NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.
Cancer and its treatment can lead to endocrine dysfunction and to clinical and laboratory abnormalities that obscure or mimic endocrine diseases. It is important for the oncologist to have an appropriate level of suspicion for endocrine sequelae in order to provide prompt and appropriate treatment that will improve the patient’s quality of life and avoid serious morbidity. This chapter focuses on hypothalamic-pituitary, thyroid, and adrenal dysfunction and an imbalance in electrolytes, water, and glucose metabolism.
Hypothalamic-Pituitary Dysfunction
Radiotherapy is a common cause of hypothalamic-pituitary dysfunction in cancer patients.1 There is no strong direct evidence to implicate chemotherapy as a cause of permanent dysfunction of the anterior pituitary. Metastasis to the hypothalamic region or the pituitary gland is uncommon,2 and clinical manifestations of endocrine dysfunction due to metastatic disease in this region are rare. However, benign tumors, such as pituitary tumors and craniopharyngiomas,3 frequently affect this anatomic region and cause endocrine dysfunction.
Development of radiation-induced hypothalamic dysfunction is insidious; the clinical manifestation of hormonal deficiency can occur years after radiation exposure. In general, the rapidity of onset and severity of dysfunction depend on the total dose of radiation and the rate of delivery. There is considerable variation in the sequence and frequency of hormonal dysfunction among the several axes of hypothalamic-pituitary functions. The somatotropic axis appears to be the most sensitive; the thyrotropic axis appears to be the least sensitive (Figure 155.1).4
The diagnosis of hypothalamic-pituitary dysfunction requires vigilance on the part of the oncologist because most of the presenting symptoms are nonspecific and can easily be attributed to other causes. For example, fatigue and weakness, symptoms of pituitary dysfunction, are common among cancer patients. A diagnostic screen for hypothalamic and pituitary dysfunction may include serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) measurement and evaluation for gonadal failure. Signs of overt hypopituitarism include hypoglycemia, hypotension, and hypothermia.
In children and teenagers, evaluation of sexual development is a useful diagnostic tool. The investigation should include staging of sexual development according to the Tanner staging criteria, examination of pubic and axillary hair, and review of menstrual history in girls and penile/testicular size in boys. In children who have had cranial irradiation, height and growth velocity should be measured at 6-month intervals. In children treated with spinal and craniospinal irradiation, local rather than general growth abnormalities may be present and, if so, require further specific evaluation. Foot size is a reliable indicator of growth that can be measured on a routine clinic visit.5 A child whose growth rate is not within the limits of a normal growth curve should be evaluated for growth hormone deficiency, hypothyroidism, and adrenal insufficiency. If the initial evaluation of GH, IGF-1, thyrotropin (TSH) and free thyroxin (T4) levels, and radiographic bone age reveal abnormality, then detailed dynamic testing with corticotropin (ACTH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (GRH) stimulation tests should be performed.
In adults who have received cranial or head and neck irradiation, detection of hypothalamic-pituitary abnormalities is more challenging. Growth and pubertal development, which are sensitive indicators of endocrine function in children and teenagers, are not helpful in these patients. One strategy to detect hypothalamic-pituitary abnormalities in adults consists of routine screening for abnormal GH and IGF-1 levels and gonadal failure, the most sensitive indicators of radiation-induced hypothalamic-pituitary damage. It is recommended that measurements of IGF-1 and testosterone levels in males and documentation of menstrual history in females be obtained annually for 5 years, and then at 5-year intervals for another 10 years. Any abnormalities noted on the screening tests should be pursued with further dynamic testing to evaluate all the axes of hypothalamic-pituitary functions.
Thyroid Disorders
Thyroid disorders and abnormalities in thyroid function are commonly associated with cancer and its therapy. These problems are discussed below.
Serum Thyroid Hormone-Binding Protein Abnormalities
The levels of thyroid hormone-binding proteins — thyroxine-binding globulin (TBG) and albumin—can be modified by sex hormone levels and nutritional factors; abnormalities of both are encountered frequently in cancer patients. Several chemotherapy drugs affect thyroid function test results. L-asparaginase appears to reversibly inhibit synthesis of albumin and TBG, resulting in low total T4 but normal free T4 levels.6,7 The combination of podophyllin and alkylating agents has also been reported to decrease TBG.8 Both 5-fluorouracil9 and mitotane10 increase the total T4 and triiodothyronine (T3) levels without suppressing TSH, suggesting that these drugs increase thyroid hormone binding capacity in the serum.
Euthyroid Sick Syndrome
Alterations in thyroid hormone metabolism occur in patients with cancer and other serious systemic illnesses.11,12 Low serum T3 levels, which may be found in up to 70% of moderately to seriously ill cancer patients, are due to a decrease in the extrathyroidal conversion of T4 to T3. Serum concentrations of free T4 are usually normal or high, while concentrations of free T3 are below normal or low. The patients are clinically euthyroid, and serum TSH level and TRH stimulation test results are normal. Thyroid hormone therapy is not indicated. With progression in the severity of nonthyroidal illness, the low-T3 syndrome may evolve into the low-T3–low-T4 syndrome, in which the low level of total T4 is caused by decreased binding of T4 to serum proteins, decreased serum TBG levels, prealbumin and/or albumin levels, or increased T4 clearance. In most of these patients, T3, T4, and TSH levels are normal. Clinical manifestations of hypothyroidism are usually absent, but assessment may be confounded by obtundation, edema, and hypothermia that may accompany severe illness. Low free T4 levels usually indicate a grave prognosis, with a mortality rate of over 50%. Thyroid hormone replacement therapy has no benefit in these patients.
Hypothyroidism
Surgery
The primary treatment of thyroid cancers is thyroidectomy. Patients are invariably hypothyroid after subtotal or total thyroidectomy. Thyroid hormone is replaced only after ablation of thyroid remnant or whole body scanning with I131 or after an assessment is made that ablation or imaging study with I131 is not necessary. For other tumors of the head and neck region, en bloc resection of the primary tumor may necessitate sacrifice of the thyroid glands. In such cases, thyroid hormone can be replaced immediately after sugery.
Radiation
Irradiation is an important cause of hypothyroidism (primary, secondary, and tertiary). Radiation-induced primary hypothyroidism is caused by thyroid-cell destruction, inhibition of cell division, vascular damage, and possibly an immune-mediated phenomenon. Factors that increase the risk of developing primary hypothyroidism include a high radiation dose to the vicinity of the thyroid gland, duration since therapy, lack of shielding of the thyroid during therapy, and combined irradiation and surgical treatments. Other factors include hemithyroidectomy during laryngectomy or damage to the thyroid vascular supply during surgery.13,14
The incidences of hypothyroidism after radiation therapy for various cancers and conditions are tabulated in Table 155.1.15–20 A relationship between radiation dose and the prevalence of hypothyroidism is clear, on the basis of studies of patients with Hodgkin’s disease.21,22 Long-term follow-up of patients treated with low-dose radiotherapy suggests that the threshold for causing clinically evident hypothyroidism is about 10 Gy. For Hodgkin’s disease patients who received > 30 Gy, the actuarial risk of hypothyroidism was up to 45% 20 years after irradiation.14 In another study, elevated TSH was seen in about 60% of Hodgkin’s disease patients who received mantle irradiation, 10 to 18 years after treatment.23 Patients with frank or subclinical hypothyroidism should receive thyroid hormone replacement therapy.
Chemotherapy
It has been suggested that immunosuppression by cytotoxic agents may prevent the development of chronic autoimmune thyroiditis and subsequent hypothyroidism. However, a protective effect of chemotherapy could not be demonstrated in patients who received higher doses of radiation (> 30 Gy) or in long-term survivors of bone marrow transplantation (BMT), 43% of whom were hypothyroid after a 13-month follow-up period.24 On the contrary, the diagnosis of hypothyroidism in 14% of BMT patients who did not receive total body irradiation25 suggests a causal relation between hypothyroidism and high-dose combination cytotoxic chemotherapy. This notion is also supported by studies that showed an increased incidence of primary hypothyroidism in patients treated with multiple combination drug regimens with26,27 or without radiation.26,28
L-asparaginase, in addition to inhibition of TBG synthesis, as discussed above, may also inhibit TSH synthesis reversibly and lead to temporary hypothyroidism with decreased free T4 levels.29,30
Thyroid dysfunction is a recognized side effect of cytokine treatments. Treatment with interleukin-2 produces thyroid dysfunction in approximately 20 to 35% of patients.31,32 These patients have hypothyroidism, hyperthyroidism, or hyperthyroidism followed by hypothyroidism.33 About 10% of interferon-treated patients develop primary hypothyroidism.34,35 Patients with antithyroid antibodies before therapy are at higher risk of cytokine-induced thyroid dysfunction.
Retinoid X receptor ligands may be used in the treatment of certain malignancies. Targretin (a retinoid X receptor–selective ligand) caused secondary or pituitary hypothyroidism in patients treated for cutaneous T-cell lymphoma.36 The effect is dose related, and central hypothyroidism occurs less frequently with lower doses. Targretin appears to inhibit transcription of the TSH gene by a yet undetermined mechanism.
Lymphangiography
Whether lymphangiography contributes to thyroid dysfunction is controversial. Ethiodized oil (ethiodol) is a fat-soluble organic iodide, and its slow release from lymph 4 months after lymphangiography carries the theoretical risk that the iodide excess that is released can inhibit thyroid hormone biosynthesis and secretion, thereby producing hypothyroidism. Lymphangiography also may increase the risk of radiation-associated thyroid dysfunction.37 The risk appears to be highest in those patients for whom more than 30 days elapsed between lymphangiography and radiotherapy.15
I131-Containing Compounds. The use of I131 for treatment of thyroid cancer requires a high serum TSH level. High TSH level is achieved by either withholding thyroid hormone replacement or administration of recombinant human TSH. The use of I131-containing compounds in the treatment of other tumors may result in hypothyroidism. For instance, using high dose (100–1,000 mCi) [I131]-metaiodobenzylguanidine (MIBG) to treat unresectable pheochromocytoma may result in primary hypothyroidism.
Screening
Children who have received either head and neck or cranial irradiation should have a free T4 measurement and a TSH measurement annually for 5 years and every 2 years thereafter. Early detection of abnormal T4 and TSH levels will permit medical intervention before hypothyroidism adversely affects physical and intellectual development and growth. In adults, neck irradiation for treatment of lymphoma and various head and neck tumors is associated with a high incidence of primary hypothyroidism. Patients who have received irradiation should have free T4 and TSH levels measured annually for 5 years, and then every other year for 10 years, and thereafter every 5 years for another 10 years. Once hypothyroidism is diagnosed, the patient should receive thyroid hormone replacement therapy.
Thyrotoxicosis
Radiation-induced painless thyroiditis with hyperthyroxinemia rarely occurs after external beam radiotherapy to the head and neck area. Transient thyroitoxicosis may occur as a result of inflammation and destruction of thyroid tissue and is usually followed by hypothyroidism. Transient thyroitoxicosis has been reported after mantle radiotherapy in patients with Hodgkin’s disease and occurs usually within 18 months of treatment.38 The low uptake of radioiodine in most of these cases suggests a diagnosis of silent thyroiditis, but some have Graves’ disease. A review of 1,787 patients with Hodgkin’s disease who were treated with radiation and/or chemotherapy showed an actuarial risk of thyroid disease of 67% after 26 years of follow-up.14 The risk of Graves’ disease in these patients was estimated to be at least 7.2 times that in a healthy population.
Ophthalmopathy similar to that in Graves’ disease has been reported within 18 to 84 months of high-dose radiotherapy to the neck for lymphoma, breast cancer, and nasopharyngeal/laryngeal cancer. Ophthalmopathy may occur without hyperthyroidism and in the absence of the human leukocyte antigen (HLA)-B8.39 This suggests that radiation-induced thyroid injury may induce an autoimmune process that is similar to Graves’ disease.
Trophoblastic tumors, hydatidiform mole, and choriocarcinoma often cause hyperthyroidism40 because they secrete very large amounts of human chorionic gonadotropin (HCG). The severity of hyperthyroidism correlates with the serum HCG, and when the serum HCG is above 200 IU/mL, hyperthyroidism is likely to occur. Resection of the tumor or effective chemotherapy (for choriocarcinoma) cures the hyperthyroidism.41
Thyroid Nodules
It is well known that low-dose radiation increases the risk of thyroid nodules and cancer. High-dose radiation therapy is also associated with an increased prevalence of thyroid nodules.42,43 In one study, 26 of 95 patients who had received high-dose radiotherapy for childhood malignancies had palpable thyroid nodules 5 to 34 years after therapy.37 Radiation-induced thyroid nodules are common sequelae of head and neck cancer treatments and are also found in breast cancer patients whose radiation field included the lower neck. The frequency of palpable abnormalities increases with time after radiation, but it is not related to radiation dose, serum TSH levels, or prior lymphangiography. Among 10 patients who underwent surgical resection, 8 had multiple follicular adenomas and extensive fibrosis, and 3 had localized papillary thyroid cancer. The presence of multiple small follicular adenomas and marked interstitial fibrosis in these patients was believed to be the result of prior radiation exposure.44
Because there is a high probability of thyroid nodules in children and adults who have received head and neck irradiation, thyroid examination should be included in the routine follow-up of these patients. Thyroid irregularities should be evaluated by ultrasonography and fine-needle aspiration biopsy. The diagnostic approach to thyroid nodules in cancer patients is outlined in Figure 155.2.
Thyroid cancer is increasingly recognized as a potential complication of high-dose radiation exposure to the thyroid, which increases the risk of thyroid cancer about three-fold in adults45 and about 13-fold in children.46 The latent period from radiotherapy to the diagnosis of thyroid cancer can be up to 30 years. Approximately 75 to 90% of radiation-induced thyroid cancers are papillary carcinomas. High-dose radiotherapy (> 40 Gy) is less frequently associated with thyroid cancer than is low-dose radiation, presumably because of the extensive cellular destruction caused by high-dose radiotherapy. In patients who have received low-dose radiation, the growth of a surviving population of cells may be stimulated by TSH. This theoretical concern increases the importance of diagnosing and treating subclinical primary hypothyroidism, a common long-term complication of radiation therapy associated with elevated TSH levels.
Metastasis to the Thyroid
In autopsy series, the incidence of metastasis to the thyroid gland varies from 1.25 to 24%. The primary tumor sites include the kidney (33%), lung (16%), breast (16%), esophagus (9%), and uterus (7%).47 Hypothyroidism secondary to metastatic infiltration and replacement of the thyroid by cancer is extremely rare. Thyrotoxicosis has also been reported in patients with thyroid metastasis from lymphoma48 and pancreatic cancer.49 In these cases, the etiology of thyroitoxicosis is probably similar to that in subacute thyroiditis, with follicular destruction resulting in unregulated release of thyroid hormone and thyroglobulin.
Diabetes Mellitus
The administration of glucocorticoids (e.g., in combination therapy regimens, for edema of brain metastasis, for prevention of transplant rejection, for graft-versus-host disease [GVHD] in BMT, and for nausea/vomiting) is probably the most common cause of diabetes mellitus in cancer patients. Therefore, patients who receive glucocorticoids must be periodically screened for diabetes, with evaluation of fasting glucose levels during therapy. Treatment with streptozocin50 or L-asparaginase51 may result in insulin-deficient diabetes mellitus. Although there is no evidence of a delayed onset of diabetes mellitus following treatment with streptozocin, follow-up has been limited and short term. For long-term survivors treated with streptozocin, periodic screening for delayed development of diabetes mellitus may be indicated. Diabetes mellitus may also develop as a consequence of serious pancreatitis secondary to treatment with L-asparaginase. Immunotherapy for cancer using cytokines, such as interleukin-252 and interferon-α,53 may cause toxicity to pancreatic β cells and lead to insulin-dependent diabetes. Tacrolimus, an immunosuppressive agent used to prevent GVHD in BMT, also increases the incidence of diabetes, perhaps by inhibiting insulin synthesis.54 Patients who received allogeneic BMT are likely to be receiving both glucocorticoids and tacrolimus and are particularly at risk for developing diabetes mellitus.55 Management of the blood glucose levels would depend on the severity of the blood glucose level abnormality and on the underlying pathophysiologic mechanism of the increase in blood sugar. In general, oral antidiabetic agents are unlikely to be effective in patients who are insulin deficient.
Metabolic Bone Diseases
Osteoporosis
Normal bone remodeling involves a delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts. Antineoplastic therapy is toxic to osteoblast function and decreases bone formation. Production by the tumor of hormonally active substances (e.g., parathyroid hormonal-related protein, lymphotoxin, interleukin-1, and interleukin-6) may contribute to the clinical picture of bone loss. In most cases, it is not clear whether bone loss is due to antineoplastic therapy or to the underlying disease process and its effects (including cachexia, malnutrition, poor calcium and vitamin D intake, or a combination of these). Bone loss is prominent in patients with disorders affecting hematopoietic cells, perhaps because of cytokine production and an intimate relationship of hematopoietic cells with bone-forming cells.
Nutritional deficiency and hypogonadism in teenagers and young adults result in lower bone mass. Attention to adequate calcium intake, prompt investigation of gonadal dysfunction in cancer survivors, and prompt replacement of gonadal steroids (in the absence of contraindications) in young hypogonadal men or women are recommended to decrease the risk of future bone fractures. The bone mass of long-term cancer survivors should be assessed when the patient is about 30 years old, the age at which most people have attained peak bone mass.56 If bone mass is normal, no further evaluation is needed beyond the usual recommendations for prevention of osteoporosis. If it is abnormal (more than 2 standard deviations below normal), the patient should be referred for evaluation of the multiple reversible causes of osteoporosis.
Four groups of adult patients are at particular risk for osteoporosis. Women with breast cancer treated with cytotoxic chemotherapy frequently undergo an early menopause57 and cannot receive estrogen replacement therapy. Bone mass should be assessed (e.g., by dual x-ray densitometry), and alternative therapies, such as bisphosphonates (alendronate or risedronate), calcitonin, or selective estrogen receptor modulators (SERMs), should be considered in addition to a daily intake of 1,200 to 1,500 mg elemental calcium. Men with prostate cancer who are on antiandrogenic therapy and made hypogonadal are at equivalent risk for development of osteoporosis. Bisphosphonates have not been carefully assessed in this context but are likely to be safe and effective as they are for other forms of male osteoporosis. A third group at risk for bone loss are patients with lymphoma, myeloma, or leukemia. The common mechanisms shared by these entities include production of bone-resorbing cytokines secreted by the neoplastic cells and the use of high-dose glucocorticoids in treatment regimens. Osteoporosis in children with leukemia will frequently reverse because the children are in the formative years of bone development; in adults, more active measures, such as bisphosphonate therapy, may be indicated.
A number of drugs can induce osteoporosis.58,59 In cancer patients, glucocorticoids, methotrexate, and cytotoxic drugs that cause renal loss of calcium, magnesium, or phosphorus (e.g., platinum compounds, cyclophosphamide, and ifosfamide) have significant impact on bone density. Osteoporosis (generalized or localized) is observed in children receiving methotrexate therapy for acute lymphoblastic leukemia (ALL).60 The osteoporosis improves significantly after cessation of methotrexate therapy. Methotrexate causes osteoporosis by a combination of decreased bone formation and increased resorption. Many combination regimens for hematopoietic malignancies include high-dose glucocorticoids and methotrexate. Both affect bone formation and resorption. There are reports that patients with ALL who were treated with cisplatin or carboplatin developed bone pain, limping, and fracture and had bone mineral densities that averaged 2.3 standard deviations below normal.61 The known effects of platinum compounds on calcium homeostasis include hypomagnesemia, hypocalcemia, and renal calcium wasting. Adjuvant chemotherapy for breast cancer (usually involving 5-fluorouracil, cyclophosphamide, and doxorubicin or methotrexate) is associated with low bone mass.62 Hypogonadism secondary to cancer treatment appears to be a major factor in these adult patients with osteoporosis. BMT usually involves treatment with high-dose cytotoxic drugs, glucocorticoids, and immunosuppressive agents. In 24 patients who underwent BMT, profound effects on bone biomarkers were observed.63 The serum osteocalcin and alkaline phosphatase levels, indicators of bone formation, were low. N-telopeptides levels, indicative of bone resorption, were increased in these patients over a 12-week period.
A key point in the management of osteoporosis syndrome in cancer patients is the use of bone mineral density measurement to assess fracture risk and to monitor the effects of therapy. This measurement should be performed early in the course of the management of the malignancy so that appropriate preventive measures can be implemented. The oncologist using medications that are likely to decrease bone mass should consider active use of antiresorptive therapy (estrogen or SERMs, if appropriate, calcitonin, or bisphosphonates) to prevent bone loss rather than waiting for the development of a fracture syndrome.
Osteomalacia
Osteomalacia, a condition characterized by unmineralized bone matrix, is a rare complication of chemotherapy but should be considered in osteopenic patients and those with osteomalacic clinical syndrome (bone pain and proximal myopathy). The most common cause is a decrease in the serum calcium and/or phosphorus concentrations due to nutritional deficiency and renal wasting of phosphorus and calcium. Patients who have received chemotherapeutic agents that cause hypophosphatemia, hypomagnesemia, or hypocalcemia are particularly at risk. Investigation of the levels of serum ionized calcium, phosphorus, magnesium, and vitamin D metabolites should be included in the initial evaluation. Appropriate replacement therapy of these vitamins and minerals should be instituted once deficiencies have been identified. Other contributing factors include systemic acidosis and drugs, such as anticonvulsants and aluminum.58
Ifosfamide causes tubular damage leading to renal phosphate wasting, hypophosphatemia, and rickets/osteomalacia.64 The toxic effects of ifosfamide on renal tubular function include Fanconi’s syndrome in adults and children.65 Tubular damage is seen most commonly when ifosfamide is administered in doses of 50 g/m2 or more, or when it is used in combination with cisplatin.66 Rickets is reported most commonly in children. Estramustine, used in the treatment of prostate cancer, has been reported to increase bone resorption and at the same time cause hypocalcemia, hypophosphatemia, and secondary hyperparathyroidism.67
Adrenal Diseases
Adrenal Metastasis
Hematogenous metastasis to the adrenal glands is common, exceeded in frequency only by hematogenous metastasis to the lung, liver, and bone.68 Autopsies have documented that 9 to 27% of patients who died from malignant illness had adrenal metastasis, with bilateral involvement in one-half to two-thirds of patients with adrenal metastasis.
The presence of adrenal metastasis may have important implications for diagnostic and therapeutic planning. When patients with cancer have an adrenal mass but no evidence of metastasis elsewhere, it is vital to determine whether this mass represents a metastatic deposit or a separate, unrelated adrenal lesion. Recent advances in imaging techniques have allowed the antemortem identification of adrenal lesions, as part of the tumor-staging evaluation. The location of the adrenal glands in the perinephric fat allows the detection of almost all normal glands and contour-deforming masses less than 5 to 10 mm. Computed tomography (CT) has a sensitivity of 86%, specificity of 97%, and accuracy of 93% in the detection of adrenal masses.69 Adrenal cysts and myelolipomas have characteristic CT appearances. Characteristics on CT examination that suggest adrenal metastasis rather than primary adrenal disease include heterogeneity, contrast enhancement, bilaterality, and size greater than 3 cm.70
In the absence of other evidence of metastatic disease, definite diagnosis of the adrenal mass may be critical in determining the appropriate therapy for the cancer. Evaluation of a patient who has a malignant adrenal mass should include a history and physical examination to elicit evidence of adrenal insufficiency, Cushing’s syndrome, mineralocorticoid excess, or pheochromocytoma. Biochemical assessment should include a short ACTH stimulation test to rule out adrenal insufficiency. A 24-hour urine collection should be obtained to measure urinary free cortisol, aldosterone, catecholamines, and metanephrines. Pheochromocytoma must be excluded, especially if an operative procedure of any type is contemplated. It has been reported that one-half of the patients who had a clinically unsuspected pheochromocytoma had clinical deterioration or even death immediately following a non–adrenal-related surgical procedure.71
If the biochemical assessment for pheochromocytoma is negative, CT-guided fine-needle aspiration should be considered. This procedure is safe in most patients72 and has a sensitivity of 70 to 85% in detecting cancer.73,74 Magnetic resonance imaging (MRI) may be helpful in the diagnosis of pheochromocytoma. Functional scintigraphy using I131-6-iodomethyl-19-nor-cholesterol (NP-59) may be used in conjunction with CT and MRI to aid in the diagnosis of a unilateral adrenal mass greater than 2 cm.75 Concordant uptake of NP-59 by a mass that was detected by CT or MRI indicates the presence of an adrenal adenoma. Discordant uptake may be associated with adrenal metastasis.
Adrenal Insufficiency
Despite the relatively high prevalence of adrenal infiltration by many common cancers, clinically evident adrenal hypofunction occurs infrequently. It has been estimated that more than 80% of adrenal tissue must be destroyed before corticosteroid production, under both basal and stress conditions, is impaired.76 Because the clinical manifestations of adrenal insufficiency are nonspecific and overlap findings in cancer patients, a high index of suspicion is required to detect this treatable condition.77 The cachexia and weakness seen in patients with adrenal insufficiency can mimic the general wasting seen in patients with extensive metastatic disease. Electrolyte abnormalities can be easily explained by poor intake, malnutrition, side effects of chemotherapeutic agents, or paraneoplastic syndromes. Adrenal insufficiency may develop so gradually that it goes unnoticed.
About 20 to 30% of the patients with bilateral adrenal metastasis will develop adrenal insufficiency.77 These patients should all be evaluated by the ACTH stimulation test and should receive glucocorticoid and mineralocorticoid replacement therapy when adrenal insufficiency is suspected and until normal adrenal function is documented. Patients who are stable should receive 20 mg of hydrocortisone in the morning and 10 mg in the early afternoon. In the event of circulatory instability, sepsis, emergency surgery, or other major complications, stress dosages of parenteral glucocorticoid should be given (e.g., hydrocortisone succinate 100 mg intravenously every 8 hours).
Other causes of primary adrenal insufficiency in cancer patients include autoimmune adrenalitis, adrenal hemorrhage, and granulomatous diseases. Many cancer patients may be immunocompromised. For example, patients with leukemia or lymphoma or patients who have undergone BMT are immunocompromised. In these patients, infection of the adrenal glands by cytomegalovirus, mycobacteria, or fungi may lead to adrenal insufficiency. Adrenal insufficiency may also occur due to bilateral adrenalectomy. For instance, renal cell carcinoma often metastasizes to both adrenal glands, and radical nephrectomy is often performed with contralateral adrenalectomy.
Adrenal insufficiency may be drug induced. Etomidate,78 a common intravenous anesthetic, and ketoconazole, an antifungal drug, both inhibit the production of cytochrome P-450–dependent enzymes in the glucocorticoid synthetic pathway. Aminoglutethimide and metyrapone are drugs that inhibit enzymes in steroidogenesis and may cause adrenal insufficiency when used in the treatment of prostate, breast, and adrenocortical cancers. Mitotane, structurally related to the insecticide dichlorodiphenyltrichloroethane, has selective toxicity for normal and neoplastic adrenocortical cells. The biochemical mechanism of action for mitotane is unclear. Adrenal insufficiency is commonly observed when mitotane is administered in doses necessary to treat adrenocortical cancer; glucocorticoid replacement therapy is mandatory in such patients. Serum levels of steroid-binding protein have also been reported to increase two- to three-fold during mitotane therapy.9 Increased protein binding may lead to an increased daily requirement of glucocorticoids during replacement therapy. Suramin, recently proposed as an anticancer agent, on the basis of its activity against the tumor growth factors, may also cause adrenal insufficiency.
Secondary adrenal insufficiency because of metastasis to the pituitary or hypothalamus may also occur. The most common cause of secondary adrenal hypofunction, however, is exogenous glucocorticoid therapy which suppresses hypothalamic-pituitary adrenal excess. A prolonged course of therapy may lead to hypothalamic-pituitary suppression lasting for many months. Short periods of steroid therapy (i.e., 1, 2, or 4 weeks) in patients with leukemia and lymphoma suppress adrenal function for 2 to 4 days in most patients, and for longer in some patients. In patients who have received glucocorticoids for more than 2 weeks, a tapering period of 10 to 14 days should be considered. This is especially true for chemotherapy regimens that include high-dose glucocorticoids, such as those used in the treatment of acute leukemia and lymphoma. In addition, patients who have been treated within the past year with prolonged glucocorticoid courses should receive stress dosages of glucocorticoid, if acute medical or surgical complications occur (e.g., neutropenic fever with hypotension, acute typhlitis). Irradiation of the hypothalamic-pituitary region causes ACTH deficiency and secondary adrenal insufficiency in 19 to 42% of treated patients.79 This may occur as early as the first 2 years after radiotherapy, although the median time for occurrence is 5 years (see Figure 155.1). Several diagnostic approaches have been used to evaluate secondary adrenal insufficiency, including basal 8 am serum cortisol measurements and dynamic tests with 1 μg of synthetic ACTH (1 - 24), insulin-induced hypoglycemia, and metyrapone.
Disorders of Growth Hormone Secretion and Growth
Childhood cancer or its treatment commonly impairs growth. Medulloblastoma and ALL, common childhood malignancies, are frequently treated with cranial or craniospinal irradiation and/or chemotherapy. GH-deficiency and damage to the osseous growth plates are two common mechanisms of growth retardation.
Cranial irradiation may cause hypothalamic or pituitary dysfunction. The hypothalamus appears to be more radiosensitive than does the pituitary gland and may be damaged by lower radiation doses (< 40 Gy). Higher doses (> 40 Gy) are likely to damage both hypothalamic and pituitary function.80 Deficiency of one or more pituitary hormones following irradiation of the hypothalamic/pituitary area occurs in almost 100% of patients 5 years after irradiation (see Figure 155.1).
GH deficiency is the most frequently noted deficiency and often the first deficiency to arise after cranial irradiation. Isolated GH deficiency following irradiation is common, and the effects are dose related. At lower doses (20–24 Gy), the only effect may be an altered GH secretory pattern and subnormal response to insulin-induced hypoglycemia.81 With intermediate and higher doses, the GH response to arginine is impaired, and the frequency and amplitude of pulsatile GH secretion is decreased.82 At doses up to 30 Gy, abnormal GH secretion and growth retardation are observed in more than 35% of patients, necessitating GH treatment.83
In addition to growth retardation caused by GH deficiency, craniospinal or spinal irradiation for hematologic malignancy or central nervous system tumors and total body irradiation prior to BMT may cause two other effects. First, irradiation affects the growth plates in the vertebral bodies and in the pelvis and decreases vertebral growth. Second, irradiation causes resistance to GH or IGFs.
Children treated with chemotherapy for malignancy frequently have a period of reduced growth velocity, followed by a “catch-up” growth phase. Systemic illness seems to be the most important component of growth retardation in these children, although chemotherapy may play a significant role. Both growth velocity and height are lower in children who are treated with higher doses of chemotherapy and for a longer duration with combination chemotherapy than in those who receive regular therapy or less intensive chemotherapy. If there is no catch-up growth after 1.5 to 2 years, it is important to exclude GH deficiency.
In adults, GH deficiency is thought to cause decreased bone and muscle mass, lower exercise capacity, increased adipose tissue, fatigue, a poor sense of well-being, impaired myocardial function, and increased cardiovascular risks. GH replacement may be indicated to improve the patients’ quality of life and sense of well-being,84 but the concern over IGF-1–induced reactivation of malignant disease should be factored into the decision.
Disorders of Electrolyte/Mineral Metabolism
Hyponatremia
The syndrome of inappropriate antidiuretic hormone (SIADH) is characterized by hyponatremia. Low serum osmolality and inappropriately high urine osmolality in the absence of diuretics, heart failure, cirrhosis, adrenal insufficiency, and hypothyroidism are required for this diagnosis. In cancer patients, SIADH may be caused by vasopressin secreted by the tumors (e.g., up to 15% of small cell lung cancers), abnormal secretory stimuli (e.g., intrathoracic infection, positive pressure ventilation), or cytotoxicity affecting paraventricular and supraoptic neurons. It is also possible that chemotherapy-induced lysis of vasopressin-containing cancer cells leads to or worsens SIADH. Drug-induced renal salt wasting or tumor-induced salt wasting (mediated by atrial natriuretic peptide)85 can also cause hyponatremia, hypo-osmolality, 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 pituitary damage in the context of SIADH. There have been at least seven reports associating vincristine with SIADH, and some of these reports documented inappropriately high serum levels of vasopressin.86 Further evidence of a drug-induced effect is the recurrence of SIADH during subsequent therapy with vincristine.87 Vinblastine has also been reported to cause severe hyponatremia and SIADH.79 The presumed mechanism of vinca alkaloid–induced SIADH is paraventricular or supraoptic cell microtubular damage. Another possible mechanism for hyponatremia, identified in rodents treated with vincristine, is gastrointestinal sodium and water loss, leading to appropriate vasopressin secretion.88
Cyclophosphamide therapy has been associated with hyponatremia and SIADH. Autopsy findings in a case of fatal hyponatremia induced by cyclophosphamide (1,800 mg/m2) suggest that cyclophosphamide directly affects the hypothalamus.89 Those findings included infundibular necrosis, decreased intra-axonal secretory granules, and depletion of posterior pituitary vasopressin. Patients treated with lower doses of cyclophosphamide also develop hyponatremia, hypotonicity, urinary hypertonicity, and increased plasma vasopressin levels. Damage to the renal tubules and resulting defects in salt and water transport may be the major cause of hyponatremia associated with low-dose cyclophosphamide therapy.90
There are many reports of cisplatin-induced hyponatremia due to renal salt wasting.91 Several reports claim that cisplatin induces SIADH. The mechanism of cisplatin-induced hyponatremia is unclear, but it has been suggested that renal toxic effects of cisplatin, that is, decreased papillary solute content and maximal urinary osmolality, are the major factors rather than a direct effect of cisplatin on vasopressin secretion. In a majority of the patients who have elevated vasopressin levels, the vasopressin levels became suppressed after correction of hypovolemia.92 Therefore, the stimulus for vasopressin release in these patients was probably hypovolemia caused by renal salt wasting. The algorithm for evaluation and treatment of hyponatremia is outlined in Figure 155.3.
Hypernatremia
Hypernatremia secondary to central diabetes insipidus occurs frequently as a complication of neurosurgery or destruction by the tumor of the anterior pituitary or the related hypothalamic nuclei. Nephrogenic diabetes insipidus can result from the effects of ifosfamide or streptozocin on tubular reabsorption of water. Ifosfamide has broad nephrotoxic effects, although tubular damage predominates. Distal tubular defects develop in about half of patients treated with ifosfamide. However, frank nephrogenic diabetes insipidus leading to hypernatremia is not common.93 Streptozocin is also nephrotoxic. In addition to causing glomerular defects, which lead to nephrogenous (proteinuria) and tubular defects, which lead to (Fanconi’s syndrome), streptozocin therapy resulting in nephrogenic diabetes insipidus has been reported.94
Hypocalcemia
Hypocalcemia can also be caused by primary hypoparathyroidism after surgical procedures in the neck that sacrificed or damaged the parathyroid glands (e.g., total laryngectomy or total thyroidectomy). Hypocalcemia is also a common complication of chemotherapy.86 Hypocalcemia has been reported in 6 to 20% cisplatin-treated patients. Effects of cisplatin on renal tubular function, magnesium metabolism, bone resorption, and vitamin D metabolism may explain the hypocalcemia. Hypomagnesemia may cause a decrease in the secretion of parathyroid hormone and a reduction in the calcium-mobilizing effects of parathyroid hormone. Hypomagnesemia also inhibits formation of 1, 25-dihydroxyvitamin D3. Cisplatin may inhibit the mitochondrial function in the kidneys and thereby inhibit conversion of 25-hydroxyvitamin D3 to 1, 25-dihydroxyvitamin D3. In addition, cisplatin may have a direct inhibitory effect on bone resorption. Carboplatin therapy, similar to cisplatin therapy, is associated with a 16 to 31% incidence of hypocalcemia. Plicamycin (mithramycin) is an antitumor antibiotic that inhibits DNA-dependent RNA polymerase. This drug has a major effect on calcium metabolism. At a dose of 25 μg/kg, which is below the dose needed for antineoplastic effects, it inhibits bone resorption and lowers serum calcium concentration within 24 to 48 hours. Plicamycin inhibits basal and thyroid hormone–stimulated osteoclast function by a mechanism that is unclear. The effect of plicamycin on osteoclast function has made plicamycin useful for treating Paget’s disease of the bone and osteoclast-mediated hypercalcemia associated with malignancy. The hypocalcemic effect of plicamycin, as well as its hepatic and renal toxicity, has limited its usefulness as an anticancer agent. Dactinomycin is another antitumor antibiotic that blocks DNA-directed RNA synthesis, causing hypocalcemia in animals. Dactinomycin also abolishes the calcium-mobilizing effect of thyroid hormone, presumably by interferring with osteoclast-mediated bone resorption. Asymptomatic hypomagnesemia, hypocalcemia, and hypoparathyroidism have also been reported in patients treated with a combination of doxorubicin and cytarabine.
Hypercalcemia
The incidence of hypercalcemia in cancer patients is approximately 1%.95 Hypercalcemia in cancer patients is a poor prognostic sign associated with a short survival. No chemotherapy has been identified as a cause of hypercalcemia. However, there is a clear association between low-dose (usually 2 to 7.5 Gy) external beam irradiation of the head and neck area and subsequent development of primary hyperparathyroidism. There is a 2.5- to 3-fold increase in the incidence of primary hyperparathyroidism after low-dose irradiation of the neck.96 Among patients who developed primary hyperparathyroidism, 14 to 30% had prior exposure to radiation. The interval from irradiation to development of hyperparathyroidism ranges from 29 to 47 years. An association of hyperparathyroidism and radiation exposure from radioactive iodine treatment has also been reported.97 Concurrent thyroid cancer is seen in more than 30% of patients with radiation-induced hyperparathyroidism.89
Hypomagnesemia
Cisplatin causes morphologic changes and necrosis in the proximal tubule, an important site of magnesium reabsorption. Hypomagnesemia occurs in about 90% of patients treated with cisplatin,98 and 10% have symptoms of muscle weakness, tremors, and dizziness. Vigorous hydration and the use of osmotic diuretics, such as mannitol, may prevent renal failure but has little effect on renal magnesium wasting. Hypomagnesemia may persist long after cessation of cisplatin therapy. There are no large series in the literature addressing the incidence of hypomagnesemia, but the information from the manufacturer indicates that 60% of those taking cisplatin may be affected. Hypomagnesemia also occurs in patients who receive cyclophosphamide and carboplatin.
Disorders of Lipid Metabolism
Short-term lipid abnormalities caused by cancer therapy are generally of little clinical significance. However, major abnormalities can lead to acute complications. Interferons and vitamin A derivatives can cause significant increases in triglycerides, which can lead to pancreatitis. Interferons cause hypertriglyceridemia by increasing hepatic and peripheral fatty acid production99 and by suppressing hepatic triglyceride lipase.100 Long-term treatment with interferon-α2 causes hypertriglyceridemia in approximately one-third of patients, most of whom had previous serum lipid abnormalities. Serum triglyceride levels of more than 1,000 mg/dL are not unusual. In a case report, a therapeutic effect of diet and gemfibrozil was observed in the presence of continued interferon-α therapy.101 All-trans-retinoic acid (tretinoin) and other derivatives, for example, 13-cis-retinoic acid (isotretinoin), have been used in the treatment of several malignancies, most notably head and neck cancers and acute promyelocytic leukemia. The effects on lipid metabolism are well characterized, although the mechanism of development of lipid abnormalities is less clear. These abnormalities include hypertriglyceridemia caused by elevated very-low-density lipoprotein levels, and hypercholesterolemia caused by increased low-density lipoprotein level. Retinoid-induced hypertriglyceridemia has been reported to cause stroke102 and pancreatitis.103 Hyperlipidemia associated with retinoid therapy has been treated with gemfibrozil or fish oil.
Sexual Dysfunction
Radiation treatment to the head may cause a broad spectrum of hypothalamic-pituitary abnormalities (see Figure 155.1). The resultant thyroid, GH, or adrenal deficiency may indirectly affect reproductive function. Sexual function is directly affected by hyperprolactinemia or gonadotropin deficiency, commonly observed in patients treated with less than 40 Gy of cranial irradiation.
Hyperprolactinemia occurs commonly (up to 50% incidence within 2 years) following head and neck irradiation with a median hypothalamic-pituitary radiation exposure of 50 to 57 Gy.104 Radiation damage to the hypothalamus leading to a loss of the normal inhibition of prolactin secretion is the proposed mechanism of hyperprolactinemia. Hyperprolactinemia inhibits the secretion of gonadotropin by the pituitary and decreases the responsiveness of the pituitary to gonadotropin-releasing hormone, thereby causing secondary hypogonadism. Dopaminergic therapy could reverse this process, and it may be reasonable to proceed with a therapeutic trial, if other anterior pituitary functions are normal.
Gonadotropin deficiency occurs commonly (up to 61%) in patients treated with irradiation for brain tumors.79 In children, delayed puberty, absent menarche, and inadequate sexual development are significant problems related to gonadotropin deficiency. In adults, gonadotropin deficiency may cause sex hormone deficiency and sexual dysfunction. Sex hormone deficiency may alter libido and adversely affect bone and lipid metabolism. Sexual dysfunction and impotence need to be evaluated and appropriately treated. A diagnostic algorithm for the evaluation of sexual dysfunction is outlined in Figure 155.4.
Early or even precocious puberty has been reported in patients treated with combined chemotherapy and cranial irradiation for ALL105 or cranial irradiation for brain tumor.106 This phenomenon occurs more frequently in female patients. 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 sexual development with a short stature. Diagnosis and appropriate intervention are dependent on awareness of these clinical syndromes.
Gonadal dysfunction caused by anticancer therapy has been extensively reviewed.86,107 Cytotoxic chemotherapeutic agents and direct radiation exposure are common causes of infertility or hypogonadism in cancer survivors. The protective effect of gonadal suppression during anticancer therapy has been discussed, and its use and efficacy remain to be defined.107 Radiation damage to the gonads is dose dependent. Radiation exposure less than 0.08 Gy is associated with increased serum follicle-stimulating hormone (FSH) levels, indicative of spermatogenesis impairment. Doses less than 0.3 Gy may also cause temporary azoospermia, and doses less than 8 Gy (as are administered in BMT) usually cause permanent azoospermia. A decrease in sperm count after irradiation usually occurs after about 7 weeks. Recovery of spermatogenesis after irradiation depends on the dose applied. Radiation doses of 2 to 6 Gy may cause oligospermia for 5 or more years, with recovery not assured.
Leydig’s cells are more resistant to radiation than are the germ cells. Radiation doses between 0.075 and 6 Gy cause Leydig’s cell dysfunction, as indicated by elevated serum luteinizing hormone (LH) concentration. High-dose exposure (24 Gy) causes complete Leydig’s cell failure in patients. High-dose radiation (24 to 25 Gy) to the gonads, combined with chemotherapy causes primary hypogonadism in nearly all pubertal males. A testicular radiation dose of 30 Gy or more will cause primary hypogonadism in most adult patients.
Although it is more difficult to estimate the effects of ovarian radiation exposure, several generalizations can be made. In women over the age of 40 years, exposure to 6 Gy can cause ovarian failure and infertility; in younger women, a dose of 20 Gy may be required to produce permanent infertility; in prepubertal girls, a dose as low as 6 Gy may cause primary amenorrhea. It seems that the ovary is most susceptible to the effects of radiation in the prepubertal period and at the end of reproductive life.
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.108 The combined use of chemotherapy and radiation, especially regimens that contain alkylating agents, worsen the gonadotoxic effects of external beam irradiation in both sexes.
Procarbazine is a derivative of methylhydrazine and is a cell cycle–nonspecific agent. No data are available about its gonadotoxic effects as a single agent. Combination regimens for Hodgkin’s disease that include procarbazine are more gonadotoxic than are the same regimens without procarbazine. The high rate of gonadal toxicity leads to the recommendation that, if a suitable alternative exists, procarbazine is to be avoided in patients wanting to preserve fertility.109
Antimetabolites are cell cycle specific and exert few, if any, toxic effects on the ovaries. In male patients, these drugs may cause a reduced sperm count and alter sperm morphology and motility; these effects are generally reversible. 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. Gonadotoxicity has not been a major problem with this class of drugs when used alone, although gonadotoxicity does occur when antitumor antibiotics are used in combination with other drugs.
Animal studies suggest that interferon-α2 may affect ovarian function. Nonpregnant rhesus monkeys treated with 5 to 25 million IU /kg/d developed reversible menstrual cycle irregularity.110 Another cytokine, interleukin-2, is a potent inhibitor of testosterone synthesis by the Leydig’s cells in vitro,111 and it depresses both adrenal and testicular androgen production in human males.112 There are no reported studies of the effect of interleukin-2 on ovarian function, although such effects are suggested by the potential paracrine effect of interleukin in normal follicular maturation.113,114
The growing success of chemotherapy in the treatment of pediatric malignancies provides another reason for developing therapies that have low gonadotoxicity. The long-term effect of sex hormone deficiency on growth and development is significant, and preservation of fertility is an important goal of long-term survivors. Table 155.2 summarizes the incidence of gonadal failure associated with some common combination chemotherapy regimens.
References
- 1.
- Littley M D, Shalet S M, Beardwell C G. Radiation and hypothalamic-pituitary function. Baillieres Clin Endocrinol Metab. 1990;4:147–175. [PubMed: 2202287]
- 2.
- Sioutos P, Yen V, Arbit E. Pituitary gland metastases. Ann Surg Oncol. 1996;3:94–99. [PubMed: 8770309]
- 3.
- Sklar C A. Craniopharyngioma: endocrine abnormalities at presentation. Pediatr Neurosurg. 1994;21:18–20. [PubMed: 7841073]
- 4.
- Lam K S, Tse V K, Wang C. et al. Effects of cranial irradiation on hypothalamic-pituitary function—a 5 year longitudinal study in patients with nasopharyngeal carcinoma. Q J Med. 1991;78:165–176. [PubMed: 1851569]
- 5.
- Vassilopoulou-Sellin R, Klein M J. Physical growth parameters in children treated for malignant diseases. Int J Hematol Oncol. 1996;3:213–219.
- 6.
- Garnick M B, Larsen P R. Acute deficiency of thyroxine-binding globulin during L-asparaginase therapy. N Engl J Med. 1979;301:252–253. [PubMed: 109764]
- 7.
- Bartalena L, Martino E, Antonelli A. et al. Effect of the antileukemic agent L-asparaginase on thyroxine-binding globulin and albumin synthesis in cultured human hepatoma (HEP G2) cells. Endocrinology. 1986;119:1185–1188. [PubMed: 3015570]
- 8.
- Djurica S N, Plecas V, Milojevic Z. et al. Direct effects of cytostatic therapy on the functional state of the thyroid gland and TBG in serum of patients. Exp Clin Endocrinol. 1990;96:57–63. [PubMed: 2279526]
- 9.
- Beex L, Ross A, Smals A, Kloppenborg P. 5-fluorouracil-induced increase of total serum thyroxine and triiodothyronine. Cancer Treat Rep. 1977;61:1291–1295. [PubMed: 589596]
- 10.
- van Seters A P, Moolenaar A J. Mitotane increases the blood levels of hormone-binding proteins. Acta Endocrinol. 1991;124:526–533. [PubMed: 1903011]
- 11.
- Chopra I J. Euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab. 1997;82:329–334. [PubMed: 9024211]
- 12.
- McIver B, Gorman C A. Euthyroid sick syndrome: an overview. Thyroid. 1997;7:125–132. [PubMed: 9086580]
- 13.
- Grande C. Hypothyroidism following radiotherapy for head and neck cancer: multivariate analysis of risk factors. Radiother Oncol. 1992;25:31–36. [PubMed: 1410587]
- 14.
- Tami T A, Gomez P, Parker G S. et al. Thyroid dysfunction after radiation therapy in head and neck cancer patients. Am J Otolaryngol. 1992;13:357–362. [PubMed: 1443391]
- 15.
- Tamura K, Shimaoka K, Friedman M. Thyroid abnormalities associated with treatment of malignant lymphoma. Cancer. 1981;47:2704–2711. [PubMed: 7260863]
- 16.
- Constine L S, Donaldson S S, McDougall I R. et al. Thyroid dysfunction after radiotherapy in children with Hodgkin’s disease. Cancer. 1984;53:878–883. [PubMed: 6692289]
- 17.
- Devney R B, Sklar C A, Nesbit M E Jr. et al. Serial thyroid function measurements in children with Hodgkin’s disease. J Pediatr. 1984;105:223–227. [PubMed: 6747754]
- 18.
- Fuks Z, Glatstein E, Marsa G W. et al. Long-term effects on external radiation on the pituitary and thyroid glands. Cancer. 1976;37:1152–1161. [PubMed: 766957]
- 19.
- Joensuu H, Viikari J. Thyroid function after postoperative radiation therapy in patients with breast cancer. Acta Radiol Oncol. 1986;25:167–170. [PubMed: 3020879]
- 20.
- Boulad F, Bromley M, Black P. et al. Thyroid dysfunction following bone marrow transplantation using hyperfractionated radiation. Bone Marrow Transplant. 1995;15:71–76. [PubMed: 7742758]
- 21.
- Hancock S L, Cox R S, McDougall I R. Thyroid diseases after treatment of Hodgkin’s disease. N Engl J Med. 1991;325:599–605. [PubMed: 1861693]
- 22.
- Schimpff S C, Diggs C H, Wiswell J G. et al. Radiation-related thyroid dysfunction: implications for the treatment of Hodgkin’s disease. Ann Intern Med. 1980;92:91–98. [PubMed: 7350879]
- 23.
- Peerboom P F, Hassink E A, Melkert R. et al. Thyroid function 10-18 years after mantle field irradiation for Hodgkin’s disease. Eur J Cancer. 1992;28A:1716–1718. [PubMed: 1389492]
- 24.
- Sklar C A, Kim T H, Ramsay N K. Thyroid dysfunction among long-term survivors of bone marrow transplantation. Am J Med. 1982;73:688–694. [PubMed: 6753576]
- 25.
- Toubert M E, Socie G, Gluckman E. et al. Short- and long-term follow-up of thyroid dysfunction after allogeneic bone marrow transplantation without the use of preparative total body irradiation. Br J Haematol. 1997;98:453–457. [PubMed: 9266950]
- 26.
- Sutcliffe S B, Chapman R, Wrigley P F. Cyclical combination chemotherapy and thyroid function in patients with advanced Hodgkin’s disease. Med Pediatr Oncol. 1981;9:439–448. [PubMed: 6795433]
- 27.
- Ogilvy-Stuart A L, Shalet S M, Gattamaneni H R. Thyroid function after treatment of brain tumors in children. J Pediatr. 1991;119:733–737. [PubMed: 1941379]
- 28.
- Stuart N S, Woodroffe C M, Grundy R, Cullen M H. Long-term toxicity of chemotherapy for testicular cancer—the cost of cure. Br J Cancer. 1990;61:479–484. [PMC free article: PMC1971302] [PubMed: 2109631]
- 29.
- Heidemann P H, Stubbe P, Beck W. Transient secondary hypothyroidism and thyroxine binding globulin deficiency in leukemic children during polychemotherapy: an effect of L-asparaginase. Eur J Pediatr. 1981;136:291–295. [PubMed: 6167443]
- 30.
- Ferster A, Glinoer D, Van Vliet G, Otten J. Thyroid function during L-asparaginase therapy in children with acute lymphoblastic leukemia: difference between induction and late intensification. Am J Pediatr Hematol Oncol. 1992;14:192–196. [PubMed: 1510186]
- 31.
- Atkins M B, Mier J W, Parkinson D R. et al. Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. N Engl J Med. 1988;318:1557–1563. [PubMed: 3259674]
- 32.
- Krouse R S, Royal R E, Heywood G. et al. Thyroid dysfunction in 281 patients with metastatic melanoma or renal carcinoma treated with interleukin-2 alone. J Immunother Tumor Immunol Emphasis. 1995;18:272–278. [PubMed: 8680655]
- 33.
- Vassilopoulou-Sellin R, Sella A, Dexeus F H. et al. Acute thyroid dysfunction (thyroiditis) after therapy with interleukin-2. Horm Metab Res. 1992;24:434–438. [PubMed: 1427615]
- 34.
- Burman P, Totterman T H, Oberg K, Karlsson F A. Thyroid autoimmunity in patients on long term therapy with leukocyte-derived interferon. J Clin Endocrinol Metab. 1986;63:1086–1090. [PubMed: 2944910]
- 35.
- Baudin E, Marcellin P, Pouteau M. et al. Reversibility of thyroid dysfunction induced by recombinant alpha interferon in chronic hepatitis C. Clin Endocrinol (Oxf). 1993;39:657–661. [PubMed: 8287583]
- 36.
- Sherman S I, Gopal J, Haugen B R. et al. Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med. 1999;340:1075–1079. [PubMed: 10194237]
- 37.
- Kaplan M M, Garnick M B, Gelber R. et al. Risk factors for thyroid abnormalities after neck irradiation for childhood cancer. Am J Med. 1983;74:272–280. [PubMed: 6824006]
- 38.
- Petersen M, Keeling C A, McDougall I R. Hyperthyroidism with low radioiodine uptake after head and neck irradiation for Hodgkin’s disease. J Nucl Med. 1989;30:255–257. [PubMed: 2738654]
- 39.
- Wasnich R D, Grumet F C, Payne R O, Kriss J P. Graves’ ophthalmopathy following external neck irradiation for nonthyroidal neoplastic disease. J Clin Endocrinol Metab. 1973;37:703–713. [PubMed: 4800434]
- 40.
- Norman R J, Green-Thompson R W, Jialal I. et al. Hyperthyroidism in gestational trophoblastic neoplasia. Clin Endocrinol (Oxf). 1981;15:395–401. [PubMed: 7318191]
- 41.
- Hershman J M. Human chorionic gonadotropin and the thyroid: hyperemesis gravidarum and trophoblastic tumors. Thyroid. 1999;9:653–657. [PubMed: 10447009]
- 42.
- Pretorius H T, Katikineni M, Kinsella T J. et al. Thyroid nodules after high-dose external radiotherapy. Fine-needle aspiration cytology in diagnosis and management. JAMA. 1982;247:3217–3220. [PubMed: 7087060]
- 43.
- Hancock S L, McDougall I R, Constine L S. Thyroid abnormalities after therapeutic external radiation. Int J Radiat Oncol Biol Phys. 1995;31:1165–1170. [PubMed: 7713780]
- 44.
- Carr R F, LiVolsi V A. Morphologic changes in the thyroid after irradiation for Hodgkin’s and non-Hodgkin’s lymphoma. Cancer. 1989;64:825–829. [PubMed: 2743276]
- 45.
- Hallquist A, Hardell L, Degerman A. et al. Medical diagnostic and therapeutic ionizing radiation and the risk for thyroid cancer: a case-control study. Eur J Cancer Prev. 1994;3:259–267. [PubMed: 8061591]
- 46.
- Tucker M A, Jones P H, Boice J D Jr. et al. Therapeutic radiation at a young age is linked to secondary thyroid cancer. The Late Effects Study Group. Cancer Res. 1991;51:2885–2888. [PubMed: 1851664]
- 47.
- Nakhjavani M K, Gharib H, Goellner J R, van Heerden J A. Metastasis to the thyroid gland. A report of 43 cases. Cancer. 1997;79:574–578. [PubMed: 9028370]
- 48.
- Shimaoka K, VanHerle A J, Dindogru A. Thyrotoxicosis secondary to involvement of the thyroid with malignant lymphoma. J Clin Endocrinol Metab. 1976;43:64–68. [PubMed: 59731]
- 49.
- Eriksson M, Ajmani S K, Mallette L E. Hyperthyroidism from thyroid metastasis of pancreatic adenocarcinoma. JAMA. 1977;238:1276–1278. [PubMed: 578180]
- 50.
- Schein P S, O’Connell M J, Blom J. et al. Clinical antitumor activity and toxicity of streptozotocin (NSC-85998). Cancer. 1974;34:993–1000. [PubMed: 4371075]
- 51.
- Gillette P C, Hill L L, Starling K A, Fernbach D J. Transient diabetes mellitus secondary to L-asparaginase therapy in acute leukemia. J Pediatr. 1972;81:109–111. [PubMed: 5034858]
- 52.
- Almawi W Y, Tamim H, Azar S T. Clinical review 103: T helper type 1 and 2 cytokines mediate the onset and progression of type I (insulin-dependent) diabetes. J Clin Endocrinol Metab. 1999;84:1497–1502. [PubMed: 10323367]
- 53.
- Fabris P, Betterle C, Greggio N A. et al. Insulin-dependent diabetes mellitus during alpha-interferon therapy for chronic viral hepatitis. J Hepatol. 1998;28:514–517. [PubMed: 9551692]
- 54.
- Drachenberg C B, Klassen D K, Weir M R. et al. Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation. 1999;68:396–402. [PubMed: 10459544]
- 55.
- Jindal R M, Sidner R A, Milgrom M L. Post-transplant diabetes mellitus. The role of immunosuppression. Drug Safety. 1997;16:242–257. [PubMed: 9113492]
- 56.
- Vassilopoulou-Sellin R, Brosnan P, Delpassand A. et al. Osteopenia in young adult survivors of childhood cancer. Med Pediatr Oncol. 1999;32:272–278. [PubMed: 10102021]
- 57.
- Headley J A, Theriault R L, LeBlanc A D. et al. Pilot study of bone mineral density in breast cancer patients treated with adjuvant chemotherapy. Cancer Invest. 1998;16:6–11. [PubMed: 9474245]
- 58.
- Jones G, Sambrook P N. Drug-induced disorders of bone metabolism. Incidence, management and avoidance. Drug Safety. 1994;10:480–489. [PubMed: 7917076]
- 59.
- Mazanec D J, Grisanti J M. Drug-induced osteoporosis. Cleve Clin J Med. 1989;56:297–303. [PubMed: 2663221]
- 60.
- Schwartz A M, Leonidas J C. Methotrexate osteopathy. Skeletal Radiol. 1984;11:13–16. [PubMed: 6424236]
- 61.
- Atkinson S A, Fraher L, Gundberg C M. et al. Mineral homeostasis and bone mass in children treated for acute lymphoblastic leukemia. J Pediatr. 1989;114:793–800. [PubMed: 2785592]
- 62.
- Bruning P F, Pit M J, de Jong-Bakker M. et al. Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. Br J Cancer. 1990;61:308–310. [PMC free article: PMC1971401] [PubMed: 2310683]
- 63.
- Carlson K, Simonsson B, Ljunghall S. Acute effects of high-dose chemotherapy followed by bone marrow transplantation on serum markers of bone metabolism. Calcif Tissue Int. 1994;55:408–411. [PubMed: 7895177]
- 64.
- Brade W P, Herdrich K, Kachel-Fischer U, Araujo C E. Dosing and side-effects of ifosfamide plus mesna. J Cancer Res Clin Oncol. 1991;117:S164–S186. [PubMed: 1795007]
- 65.
- Garcia A A. Ifosfamide-induced Fanconi syndrome. Ann Pharmacother. 1995;29:590–591. [PubMed: 7663031]
- 66.
- Moncrieff M, Foot A. Fanconi syndrome after ifosfamide. Cancer Chemother Pharmacol. 1989;23:121–122. [PubMed: 2910509]
- 67.
- Taube T, Kylmala T, Lamberg-Allardt C. et al. The effect of clodronate on bone in metastatic prostate cancer. Histomorphometric report of a double-blind randomised placebo-controlled study. Eur J Cancer. 1994;30A:751–758. [PubMed: 7917532]
- 68.
- Abrams H, Spiro R, Goldstein N. Metastasis in carcinoma—one thousand autopsied cases. Cancer. 1950;3:74. [PubMed: 15405683]
- 69.
- Abrams H L, Siegelman S S, Adams D F. et al. Computed tomography versus ultrasound of the adrenal gland: a prospective study. Radiology. 1982;143:121–128. [PubMed: 7063713]
- 70.
- Hussain S, Belldegrun A, Seltzer S E. et al. CT diagnosis of adrenal abnormalities in patients with primary non-adrenal malignancies. Eur J Radiol. 1986;6:127–131. [PubMed: 3013634]
- 71.
- Platts J K, Drew P J, Harvey J N. Death from phaeochromocytoma: lessons from a post-mortem survey. J R Coll Physicians Lond. 1995;29:299–306. [PMC free article: PMC5401324] [PubMed: 7473324]
- 72.
- Nguyen G K, Akin M R. Fine needle aspiration cytology of the kidney, renal pelvis, and adrenal Clin Lab Med 199818429–459., vi. [PubMed: 9742378]
- 73.
- Katz R L, Patel S, Mackay B, Zornoza J. Fine needle aspiration cytology of the adrenal gland. Acta Cytol. 1984;28:269–282. [PubMed: 6587703]
- 74.
- de Agustin P, Lopez-Rios F, Alberti N, Perez-Barrios A. Fine-needle aspiration biopsy of the adrenal glands: a ten-year experience. Diagn Cytopathol. 1999;21:92–97. [PubMed: 10425045]
- 75.
- Francis I R, Smid A, Gross M D. et al. Adrenal masses in oncologic patients: functional and morphologic evaluation. Radiology. 1988;166:353–356. [PubMed: 3336710]
- 76.
- Cedermark B J, Sjoberg H E. The clinical significance of metastases to the adrenal glands. Surg Gynecol Obstet. 1981;152:607–610. [PubMed: 6261412]
- 77.
- Redman B G, Pazdur R, Zingas A P, Loredo R. Prospective evaluation of adrenal insufficiency in patients with adrenal metastasis. Cancer. 1987;60:103–107. [PubMed: 3581024]
- 78.
- Wagner R L, White P F, Kan P B. et al. Inhibition of adrenal steroidogenesis by the anesthetic etomidate. N Engl J Med. 1984;310:1415–1421. [PubMed: 6325910]
- 79.
- Constine L S, Woolf P D, Cann D. et al. Hypothalamic-pituitary dysfunction after radiation for brain tumors. New Engl J Med. 1993;328:87–94. [PubMed: 8416438]
- 80.
- Sklar C A, Constine L S. Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys. 1995;31:1113–1121. [PubMed: 7713777]
- 81.
- Blatt J, Bercu B B, Gillin J C. et al. Reduced pulsatile growth hormone secretion in children after therapy for acute lymphoblastic leukemia. J Pediatr. 1984;104:182–186. [PubMed: 6582247]
- 82.
- Shalet S M. Disorders of the endocrine system due to radiation and cytotoxic chemotherapy. Clin Endocrinol (Oxf). 1983;19:637–659. [PubMed: 6357555]
- 83.
- Shalet S M, Clayton P E, Price D A. Growth and pituitary function in children treated for brain tumours or acute lymphoblastic leukaemia. Hormone Res. 1988;30:53–61. [PubMed: 3074030]
- 84.
- Burman P, Broman J E, Hetta J. et al. Quality of life in adults with growth hormone (GH) deficiency: response to treatment with recombinant human GH in a placebo-controlled 21-month trial. J Clin Endocrinol Metab. 1995;80:3585–3590. [PubMed: 8530603]
- 85.
- Johnson B E, Damodaran A, Rushin J. et al. Ectopic production and processing of atrial natriuretic peptide in a small cell lung carcinoma cell line and tumor from a patient with hyponatremia. Cancer. 1997;79:35–44. [PubMed: 8988724]
- 86.
- Yeung S C, Chiu A C, Vassilopoulou-Sellin R, Gagel R F. The endocrine effects of nonhormonal antineoplastic therapy. Endocr Rev. 1998;19:144–172. [PubMed: 9570035]
- 87.
- Stuart M J, Cuaso C, Miller M, Oski F A. Syndrome of recurrent increased secretion of antidiuretic hormone following multiple doses of vincristine. Blood. 1975;45:315–320. [PubMed: 1054263]
- 88.
- Jojart I, Laczi F, Laszlo F A. et al. Hyponatremia and increased secretion of vasopressin induced by vincristine administration in rat. Exp Clin Endocrinol. 1987;90:213–220. [PubMed: 3428363]
- 89.
- Harlow P J, DeClerck Y A, Shore N A. et al. A fatal case of inappropriate ADH secretion induced by cyclophosphamide therapy. Cancer. 1979;44:896–898. [PubMed: 476599]
- 90.
- Bode U, Seif S M, Levine A S. Studies on the antidiuretic effect of cyclophosphamide: vasopressin release and sodium excretion. Med Pediatr Oncol. 1980;8:295–303. [PubMed: 7464688]
- 91.
- Anand A J, Bashey B. Newer insights into cisplatin nephrotoxicity. Ann Pharmacother. 1993;27:1519–1525. [PubMed: 8305788]
- 92.
- Hutchison F N, Perez E A, Gandara D R. et al. Renal salt wasting in patients treated with cisplatin. Ann Intern Med. 1988;108:21–25. [PubMed: 3337511]
- 93.
- Skinner R, Pearson A D, Price L. et al. Nephrotoxicity after ifosfamide. Arch Dis Child. 1990;65:732–738. [PMC free article: PMC1792439] [PubMed: 2386379]
- 94.
- Delaney V, de Pertuz Y, Nixon D, Bourke E. Indomethacin in streptozocin-induced nephrogenic diabetes insipidus. Am J Kidney Dis. 1987;9:79–83. [PubMed: 2949606]
- 95.
- Vassilopoulou-Sellin R, Newman B M, Taylor S H, Guinee V F. Incidence of hypercalcemia in patients with malignancy referred to a comprehensive cancer center. Cancer. 1993;71:1309–1312. [PubMed: 8382106]
- 96.
- Cohen J, Gierlowski T C, Schneider A B. A prospective study of hyperparathyroidism in individuals exposed to radiation in childhood. JAMA. 1990;264:581–584. [PubMed: 2366296]
- 97.
- Rosen I B, Palmer J A, Rowen J, Luk S C. Induction of hyperparathyroidism by radioactive iodine. Am J Surg. 1984;148:441–445. [PubMed: 6486309]
- 98.
- Stewart A F, Keating T, Schwartz P E. Magnesium homeostasis following chemotherapy with cisplatin: a prospective study. Am J Obstet Gynecol. 1985;153:660–665. [PubMed: 4061536]
- 99.
- Ehnholm C, Aho K, Huttunen J K. et al. Effect of interferon on plasma lipoproteins and on the activity of postheparin plasma lipases. Arteriosclerosis. 1982;2:68–73. [PubMed: 6174110]
- 100.
- Yamagishi S, Abe T, Sawada T. Human recombinant interferon alpha-2a (r IFN alpha-2a) therapy suppresses hepatic triglyceride lipase, leading to severe hypertriglyceridemia in a diabetic patient [letter] Am J Gastroenterol. 1994;89:2280. [PubMed: 7977268]
- 101.
- Berruti A, Gorzegno G, Vitetta G. et al. Hypertriglyceridemia during long-term interferon-alpha therapy: efficacy of diet and gemfibrosil treatment. A case report. Tumori. 1992;78:353–355. [PubMed: 1494811]
- 102.
- Fujiwara H, Umeda Y, Yonekura S. Cerebellar infarction with hypertriglyceridemia during all-trans retinoic acid therapy for acute promyelocytic leukemia. Leukemia. 1995;9:1602–1603. [PubMed: 7658733]
- 103.
- McCarter T L, Chen Y K. Marked hyperlipidemia and pancreatitis associated with isotretinoin therapy. Am J Gastroenterol. 1992;87:1855–1858. [PubMed: 1449157]
- 104.
- Samaan N A, Schultz P N, Yang K P. et al. Endocrine complications after radiotherapy for tumors of the head and neck. J Lab Clin Med. 1987;109:364–372. [PubMed: 3819573]
- 105.
- Quigley C, Cowell C, Jimenez M. et al. Normal or early development of puberty despite gonadal damage in children treated for acute lymphoblastic leukemia. N Engl J Med. 1989;321:143–151. [PubMed: 2501681]
- 106.
- Brauner R, Rappaport R. Precocious puberty secondary to cranial irradiation for tumors distant from the hypothalamo-pituitary area. Horm Res. 1985;22:78–82. [PubMed: 4029883]
- 107.
- Meistrich ML, Vassilopoulou-Sellin R, Lipshultz LI. Adverse effects of treatment: gonadal dysfunction. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer, principles and practice of oncology. 5th ed. New York: Lippincott-Raven Publishers; 1997. p. 2758–2773.
- 108.
- Chapman RM. Gonadal toxicity and teratogenicity. In: Perry MC, editor. The chemotherapy source book. Baltimore: Williams & Wilkins; 1992. p. 710–753.
- 109.
- Bokemeyer C, Schmoll H J, van Rhee J. et al. Long-term gonadal toxicity after therapy for Hodgkin’s and non-Hodgkin’s lymphoma. Ann Hematol. 1994;68:105–110. [PubMed: 8167175]
- 110.
- Trown P W, Wills R J, Kamm J J. The preclinical development of Roferon-A. Cancer. 1986;57:1648–1656. [PubMed: 3081245]
- 111.
- Guo H, Calkins J H, Sigel M M, Lin T. Interleukin-2 is a potent inhibitor of Leydig cell steroidogenesis. Endocrinology. 1990;127:1234–1239. [PubMed: 2167211]
- 112.
- Meikle A W, Cardoso de Sousa J C, Ward J H. et al. Reduction of testosterone synthesis after high dose interleukin-2 therapy of metastatic cancer. J Clin Endocrinol Metab. 1991;73:931–935. [PubMed: 1834690]
- 113.
- Takakura K, Taii S, Fukuoka M. et al. Interleukin-2 receptor/p55(Tac)-inducing activity in porcine follicular fluids. Endocrinology. 1989;125:618–623. [PubMed: 2787741]
- 114.
- Maccio A, Mantovani G, Turnu E. et al. Evidence that granulosa cells inhibit interleukin-1 alpha and interleukin-2 production from follicular lymphomonocytes. J Assist Reprod Genet. 1993;10:517–522. [PubMed: 8081089]
- Endocrine Complications - Holland-Frei Cancer MedicineEndocrine Complications - Holland-Frei Cancer Medicine
Your browsing activity is empty.
Activity recording is turned off.
See more...