Metabolic Disorders in the Cancer Patient

Irene M. O’Shaughnessy

Albert L. Jochen

Endocrine disorders occur in individuals with advanced malignancy under various circumstances. Cancer may produce effects through the excess production of hormones, cytokines, and growth factors—the so-called paraneoplastic syndromes (Table 35.1). Conversely, cancer or its metastases may interfere with the normal function of endocrine organs, resulting in hormone-deficiency states. Most commonly, patients may have a metabolic disorder such as diabetes, thyroid dysfunction, or hyperparathyroidism that predates the diagnosis of their malignancy or is diagnosed incidentally during the course of their malignancy. This chapter discusses the most common paraneoplastic syndromes and hormone-deficiency states associated with malignancy, as well as the management of diabetes and thyroid disease in the patient with cancer.

Endocrine Paraneoplastic Syndromes

Inappropriate Antidiuresis

The differential diagnosis of hyponatremia in the patient with cancer is similar to that in the general population and includes hepatic and cardiac failure, renal disease, overdiuresis, factitious hyponatremia associated with hyperglycemia, and other conditions. In the syndrome of inappropriate antidiuretic hormone (SIADH), hyponatremia results from the overproduction of arginine vasopressin (AVP) by the posterior pituitary gland in response to a stimulus by tumor cells, by the actual production of AVP or AVP-like peptides by tumor cells, or as a side effect of medications that are able to stimulate AVP production.

Epidemiology

The most common malignancies causing SIADH are small cell lung cancer and carcinoid tumors; SIADH is also seen with cancers of the esophagus, pancreas, duodenum, colon, adrenal cortex, prostate, thymomas, and lymphomas. In one series, the incidence of clinically significant SIADH was 9% among 523 patients with small cell lung cancer. A larger fraction of patients had milder abnormalities in AVP metabolism without hyponatremia. Therefore, approximately one half of patients had abnormal renal handling of water loads that were subclinical (1, 2). Another study found that 41% of patients with all types of lung cancers and 43% of patients with colon cancer had significantly elevated levels of AVP without evidence of clinically significant SIADH (3). Hyponatremia is also a common electrolyte disorder in patients hospitalized with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC). Often it is associated with gastrointestinal losses or SIADH and an increase in morbidity and mortality (4).

Clinical Features

The clinical features of hyponatremia depend on the degree of hyponatremia and the rate of its development. Most patients with chronic hyponatremia are asymptomatic. Generally, symptoms do not occur until the serum sodium falls below 115–120 mEq per L (5). When they occur, the signs and symptoms of SIADH are caused by water intoxication (i.e., hypo-osmolality and hyponatremia) and are manifested as confusion, lethargy, seizures, or coma. Occasionally, patients may present with focal neurologic deficits.

Diagnosis

Because most cases of SIADH are asymptomatic, the diagnosis is usually first suspected by noting a low serum sodium on routine chemistries. Other causes of hyponatremia, such as hypovolemia, hypervolemia (occurring in renal or hepatic disease or cardiac failure), hypothyroidism, and adrenal insufficiency, must be excluded before the diagnosis of SIADH can be considered. Urine chemistries show urinary osmolality that is greater than serum osmolality and a high urinary sodium concentration (Table 35.2). Medications commonly used by patients with cancer associated with SIADH include morphine sulfate, vincristine sulfate, cyclophosphamide, phenothiazines, and tricyclic antidepressants. Most drugs cause SIADH by stimulating posterior pituitary secretion of AVP.

Treatment

The treatment of SIADH is determined by the rate of development of hyponatremia and the presence of neurologic sequelae (Table 35.3). If the patient is symptomatic and has a serum sodium level below 130 mEq per L, fluid restriction to 800–1000 mL per 24 hours is effective in slowly raising serum osmolality over a period of 3–10 days. Acute hyponatremia with neurologic symptoms has a mortality rate of 5–8% and warrants more aggressive treatment. For patients with
more severe hyponatremia, the intravenous administration of hypertonic saline (3% saline at a rate of 0.1 mg/kg/minute) and furosemide may be necessary (6). Careful monitoring of vital signs and urinary losses of sodium and potassium is indicated. Rapid correction of severe hyponatremia has been associated with central pontine myelinosis, which presents with quadriparesis and bulbar palsy 1–2 days after hyponatremia is corrected. A safe rate of correction in severe hyponatremia is 0.5–1.0 mEq/L/hour until the sodium concentration reaches 125 mEq per L (7, 8).

Table 35.1 Common Paraneoplastic Syndromes

Syndrome	Tumor type
Inappropriate antidiuresis (hormone vasopressin)	Lung cancer, all types
Cushing’s syndrome (adrenocorticotropic hormone, corticotropic hormone)	Lung cancer, all types
Hypocalcemia	Bone metastases
Hypophosphatemia (“phosphatonin”)	Mesenchymal tumors
Hyperthyroidism (human chorionic gonadotropin)	Lung cancer, all types
Gynecomastia (estrogens, follicle-stimulating hormone, luteinizing hormone)	Lung cancer, all types
Calcitoninemia (calcitonin)	Medullary carcinoma of the thyroid, lung cancer, breast cancer
Acromegaly (growth hormone, growth hormone–releasing hormone)	Carcinoids, pheochromocytoma, pancreatic cancer

Fluid restriction is not feasible in some patients who require long-term treatment of SIADH. In these patients, medications, including demeclocycline hydrochloride, lithium carbonate, and urea, have been tried. Demeclocycline is the drug of choice and causes partial nephrogenic diabetes insipidus by inhibiting the formation of AVP-induced cyclic adenosine monophosphate in distal tubules. It is initially administered orally in divided doses of 900–1200 mg per day and then reduced to maintenance doses of 600–900 mg per day. Side effects are mainly gastrointestinal, although hypersensitivity and nephrotoxicity can occur. Similar to demeclocycline hydrochloride, lithium carbonate also causes a reversible, partial form of nephrogenic diabetes insipidus but is less effective. Urea acts as an osmotic diuretic and allows the patient to maintain a normal fluid intake. Urea can be administered intravenously or orally. When given by mouth, the usual dosing is 30 g of urea dissolved in 100 mL of orange juice or water once daily (9).

Cushing’s Syndrome

Endogenous Cushing’s syndrome is due to one of three causes: overproduction of glucocorticoid by a primary adrenal neoplasm, excessive production of adrenocorticotropic hormone (ACTH) by a pituitary adenoma, or a paraneoplastic syndrome in which either ACTH or corticotropin-releasing hormone (CRH) are produced ectopically by the tumor. A number of tumors are capable of producing ACTH, its prohormone “big ACTH,” or proopiomelanocortin (POMC) (Table 35.4). The POMC gene is located at p23 on the short arm of chromosome 2 near N-myc oncogene at p24. Normally the expression of the POMC gene is influenced by glucocorticoids, which suppress transcription, and CRH, which stimulates transcription through cyclic adenosine monophosphate. The activation of alternative steroid-insensitive promoters may result in ectopic ACTH production that is insensitive to glucocorticoid suppression. Pituitary cells and some tumors produce the normal 1200-base mRNA transcript; however, some nonpituitary tissues produce either a larger or smaller POMC mRNA transcript. Alternative post-transcription processing of POMC gives rise to a large number of biologically active peptides in addition to ACTH. These include pro-ACTH and a number of different peptides containing melanocyte-stimulating hormone (MSH) (α-MSH, ACTH, pro-ACTH, β-MSH, τ-lipotropin, β-lipotropin, τ-MSH, N-POMC, pro-τ-MSH), all of which can lead to generalized hyperpigmentation (10, 11). Radioimmunoassays differ in their abilities to detect aberrant ACTH. The immunoradiometric assay for ACTH is able to distinguish between ACTH and its larger precursors, pro-ACTH, and POMC (12).

Table 35.2 Diagnosis of Syndrome of Inappropriate Antidiuresis

Plasma sodium level below 135 mEq/L

Urine osmolality greater than serum osmolality

Elevated urine sodium (>20 mEq/L)

Normal extracellular fluid volume

Rule out other causes of euvolemic hyponatremia

Epidemiology

Ectopic ACTH is most frequently secreted by lung carcinomas. A number of other tumor types are also capable of producing this syndrome (Table 35.4). In the general population, approximately 65% of patients with Cushing’s syndrome have pituitary adenomas producing ACTH (Cushing’s disease), 20% have primary adrenal tumors, and 14% have ectopic ACTH. Therefore, ectopic ACTH production is the least common of the three major causes in the general population.

Clinical Features of Ectopic Adrenocorticotropic Hormone Syndrome

Manifestations of the ectopic ACTH syndrome include hypokalemia, hyperglycemia, edema, muscle weakness (especially proximal) and atrophy, hypertension, and weight loss. Features
typically seen in long-standing pituitary or adrenal Cushing’s syndrome (e.g., central obesity, plethoric facies, cutaneous striae, “buffalo hump,” and hyperpigmentation) are less common in highly malignant tumors such as small cell lung carcinoma but occur more frequently in more indolent tumors such as carcinoids, thymomas, and pheochromocytomas.

Table 35.3 Usual Treatment of Hyponatremia

Treatment	Dosage	Uses
Fluid restriction	800–1000 mL limit/24 h	Serum sodium <130 mEq/L and symptomatic
		Acute and chronic hyponatremia
Hypertonic saline (3% saline)	0.1 mg/kg/min	Rarely used
		Acute severe hyponatremia (mental status changes, coma)
Demeclocycline	Initial dose: 900–1200 mg/d in divided doses	Chronic hyponatremia
	Maintenance: 600–900 mg/d
Lithium carbonate (rarely used)	600–900 mg p.o. daily	Chronic hyponatremia
		Significant toxicity
Urea (rarely used)	30 g in 100 mL orange juice or water daily	Chronic hyponatremia

Diagnosis

The biochemical diagnosis of Cushing’s syndrome is suggested by an elevated 24-hour urinary-free cortisol (>100 μg per 24 hours). The other principal screening test is the overnight low-dose dexamethasone suppression test. The test is positive when 1 mg of dexamethasone given at midnight is unable to suppress the following 8:00 AM cortisol to <5 μg per dL. Failure of cortisol to suppress after high-dose dexamethasone (8 mg at midnight) suggests either ectopic ACTH or a primary adrenal tumor (13). These two are differentiated by measuring plasma ACTH. In primary adrenal tumors, ACTH levels are below 20 pg per mL, whereas in ectopic ACTH levels are generally >100–200 pg per mL and frequently are elevated above 1000 pg per mL. Inferior petrosal sinus sampling of ACTH is useful in confirming the diagnosis of pituitary Cushing’s syndrome (14), but it is rarely indicated in the patient with advanced malignancy secreting ectopic ACTH.

Difficulties arise in differentiating those rare tumors producing ectopic CRH from the more common ectopic ACTH production; CRH stimulates release of pituitary ACTH. The clinical presentation and biochemical results are identical for ectopic CRH and ACTH. The prognosis and therapy are identical for the two disorders.

Table 35.4 Tumors Associated With Ectopic Adrenocorticotropic Hormone/Corticotropic Hormone Syndrome

Small cell lung carcinoma

Thymoma

Pancreatic islet cell tumor

Carcinoid tumors (lung, gut, pancreas, ovary)

Medullary carcinomas of the thyroid

Pheochromocytomas

Treatment of Ectopic Adrenocorticotropic Hormone Syndromes

Where possible, the treatment of ectopic ACTH syndrome should be directed primarily at the tumor. Palliative treatment of Cushing’s syndrome involves inhibition of steroid synthesis. Drugs successfully used include aminoglutethamide, metyrapone, mitotane, ketoconazole, and octreotide acetate (15). Rarely, bilateral adrenalectomy is considered.

Aminoglutethamide blocks the first step in cortisol biosynthesis. At higher doses, it inhibits production of glucocorticoids, mineralocorticoids, and androgens, whereas at lower doses it primarily inhibits the conversion of androgens to estrogens, contributing to its efficacy in the treatment of postmenopausal breast cancer. At the higher doses required to treat ectopic ACTH syndrome, many patients experience sedation, ataxia, and skin rashes. Metyrapone inhibits 11-β-hydroxylase and 18-hydroxylase, resulting in adrenal atrophy and necrosis. It is a toxic drug with significant gastrointestinal side effects, including anorexia, nausea, vomiting, and diarrhea, and central nervous system (CNS) toxicity, including lethargy and somnolence. For these reasons, it is used as second-line therapy.

Ketoconazole acts mainly on the first step of cortisol biosynthesis but also inhibits the conversion of 11-deoxycortisol to cortisol. It can cause rare but significant reversible hepatotoxicity and is associated with nausea and vomiting.

Octreotide acetate, a long-acting analog of somatostatin, can reduce ectopic ACTH secretion. It must be injected, is expensive, and is only partially effective in most patients. The efficacy of these treatments can be monitored by 24-hour urine cortisol measurements. As levels return to normal and then fall below normal, replacement with glucocorticoids and mineralocorticoids in physiologic doses similar to patients with Addison’s disease is frequently necessary. In cases of stress, these patients require stress doses of glucocorticoids (e.g., hydrocortisone 100 mg intravenously every 8 hours).

Hypercalcemia

Malignancies are frequently associated with disorders of calcium metabolism, including hypercalciuria and hypercalcemia, and are the most common cause of hypercalcemia in hospitalized patients. After primary hyperparathyroidism, they are the second most common cause overall. Malignancies produce hypercalcemia by one of three mechanisms. Neoplasms may secrete parathyroid hormone-related protein (PTHrP), which,
although distinct from PTH, has sufficient amino-terminal homology with PTH to mimic its effects on PTH receptors. This is the most common mechanism subserving malignancy-associated hypercalcemia, accounting for 80% of all cases (16). PTHrP is produced most commonly by squamous cell cancers (head, neck, lung, and esophagus), renal cell carcinoma, and breast cancer. Metastases with extensive localized bone destruction constitute the second most common mechanism of tumor-related hypercalcemia. Finally, hematologic neoplasms (e.g., multiple myeloma and lymphoma) cause hypercalcemia by releasing osteoclast-activating cytokines, and occasionally (in lymphomas), 1,25-dihydroxy-vitamin D. Patients with malignancy may also have hypercalcemia from a cause unrelated to their cancer. In particular, hypercalcemia from primary hyperparathyroidism is a common disorder in the general population.

Most cancer-related hypercalcemia complicates an advanced malignancy that is already diagnosed and associated with a poor prognosis. Rarely, the tumor is occult and requires an extensive workup to unmask it. The features of advanced cancer typically dominate the presentation, with weight loss, anorexia, fatigue, and pain from bone metastases. The hypercalcemia is more acute and severe (often >14 mg/dL) than is typical for primary hyperparathyroidism and is more likely to cause nausea, vomiting, dehydration, and changes in mentation (hypercalcemic crisis). When possible, treatment is directed toward the primary tumor. Hypercalcemic crisis is treated medically (Table 35.5). Patients with severe hypercalcemia are typically dehydrated, with resultant diminished urine output. This further exacerbates the hypercalcemia by reducing the ability of the kidneys to eliminate calcium in the urine. Therefore, the first step in treating hypercalcemia is vigorous hydration to reestablish urine output and calciuresis. After adequate rehydration, loop diuretics such as furosemide can be used to further promote a calciuric diuresis. This therapy has the advantage of working rapidly (over hours) but is limited by incomplete calcium-lowering effects and the need for intravenous fluids. Calcitonin injections are often used concomitantly with hydration because of their rapid action, although their efficacy is somewhat limited by modest calcium-lowering effects and by tachyphylaxis. Intravenous infusion of a bisphosphonate, either pamidronate or zoledronate, is the most consistently effective treatment of cancer-related hypercalcemia, although the infusion has a delay in of 1–2 days in the onset of action. A single infusion will normalize calcium levels in most patients with a persistent duration of action lasting a few weeks to several months. Increased bone resorption by PTHrP-activated osteoclasts is the mechanism subserving most cancer-related hypercalcemia and intravenous bisphosphonates effectively block this pathway. Therefore, the usual therapy in hypercalcemic crisis is to begin rapid onset, partially effective therapy with hydration and calcitonin, while giving an infusion of a bisphosphonate that will have potent calcium-lowering effects in a day or two. Other therapies are used in selected cases of hypercalcemia. For example, glucocorticoids are useful calcium-lowering agents in hematologic malignancies and in hypercalcemia mediated by vitamin D intoxication. Many other therapies, commonly used in the past, have been supplanted by the safety and potency of bisphosphonates. These include intravenous and oral phosphates, gallium nitrate, plicamycin, and indomethacin.

Hypocalcemia

Hypocalcemia is an uncommon paraneoplastic syndrome occurring primarily in patients with bony metastases. It occurs most commonly in association with osteoblastic metastases of the breast, prostate, and lung; its incidence is approximately 16% (17). Tetany is a rare complication of tumor-associated hypocalcemia. The etiology of the hypocalcemia is not understood. Ectopic calcitonin secretion from the underlying tumor has been rarely implicated. Acute hypocalcemia is treated by i.v. calcium gluconate or calcium chloride (Table 35.6). Vitamin D and calcium supplements are the therapeutic mainstays of all forms of chronic hypocalcemia.

Table 35.5 Usual Treatment of Hypercalcemic Crisis

Treatment	Dosage	Advantages	Disadvantages
Rehydration	As needed	Rapid action	None
Saline diuresis (optional)	150–200 mL/h of normal saline with or without 40 mg/d furosemide	Rapid action	Partial response, risk of fluid overload
Calcitonin (optional)	200 units SQ q 6 h	Rapid action	Partial response, tachyphylaxis
Pamidronate	60 or 90 mg i.v. over 4 h	Potent, normalizes calcium in over 90% of cases. Prolonged response.	1–2 day delay in action
Zoledronate	4 mg i.v. over 30 min	Potent, normalizes calcium in over 90% of cases. Prolonged response.	1–2 day delay in action
Prednisone (in select cases)	60 mg daily	Suitable for oral outpatient therapy	Effective only in select patients, for example, some hematologic malignancies

Oncogenic Hypophosphatemic Osteomalacia

Oncogenic hypophosphatemic osteomalacia, an acquired form of adult-onset, vitamin D–resistant rickets, is associated with mesenchymal tumors, often benign, that occur in soft tissues or bones (18). These tumors are also referred to as ossifying mesenchymal tumors, giant cell tumors of bone, sclerosing hemangioma, or cavernous hemangioma. This syndrome has been rarely reported with other cancers, such as lung and prostate. The clinical syndrome can precede the
discovery of the tumor by several years. Clinical and laboratory features include osteomalacia, severe phosphaturia, renal glycosuria, hypophosphatemia, normocalcemia (normal parathyroid hormone levels), and increased alkaline phosphatase. The proposed mechanisms for this syndrome include inhibition of the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D and through a substance produced by the tumor with a phosphaturic effect, “phosphatonin.” A candidate gene for “phosphatonin” has recently been described—fibroblastic growth factor 23 (19). Treatment is directed at surgical resection of the underlying tumor. When this is not possible, treatment with high doses of vitamin D and phosphate is often required.

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