Endocrine Reviews 19 (2): 144-172
Copyright © 1998 by The Endocrine Society
The Endocrine Effects of Nonhormonal Antineoplastic Therapy
Sai-Ching Jim Yeung,
Alice Cua Chiu,
Rena Vassilopoulou-Sellin and
Robert F. Gagel
Joint Baylor College of Medicine-The University of Texas M. D.
Anderson Cancer Center Endocrinology Fellowship Program (S.-C.J.Y.,
A.C.C.); and Section of Endocrinology (R.V.-S., R.F.G.), Department of
Medical Specialties, The University of Texas M. D. Anderson Cancer
Center, Houston, Texas 77030
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Abstract
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- I. Introduction
- II. Disorders of Glucose Metabolism
- A. Diabetes mellitus
- B. Glycosuria and ketonuria
- III. Disorders of Free Water Clearance
- A. Syndrome of inappropriate ADH (SIADH)
- B. Nephrogenic diabetes insipidus
- IV. Disorders of Mineral Metabolism
- A. Hypocalcemia
- B. Hypercalcemia
- C. Hypomagnesemia
- V. Metabolic Bone Diseases
- A. Osteoporosis
- B. Rickets or osteomalacia
- VI. Thyroid Disorders
- A. Serum thyroid hormone-binding protein abnormalities
- B. Hypothyroidism
- C. Thyrotoxicosis
- D. Thyroid neoplasm
- VII. Disorders of Lipid Metabolism
- A. Hypertriglyceridemia
- B. Hypercholesterolemia
- VIII. Adrenal Dysfunction
- A. Primary adrenal insufficiency
- B. Secondary adrenal insufficiency
- IX. Disorders of GH Secretion and Growth
- A. GH deficiency
- B. Growth retardation
- X. Reproductive Dysfunction
- A. Reproductive dysfunction due to hypothalamic-pituitary damage
- B. Gonadal toxicity
- XI. Prevention and Surveillance of Endocrine Side Effects
- A. Pediatric screening
- B. Adult screening.
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I. Introduction
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ADVANCES in chemotherapy and radiotherapy have had a
profound effect on the outcome of certain cancers. These cytotoxic
therapies may be associated with side effects, some immediate and
others delayed in onset. Effects of antineoplastic therapy on
hematological, renal, hepatic, and gastrointestinal systems are common
and thoroughly chronicled. Adverse effects of cancer therapy on the
endocrine system are no less important but, except for gonadotoxic
effects (1, 2), have not been as thoroughly organized. Abnormalities of
the thyroid and adrenal glands are common but may be subtle in
presentation. Other side effects that affect the endocrine systems are
less common, sometimes difficult to identify, and even more difficult
to relate to a particular chemotherapeutic regimen unless the physician
performs a dedicated literature search.
The goal of this review is to compile and organize a complicated and
incomplete literature. In our review of the subject, we encountered
several significant challenges. The first was the fragmented nature of
the literature, composed of case and small series reports, and
information provided by manufacturers. It was difficult in most cases
to determine the incidence or prevalence of side effects associated
with individual agents because most chemotherapeutic protocols involve
multiple agents, and the protocols being used to treat individual
malignancies are changing continuously. A second challenge was the lack
of information on newer therapies in which endocrine complications may
be delayed. As we contemplated the best medium to present this
information, we decided to combine a written review with an interactive
hypertext-based medium accessible on the
Internet.2 The resulting document is
intended to be a fluid medium that will, we hope, change and grow over
time as more information becomes available. Our position in a major
cancer center provides us with a unique opportunity to evaluate
complications of new therapies and to observe the long-term effects of
established therapies. The focus of this paper will be on endocrine
side effects of nonhormonal therapies, excluding drugs with endocrine
actions because of the general familiarity of these drugs within the
community of endocrinologists. In cases where an endocrine agent is
used in combination with other nonendocrine agents that have similar
side effects, the relationship will be discussed.
This review will be organized according to endocrine system
component or side effect, which is the most likely point of access for
the practicing physician. A pharmacological classification of
nonhormonal chemotherapeutic agents and their toxic effects on the
endocrine system will permit rapid evaluation of individual drugs
(Table 1
), and a list of these endocrine
effects and the drugs that cause them will provide disease-oriented
information (Table 2). These tables in
the on-line version will contain hypertext links for exploration of
specific drugs or complications to the endocrine system.
Several characteristics of an individual endocrine gland determine its
susceptibility to chemotherapeutic agents. Endocrine organs, such as
the testis, that have high rates of cell division may be more
susceptible to cytotoxic therapy. In other cases, the drug may target a
particular biosynthetic pathway, making cells that utilize these
pathways susceptible to injury. Another factor is the distribution of
the chemotherapeutic agent, which depends on a variety of factors such
as lipophilicity, metabolism and elimination of individual drugs, and
the ability of a particular endocrine tissue to concentrate the drug.
Glands that have higher concentrations of a drug are more likely to
manifest adverse effects of that drug.
Several different mechanisms can be postulated in the pathogenesis of
endocrine complications from nonhormonal cancer therapy. First,
nonhormonal antineoplastic agents, in general, are cytotoxic, and the
majority affect DNA replication, transcription, protein synthesis, or
microtubule function, which are essential processes for cell division,
growth, and regeneration. The subsequent death or injury of endocrine
cells can result in glandular dysfunction. Second, an agent can
interfere with the synthesis or normal processing of a hormone at the
transcriptional, translational, or posttranslational levels. Third, an
agent can enhance or inhibit secretion of a hormone through interaction
with receptors or perturbation of second or third messenger metabolism.
Fourth, an agent can perturb hormone delivery by changing the level of
a carrier protein in serum or by competing for the binding sites on the
carrier protein. Finally, a nonhormonal antineoplastic agent can
potentiate or block hormone action at the end organ by interacting with
the signal transduction pathway. Specific mechanism(s) of an endocrine
effect will be discussed where available, although we will avoid a
general discussion of the mechanism of antineoplastic effects of
particular drugs, which is available elsewhere (3).
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II. Disorders of Glucose Metabolism
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A. Diabetes mellitus
Serum glucose is regulated by absorption, cellular uptake,
gluconeogenesis, and glycogenolysis, which are processes regulated by
the pancreas, intestine, liver, kidney, and muscle. Hyperglycemia can
result from perturbation of the hormones involved in glucose
regulation, such as insulin or glucagon, or from dysfunction of the
organs involved in glucose homeostasis. Given the effects of
glucocorticoids on glucose metabolism (4, 5, 6), the most frequent
pharmacological cause of insulin resistance and hyperglycemia in cancer
therapy is the administration of high-dose glucocorticoids, usually in
combination with chemotherapeutic or antiemetic regimens. This hormonal
effect will not be discussed in this review.
1. Interferon-
2. Interferons are small peptide cytokines
(molecular masses of 16–27 kDa) that interact with specific cell
surface receptors and modulate several cellular functions (7, 8, 9). The
endocrine effects of these cytokines have recently been reviewed (10).
In the United States, only recombinant forms of interferon-2 have
been approved by the Food and Drug Administration for treatment of
certain types of malignancy, and we shall limit our discussion to this
drug agent.
Use of recombinant interferon-2a and 2b to treat malignancies has
been associated with the development of hyperglycemia in previously
nondiabetic patients and worsening of glycemic control in known
diabetics (11, 12, 13, 14). Similar association of interferon- and diabetes
mellitus is found in the treatment of viral hepatitis (15, 16, 17, 18).
Although the incidence of interferon--induced diabetes mellitus in
cancer patients is unclear, the incidence of diabetes mellitus is about
0.7% among patients who received 480–800 MU of
interferon- over 24 weeks for chronic active hepatitis C (19).
Diabetic ketoacidosis has been reported in a variety of conditions
treated with interferon-2 (13, 14, 20). Several mechanisms have been
described for interferon--induced diabetes, the most important of
which is the effect of interferon- to induce or enhance an existing
immune response (15, 21, 22, 23). Antiislet antibodies, or cell- or
antibody-mediated cytotoxicity, are perhaps involved in causing insulin
deficiency. A direct inhibition of preproinsulin synthesis in islet
ß-cells by interferons may also contribute to insulin deficiency
(24). Enhanced peripheral resistance to insulin has been suggested by
insulin clamp studies and by glucose tolerance test results (20).
Interferon-induced increase in cortisol, GH, and glucagon secretion may
contribute to the insulin resistance (20, 25). Induction of insulin
autoantibodies by interferon- has also been reported (26, 27).
2. L-Asparaginase. L-Asparaginase is
an enzyme derived from microorganisms. It inhibits protein synthesis by
depletion of L-asparagine and is used primarily in the
treatment of hematological malignancies. Hyperglycemia and glycosuria
without ketonemia occurs in 1–14% of patients treated with
L-asparaginase, an effect that is reversible upon
discontinuation of the drug (28, 29, 30). Insulin therapy is frequently
required, but close monitoring of blood glucose is necessary to avoid
hypoglycemia after cessation of L-asparaginase.
Hyperglycemia can be worsened by the concurrent administration of
high-dose glucocorticoid in combination regimens (31, 32). Diabetic
ketoacidosis has been reported (28, 33); after cessation of
L-asparaginase, normalization of all laboratory parameters
and no recurrence of diabetes or diabetic ketoacidosis in the absence
of insulin therapy has occurred in at least one case (R. F. Gagel
and R. V. Sellin, personal observation).
Inhibition of insulin (29, 30, 33, 34) or insulin receptor synthesis
(35), leading to a combined insulin deficiency/resistance syndrome, is
the presumed mechanism of the L-asparaginase effect.
Paradoxically, hyperglucagonemia has been demonstrated in a single case
of L-asparaginase-induced hyperglycemia (36). Why
L-asparaginase targets insulin, insulin receptors, thyroid
hormone-binding protein, and albumin synthesis, but not other proteins
such as glucagon, is not clear.
Pancreatitis, which occurs in 1–2% of
L-asparaginase-treated patients, provides yet another
mechanism for the development of transient or permanent diabetes
mellitus. The incidence of pancreatitis rises when
L-asparaginase is combined with other drug therapy,
i.e., 6.2% in the combined regimen of
L-asparaginase, doxorubicin, vincristine, and prednisone
(L-AdVP) (37).1
3. Streptozocin. Streptozocin (formerly called streptozotocin)
is an N-nitrosourea derivative of glucosamide that is primarily used to
treat malignant islet cell tumors and carcinoid tumors (38, 39).
Streptozocin causes islet cell inflammation and destruction (40). This
effect is species-specific and dose-related. Rats are most susceptible,
and streptozocin has been used to create experimental models of
diabetes mellitus (41, 42). The initial effect of streptozocin is
degranulation of ß-cells (40), which can cause hypoglycemia in
patients with insulin-secreting tumors. Human islet cells are less
susceptible to the deleterious effects of streptozocin (43), and most
streptozocin effects are reversible after cessation of therapy.
Although the incidence of glucose intolerance is 6–60%, most cases
are of mild to moderate severity and reversible upon discontinuation of
the drug (38, 39, 44). In one study, about 1% of patients had
persistent hyperglycemia during short-term follow-up of five months
(38). The generally poor prognosis of metastatic islet cell carcinoma
has made it difficult to determine whether streptozocin has deleterious
long-term effects on human islet cell function, leading to diabetes
mellitus.
B. Glycosuria and ketonuria
Some antineoplastic drugs affect the renal excretion of glucose
without actually affecting glucose metabolism. Drugs such as ifosfamide
or mercaptopurine can damage the renal tubules and cause glycosuria or
Fanconi syndrome (45, 46, 47, 48). A false positive reaction with the testing
agent for urinary ketones can be caused by mesna (2-mercaptoethane
sulfonate sodium) (49), an agent usually given together with ifosfamide
to decrease the incidence of hemorrhagic cystitis.
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III. Disorders of Free Water Clearance
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Serum osmolality is regulated primarily by hypothalamic
osmoreceptors that regulate secretion of antidiuretic hormone (ADH) by
cells of the paraventricular and supraoptic nuclei. The hypothalamic
thirst center, which stimulates drinking behavior, helps to regulate
the intake of free water. The hypothalamic mechanisms controlling
thirst or vasopressin secretion are targets for antineoplastic agents
and may cause dysregulation of free water clearance.
A. Syndrome of inappropriate ADH (SIADH)
Toxicity or damage to nerve terminals in the posterior pituitary
may cause inappropriate release of ADH [also known as arginine
vasopressin (AVP)], which leads to retention of free water and
hyponatremia. SIADH is characterized by hyponatremia, low serum
osmolality, and an inappropriately high urine osmolality in the absence
of diuretics, heart failure, cirrhosis, adrenal insufficiency, and
hypothyroidism. In cancer patients, SIADH may be caused by AVP
production by the tumors (e.g., up to 15% of small cell
lung cancer), abnormal secretory stimuli (e.g.,
intrathoracic infection, positive pressure ventilation), or
cytotoxicity affecting paraventricular and supraoptic neurons (50). It
is also possible that chemotherapy-induced lysis of AVP-containing
cancer cells leads to or worsens SIADH. Most of the literature
regarding SIADH caused by chemotherapeutic agents developed before the
availability of reliable AVP assays, and inappropriate elevation of
plasma AVP is not included in the definition of SIADH. Drug-induced
renal salt wasting [mediated by renal tubular toxicity,
e.g., cisplatin (51, 52)] or tumor-induced renal salt
wasting (mediated by atrial natriuretic peptides) (53, 54, 55) can also
cause hyponatremia, hypoosmolality, elevated urinary sodium, and
urinary osmolality. These SIADH-like syndromes are difficult to
distinguish from SIADH when signs and symptoms of fluid volume
depletion are subtle or absent. Nonetheless, there are convincing
reports that provide evidence of chemotherapy-induced hypothalamic or
posterior pituitary damage in the context of SIADH (56, 57, 58).
1. Vinca alkaloids. Vincristine and vinblastine are vinca
alkaloids that inhibit tubulin polymerization. There have been at least
seven reports associating vincristine use with SIADH (56, 59, 60, 61, 62, 63, 64), and
some of these reports documented inappropriately high serum levels of
ADH (61, 62). Further evidence for a drug effect is the recurrence of
SIADH during subsequent therapy with vincristine (61). Vinblastine has
also been reported to cause severe hyponatremia (65), and SIADH
(66, 67, 68, 69). The incidence of SIADH induced by a vinca alkaloid alone has
not been addressed in any large series. When vincristine is used in
combination with cyclophos-phamide, doxorubicin, methotrexate, and
prednisolone (CHOP-M), the incidence of hyponatremia is about 17%
(70). In another series in which high-dose vinblastine, cisplatin, and
bleomycin therapy were combined, eight of 12 patients developed
hyponatremia and hypoosmolality (71). The presumed mechanism of vinca
alkaloid-induced SIADH is paraventricular or supraoptic cell
microtubular damage (56, 57). Another contributing factor, identified
in rodents treated with vincristine, is gastrointestinal sodium and
water loss leading to appropriate AVP secretion (72).
2. Cyclophosphamide. Cyclophosphamide therapy has been
associated with hyponatremia (73, 74, 75) and SIADH (58, 76, 77, 78).
Reversible SIADH has been reported in two patients treated with
high-dose cyclophosphamide (50 mg/kg) (77, 78). A direct effect of
cyclophosphamide on the hypothalamus is supported by autopsy findings
of infundibular necrosis, decreased intraaxonal secretory granules, and
depletion of posterior pituitary AVP in a case of fatal
cyclophosphamide (1800 mg/m2)-induced hyponatremia (58).
Other mechanisms have also been invoked. In a small series of 19
chemotherapy courses with lower dosages of cyclophosphamide, there was
development of hyponatremia, plasma hypotonicity, and urinary
hypertonicity without an increase in plasma AVP levels (79). This
suggests that damage to the renal tubules and resultant defects of salt
and water transport is the major cause of hyponatremia associated with
low-dose therapy.
3. Cisplatin. There are many reports of cisplatin-induced
hyponatremia due to renal salt wasting (51, 52, 80, 81, 82, 83, 84, 85). Several
reports claim that cisplatin induces SIADH (86, 87, 88), and there is a
case report in which the hyponatremia occurred because of combined
effects of cisplatin, thiazide, and chlorpropamide (89). The mechanism
of cisplatin-induced hyponatremia is unclear, but it has been suggested
that renal toxic effects of cisplatin, causing a decrease of papillary
solute content and maximal urinary osmolality (90, 91), is the major
factor, rather than a direct effect, of AVP secretion. In a study of 70
patients, seven developed salt-wasting nephropathy and hyponatremia
after receiving 342 mg/m2 (range: 200–600
mg/m2) of cisplatin-based chemotherapy (85). Five of these
patients had elevated levels of AVP that became suppressed with
correction of hypovolemia. The stimulus for AVP release in these
patients was probably hypovolemia caused by renal salt wasting.
4. Melphalan. Melphalan-induced hyponatremia and urinary
sodium loss, thought to be SIADH, has been reported in two patients who
received high-dose melphalan (2 mg/kg) in combination with vincristine
and cyclophosphamide (92). Melphalan was implicated in the causation
because challenge with the same regimen but a lower dose of melphalan
(0.5 mg/kg) in one patient several weeks later did not cause
hyponatremia. Whether melphalan potentiated the effect of the
vincristine/cyclophosphamide combination or had a direct effect is
unclear.
B. Nephrogenic diabetes insipidus
Nephrogenic diabetes insipidus can result from the effects of
ifosfamide or streptozocin on tubular reabsorption of water. Although
both drugs have cytotoxic effects on renal tubular cells, the cellular
mechanism of nephrogenic diabetes insipidus is unclear.
1. Ifosfamide. Ifosfamide has broad nephrotoxic effects,
although tubular damage predominates (48, 93, 94, 95, 96, 97). In 11 young patients
treated with ifosfamide alone, proximal renal tubular effects developed
in all (96). Distal renal tubular defects developed in approximately
one half of these, including one with nephrogenic diabetes insipidus.
2. Streptozocin. Streptozocin (also known as streptozotocin)
is also nephrotoxic (98, 99). In addition to glomerular (proteinuria)
and tubular (Fanconi syndrome) defects (99), two cases of nephrogenic
diabetes insipidus have been reported after streptozocin therapy (100, 101). One case recovered spontaneously, and the other showed
improvement after indomethacin therapy.
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IV. Disorders of Mineral Metabolism
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Calcium homeostasis is normally maintained by the interplay of
PTH, calcitonin, and vitamin D metabolites on several target organs,
including bone, intestine, and kidney. The complexity of this system
and the large number of potential sites at which nonhormonal
antineoplastic agents could cause disruption provide a variety of
interesting clinical syndromes.
A. Hypocalcemia
1. Chemotherapy-induced tumor lysis syndrome. Massive cell
death resulting from cytotoxic chemotherapy can result in severe
hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia
(102, 103, 104). Several factors contribute to the development of tumor
lysis syndrome, including the type of malignancy, the responsiveness of
the malignancy to therapy, and tumor burden. Hyperuricemia,
hyperkalemia, and hypocalcemia may contribute to the development of
cardiac arrhythmia, tetany, and sudden death. Tumor lysis syndrome
occurs most frequently in hematological malignancies (104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120). In a
series of 41 patients with acute leukemia, 25 developed tumor lysis
syndrome, three of which were moderate to severe (109). In another
retrospective review of 102 cases of high-grade non-Hodgkin’s
lymphoma, evidence of tumor lysis syndrome was present in 42% of
cases; the syndrome was severe and life-threatening in 6% (115). The
syndrome has been reported in nonhematological malignancies (121, 122, 123, 124, 125, 126, 127),
but these cases are relatively rare.
The occurrence of tumor lysis syndrome has been associated with a wide
variety of therapeutic agents: fludarabine (105, 108, 110, 111, 114, 116), mitoxantrone (106), 6-mercaptopurine (128), methotrexate (129),
chemotherapeutic conditioning for bone marrow transplant (112, 118) or
total body irradiation for bone marrow transplant (130), and various
combination chemotherapy regimens (115, 119)
Appropriate therapy to prevent complications of tumor lysis includes
hydration, alkaline diuresis (131), inhibition of uric acid synthesis
by allopurinol, and oral calcium or aluminum-based compounds to bind
intestinal phosphate. In a hyperphosphatemic patient with hypocalcemia,
the addition of an oral calcium-based compound will reduce phosphate
and enhance calcium absorption. Intravenous calcium administration can
potentially cause calcium phosphate precipitation in the presence of
severe hyperphosphatemia and should be used cautiously. Dialysis (111, 132, 133) may be required for patients with symptomatic hypocalcemia
and a serum phosphorus level > 3.3 mmol/liter (>10.2 mg/dl).
2. Platinum compounds. Hypocalcemia has been reported to occur
in 6–20% of cisplatin-treated patients (134). Effects of cisplatin on
renal tubular function (90, 91, 135), magnesium metabolism (see
Section IV. C), bone resorption, and vitamin D metabolism
may explain the hypocalcemia. Hypomagnesemia may cause a decrease in
PTH secretion and a reduction in the calcium-mobilizing effects of PTH
(136, 137, 138, 139, 140, 141). Hypomagnesemia also inhibits formation of
1,25-dihydroxyvitamin D (137, 142). In addition, cisplatin may have a
direct inhibitory effect on bone resorption. In a prospective study of
13 cancer patients with hypercalcemia refractory to rehydration,
treatment with a 24-h infusion of cisplatin (100 mg/m2)
resulted in normalization of the serum level of calcium in nine
patients (69%), with a mean duration of benefit of 38 days (143).
There was no reduction in tumor size in any of these patients, and
eight of the nine responders died of progressive cancer while remaining
normocalcemic. An abnormality in vitamin D metabolism has also been
observed in patients who received chemotherapy that included cisplatin
(144). The level of 1,25-dihydroxyvitamin D decreased significantly
after chemotherapy, whereas its precursors remained unchanged. The
effect was attributed to inhibition of mitochondrial function in the
kidney by cisplatin (144).
Carboplatin therapy, like cisplatin, is associated with a 16–31%
incidence of hypocalcemia, as reported by the manufacturer in the
product package insert. There are, however, no reports in the medical
literature corroborating this finding.
3. Antitumor antibiotics. Plicamycin (mithramycin) is an
antitumor antibiotic that inhibits DNA-dependent RNA polymerase. This
drug has a major effect on calcium metabolism (145, 146). It inhibits
bone resorption at doses (25 µg/kg) that are ineffective for
antineoplastic effects (147), resulting in a lowering of the serum
calcium concentration within 24–48 h. Plicamycin inhibits basal and
PTH-stimulated osteoclast function by unclear mechanisms (148). The
inhibitory effect of plicamycin on osteoclast function has made it a
useful therapeutic agent for treatment of Paget’s disease of bone and
osteoclast-mediated hypercalcemia associated with malignancy (145). The
hypocalcemic effect of plicamycin, as well as its hepatic and renal
toxicity, has limited its usefulness as an antineoplastic agent.
Dactinomycin is another antitumor antibiotic that blocks DNA-directed
RNA synthesis, causing hypocalcemia in animals. Dactinomycin abolishes
the calcium-mobilizing activity of PTH, presumably by interfering with
osteoclast-mediated bone resorption (149, 150, 151).
A syndrome of hypomagnesemia, hypocalcemia, and hypoparathyroidism has
been reported with doxorubicin and cytarabine treatment in nine
patients (152). Three of the nine patients had elevated phosphate
levels of 1.34–1.92 mmol/liter (normal range: 0.7–1.25 mmol/liter).
The exact mechanism for this effect is not clear.
4. L-Asparaginase. Thirty-seven to 60% of
patients treated with L-asparaginase for more than 1 week
developed hypoalbuminemia with an associated decrease of total serum
calcium (32). The patients had no symptoms of hypocalcemia, and the
corrected calcium concentration was normal.
B. Hypercalcemia
The incidence of hypercalcemia in cancer patients is 1.15% (153).
Approximately one fourth of these patients have identifiable bone
metastases. Hypercalcemia in the context of cancer is a poor prognostic
sign, associated with a shorter survival. Renal cell carcinoma,
non-small cell lung carcinoma, and myeloma are most commonly associated
with hypercalcemia. Despite the high prevalence of hypercalcemia in
cancer patients, we were unable to identify any reports of
hypercalcemia caused by an antineoplastic agent. However, the increased
interest in vitamin D analogs for treatment of cancer, and the
increased incidence of parathyroid tumors after head and neck
irradiation, may provide exceptions to this observation.
1. Radiation-induced hyperparathyroidism. Numerous studies
have documented the association of low-dose (usually 2–7.5 Gy)
external irradiation to the head and neck area and subsequent
development of hyperparathyroidism (154, 155, 156, 157, 158, 159, 160, 161, 162, 163). There is an increased
incidence (2.5- to 3-fold increase) of primary hyperparathyroidism
after low-dose radiation exposure to the neck (162, 164). Among
patients who develop primary hyperparathyroidism, 14–30% had prior
exposure to radiation (155, 158, 160). The mean interval from
irradiation to development of hyperparathyroidism ranges from 29–47 yr
(154, 158, 165). An association of hyperparathyroidism and radiation
exposure from radioactive iodine treatment has also been reported (166, 167). Experiments in animals support a causal relationship of
irradiation and parathyroid tumors (168, 169). Concurrent thyroid
cancer may be seen in more than 30% of patients with radiation-induced
hyperparathyroidism (158, 164, 170). The clinical features of
radiation-induced and non-radiation-induced hyperparathyroidism are
similar (171, 172).
Hyperparathyroidism after high-dose irradiation is uncommon. In a
report by Holten and Christiansen (173), there were no notable changes
in the parathyroid function in the first 2 months after irradiation for
head and neck cancers. In a subsequent prospective study, Holten and
Petersen (174) noted a trend toward higher PTH serum levels 3 yr after
irradiation, although there was no definite evidence of
hyperparathyroidism (174). In a review of 220 cases of Hodgkin’s
disease treated with neck irradiation, Nader et al. (175)
were able to document only one case of primary hyperparathyroidism. In
a case of breast cancer treated after mastectomy with multiple
radiation sessions including the lower neck, a parathyroid adenoma was
identified 21 yr after the last radiation treatment (176).
C. Hypomagnesemia
1. Platinum compounds. Cisplatin has toxic effects on the
kidney, the principal regulatory site for magnesium homeostasis.
Cisplatin causes morphological changes (91, 135) and necrosis (177) in
the proximal tubule, an important site of magnesium reabsorption.
Hypomagnesemia occurs in more than 90% of patients treated with
cisplatin (80, 134, 178, 179, 180, 181, 182, 183), and 10% are symptomatic with muscle
weakness, tremulousness, and dizziness. Vigorous hydration and use of
osmotic diuretics such as mannitol may prevent renal failure but has
little effect on renal magnesium wasting. Hypomagnesemia may persist
long after cisplatin has been discontinued (178, 179, 182).
Carboplatin may also cause hypomagnesemia. There are no large series in
the literature, but the information available from the manufacturer
(package insert) indicates that 60% of those taking the drug may be
affected.
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V. Metabolic Bone Diseases
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A. Osteoporosis
Normal bone remodeling involves a delicate balance between bone
formation, mediated by osteoblasts, and bone resorption by osteoclasts.
Antineoplastic therapy may upset this balance in a variety of ways. The
easiest to conceptualize is enhanced osteoclast resorption. Examples
include cytokine (e.g., interleukin-2)-stimulated osteoclast
resorption or a premature menopause causing enhanced bone resorption.
Although less easy to characterize, it seems likely that chemotherapy
has direct toxic effects on osteoblast function with consequent
diminution of bone formation. It is also important to recognize that
these effects occur on a background of cancer and that production of
hormonally active substances by the tumor (e.g., PTH-related
protein, lymphotoxin, or interleukins 1 and 6) may contribute to the
clinical picture of bone loss.
In most cases it is not clear whether bone loss is due to the therapy,
the underlying disease process (including the impact of cachexia,
malnutrition, poor calcium and vitamin D intake), or a combination of
the two (184). Bone loss is prominent in patients with disorders
affecting hematopoietic cells, perhaps because of cytokine production
and their intimate relationship with bone-forming cells (185). For
instance, radiographic changes and bone pain are frequent presenting
abnormalities of acute lymphocytic leukemia (ALL), a fact that suggests
direct impact of ALL on bones (186). In the absence of an adequate
control group and control for nutritional variables, it is difficult to
ascertain the relative importance of the anticancer agents in causing
osteoporosis in the series discussed below.
1. Methotrexate. Osteoporosis (generalized or localized) is
observed in children receiving methotrexate therapy for ALL. In one
series, five of 11 children treated with oral methotrexate for periods
of 7–62 months developed severe osteoporosis, distal extremity pain,
and associated fractures (187). In a second series, five children with
ALL developed osteoporosis and lower extremity pain after treatment
with methotrexate (30 mg/m2/week ip) for 12–17 months. The
bone pain resolved promptly upon discontinuation of methotrexate, but
radiographic changes in bone persisted for longer periods (188). In a
third series, 26 of 216 children treated with methotrexate for ALL
developed osteoporosis, bone pain, and fractures (189). In general, the
osteoporosis improves significantly after cessation of methotrexate
therapy (189, 190). Because ALL can cause osteopenia and bone pain
independently (185), perhaps by bone infiltration and cytokine
secretion, it is difficult to assess the independent roles of disease
and drug in these small series. A role for methotrexate is suggested by
the fact that 20 of 37 children treated with methotrexate for leukemias
developed osteoporosis and bone pain. In seven of these children,
fractures and nonunion or delayed union of fractures were significant
problems until methotrexate was discontinued (191).
The mechanism by which methotrexate causes osteoporosis is unclear.
There are reports of increased urinary and fecal calcium excretion in
some cancer patients treated with methotrexate (189, 192) and decreased
bone formation with methotrexate administration in rats (193). These
results suggest that methotrexate causes osteoporosis by a combination
of decreased bone formation and increased resorption, although firm
conclusions are difficult to draw.
2. Platinum compounds. Eleven of 16 ALL patients whose
treatment included cisplatin or carboplatin had bone pain, limping, and
fracture, with bone mineral densities that averaged 2.3 SDs
below normal (194). The known effects of platinum compounds on calcium
homeostasis include hypomagnesemia (see Section IV.C),
hypocalcemia (see Section IV.A.2), and renal calcium
wasting. These effects may cause enhancement of bone loss associated
with ALL (186).
3. Combination chemotherapy. The majority of combination
regimens for hematopoietic malignancies include high-dose
glucocorticoids or methotrexate. Both have effects on bone formation
and resorption. In one study, 29 men in complete remission after
treatment for Hodgkin’s disease had reduced cortical and trabecular
bone mineral density. There was no correlation in this group with the
time since chemotherapy, the chemotherapeutic regimens, or the number
of cycles of chemotherapy (195). Hypogonadism resulting from
chemotherapy, high-dose glucocorticoid therapy, and Hodgkin’s disease
per se were cited as possible causes of bone loss in these
men. In another study of Hodgkin’s disease patients, no significant
bone loss was found in men, but chemotherapy-induced menopause was
associated with significant bone loss in women (196). In young women
treated for lymphoma, chemotherapy-induced menopause was a more
important cause of osteoporosis than cytotoxic agents and
glucocorticoids (184).
Adjuvant chemotherapy for breast carcinoma (usually involving
5-fluorouracil, cyclophosphamide, and doxorubicin or methotrexate) is
associated with low bone mass. Chemotherapy-induced premature menopause
appears to be a major factor. Women with adjuvant chemotherapy-induced
ovarian failure have lower cortical and trabecular bone mass than
age-matched controls without breast carcinoma (197). The avoidance of
estrogen replacement therapy in young women with breast carcinoma and
premature ovarian failure compounds the problem and portends a major
future health problem.
Bone marrow transplantation has profound effects on the marrow-bone
interface. Patients receive large doses of cytotoxic drugs and
irradiation designed to eradicate all cells in the marrow. It is
therefore not surprising that bone-forming cells are also affected. In
24 patients undergoing bone marrow transplantation, profound effects on
bone biomarkers were observed. The serum osteocalcin and alkaline
phosphatase levels, thought to be indicators of bone formation, were
low. N-telopeptides, bone collagen degradation products thought to be
indicative of bone resorption, were increased in this group, which was
studied over a 12-week period (198). There are no large-scale studies
that address this issue.
B. Rickets or osteomalacia
Osteomalacia results from the failure of the organic bone matrix
to mineralize normally. Rickets is a unique variant in which there is
abnormal mineralization and maturation of the growth plate at the
epiphysis in children. The most common cause for these two conditions
is a decrease in the concentration of serum calcium and/or phosphorus
concentration. Nutritional deficiency and renal wasting of phosphorus
are common causes. Other contributing factors include systemic acidosis
and drugs such as anticonvulsants or aluminum.
1. Ifosfamide. Ifosfamide causes tubular damage leading to
renal phosphate wasting, hypophosphatemia, and rickets. The toxic
effects of ifosfamide on renal tubular function (see Section
III.B.1) include Fanconi syndrome in adults (45, 46) and children
(48). Tubular damage is seen most commonly with doses of ifosfamide
50 g/m2 or when used in combination with cisplatin.
Rickets is reported most commonly in the pediatric population (48, 95, 96, 97, 199, 200) with two of 11 children affected in one series (96).
The long-term outcome has not been reported.
2. Estramustine. In a prospective trial in prostate cancer
metastatic to bone, which compared estramustine and clodronate to
estramustine and placebo, both treatment groups developed hypocalcemia,
secondary hyperparathyroidism, hypophosphatemia, and osteomalacia, with
normal vitamin D levels (201). Bone resorption, quantitated by bone
biopsy at 3 months, was decreased in both groups. The proposed
mechanism for this striking clinical picture is suppression of bone
resorption by estramustine, alone or in combination with clodronate,
leading to hypocalcemia and secondary hyperparathyroidism, with renal
phosphate wasting.
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VI. Thyroid Disorders
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Disorders of the thyroid gland are commonly associated with cancer
or its therapy. These disorders encompass a broad variety of
pathophysiological mechanisms. Some are artifactual, such as the
altered synthesis or clearance of thyroid hormone-binding proteins
observed in certain malignancies, or caused by treatment that modifies
total but not free concentration of thyroid hormone. Alteration of
thyroid hormone metabolism, more commonly known as euthyroid sick
syndrome, may also occur in chronically ill cancer patients. Finally,
cancer therapy can disrupt normal thyroid function in a variety of
ways. Cytotoxic chemotherapy may disrupt hypothalamic, pituitary, or
thyroid function. Cytokines used for cancer therapy can enhance a
thyroid autoimmune process, leading to dysfunction (10). Radiotherapy
is associated with immediate and long-term effects, which can include
hypothyroidism, thyroid neoplasm, and Graves’ disease.
A. Serum thyroid hormone-binding protein abnormalities
Thyroid hormone is bound preferentially in serum to thyroid
hormone-binding globulin (TBG) and albumin. The levels of these binding
proteins can be modified by sex hormones, glucocorticoids, narcotic
use, and nutritional and other factors. The observations presented
below describe changes in thyroid hormone binding garnered from small
published series. These reports describe thyroid hormone abnormalities,
but, in general, lack adequate controls for nutritional status, effects
of chronic illness, and non-antineoplastic drugs and do not provide any
sense of the true incidence of these effects.
1. L-Asparaginase. L-Asparaginase has
been shown to affect serum thyroid hormone levels. It may inhibit
synthesis of albumin and TBG, resulting in low total but normal free
T4 values (202). This effect on TBG synthesis is
reversible. Administration of glucocorticoids, frequently used in
combination with L-asparaginase (31, 32), may also inhibit
TBG synthesis, further lowering total T4 values.
L-Asparaginase may also have effects on the pituitary or
hypothalamus, causing hypothyroidism, which is discussed later (see
Section VI.B.5).
2. 5-Fluorouracil. 5-Fluorouracil increases total
T4 and T3 levels, but the patients are
clinically euthyroid with a normal free T4 index and normal
level of TSH, suggesting that this drug exerts its effect by increasing
serum thyroid hormone-binding proteins (203).
3. Mitotane. Mitotane (o,p'-DDD) increases total
T4 and T3 levels but without suppression of the
TSH levels. In three patients with adrenocortical carcinoma treated
with mitotane, the serum TBG level was found to be elevated (204).
4. Combined alkylating agent and podophylline therapy. In 27
patients treated with alkylating agents and podophylline derivatives,
there were minor changes in thyroid hormone levels. The serum level of
T4 and TBG decreased slightly over a 5-day period (still
within the normal range). The serum levels of TSH, rT3, and
thyroglobulin and the T4/TBG ratio were not changed (205).
B. Hypothyroidism
1. Irradiation. Irradiation to the head and neck is an
important cause of thyroid dysfunction. Radiation doses greater than 25
Gy to the thyroid gland can result in primary hypothyroidism; doses of
50 Gy or more to the hypothalamic-pituitary region are associated with
primary or secondary/tertiary hypothyroidism (206, 207, 208). The
probability of hypothyroidism after irradiation for lymphoma (209),
Hodgkin’s disease (210, 211, 212, 213), head and neck carcinoma (214, 215, 216, 217, 218, 219, 220, 221),
breast cancer (222), and bone marrow transplantation (223, 224) ranges
from 15–20% (Table 3). Doses greater
than 30 Gy were associated with a 25–50% incidence of primary
hypothyroidism, with most cases identified 4–5 yr after the
irradiation. The relationship between the probability of hypothyroidism
and time of exposure or radiation dose is most clearly shown in Fig. 1 (210).
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Figure 1. Actuarial risk of hypothyroidism for different
levels of radiation exposure to the thyroid in the treatment for
Hodgkin’s disease. Plot 1 represents the risk in 110 patients whose
thyroid glands were not irradiated. Plot 2 represents the risk in 140
patients who received 7.5–30 Gy, and plot 3 represents 1537 patients
who received more than 30 Gy. [Reprinted with permission from S. L.
Hancock et al.: N Engl J Med
325:599–605, 1991 (210). © 1991 Massachusetts Medical Society. All
rights reserved.]
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Radiation doses less than 40 Gy are associated with a lower incidence
of overt hypothyroidism, but a significant percentage of patients have
subclinical hypothyroidism based on an exaggerated TSH response to TRH
(225, 226). Experience with total body radiation doses of 13.75–15 Gy
for bone marrow transplantation protocols showed a 15% incidence of
primary hypothyroidism (inclusive of about 13% of compensated or
subclinical hypothyroidism) 11–88 months (median, 49 months) after
transplantation (224).
Factors that enhance the risk for development of hypothyroidism include
a high radiation dose to the head and neck, duration since therapy,
lack of shielding for midline structures, and combined radiation and
surgical treatments. Other risk factors include hemithyroidectomy
performed during the course of laryngectomy, or damage to the thyroid
vascular supply during surgery (219).
There are also significant effects of brain or head and neck
irradiation on hypothalamic and pituitary regulation of TSH secretion.
In the series shown in Fig. 2, there is
an almost linear time-related diminution in TSH secretion after
treatment with 38–75 Gy for brain tumors (227) or nasopharyngeal
carcinoma (215, 228). Fifteen to 20% had diminished TSH secretion at 5
yr and approximately 35% at 10 yr (Fig. 2). The combined effect of
irradiation on the thyroid and pituitary-hypothalamic area is so
striking that prudence suggests routine screening for this group of
patients. Measurement of both serum T4 and a TSH
concentration at 2- to 4-yr intervals is advisable.
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Figure 2. Probability of normal pituitary hormone secretion
over time after radiation exposure to the hypothalamic-pituitary areas.
Data from three studies were replotted on this single figure. The first
set of values (solid circle with solid line) are from
Shalet et al. (227), where patients with pituitary
tumors were treated with 37.5–42.5 Gy. The second series (open
circle with solid line) from Lam et al. (228)
shows the effect of radiation treatment with 39.8–61.7 Gy, given for
nasopharyngeal carcinoma. The final group (solid circle with
dotted line) represents data from Samaan et al.
(215), in which 11–75 Gy were administered for treatment of head and
neck tumors.
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2. 131I-containing compounds. The use of
Na131I for therapeutic ablation of thyroid tissue after
thyroidectomy for differentiated thyroid carcinoma invariably causes
hypothyroidism. The use of 131I in other compounds may
result in thyroid dysfunction. For example, high-dose (100–1000 mCi)
of [131I]metaiodobenzylguanidine (MIBG) has been used to
treat unresectable pheochromocytoma. Three of 28 patients developed
primary hypothyroidism in one series (229). Routine use of inorganic
iodide to block thyroidal uptake of the 131I will reduce
the frequency of or prevent this complication.
3. Interferon-2. Thyroid dysfunction is a recognized side
effect of interferon- administration (15). Ten to 15% of
interferon-treated patients develop primary hypothyroidism; 50% have
detectable thyroid antibodies indicative of an underlying thyroiditis
(230, 231, 232, 233, 234). Patients with antithyroid antibodies before interferon
therapy are at higher risk for development of interferon-induced
thyroid dysfunction.
Two different mechanisms have been proposed for the effects of
interferon-2 on thyroid function. In vitro studies have
shown an inhibition by interferon-2b of thyroid follicular cell
proliferation and thyroglobulin release, suggesting a direct effect on
thyroid cell function. A second effect is stimulation of cell surface
expression of major histocompatibility class 1 and intercellular
adhesion molecules, with no apparent effect on major histocompatibility
class 2 molecules (235). These findings are thought to explain the
increase of thyroid autoimmunity found in patients with thyroid
effects.
Interferon-induced thyroid dysfunction is generally reversible. In a
study of 68 patients receiving a 24-week course of interferon for
hepatitis C, five developed primary hypothyroidism. Thyroid function
test results in all normalized within 1.5 yr after cessation of
interferon (234). The high prevalence of antithyroid antibodies in
these patients, however, suggests the possibility of long-term
development of thyroid dysfunction.
4. Interleukin-2 (Aldesleukin). Interleukin-2 causes thyroid
impairment in 20–35% of treated patients. A common presentation is
the acute onset of painless thyroiditis with hyperthyroxinemia followed
by the development of primary hypothyroidism (236, 237, 238, 239). The
hyperthyroid phase is usually brief and may go unnoticed, whereas
hypothyroidism may last for months and may even become permanent in
some patients. Replacement thyroid hormone therapy is required in about
9% of these hypothyroid patients (238). Thyroid autoantibodies
developed in 28% of the interleukin-2-treated patients (240). Thyroid
dysfunction correlates with the duration and cumulative dose of
interleukin-2 (240). The combination of interferon- and
interleukin-2 results in a similar clinical picture of thyroiditis
followed by hypothyroidism (236, 241).
5. L-Asparaginase. In addition to the inhibition
of TBG synthesis discussed above, there is some evidence that
L-asparaginase can cause hypothalamic or pituitary
hypothyroidism (242). Nine of 14 children with ALL had a free
T4 level less than 1 ng/dl (hypothyroid range) and a normal
basal level of TSH after 3 weeks of treatment with
L-asparaginase and prednisone, with return of the free
T4 level to normal 2–3 weeks after cessation of
L-asparaginase. In this same series, six patients who had a
normal baseline TSH response to TRH stimulation before therapy showed
no response to TRH after 3 weeks of combined treatment with
L-asparaginase and prednisone. A control group of three
patients with Hodgkin’s disease who received similar doses of
prednisone plus other cytotoxic agents also showed blunted TSH response
to TRH. These results suggest that L-asparaginase combined
with prednisone or systemic illness (ALL) reduces the TSH response to
TRH. This possibility should be considered in the differential
diagnosis of a low serum T4 in this clinical setting.
6. Combination therapy. Several studies have documented an
increased incidence of primary hypothyroidism in patients treated with
multiple drug regimens with or without radiation. Specific combinations
where substantial evidence supports a causative role are presented
below.
a. Cisplatin, bleomycin, vinblastine, etoposide, and
dactinomycin.
Fifteen percent of patients who received a
combination of cisplatin, bleomycin, vinblastine, etoposide, and
dactinomycin developed primary hypoparathyroidism, whereas a control
group without chemotherapy did not (243). The correlation of
hypothyroidism and the cumulative doses of cisplatin and vincristine
implicates these two drugs in the causation (243).
b. Mechlorethamine, vinblastine, procarbazine, and
prednisolone.
Forty-four percent of patients who received six
cycles of this regimen for Hodgkin’s disease developed an elevated
serum TSH concentration; 6% had decreased T4 and free
thyroid index (244). None received irradiation. The length of follow-up
in this study was 1–64 months (median, 28 months).
c. Brain irradiation and vincristine, carmustine or lomustine, and
procarbazine.
Children with brain tumors (not involving the
hypothalamic-pituitary axis) who receive this chemotherapy combination
and brain irradiation have a 35% incidence of hypothyroidism, compared
with a 10% incidence for brain irradiation alone (245). The highest
incidence occurred when the thyroid gland was included in the radiation
field.
C. Thyrotoxicosis
1. Irradiation. Hyperthyroidism as a result of radiation
therapy is far less common than hypothyroidism (246), but several
studies have described this association (206, 246, 247). Two forms have
been described: radiation-induced thyroiditis and Graves’ disease.
a. Thyroiditis.
Silent thyroiditis with transient
thyrotoxicosis and low-to-absent radioactive iodine uptake has been
reported with an incidence of 0.6% in patients treated with
radiotherapy alone or in combination with chemotherapy for Hodgkin’s
disease (210, 247, 248). Most cases of thyroiditis-induced
thyrotoxicosis occurred within 2 yr of radiotherapy and were followed
by hypothyroidism several months later.
b. Graves’ disease.
Graves’ disease after radiation therapy
occurs most commonly after treatment of Hodgkin’s disease (210, 246, 249). Estimates of actuarial risk are 3–7%, with a relative risk of
7.2–20.4 in treated patients. The presence of human leukocyte antigen
B8 or DR5 is associated with an increased probability of Graves’
disease in this context (249). The finding of the largest number of
affected patients among those treated for lymphoma has suggested a
relationship between the lymphoma and development of Graves’ disease,
although the syndrome has also been described in patients treated with
radiation for breast, laryngeal, and nasopharyngeal carcinomas (250).
2. Cytokines. Two cytokines, interferon-2 and
interleukin-2, have been shown to cause hyperthyroidism. Three of 68
patients receiving a 24-week course of interferon for hepatitis C
developed hyperthyroidism; thyroid function tests normalized in all
three within 1.5 yr after discontinuing therapy (234). Graves’ disease
following transient thyrotoxicosis after interferon therapy has also
been reported (238).
Thyroiditis causing thyrotoxicosis has been reported after
interferon-2 (251, 252) or combined therapy with interferon- and
interleukin-2 (236, 241, 253). Interleukin-2 treatment by itself, in
the context of cancer therapy, causes transient hyperthyroidism in
6–7% (238, 239, 254). Hyperthyroidism was followed by hypothyroidism
in approximately one half of these patients (254). The mechanism of
interleukin-2-induced autoimmune thyroid dysfunction is unclear,
although interleukin-2-induced disruption of self-tolerance has been
suggested as a mechanism (255).
D. Thyroid neoplasm
1. Irradiation. Low-dose radiation exposure is a known cause
of thyroid neoplasia (206, 256, 257, 258, 259, 260, 261, 262, 263, 264). A pooled analysis of multiple
studies defined a dose-response relationship between radiation exposure
and relative risk of thyroid cancer for radiation doses of 0–5 Gy
(Fig. 3) (265). Factors that enhance the
risk of radiation-induced thyroid cancer included the female gender
(a 40% higher rate), an age at radiation exposure of less than 15 yr,
and a period of 20–30 yr since radiation exposure. Hypothyroidism
per se does not appear to increase the risk of thyroid
cancer, but experimental studies in a rat model have shown accelerated
progression of a radiation-induced thyroid carcinoma by an elevated TSH
level (266).
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Figure 3. Relationship of the relative risk of developing
thyroid cancer and the dose of radiation exposure in childhood. Five
cohort studies and two case-control studies were pooled for this
analysis of radiation-induced thyroid cancer. Radiation exposure
resulted from treatment of several medical conditions, including tinea
capitus, tonsillar or thymic enlargement, carcinoma of the cervix, and
childhood cancer, as well as exposure from explosion of a nuclear
weapon. The relative risk of radiation-induced thyroid cancer from
exposure in childhood (<15 yr old) was fitted to two models using
Poisson regression analysis. The solid line is the
dose-response relationship based on the model [r(x, d) =
r0(x) (1 + ßd)], and the dotted line is
based on a variant of this model that allowed the y intercept to be
different from 1. [Reprinted with permission from E. Ron et
al.: Radiat Res 141:259–277, 1995 (265).]
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Ninety percent of radiation-induced thyroid cancers are papillary
thyroid carcinoma. The remaining 9–10% are follicular carcinomas;
anaplastic or medullary carcinomas are rare. There is a higher
incidence of multicentric disease, local invasion, and distant
metastasis upon presentation in radiation-induced thyroid cancer,
rather than in sporadic thyroid cancer (258, 267). Nevertheless,
patients with radiation-induced papillary thyroid carcinoma have the
same good prognosis (in terms of recurrence and mortality) as patients
with sporadic thyroid cancer (267). The size distribution of
radiation-induced thyroid cancers varies among studies (268, 269, 270, 271).
A variety of molecular abnormalities have been identified in papillary
thyroid carcinomas (272). Two specific molecular defects have been
identified in radiation-induced papillary carcinoma. The first is the
presence of ras mutations in about 30% of radiation-induced
tumors. There is disagreement about whether K-ras mutations
are more common than mutations of the other ras genes in
radiation-induced thyroid cancer (273, 274). The second oncogene
involved is c-ret. Rearrangements of the c-ret
protooncogene (the PTC rearrangement) have been identified in a high
percentage of papillary thyroid carcinomas from children exposed to
radiation after the Chernobyl nuclear disaster (275, 276, 277). The
importance of these oncogene mutations and rearrangement in the genesis
of these tumors is unclear.
a. Effects of low-dose radiation exposure to the neck from therapy
of other cancers.
Therapeutic irradiation of anatomical locations
other than the head and neck can result in unintended exposure of the
thyroid gland to low levels of radiation. In an international
case-matched control study of more than 4000 women with second cancers
after radiation treatment for cancer of the cervix, a 2-fold risk of
radiation-induced thyroid cancer was observed with an average dose of
0.11 Gy to the thyroid (278). However, this observation was not
significant statistically. In a Japanese study of women with second
cancers after chemotherapy and irradiation for breast cancer, the
relative risk of thyroid cancer was found to be 3.2, with chest and
supraclavicular exposure responsible for most cases (279).
b. Effects of high-dose radiation exposure to the neck from therapy
of other cancers.
Direct exposure of the thyroid gland to
tumoricidal doses of radiation increases the risk of papillary or
follicular thyroid carcinoma by 2.7- to 3.1-fold (264). The risk in
children is even higher, with a 13-fold increase seen in one series
(280). The development of thyroid carcinoma is most evident in
Hodgkin’s disease and non-Hodgkin’s lymphoma where long-term survival
is now common (210, 211, 280). In one series, 12 of 166 children who
had childhood neck irradiation for Hodgkin’s disease developed thyroid
cancer 7–19 yr later, compared with two of 750 adults treated
similarly (281). These findings point to a particular sensitivity of
children and indicate that long-term survival is a prerequisite for
development of thyroid cancer.
2. Chemotherapy. There is no convincing evidence that
chemotherapy by itself is a risk factor for development of thyroid
tumors, although this possibility has been suggested by two case
reports, both in children with ALL (282, 283).
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VII. Disorders of Lipid Metabolism
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Investigation or treatment of mild lipid abnormalities is
frequently deferred in the interest of maintaining the patient in a
positive caloric balance during treatment of cancer. Weight loss
associated with treatment or as a response to the underlying neoplasm,
however, will frequently have a salutary effect on lipid abnormalities.
Short-term lipid abnormalities caused by cancer therapy are generally
of little clinical significance unless major abnormalities occur that
lead to acute complications. Mild abnormalities in lipid metabolism
during chronic therapy of cancer may become clinically significant,
e.g., by increasing the risk for atherosclerotic diseases
(284).
A. Hypertriglyceridemia
1. L-Asparaginase. L-Asparaginase
depletes asparagine, thereby affecting the synthesis of lipolytic
enzymes, lipoproteins, and lipoprotein receptors. Studies in adults by
Oettgen et al. (34) showed L-asparaginase to
have an initial hypolipidemic effect in most patients. Two adult
patients in this series subsequently developed hyperlipidemia with
increased levels of cholesterol, phospholipids, triglycerides, and
chylomicrons. In a study of 32 children with ALL treated with
L-asparaginase in combination with prednisone, vincristine,
and daunorubicin, hyperchylomicronemia with elevation of total
triglycerides was noted (285). This effect was reversible upon
discontinuance of the drug. The aforementioned ability of
L-asparaginase to inhibit insulin synthesis (see
Section II.A.2) may contribute to hypertriglyceridemia
although no studies have been performed to characterize this specific
effect. Another potential factor in the development of lipid
abnormalities is pancreatitis induced by L-asparaginase
(286, 287, 288, 289), although this relationship has not been proved.
2. Interferon-2. Interferons cause hypertriglyceridemia by
increasing hepatic and peripheral fatty acid production (290) and by
suppressing hepatic triglyceride lipase (291). Long-term treatment with
interferon-2 causes hypertriglyceridemia in approximately one third
of patients, most of whom have had previous serum lipid abnormalities
(292). Elevation of serum triglyceride levels to more than 1000 mg/dl
is not unusual. In one case, a therapeutic effect of diet and
gemfibrozil was observed in the presence of continued interferon-
treatment (293).
3. Retinoic acid derivatives. All-trans-retinoic
acid (tretinoin) and other retinoic acid derivatives have been used in
the treatment of several malignancies, most notably head and neck
cancer and acute promyelocytic leukemia (294, 295). These compounds
interact with one of several retinoic acid receptors to modify cell
growth and induce terminal differentiation (296, 297). Their effects on
lipid metabolism are well characterized (298, 299, 300, 301, 302, 303, 304, 305, 306, 307), although the
mechanism of development of lipid abnormality is less clear. These
abnormalities include hypertriglyceridemia (294, 295, 308) caused by
elevated very-low-density lipoprotein (300, 306) and
hypercholesterolemia associated with increased low-density lipoproteins
(LDL) (306). Retinoid-induced hypertriglyceridemia has been reported to
cause cerebrovascular infarction (308) and pancreatitis (304, 309).
Hyperlipidemia associated with retinoid therapy has been treated with
gemfibrozil (310, 311) or fish oil (312, 313).
B. Hypercholesterolemia
1. Mitotane. Several reports have documented new onset or
worsening of hypercholesterolemia in patients receiving mitotane for
treatment of adrenocortical carcinoma (314, 315). The etiological
mechanism may be related to inhibition of cholesterol oxidase (316).
Total cholesterol ranged from 368 mg/dl to about 560 mg/dl after 3
months or more of therapy, and the magnitude of the abnormality
appeared to be dose-related (314). The poor prognosis associated with
adrenocortical carcinoma suggests that a mild to moderate elevation of
cholesterol may have little importance in patients with aggressive
disease. However, in long-term (5–10 yr) survivors, continued
treatment with mitotane may result in the accelerated development of
atherosclerotic disease. Management of mitotane-induced lipid
abnormality in long-term survivors has not been addressed.
2. Cisplatin-based combination chemotherapy. A prospective
study showed that cisplatin-based combination chemotherapy regimens for
testicular cancer [cisplatin, etoposide, and bleomycin (PEB);
alternating cisplatin, vincristine, methotrexate, and bleomycin with
dactinomycin, cyclophosphamide, and etoposide (POMBACE)] increased the
total cholesterol and LDL in 14 of 17 patients treated for 6–24 months
(317). Seven of these patients had significant elevations of total
cholesterol, although the long-term significance of these findings is
not clear.
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VIII. Adrenal Dysfunction
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The most frequent cause of adrenal dysfunction in cancer patients
is glucocorticoid treatment. Clinical features of glucocorticoid excess
are common in patients treated with pharmacological doses for a
prolonged period. Secondary adrenal insufficiency may develop upon
discontinuation of glucocorticoids and may persist for months. Effects
of glucocorticoids have been adequately reviewed elsewhere and will not
be discussed further. There are a number of drugs that inhibit
steroidogenesis (e.g., ketoconazole, aminoglutethimide, and
metyrapone) and are used in the treatment of hormone-responsive
cancers, including prostate, breast, and adrenocortical carcinoma.
These will not be reviewed here because their general effects on
adrenal function are well known to endocrinologists. This section will
focus on agents used to treat neoplastic disorders.
A. Primary adrenal insufficiency
1. Mitotane. Mitotane (o,p'-DDD) is structurally related to
dichlorodiphenyltrichloroethane (DDT), an insecticide, and has
selective toxicity for normal and neoplastic adrenocortical cells. The
biochemical mechanism of action is unclear. Adrenal insufficiency is
commonly observed at doses used to treat adrenal cortical cancer,
making glucocorticoid replacement therapy mandatory. Serum levels of
cortisol-binding protein have also been reported to increase 2- to
3-fold during mitotane therapy and return to normal within 1 yr after
cessation of therapy (204). Increased protein binding may lead to an
increase in dosage of glucocorticoid required for adequate replacement.
B. Secondary adrenal insufficiency
1. Irradiation. Irradiation to the hypothalamic-pituitary
region causes ACTH deficiency and secondary adrenal insufficiency in
19–42% of treated patients. This may occur as early as the first 2 yr
after radiotherapy (318), although the median time for occurrence is 5
yr, reported in a prospective study (215) (see Fig. 2
). Several
diagnostic approaches have been used to screen for secondary adrenal
insufficiency, including basal (0800 h) serum cortisol measurements,
and dynamic tests, including a low-dose (1 µg) synthetic
ACTH1–24 stimulation, insulin-induced hypoglycemia, or a
metyrapone test.
2. Busulfan. Busulfan was reported in the 1960s to cause a
clinical syndrome resembling adrenal insufficiency after prolonged
therapy (319, 320). This reversible syndrome is characterized by
weakness, severe fatigue, anorexia, weight loss, nausea, vomiting, and
melanoderma. Two of four patients on long-term busulfan therapy
developed this syndrome. In these patients, adrenal response to
exogenously administered ACTH was normal, but metyrapone testing
revealed a blunted urinary level of 17-hydroxycorticosteroid excretion,
indicative of pituitary-hypothalamic abnormality. Overall, the evidence
for adrenal insufficiency was weak, and we have not identified any
recent reports corroborating adrenal insufficiency induced by busulfan.
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IX. Disorders of GH Secretion and Growth
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Growth impairment is a common consequence of childhood cancer or
its treatment. Medulloblastoma or ALL, common childhood malignancies,
are frequently treated with cranial or craniospinal irradiation and/or
chemotherapy. Hypothalamic-pituitary damage leading to GH deficiency or
damage to osseous growth plates are two common mechanisms of growth
retardation. In adults, GH deficiency is thought to cause decreased
bone and muscle mass, lowered exercise capacity, and altered myocardial
function, including effects on cardiac output and increased
cardiovascular disease risk (321).
A. GH deficiency
1. Irradiation.
a. Children.
Cranial irradiation may cause hypothalamic or
pituitary dysfunction (322, 323). The hypothalamus appears to be more
radiosensitive than the pituitary gland and may be damaged by lower
radiation doses (<40 Gy). Higher doses are likely to damage both
hypothalamic and pituitary function (324). Deficiency of one or more
pituitary hormones occurs after irradiation of the
hypothalamic-pituitary areas in almost 100% of patients 5 yr after
radiation (Fig. 2) (215, 227, 228, 325).
GH deficiency is often the first and most frequently noted deficiency
after cranial irradiation (227, 318, 326). Isolated GH deficiency after
irradiation is common (227, 318, 326), and the effects are
dose-related. At lower doses (20–24 Gy), the only effect may be an
altered secretory pattern and response to insulin-induced hypoglycemia
(327). With intermediate and higher doses, GH response to arginine is
impaired, and the frequency and amplitude of pulsatile GH secretion is
decreased (328, 329). At doses greater than 30 Gy, abnormal GH
secretion and growth retardation are observed in more than 35% of
patients (227), necessitating GH treatment (330).
b. Adults.
GH deficiency is also common in adults who have had
cranial radiation therapy (Fig. 2). The clinical effects of GH
deficiency in adults include a decreased muscle mass, increased volume
of adipose tissue, fatigue, and a poor sense of well-being (321, 331, 332). GH replacement in these patients can restore normal soft tissue
composition (333, 334, 335), bone metabolism (336), and cardiac function
(337). It may also improve the lipid profile and correct impaired
glucose tolerance (338). GH replacement may improve the quality of life
and the sense of well-being (339, 340), although the impact on
mortality in long-term survivors of cancer is unclear.
B. Growth retardation
1. Irradiation-induced effects on bone. In addition to growth
retardation caused by GH deficiency, craniospinal or spinal irradiation
for hematological malignancy or tumors of the central nervous system
may cause indirect effects (341). Two mechanisms have been identified.
The first is a direct effect of radiation on the growth plates in
vertebral bodies or in the pelvis, mainly manifested as decreased
vertebral growth. A second mechanism is resistance to GH or
insulin-like growth factor (IGF-1 or somatomedin C) in patients who
receive total body irradiation before bone marrow transplantation (329, 342, 343).
2. Combination chemotherapy. Children treated with
chemotherapy for malignancy frequently have a reduced growth velocity,
followed by a period of "catch up" growth. Growth retardation
caused by systemic illness appears to be the single most important
component, although chemotherapy may play a secondary role (344, 345).
It is important to exclude GH deficiency in these children if there is
no "catch up" growth.
It seems likely that the effects of the underlying disease,
irradiation, and chemotherapy may be additive or synergistic. Several
combinations of adjuvant chemotherapy (vincristine, lomustine,
cisplatin, cytosine arabinoside, or methotrexate) have been reported to
potentiate the adverse effects of radiation on growth in prepubertal
children with medulloblastoma (346). In a study of 13 children with
medulloblastoma treated with surgery, radiotherapy, and chemotherapy
(methotrexate and carmustine), 11 showed a significant decrease of
growth velocity. This was attributed in part to GH deficiency or
thyroid dysfunction in nine children (347).
In other studies, chemotherapy appears to be a major factor in growth
retardation. In one study of 82 children with ALL, chemotherapy had
adverse effects on growth (348). In another study of 30 children with
ALL or non-Hodgkin’s lymphoma, growth velocity and height were
significantly lower in children treated with higher dose and for longer
duration combination chemotherapy than in those who received
radiotherapy or less intensive chemotherapy (349).
|
X. Reproductive Dysfunction
|
|---|
A. Reproductive dysfunction due to hypothalamic-pituitary damage
1. Irradiation. Radiation treatment to the head may cause a
broad spectrum of hypothalamic-pituitary abnormalities. The resultant
thyroid, GH, or adrenal cortical deficiency may have indirect effects
on reproductive function (Fig. 2). Reproduction is also affected by
hyperprolactinemia or gonadotropin deficiency, commonly observed in
patients treated with more than 40 Gy of cranial irradiation.
a. Hyperprolactinemia.
Hyperprolactinemia occurs commonly
after head and neck irradiation. In one series, approximately one third
of 64 patients treated with radiation therapy for head and neck cancer
developed hyperprolactinemia, 50% within 2 yr (215). The median
hypothalamic and pituitary exposures in this series were 50 and 57 Gy,
respectively. In other series, the incidence of hyperprolactinemia
ranged from 20–50% (215, 228, 318, 324). Radiation damage to the
hypothalamus leading to a loss of the normal inhibition of PRL
secretion is the proposed mechanism for this effect.
Hyperprolactinemia inhibits gonadotropin secretion from the pituitary
and decreases the responsiveness of the pituitary to GnRH (350),
thereby causing secondary hypogonadism. Dopamine agonist therapy could
reverse this process, and it may be reasonable to proceed with a
therapeutic trial if anterior pituitary function is normal.
b. Gonadotropin deficiency.
Gonadotropin deficiency occurs
commonly (up to 61%) in patients treated with irradiation for brain
tumor (318). In children, delayed puberty, absent menarche, and
inadequate sexual development is a significant problem. In adults,
gonadotropin deficiency may cause sex steroid hormone deficiency and
infertility. Sex steroid hormone deficiency may alter libido and have
deleterious effects on bone and lipid metabolism.
Early or even precocious puberty has also been reported in patients
treated with combined chemotherapy and cranial irradiation for ALL
(351) or cranial irradiation for brain tumors (352, 353). This
phenomenon occurs more commonly in females. Concomitant GH deficiency
is frequently noted, although its role in the development of precocious
puberty is unclear. The combination of precocious puberty and GH
deficiency may result in a confusing clinical picture of apparent
sexual development combined with short stature. Diagnosis and
appropriate intervention are dependent upon an awareness of the
clinical syndrome.
B. Gonadal toxicity
Gonadal dysfunction caused by anticancer therapy has been
extensively reviewed (1, 2). Cytotoxic chemotherapeutic agents and
direct radiation exposure are common causes of infertility or
hypogonadism in cancer survivors. In the discussion that follows,
several risk factors for development of gonadal toxicity after
treatment for Hodgkin’s and non-Hodgkin’s lymphoma, ALL, and breast
carcinoma are discussed. These include the specific chemotherapeutic
combination, the dose intensity, and the age and sex of the patient.
There are important differences between male and female gametogenesis
relevant to the effects of cancer therapy on fertility. Spermatogenesis
occurs in a continuous cycle of mitosis, meiosis, differentiation, and
maturation, resulting in the production of approximately 2 million
sperm per day from puberty to old age. The high rate of cell division
makes these germ cells particularly sensitive to cytotoxic agents, in
contrast to the Leydig or Sertoli cells. Among the germ cells,
spermatogonia are the most sensitive to cytotoxic effects, followed in
order by stem cells, maturing spermatocytes, spermatids, and
spermatozoa. Cytotoxic effects at any point along this developmental
pathway can lead to reduced sperm production and an elevation of
pituitary FSH production. Age at exposure of radiation does not seem to
be a major factor in postpubertal males. If there are sufficient germ
cells remaining after cytotoxic chemotherapy, repopulation of the
testis and resumption of spermatogenesis will occur. The probability of
recovery of spermatogenesis decreases with increasing duration of
azoospermia (354, 355). However, examples of recovery of
spermatogenesis after 20 yr have been reported (356).
In contrast, oogenesis occurs during embryonic life. The quiescent
status of the oocyte during most of its life makes it resistant to the
effects of cytotoxic chemotherapy. There is, however, no mechanism to
replace oocytes damaged or killed by chemotherapy. The net effect of a
reduction in the number of oocytes is a shortened reproductive period.
The granulosa cells are also susceptible to cytotoxic drugs. Ovarian
biopsies after chemotherapy show flattened, nonproliferating granulosa
cells with little follicular development observed around the remaining
ova. Women with complete ovarian failure and amenorrhea will have
menopausal levels of LH, FSH, and estradiol, reflecting mainly
granulosa cell dysfunction (357). Infertility may occur as a result of
either oocyte or granulosa cell impairment. Temporary cessation of
ovulation and menstruation will result from damage to maturing
follicles; permanent effects will occur when the number of surviving
primordial follicles cannot sustain hormonal cyclicity.
The protective effect of gonadal suppression during anticancer therapy
has been discussed (1), and its use and efficacy remain to be defined.
1. Irradiation.
a. Effects in males.
Radiation damage to the gonads is
dose-dependent (358). Radiation exposure greater than 0.08 Gy was
associated with increased serum FSH, indicative of impairment of
spermatogenesis (358). Doses greater than 0.3 Gy may also cause
temporary azoospermia (359), and doses greater than 8 Gy (as in bone
marrow transplantation) usually causes permanent azoospermia (360). A
decrease in sperm count after irradiation usually occurs after a lag
period of about 7 weeks (359).
Recovery of spermatogenesis after irradiation depends on the radiation
dose (358, 361). Males who received doses greater than 0.1 Gy recovered
in 9–18 months. Oligospermia persisted for 10–18 months in those who
received 0.15–0.4 Gy. Periods of 2–5 yr were required for sperm count
to normalize in individuals who received 0.4–2 Gy (362, 363, 364).
Radiation doses of 2–6 Gy may cause oligospermia for 5 yr or more,
with recovery not assured.
Leydig cells are more resistant to radiation effects than are germ
cells. Doses between 0.075 and 6 Gy cause Leydig cell dysfunction, as
indicated by an elevated serum LH concentration (358). High-dose
exposure (24 Gy) caused complete Leydig cell failure in the two
reported patients (365). High-dose radiation (24–25 Gy) to the gonads,
combined with chemotherapy, caused primary hypogonadism in six of seven
prepubertal males (366). A testicular radiation dose of 30 Gy or more
will cause primary hypogonadism in most adult patients (367, 368).
b. Effects in females.
Although it is more difficult to
estimate ovarian radiation exposure, several generalizations can be
made. In women over the age of 40 yr, exposure to 6 Gy can cause
ovarian failure and infertility, whereas doses of 20 Gy may be required
to produce permanent infertility in younger women (369). In prepubertal
girls, doses as low as 6 Gy may cause primary amenorrhea (370). These
results suggest that the ovary is most susceptible to the effects of
radiation in the prepubertal period and at the end of reproductive
life.
2. Alkylating agents. Alkylating agents are cell-cycle
nonspecific drugs that form DNA adducts and cross-links and are
generally highly gonadotoxic. Mechlorethamine, chlorambucil, melphalan,
busulfan, and cyclophosphamide commonly cause sterility and premature
menopause (2). The concomitant use of chemotherapy, especially of
regimens that contain alkylating agents, worsen the gonadotoxic effects
of external radiation therapy in both sexes (354, 371).
a. Effects in males.
Cyclophosphamide (372) (cumulative dose
of 18.8 g/m2) and chlorambucil (373) are the two alkylating
agents that can cause prolonged reversible azoospermia when used as
monotherapy.
Chlorambucil. Azoospermia occurs with cumulative doses
of 400–800 mg (374, 375). For mean total doses of about 750 mg/m2,
recovery of azoospermia may require 3–4 yr after cessation of
chlorambucil (376).
Cyclophosphamide. Spermatogenesis is more susceptible to
the effects of cyclophosphamide than Leydig cell function. Azoospermia
or oligospermia has been reported in men with compensated Leydig cell
dysfunction, characterized by elevated LH and FSH levels but a normal
serum testosterone concentration (377).
b. Effects in females:
Mechlorethamine. The effect of this drug as a single
agent is not clear. It is usually used in combination with vincristine,
procarbazine, and prednisone (MOPP), a highly gonadotoxic combination,
as discussed below. The relative contribution of mechlorethamine to the
gonadotoxicity of MOPP is difficult to ascertain.
Chlorambucil. Cumulative doses of 535–750
mg/m2 caused ovarian failure in women treated for breast
cancer (378). A cumulative dose of 236 mg/m2 for lymphoma
or chronic lymphocytic leukemia caused two of 126 women (median age 47
yr) to develop ovarian failure (379).
Melphalan. Seventy-three percent of older women who
received a cumulative dose of 340 mg/m2 developed ovarian
failure, whereas a higher cumulative dose (510 mg/m2) led
to ovarian failure in only 22% of women less than 39 yr of age (380).
Busulfan. Monotherapy with busulfan caused amenorrhea in
all of ten women treated with doses of 150–405 mg before the cessation
of menses. The onset of amenorrhea occurred 1–6 months after
initiation of therapy with a median time of 2 months. The amenorrhea
reversed after 4 and 6 months in two patients but lasted for 6–41
months (until death) in the remainder (381). Ovarian biopsies confirmed
gonadal failure (381, 382).
Cyclophosphamide. Ovarian failure occurs commonly in
women treated with cyclophosphamide for malignancy(383) or autoimmune
disease (384). In a large Japanese series, 15 of 18 premenopausal women
(83%) treated with 8.4–40 g cyclophosphamide as monotherapy developed
permanent amenorrhea (383). Patients in their thirties required longer
mean doses to induce amenorrhea (9.3 g) than women in their forties
(5.2 g). Histological findings in three patients confirmed ovarian
follicle destruction. In two other series, the mean total dose to onset
of amenorrhea was 20.8–25.5 g/m2 in women younger than 29
yr, 6.3–8.8 g/m2 in women 30–39 yr of age, and 2.34–6.79
g/m2 in women older than 40 yr (385, 386).
c. Effects in prepubertal children.
In prepubertal
children of either sex treated with alkylating agents, no hormonal
abnormalities may be seen after chemotherapy. This led to an earlier
belief that gonadotoxic effects do not occur in patients of this age
group. However, biopsies of the gonadal tissues in these patients may
show evidence of fibrosis and germ cell damage (387). In one case,
complete destruction of the ovaries was found at autopsy in a 13-yr-old
girl who died after receiving 60.4 g/m2 of cyclophosphamide
over 29 months (388). Because young girls have a greater reserve of
germ cells and primary follicles, normal puberty occurs in most of
these patients (389). In boys, recovery of spermatogenesis and
compensated Leydig cell function usually leads to normal pubertal
development and fertility, despite histological evidence of testicular
damage.
3. Procarbazine. Procarbazine is a derivative of
methylhydrazine and is a cell cycle-nonspecific agent. No data are
available concerning its gonadotoxic effects as a single agent.
Combination regimens for Hodgkin’s disease that include procarbazine
are gonadotoxic when compared with the same regimen without
procarbazine. Gonadal toxicity tends to be greatest in patients who
receive higher cumulative doses of procarbazine. The high rate of
gonadal toxicity led to the recommendation that procarbazine be avoided
in patients who want to preserve fertility, if a suitable alternative
exists (390).
a. Effects in males.
Procarbazine use is associated with a
high rate of permanent testicular dysfunction and differs in this
regard from other cytotoxic agents that cause transient toxicity. In
one study, 70% of 10 middle-aged men recovered normal testicular
function by 34 months after COP (cyclophosphamide, vincristine, and
prednisone) or CVP (cyclophosphamide, vinblastine, and prednisone)
therapy (391). None of 19 younger men normalized spermatogenesis or
normal FSH levels 11 yr after COPP (cyclophosphamide, vincristine,
procarbazine, and prednisone) therapy (392). In another series of 92
patients, six or more cycles of COPP led to permanent sterility in all.
Testicular histological analysis revealed germinal aplasia in all 19
patients biopsied (393). In another series comparing the chemotherapy
regimens used for non-Hodgkin’s lymphoma with those for Hodgkin’s
disease, both groups of patients received comparable median cumulative
doses of vincristine, cyclophosphamide, and doxorubicin, but only
patients with Hodgkin’s disease received procarbazine (cumulative dose
of 13.3 g). The frequency of testicular dysfunction was 65% in
procarbazine-treated patients and 21% in patients who did not receive
procarbazine (390).
b. Effects in females.
In a retrospective analysis comparing
chemotherapy-induced gonadal toxicity in patients with Hodgkin’s
disease or non-Hodgkin’s lymphoma, the addition of procarbazine to the
therapeutic regimen resulted in gonadal toxicity in 50% of women,
compared with an incidence of 10% in women who did not receive
procarbazine (390). These results suggest, but do not prove, a
procarbazine effect.
4. Nitrosoureas. The nitrosoureas, carmustine or lomustine,
alone or in combination with other agents, have been implicated in
gonadal failure in boys and girls who were treated for brain tumors
during the prepubescent period (394). Both groups of patients had also
received craniospinal irradiation, but the scatter dose to the gonads
was thought to be insufficient to cause gonadal damage. In another
report, nine of 13 prepubertal girls developed primary ovarian failure
after treatment with carmustine or lomustine and procarbazine (395).
Procarbazine was thought to be the major cause of gonadal toxicity in
these girls.
5. Platinum compounds.
a. Effects in males.
A combination therapy for treatment of
testicular carcinoma with cisplatin, etoposide, and bleomycin (PEB)
caused a dose-related impairment of spermatogenesis (396). Doubling the
cisplatin and etoposide doses increased the incidence of azoospermia
from 19–47% and was associated with a 2-fold increase in the median
serum FSH level. The median total dose of cisplatin in those with
gonadal damage was 490 mg compared with 300 mg in those with normal
function. In another study, persistent infertility and diminished
Leydig cell function developed in more than 50% of patients with
testicular cancer who received cisplatin-based chemotherapy (397). In
another study, cisplatin use was associated with lower sperm counts and
testicular volume, although the small sample size in this report
precludes a definite statement (398).
b. Effects in females.
The extent of cisplatin toxicity in
females is less well defined. In a study with 12 female patients in
whom cisplatin (0.4–0.6 g/m2) was used in combination with
vinblastine and bleomycin to treat ovarian germ cell tumors, temporary
amenorrhea developed in two patients and lasted from 12–15 months
after the cessation of chemotherapy (399).
6. Etoposide. Etoposide (VP-16; 3–6 g/m2 orally)
has been reported to cause ovarian dysfunction in a small number of
patients treated for gestational trophoblastic neoplasia (400). The
ovarian failure may be transient or permanent and is characterized by
low estrogen and progesterone levels and a compensatory increase in the
serum FSH concentration. In older women nearing natural menopause (ages
>50 yr), approximately 3–4% of women treated with etoposide at doses
of 3–10 g/m2 developed permanent ovarian failure (401).
7. Antimetabolites. Antimetabolites are cell cycle specific
and exert few, if any, toxic effects on the ovaries. In males, these
drugs may cause a reduced sperm count and altered sperm morphology or
motility; these effects are generally reversible.
a. Effects in females.
In seven women treated with more than
(150 g/m2 of methotrexate and leucovorin rescue, there were
no discernible effects on either menstrual regularity or hormone levels
(402).
Another antimetabolite, 5-fluorouracil, appears to have no toxic effect
on the ovaries. In a study of Chinese women treated for gestational
trophoblastic tumors with doses of 5-fluorouracil exceeding 66
g/m2, there was no amenorrhea or infertility (403).
b. Effects in males.
High-dose intravenous methotrexate
(157–198 g/m2) plus leucovorin caused transient
oligospermia and elevated FSH levels in five of ten treated males.
Sperm production recovered in all patients after 15–34 days. Serum LH
and testosterone levels were not affected (402).
8. Antitumor antibiotics. Antitumor antibiotics, widely used
to treat solid tumors, are a group of cell cycle-nonspecific agents
that bind to nucleic acids, resulting in DNA damage or inhibition of
DNA synthesis. Gonadal toxicity has not been a major problem with this
class of drugs when used alone, although gonadal toxicity does occur
when they are used in combination with other drugs.
a. Effects in males.
The effect of doxorubicin as a single
agent on male testicular function has not been well studied. When used
in combination with bleomycin, vinblastine, and dacarbazine (ABVD),
there is no evidence of long-term azoospermia (404).
b. Effects in females.
When used alone, doxorubicin probably
has little or no adverse effect on ovarian function (405). There is
concern about a synergistic effect of doxorubicin combined with
cyclophosphamide, but no data are available. Information on permanent
ovarian toxicity is lacking for bleomycin, dactinomycin, and mitomycin
C.
9. Vinca alkaloids. Vinca alkaloids inhibit microtubular
function and are cell cycle-specific. Vinblastine, when used in
combination with alkylating agents, has been reported to cause
reversible and dose-related amenorrhea (406). Vinblastine, cisplatin,
and bleomycin (PVB) caused reversible amenorrhea with vinblastine doses
up to 78 mg/m2 (407, 408). Another combination, vincristine
(mean of 13.8 mg/m2) and dactinomycin (mean of 18
mg/m2), caused no ovarian dysfunction in five treated women
(409).
10. Cytokines.
a. Effects in males.
A retrospective analysis of 48 male
patients treated for hairy cell leukemia failed to identify any
significant effect of interferon-2a on testicular function (410).
Another cytokine, interleukin-2, is a potent inhibitor of mouse (411)
and rat (412) Leydig cell testosterone synthesis in
vitro and depresses both adrenal and testicular androgen
production in human males (413).
b. Effects in females.
Animal studies with interferon-2
suggest possible effects on ovarian function. Nonpregnant rhesus
monkeys treated with 5 or 25 million IU/kg/day developed reversible
menstrual cycle irregularities (414). In one report, human leukocyte
interferon caused decreased serum estradiol and progesterone
concentrations, associated with normal pituitary gonadotropin function,
which suggested an ovarian effect (415). There are no studies of the
effect of interleukin-2 on ovarian function, although such effects are
suggested by the potential paracrine effect of interleukin-2 in the
normal follicular maturation (416).
11. Combination chemotherapy. There may be additive or
synergistic effects of multiple chemotherapeutic agents on gonadal
function. Combination chemotherapy regimens are generally more
gonadotoxic than individual agents. Table 4 summarizes the incidence of gonadal
failure associated with some common combination regimens. For example,
the regimen of methotrexate, vincristine, prednisone, and procarbazine
(MOPP), used to treat Hodgkin’s disease, causes germinal cell
dysfunction and increased FSH levels in more than 80% of men (417).
Another combination regimen, cyclophosphamide, vincristine, prednisone,
and procarbazine (COPP), causes azoospermia in 100% of males treated
with six or more cycles for Hodgkin’s disease (393). This effect
commonly persists for 1 yr and may last up to 7 yr. Normal testosterone
with slight elevations of the serum LH concentration suggests a subtle
effect on Leydig cell function. Similar effects are observed with
mechlorethamine, vinblastine, prednisolone, and procarbazine (MVPP),
and a hybrid combination of chlorambucil, vinblastine, prednisolone
plus procarbazine, with doxorubicin, vincristine plus etoposide
(ChIVPP/EVA). These latter two chemotherapy regimens cause substantial
damage to gonadal function in both sexes (418, 419).
The gonadal toxicity of these earlier protocols has led to the search
for chemotherapeutic combination regimens of comparable efficacy but
lower toxicity. The combination of vincristine, epirubicin, etoposide,
and prednisolone (VEEP) is comparable in efficacy to established
regimens for Hodgkin’s disease. This combination has modest toxicity
that preserves fertility (normal posttreatment gonadal function in 92%
of males and 100% of females) (420). Similarly, the combination
regimen of ABVD has been used to treat Hodgkin’s disease with
preservation of fertility in 100% of patients (421).
The growing success of chemotherapy in the treatment of pediatric
malignancy provides another reason for developing therapies that have
low gonadal toxicity. The long-term effects of sex hormone deficiency
on growth and development are significant, and preservation of
fertility is an important goal for long-term survivors (370).
|
XI. Prevention and Surveillance of Endocrine Side Effects
|
|---|
Early detection and treatment of endocrine deficiency may have a
significant impact on the quality and duration of life in a cancer
survivor. The number and variety of endocrine side-effects make it
difficult and prohibitively expensive to screen patients for all
possible long-term effects. What follows is a focused approach designed
to incorporate endocrine screening into routine office visits. In most
cases the endocrinologist will not become involved with the patient
until a deficiency develops; therefore, these recommendations are more
likely to be implemented by primary care physicians and oncologists
during routine oncology follow-up. The simplified schema presented
below are used at the M. D. Anderson Cancer Center for follow-up
of children and adults who have received specific types of therapy.
A. Pediatric screening
1. Growth, development, and other hypothalamic-pituitary
dysfunction. In children who have had cranial irradiation,
measurement of height and growth velocity should be performed at
6-month intervals. In children treated with spinal or craniospinal
irradiation, there may be local rather than generalized growth
abnormalities requiring more specific evaluation. Protocols for
evaluation of these children should be simple and straightforward. Foot
size is a reliable measure of growth that can be added easily to
routine office visits (422). A child who does not meet expected growth
standards should have a more detailed evaluation that includes GH,
IGF-1, IGF-binding protein 3, bone age assessment, and thyroid
function. Testing GH response to provocative stimuli should be
performed if these screening tests identify an abnormality. GH
replacement therapy in children with documented GH deficiency is
effective and has been reviewed (330, 423). In a child with a low serum
level of T4, measurement of the serum TSH and, if
necessary, thyroid-binding proteins should be performed to determine
the specific cause. In those with primary thyroid failure characterized
by an elevated TSH, T4 treatment should be initiated. If
the growth rate remains low, testing of the GH axis should be pursued.
In patients who had total body irradiation (in preparation for bone
marrow transplant), primary hypothyroidism and pituitary failure (GH
and gonadotropin deficiency) can coexist. In children with a central
hypothyroidism, a more thorough evaluation of pituitary-hypothalamic
function to include assessment of the pituitary-adrenal and
pituitary-gonadal axes is appropriate. Dynamic testing, such as the
ACTH-, TRH-, and/or GnRH-stimulation test, may be used to confirm
hormone deficiencies before initiation of treatment.
Evaluation of sexual development should include Tanner staging and
review of menstrual history in girls and examination of pubic and
axillary hair and penile and testicular size in boys.
2. Thyroid dysfunction. Children who have received either
pituitary-hypothalamic or neck irradiation should have a free
T4 and TSH measurement annually for 5 yr and every 2 yr
thereafter. Early detection will permit intervention before
hypothyroidism causes adverse effects on physical and intellectual
development and growth.
3. Thyroid nodules. Thyroid examination should be included in
the routine follow-up examination of children who receive head and neck
irradiation, because a high percentage will develop thyroid nodules
(281, 424). Thyroid irregularities should be evaluated by
ultrasonography and biopsied by fine needle aspiration if there are two
dominant nodules.
4. Diabetes mellitus. Screening for diabetes mellitus should
be performed in children who have had pancreatic surgery, were treated
with streptozocin, or who developed pancreatitis as a result of
L-asparaginase treatment.
5. Impaired skeletal mass development. Increasing attention is
being focused on the effects of early nutritional or hormonal
deficiency on normal bone growth. There is compelling evidence that
nutritional or estrogen deficiency in teenagers and young adults during
the period of greatest bone accretion will result in a lower peak bone
mass. Unless steps are taken to enhance bone mass or prevent subsequent
bone loss, this group of patients will be at greater risk for later
fracture. Attention to adequate calcium intake and prompt investigation
of primary or secondary amenorrhea or menstrual irregularity in female
cancer survivors, with prompt replacement of gonadal steroids in young
men or women with gonadal failure, is recommended. Combined or cyclic
estrogen/progesterone therapy is recommended for young women with an
intact uterus; males should be treated with parenteral or cutaneous
testosterone.
The recognition that peak bone mass may be lower in patients who
receive several types of chemotherapy suggests that bone mass should be
assessed in the early thirties, an age at which peak bone mass has been
attained in most people. If bone mass is normal, no further evaluation
is needed beyond the usual recommendations for prevention of
osteoporosis. In those with osteopenia (1–2 SDs below
normal), an active program of calcium supplementation and exercise
should be initiated and combined with periodic assessment of bone mass.
There is evidence that women who receive cytotoxic chemotherapy may
undergo an earlier menopause. Estrogen/progesterone replacement should
be considered in those patients.
B. Adult screening
1. Hypothalamic-pituitary dysfunction. In adults who have
received cranial or head and neck irradiation, detection of
hypothalamic-pituitary abnormalities is more challenging. Growth and
pubertal development, sensitive indicators of endocrine function in
children and teenagers, are not useful indicators of dysfunction in
adults. One strategy in adults is to screen routinely for GH and
gonadal failure, known to be the most sensitive indicators of
radiation-induced hypothalamic-pituitary damage. In adults who have had
cranial irradiation, we recommend annual measurement of serum IGF-I and
testosterone levels in males and documentation of menstrual history in
females for 5 yr, after which measurements/documentation are repeated
at 5-yr intervals for another 10 yr. Physical examination should focus
on signs of hypopituitarism, such as hypotension, loss of axillary or
pubic hair, and hypothyroidism. If a defect of GH or gonadotropin
secretion is detected, a more careful evaluation of thyroid and adrenal
function should be initiated.
2. Thyroid dysfunction. Neck irradiation for treatment of a
variety of head and neck tumors or lymphoma is associated with a high
incidence of primary hypothyroidism. Patients who have received
radiation should have free T4 and TSH levels measured
annually for 5 yr, then biannually for 10 yr, and thereafter, every 5
yr for another 10 yr.
3. Thyroid nodules. Radiation-induced thyroid nodules are
common sequelae of head and neck cancer (210, 280) and are also found
in breast cancer patients whose radiation field includes the lower
neck. Development of a cost-effective strategy to detect thyroid
nodules is difficult. Ultrasound examination on a regular basis is an
effective but unduly expensive method for detection. We recommend an
annual thyroid physical examination in all patients. Palpable nodules
should be further evaluated by ultrasound examination and fine needle
aspiration biopsy.
4. Diabetes mellitus.
a. Type I diabetes mellitus.
Treatment with streptozocin or
L-asparaginase may result in type I diabetes mellitus.
Patients receiving these drugs should be screened routinely by fasting
blood glucose measurement, during and 6 months after therapy. Although
there is no evidence of a delayed onset of diabetes mellitus after
treatment with streptozocin, follow-up has been limited and short-term.
For long-term survivors treated with streptozocin, one may consider
screening for delayed development of diabetes mellitus. Patients who
have suffered from severe pancreatitis as a consequence of
L-asparaginase should be screened periodically for diabetes
mellitus.
b. Type II diabetes mellitus.
Combination therapy that
includes glucocorticoids is the most common cause of diabetes mellitus,
necessitating periodic monitoring of the level of blood glucose during
therapy. Patients treated with interferon- should also be screened
periodically for diabetes mellitus.
5. Metabolic bone diseases. Osteoporosis may occur as a direct
result of toxic effects of chemotherapy on bone formation or, more
commonly, as a result of estrogen or androgen deficiency caused by
gonadal failure. It is important to consider the possibility of bone
loss or osteoporosis in androgen- or estrogen-deficient patients.
Particularly problematic are young or middle-aged women with breast
carcinoma who develop premature menopause as a result of cytotoxic
chemotherapy. It is important to assess bone mass in this type of
patient and to take active steps to preserve or enhance bone mass by
alternative drug therapies such as bisphosphonates or calcitonin.
Osteomalacia is a rare complication of chemotherapy but should be
considered in osteopenic patients or those with an osteomalacic
clinical syndrome (bone pain and proximal myopathy). Patients who have
received chemotherapeutic agents that cause hypophosphatemia,
hypomagnesemia, or hypocalcemia such as ifosfamide, platinum compounds,
fludarabine, or estramustine, are particularly at risk. Serum ionized
calcium, phosphorus, magnesium, and vitamin D metabolites should be
included in the initial evaluation.
|
Footnotes
|
|---|
Address reprint requests to: Robert F. Gagel, M.D., Section of Endocrinology, Box 015, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030. E-mail:
rgagel{at}endocrine.mdacc.tmc.edu
1 Abbreviations of chemotherapeutic regimens: ABVD,
doxorubicin, bleomycin, vinblastine, and dacarbazine; CAM,
cyclophosphamide, doxorubicin, and methotrexate; ChlVPP/EVA,
chlorambucil, vinblastine, procarbazine, and prednisolone, with
etoposide, vincristine, and doxorubicin; CHOP-Bleo, cyclophosphamide,
doxorubicin, vincristine, prednisone, and bleomycin; CHOP-M,
cyclophosphamide, doxorubicin, methotrexate, and prednisolone; CMF,
cyclophosphamide, methotrexate, and fluorouracil; COP,
cyclophosphamide, vincristine, and prednisone; COPP, cyclophosphamide,
vincristine, procarbazine, and prednisone; CVP, cyclophosphamide,
vinblastine, and prednisone; CY-VA-DIC, cyclophosphamide, vincristine,
Adriamycin (doxorubicin), and dacarbazine; CY-A-DIC, cyclophosphamide,
Adriamycin (doxorubicin), and dacarbazine; FAC, fluorouracil,
doxorubicin, and cyclophosphamide; L-AdVP, L-asparaginase, doxorubicin,
vincristine and prednisone; MOPP, mechlorethamine, vincristine,
procarbazine, and prednisone; MVPP, mechlorethamine, vinblastine,
procarbazine, and prednisolone; PEB, cisplatin, etoposide, and
bleomycin; POMBACE, cisplatin, vincristine, methotrexate, and
bleomycin, alternated with dactinomycin, cyclophosphamide, and
etoposide; PVB, cisplatin, vinblastine and bleomycin; VEEP,
vincristine, epirubicin, etoposide, and prednisolone. Other
abbreviations used: ADH, antidiuretic hormone; ALL, acute lymphocytic
leukemia; AVP, vasopressin, antidiuretic hormone; IGF-I, insulin-like
growth factor-1; LDL, low-density lipoprotein; MIBG,
131I-metaiodobenzylguanidine; PTC, papillary thyroid
carcinoma; SIADH, syndrome of inappropriate antidiuretic hormone; TBG,
thyroid hormone-binding protein. 
2 Use your World Wide Web browser software
(e.g., Microsoft Internet Explorer or Netscape) and open
location at Uniform Resource Locator (URL):
http://endocrine.mdacc.tmc.edu/yeung/index.html
|
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Top
Abstract
I. Introduction