Serum thyroid hormone-binding protein abnormalities

The levels of thyroid hormone-binding proteins [thyroxine-binding globulin (TBG), prealbumin, 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 thyroxine (T₄), but normal free T₄ levels.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 Low serum T₃ levels, which may be found in up to 70% of moderately to seriously ill cancer patients, are caused by 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.

In most patients with euthyroid sick syndrome, 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 in the context of euthyroid sick syndrome usually indicate a grave prognosis, with a mortality rate of more than 50%. Although it is generally accepted that thyroid hormone therapy has no benefit, in practice it is sometimes difficult to differentiate between the euthyroid sick syndrome and secondary hypothyroidism. Judicious replacement of T₄ at physiologic levels in these uncommon patients may be appropriate if there are no contraindications (e.g., active ischemic heart disease).

Hypothyroidism

Hyperthyroidism

Radiation-induced painless thyroiditis with hyperthyroxinemia is an uncommon side effect of external-beam radiotherapy to the head and neck area. Transient hyperthyroidism may occur as a result of inflammation and destruction of thyroid tissue with release of thyroglobulin (containing T₄ and T₃), and is usually followed by hypothyroidism. Transient hyperthyroidism has been reported after mantle radiotherapy in Hodgkin disease patients, and occurs usually within 18 months of treatment.³⁸ A low uptake of radioiodine in most of these cases suggests a diagnosis of silent thyroiditis, but some have Graves’ disease. In one series of Hodgkin disease patient treated with radiation, the risk of Graves’ disease in these patients was estimated to be at least 7.2 times that in a healthy population.¹⁵

Ophthalmopathy similar to that in Graves’ disease has been reported within 18–84 months of high-dose radiotherapy to the neck for lymphoma, breast cancer, and nasopharyngeal or laryngeal cancer. Ophthalmopathy may occur without hyperthyroidism and in the absence of the human leukocyte antigen-B8.³⁹ This suggests that radiation-induced thyroid injury may induce an autoimmune process that is similar to Graves’ disease.

There have also been examples of TKI-associated hyperthyroidism, including two deaths (sorafenib and sunitinib associated).⁴⁰ The presumed mechanism of hyperthyroidism is thyroiditis. Patients with severe hyperthyroidism should be treated aggressively for thyroid storm; consideration should be given to holding TKI therapy until the patient is stabilized in such cases.³⁴

Thyroid nodules and cancers

Low-dose radiation increases the risk of thyroid nodules and cancer. The association between thyroid cancer and low-dose irradiation has been extensively examined,⁴¹ and is discussed in the chapter about thyroid cancer (see 81).

Obesity and metabolic syndrome

Cancer treatments may lead to obesity and the metabolic syndrome.^42–44 The metabolic syndrome is a cluster of abnormalities consisting of central obesity, dyslipidemia, hyperglycemia, and hypertension that increases the risk of type 2 diabetes and cardiovascular disease. Obesity is a modifiable risk factor for carcinogenesis as well as cancer progression. The mechanisms by which obesity promotes cancer include: hyperinsulinemia due to insulin resistance, high IGF-1, adipokines, low adiponectin, increased production of estrogens by adipose tissue, and increased inflammation. Obesity in cancer survivors may place them at increased risk for poor disease outcomes.^{42, 45, 46} Obesity increases the risk of colorectal and genitourinary second primary cancers.⁴⁷ Although low levels of physical activity in cancer survivors can contribute to obesity, the pathophysiologic basis of the weight gain is unclear. As obesity is an adverse prognostic factor for many cancers and is a modifiable risk factor, secondary obesity after cancer treatment needs to be addressed.

Diabetes mellitus

Diabetes mellitus type 2 (DM2) is associated with an elevated risk of pancreatic, liver, colon, gastric, breast, and endometrial cancer.^48–53 Extensive epidemiologic data suggest important roles of diabetes in carcinogenesis^48–53 and cancer survival.⁵⁴ The strongest association is perhaps with pancreatic cancer.^55–59 Apart from the frequently coexisting obesity, the mechanisms by which diabetes promotes cancer include: hyperinsulinemia, high IGF-1, and hyperglycemia. Hyperglycemia per se has a promoting effect on cancer proliferation. In male, cancer survivors with a fasting serum glucose concentration ≥126 mg/dL had a higher relative risk for hepatopancreatobiliary second primary cancer.⁴⁷ Evidence-based guidelines for the management of DM2 in cancer patients to optimize patient survival are lacking.

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 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 streptozocin⁶⁰ or L-asparaginase⁶¹ 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-2 and interferons may cause toxicity to pancreatic β cells and lead to insulin-dependent diabetes.⁶² Tacrolimus, an immunosuppressive agent used to prevent graft-versus-host disease in BMT, also increases the incidence of diabetes, perhaps by damaging pancreatic β cells.⁶³ Patients who received allogenic BMT are likely to be receiving both glucocorticoids, cyclosporine A and tacrolimus, and are particularly at risk for developing diabetes mellitus.⁶⁴ 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, insulin will be needed in patients who are insulin deficient.

Osteoporosis

Four groups of adult patients are at particular risk for accelerated bone loss and osteoporosis: (i) patients with lymphoma, myeloma, or leukemia; (ii) women with breast cancer treated with cytotoxic chemotherapy frequently undergo an early menopause⁶⁵ and cannot receive estrogen-replacement therapy; (iii) postmenopausal women with estrogen-receptor positive breast cancer; and (iv) men with prostate cancer who are on antiandrogenic therapy and made hypogonadal. 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 hormone-related protein (PTHrP), lymphotoxin, interleukin-1, and interleukin-6] may contribute to bone loss. In most cases, it is not clear whether bone loss is caused by antineoplastic therapy or by the underlying disease process and its effects (including cachexia, malnutrition, poor calcium and vitamin D intake, or a combination of these). In patients with breast or prostate cancer, sex steroid hormone deficiency induced by therapy is the most important cause of bone loss. Bone loss is prominent in patients with several disorders (myeloma, leukemia, and lymphoma), affecting the hematopoietic cells, perhaps because of cytokine production and an intimate relationship of hematopoietic cells with bone-forming cells or the use of high-dose or prolonged therapy with glucocorticoids.

A number of drugs can induce osteoporosis.⁶⁶ 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).⁶⁷ The osteoporosis improves significantly after cessation of methotrexate therapy. Longitudinal study of ALL patients showed that the leukemic process, high-dose glucocorticoids, and hypomagnesemia (owing to renal wastage following cyclical glucocorticoid and nephrotoxic chemotherapy or antiinfective agents) contributed to the impairment of calcium and vitamin D metabolism and decrease in bone mass at different stages of the treatment process.⁶⁸ Adjuvant chemotherapy for breast cancer (usually involving 5-fluorouracil, cyclophosphamide, and doxorubicin or methotrexate) is associated with low bone mass in premenopausal patients.⁶⁹ Bone loss during chemotherapy is substantial and may lead to increased risk of fracture. Posttreatment hypogonadism appears to be a major factor in these adult women with osteoporosis. While tamoxifen has a slight protective effect on bone loss, the opposite is true for aromatase inhibitors. BMT usually involves treatment with high-dose cytotoxic drug, glucocorticoids, and immunosuppressive agents. In 24 patients who underwent BMT with high-dose chemotherapy, profound effects on bone biomarkers were observed.⁷⁰

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.⁷¹ 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.

A key point in the management of the osteoporosis syndrome in cancer patients is the use of bone mineral density measurement (e.g., by dual-energy X-ray absorptiometry) to assess fracture risk and to monitor the effects of therapy. This measurement should be performed early in the course of management of the malignancy so that appropriate preventive measures can be implemented. The oncologist who is prescribing medications that are likely to decrease bone mass should consider active use of bisphosphonates (e.g., alendronate, risedronate, ibandronate, or zoledronate), calcitonin, selective estrogen-receptor modulators (SERMs), or denosumab, in addition to a daily intake of 1200–1500 mg elemental calcium and vitamin D supplementation. Bisphosphonates and denosumab are effective therapies for prevention of bone loss. While 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 or teriparatide therapy to prevent bone loss should be considered, rather than waiting for the development of a fracture syndrome.

Another key point is correction of abnormal mineral and vitamin D metabolism by dietary supplements. Nutritional deficiency in teenagers and young adults results in lower bone mass. Treatment of hypocalcemia, hypomagnesemia, and vitamin D deficiency is integral to the successful therapy of osteoporosis in cancer patients. Recent studies document that clinically relevant vitamin D deficiency is present in 50% of the normal population; the percentage is almost certainly higher in patients undergoing cancer therapy.

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 caused by 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.⁶⁶ Tumor-induced osteomalacia will be addressed in the section that follows discussing paraneoplastic syndromes.

Ifosfamide causes tubular damage leading to renal phosphate wasting, hypophosphatemia, and rickets/osteomalacia.⁷² The toxic effects of ifosfamide on renal tubular function include Fanconi syndrome in adults and children. 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.⁷³ 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.⁷⁴

Adrenal metastasis

Hematogenous metastasis to the adrenal glands is common, exceeded in frequency only by hematogenous metastasis to the lung, liver, and bone.⁷⁵ Autopsies have documented that 9–27% 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 important to determine whether this mass represents a metastatic tumor or a separate, unrelated adrenal lesion. Recent advances in imaging techniques have allowed the identification of adrenal lesions antemortem 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 as small as 5–10 mm. Computed tomography (CT) has a sensitivity and specificity in the detection of adrenal masses. Characteristics on CT examination that suggest adrenal metastasis rather than primary adrenal disease include heterogeneity, contrast enhancement, bilaterality, and size >3 cm.⁷⁶

Without other evidence of metastatic disease, whether the adrenal mass is actually a metastatic tumor is critical information 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 syndrome, mineralocorticoid excess, or pheochromocytoma. Biochemical assessment should include a short ACTH stimulation test with measurements of serum cortisol to rule out adrenal insufficiency. A 24-h urine collection should be obtained to measure urinary free cortisol, aldosterone, catecholamines, and metanephrines. Pheochromocytoma must be excluded, especially if there is hypertension, or 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.⁷⁷

If the biochemical assessment for pheochromocytoma is negative, CT-guided fine-needle aspiration should be considered. This procedure has a sensitivity of 85% in detecting cancer.⁷⁸

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Aberrant signaling pathways in cancer Disparities in cancer care Monoclonal serotherapy Neoplasms in acquired immunodeficiency syndrome Chemical carcinogenesis Infections in patients with cancer

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