103,104 The precise exposures ranging from 1–3 Gy. Testicular doses between 4–6 Gy
mechanisms by which cranial irradiation induces short stature are not have been associated with prolonged azoospermia and decreased
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clear. Disturbances in growth hormone production have not been testicular volume. Spermatogenesis is impaired in 75% to 100%
found to correlate well with observed growth patterns in these of male childhood HL survivors in whom radiation and chemo-
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patients. 105,106 The phenomenon of early onset of puberty in girls therapy were combined. Leydig cells, although also affected by
receiving cranial irradiation may play some role in the reduction of radiation in a dose-dependent fashion, require higher exposure levels
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final height. 107,108 In childhood leukemia survivors not treated with to sustain damage than those seen for the germ cells. Testicular
cranial irradiation, there are conflicting results regarding the impact doses of 24 Gy among prepubertal males have been reported to be
of chemotherapy on final height. 100,109 associated with delayed pubertal development and abnormal testos-
Impaired linear growth after HCT is likely due to an interaction terone and gonadotropin levels. 127–129
of multiple factors, including host characteristics (young age), treat- Ovarian and testicular damage can also result from chemothera-
ment exposures (prior cranial irradiation, TBI), and post-HCT peutic agents, with alkylating agents showing the strongest associa-
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complications, such as chronic GVHD. Findings suggest that final tion. Effects of chemotherapy on gonadal function are typically sex,
height is unaffected in children who receive busulfan or cyclophos- age, and dose dependent. While older studies have suggested that the
phamide as pretransplant conditioning. 110 ovaries tend to be less sensitive to the effects of alkylating agent
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Survivors should be monitored using standardized growth curves exposure compared with the testes, this may have been due to a
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until final height is achieved. An endocrine consultation should be lack of reliable markers for measuring ovarian function. Ovarian
obtained for children who received cranial radiation in doses ≥30 Gy dysfunction has been well documented in HL patients treated with
and for those whose height is less than the third percentile, or who alkylating agents, singly or in combination (e.g., MOPP regimen
have poor growth for age or pubertal stage. 82,104 consisting of mechlorethamine, vincristine [Oncovin], procarbazine,
and prednisolone, or a COPP regimen consisting of cyclophospha-
mide, vincristine [Oncovin], procarbazine, and prednisolone) 130–133
Obesity MOPP and COPP regimens have been reported to result in azoosper-
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mia in more than 90% of exposed males, with a negative correlation
An increased prevalence of obesity has been reported among survivors seen between cumulative doses of alkylating agents and sperm con-
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of childhood ALL. 111–113 In an analysis from the Childhood Cancer centration. Even with a reduction in the dose of cyclophosphamide
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Survivor Study, Oeffinger et al compared the distribution of the in the hybrid COPP/adriamycin, bleomycin, and vinblastine (ABV)
body mass index (BMI) of 1765 adult survivors of childhood ALL regimen for HL, the majority of young males are infertile, likely due
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with that of 2565 adult siblings of childhood cancer survivors. Sur- to the procarbazine component in this regimen. In a study of 6224
vivors were significantly more likely to be overweight (BMI of male survivors of childhood cancer between 15 and 44 years of age,
25 to <30) or obese (BMI ≥30). Risk factors for obesity were cranial those with a diagnosis of hematologic malignancy were significantly
irradiation, female sex, and age 0–4 years at diagnosis of leukemia. less likely to sire a pregnancy compared with sibling controls; those
Females diagnosed under the age of 4 years who received a cranial with a diagnosis of HL were least likely to sire a pregnancy (RR of
radiation dose of more than 20 Gy were found to have a 3.8-fold fertility: 0.34; 95% confidence interval [CI]: 0.28–0.41), followed by
increased risk for obesity. In a recent report of survivors of standard- NHL (RR: 0.60; 95% CI: 0.48–0.74), and leukemia (RR: 0.70; 95%
risk childhood ALL treated without cranial radiation, there was no CI: 0.59–0.84); p < .001 for all comparisons. 137
increased risk of overweight or obesity compared with general popula- Young boys and adolescent males with aplastic anemia who receive
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tion health data. Obesity has the potential to adversely impact the standard-dose cyclophosphamide alone (200 mg/kg) as the pretrans-
overall health status in survivors and is associated with insulin resis- plant conditioning regimen appear to retain normal Leydig cell
tance, diabetes mellitus, hypertension, and dyslipidemia. The preva- function, as do males who receive busulfan and cyclophosphamide,
lence of growth hormone deficiency related to cranial radiation in with normal plasma concentrations of luteinizing hormone and