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*Endocrine Diseases
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


    Abstract
 Top
 Abstract
 I. Introduction
 II. Disorders of Glucose...
 III. Disorders of Free...
 IV. Disorders of Mineral...
 V. Metabolic Bone Diseases
 VI. Thyroid Disorders
 VII. Disorders of Lipid...
 VIII. Adrenal Dysfunction
 IX. Disorders of GH...
 X. Reproductive Dysfunction
 XI. Prevention and Surveillance...
 References
 

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.


    I. Introduction
 Top
 Abstract
 I. Introduction
 II. Disorders of Glucose...
 III. Disorders of Free...
 IV. Disorders of Mineral...
 V. Metabolic Bone Diseases
 VI. Thyroid Disorders
 VII. Disorders of Lipid...
 VIII. Adrenal Dysfunction
 IX. Disorders of GH...
 X. Reproductive Dysfunction
 XI. Prevention and Surveillance...
 References
 
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 1Go), and a list of these endocrine effects and the drugs that cause them will provide disease-oriented information (Table 2Go). These tables in the on-line version will contain hypertext links for exploration of specific drugs or complications to the endocrine system.


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Table 1. Endocrine effects of anticancer therapeutic agents

 

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Table 2. Endocrine abnormalities caused by antineoplastic agents

 
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).


    II. Disorders of Glucose Metabolism
 Top
 Abstract
 I. Introduction
 II. Disorders of Glucose...
 III. Disorders of Free...
 IV. Disorders of Mineral...
 V. Metabolic Bone Diseases
 VI. Thyroid Disorders
 VII. Disorders of Lipid...
 VIII. Adrenal Dysfunction
 IX. Disorders of GH...
 X. Reproductive Dysfunction
 XI. Prevention and Surveillance...
 References
 
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-{alpha}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-{alpha}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-{alpha}2a and {alpha}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-{alpha} and diabetes mellitus is found in the treatment of viral hepatitis (15, 16, 17, 18). Although the incidence of interferon-{alpha}-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-{alpha} over 24 weeks for chronic active hepatitis C (19). Diabetic ketoacidosis has been reported in a variety of conditions treated with interferon-{alpha}2 (13, 14, 20). Several mechanisms have been described for interferon-{alpha}-induced diabetes, the most important of which is the effect of interferon-{alpha} 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-{alpha} 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.


    III. Disorders of Free Water Clearance
 Top
 Abstract
 I. Introduction
 II. Disorders of Glucose...
 III. Disorders of Free...
 IV. Disorders of Mineral...
 V. Metabolic Bone Diseases
 VI. Thyroid Disorders
 VII. Disorders of Lipid...
 VIII. Adrenal Dysfunction
 IX. Disorders of GH...
 X. Reproductive Dysfunction
 XI. Prevention and Surveillance...
 References
 
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.


    IV. Disorders of Mineral Metabolism
 Top
 Abstract
 I. Introduction
 II. Disorders of Glucose...
 III. Disorders of Free...
 IV. Disorders of Mineral...
 V. Metabolic Bone Diseases
 VI. Thyroid Disorders
 VII. Disorders of Lipid...
 VIII. Adrenal Dysfunction
 IX. Disorders of GH...
 X. Reproductive Dysfunction
 XI. Prevention and Surveillance...
 References
 
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.


    V. Metabolic Bone Diseases
 Top
 Abstract
 I. Introduction
 II. Disorders of Glucose...
 III. Disorders of Free...
 IV. Disorders of Mineral...
 V. Metabolic Bone Diseases
 VI. Thyroid Disorders
 VII. Disorders of Lipid...
 VIII. Adrenal Dysfunction
 IX. Disorders of GH...
 X. Reproductive Dysfunction
 XI. Prevention and Surveillance...
 References
 
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.


    VI. Thyroid Disorders
 Top
 Abstract
 I. Introduction
 II. Disorders of Glucose...
 III. Disorders of Free...
 IV. Disorders of Mineral...
 V. Metabolic Bone Diseases
 VI. Thyroid Disorders
 VII. Disorders of Lipid...
 VIII. Adrenal Dysfunction
 IX. Disorders of GH...
 X. Reproductive Dysfunction
 XI. Prevention and Surveillance...
 References
 
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 3Go). 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. 1Go (210).


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Table 3. Incidence of hypothyroidism (including compensated hypothyroidism) after radiation therapy1

 


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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.]

 
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. 2Go, 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. 2Go). 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.

 
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-{alpha}2. Thyroid dysfunction is a recognized side effect of interferon-{alpha} 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-{alpha}2 on thyroid function. In vitro studies have shown an inhibition by interferon-{alpha}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-{alpha} 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-{alpha}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-{alpha}2 (251, 252) or combined therapy with interferon-{alpha} 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. 3Go) (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).]

 
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).


    VII. Disorders of Lipid Metabolism
 Top
 Abstract
 I. Introduction
 II. Disorders of Glucose...
 III. Disorders of Free...
 IV. Disorders of Mineral...
 V. Metabolic Bone Diseases
 VI. Thyroid Disorders
 VII. Disorders of Lipid...
 VIII. Adrenal Dysfunction
 IX. Disorders of GH...
 X. Reproductive Dysfunction
 XI. Prevention and Surveillance...
 References
 
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-{alpha}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-{alpha}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-{alpha} 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.


    VIII. Adrenal Dysfunction
 Top
 Abstract
 I. Introduction
 II. Disorders of Glucose...
 III. Disorders of Free...
 IV. Disorders of Mineral...
 V. Metabolic Bone Diseases
 VI. Thyroid Disorders
 VII. Disorders of Lipid...
 VIII. Adrenal Dysfunction
 IX. Disorders of GH...
 X. Reproductive Dysfunction
 XI. Prevention and Surveillance...
 References
 
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. 2Go). 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.


    IX. Disorders of GH Secretion and Growth
 Top
 Abstract
 I. Introduction
 II. Disorders of Glucose...
 III. Disorders of Free...
 IV. Disorders of Mineral...
 V. Metabolic Bone Diseases
 VI. Thyroid Disorders
 VII. Disorders of Lipid...
 VIII. Adrenal Dysfunction
 IX. Disorders of GH...
 X. Reproductive Dysfunction
 XI. Prevention and Surveillance...
 References
 
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. 2Go) (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. 2Go). 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
 Top
 Abstract
 I. Introduction
 II. Disorders of Glucose...
 III. Disorders of Free...
 IV. Disorders of Mineral...
 V. Metabolic Bone Diseases
 VI. Thyroid Disorders
 VII. Disorders of Lipid...
 VIII. Adrenal Dysfunction
 IX. Disorders of GH...
 X. Reproductive Dysfunction
 XI. Prevention and Surveillance...
 References
 
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. 2Go). 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-{alpha}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-{alpha}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 4Go 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).


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Table 4. Probability of germ cell dysfunction after common combination chemotherapy regimens1

 
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
 Top
 Abstract
 I. Introduction
 II. Disorders of Glucose...
 III. Disorders of Free...
 IV. Disorders of Mineral...
 V. Metabolic Bone Diseases
 VI. Thyroid Disorders
 VII. Disorders of Lipid...
 VIII. Adrenal Dysfunction
 IX. Disorders of GH...
 X. Reproductive Dysfunction
 XI. Prevention and Surveillance...
 References
 
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-{alpha} 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. Back

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    References
 Top
 Abstract
 I. Introduction
 II. Disorders of Glucose...
 III. Disorders of Free...
 IV. Disorders of Mineral...
 V. Metabolic Bone Diseases
 VI. Thyroid Disorders
 VII. Disorders of Lipid...
 VIII. Adrenal Dysfunction
 IX. Disorders of GH...
 X. Reproductive Dysfunction
 XI. Prevention and Surveillance...
 References
 

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