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Glucose Metabolism Disorders
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Serum glucose is under continuous complex regulation. Many processes can affect glucose levels, including gut absorption, cellular uptake, gluconeogenesis, and glycogenolysis. Multiple hormones also play important roles in overall glucose homeostasis, including insulin, glucagon, growth hormone (GH), cortisol, somatostatin, and incretins.
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Glucocorticoids are frequently used with many chemotherapy protocols and can have profound effects on glucose levels by increasing insulin resistance. Glucocorticoids can unmask preexisting prediabetic states by precipitating overt diabetes or make diabetes more difficult to control. The severity may range from asymptomatic hyperglycemia to nonketotic hyperosmolar coma. Most patients taking glucocorticoids with elevated glucose require insulin therapy to achieve blood glucose control, especially when given high-dose steroids. Long-acting and intermediate-acting insulin formulations are often combined with mealtime rapid-acting or short-acting insulins. Currently, there emerging studies about the management of steroid-induced diabetes mellitus in cancer patients by using multiple daily injections including mealtime short-acting insulin to counteract postprandial glucose excursions. Recent concerns about the promotion of malignancy by the mitogenic effect of insulin (1) and especially insulin analogs (2) that cross-activate insulin-like growth factor 1 (IGF-1) receptors (3), in combination with conflicting clinical study results on insulin glargine and cancer, have brought attention to the gap in knowledge about proper diabetes management for maximization of survival in cancer patients and survivors. A large cohort study showed that insulin analogs including insulin glargine are associated with a lower risk of cancer in general than human insulin (4).
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Mammalian target of rapamycin (mTOR) inhibitors, L-asparaginase, streptozocin, and interferon-α (IFN-α) have also been associated with impaired glucose homeostasis and frank diabetes mellitus (5).
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Phosphoinositide-3 (PI3) kinase/Akt/mTOR pathway–targeted therapy can cause hyperglycemia. Inhibition of this pathway results in peripheral insulin resistance, increased gluconeogenesis, and hepatic glycogenolysis (5). Everolimus, a tyrosine kinase inhibitor, is used in patients with advanced breast cancer, progressive neuroendocrine tumors of pancreatic origin, and advanced renal cell carcinoma. Fifty percent of patients taking everolimus have hyperglycemia (Table 52-1) (6). Temsirolimus is another kinase inhibitor used in patients with advanced renal cell carcinoma. The incidence of hyperglycemia in patients using this drug is 26% (7). The mechanism by which temsirolimus leads to diabetes may be similar to that of tacrolimus, which decreases glucose-stimulated insulin release in the pancreatic islets by reducing adenosine triphosphate (ATP) production and glycolysis (8).
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Idelalisib, a PI3 kinase inhibitor, is indicated in patients with chronic lymphocytic leukemia. One of the idelalisib’s emergent laboratory abnormalities is hyperglycemia, which occurred in 54% of patients taking both idelalisib and rituximab in a phase III study (9,10). Another study showed that idelalisib alone in different dose regimens increased serum glucose in 40% of patients (11).
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L-Asparaginase is used mainly to treat hematologic malignancies. The risk of hyperglycemia associated with pegylated Escherichia coli asparaginase has been reported to be similar to the risk associated with native asparaginase; in one study, the risk was about 20% in children with acute lymphoblastic leukemia treated with either agent. The exact mechanism of L-asparaginase–associated hyperglycemia is not known, although it has been postulated that inhibition of insulin, insulin receptor synthesis, or both may be the cause, leading to a combined insulin deficiency–insulin resistance syndrome (12). Pancreatitis, which can occur with L-asparaginase therapy, is another possible mechanism for hyperglycemia. Pancreatitis can cause islet cell destruction, and some patients might require insulin therapy (13). One potential complication is hypoglycemia after cessation of L-asparaginase; thus, close monitoring of blood glucose is recommended. Diabetic ketoacidosis has been reported during L-asparaginase therapy. Long-term insulin therapy may not be needed in some cases of L-asparaginase–induced diabetes mellitus (12).
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Streptozocin, used primarily to treat malignant islet cell tumors and other neuroendocrine tumors, is an N-nitrosourea derivative of glucosamide. Streptozocin’s effect on islet cells is species specific and dose related; rat islet cells appear to be more susceptible to the cytotoxic effects of streptozocin than human islet cells. Most of streptozocin’s effects are reversible upon discontinuation of the drug. Although the reported incidence of glucose intolerance varies from 6% to 60%, most cases are mild to moderate in severity (14).
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Interferon therapy activates immune system cells to fight some cancers and certain infections. According to a survey on IFN therapy in Japan, some patients may experience earlier development of type 1 diabetes, resulting in initiation of insulin therapy (15). These patients were positive for islet cell antibody and anti-glutamic acid decarboxylase antibodies (16).
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We recommend monitoring of fasting serum glucose levels prior to the start of and during these therapies and possibly determining the levels of anti-islet autoantibodies before IFN therapy in patients with family history of type 1 diabetes mellitus (15).
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Some antineoplastic drugs (eg, ifosfamide and mercaptopurine) cause a proximal tubular defect and lower the renal threshold for glucosuria without affecting glucose metabolism. Glucosuria has been detected with an increased incidence in 67% of adult and 75% of pediatric patients treated with high-dose ifosfamide, cisplatin, and high-dose methotrexate, compared to the early postchemotherapy assessment (13% adults and 29% children) (17).
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Lipid disorders are seldom evaluated in the process of active anticancer therapy, because patients are often encouraged to maintain a positive metabolic balance via liberal oral intake. Investigation or treatment of mild lipid abnormalities is often overlooked because the focus is on maintaining a positive caloric balance during cancer treatment. Some lipid disorders may be short-lived without clear clinical consequences, but some may be of clinical importance and need to be detected and treated. In general, triglyceride levels higher than 1,000 mg/dL increase the rate of complications, including pancreatitis.
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Lipid disorders are among the main side effects of vitamin A derivatives, which are commonly used in dermatologic disorders. One vitamin A derivative, bexarotene, has been used against malignancies like cutaneous T-cell lymphoma, acute promyelocytic leukemia, and head and neck cancer. Bexarotene is an agonist of retinoid X receptors, a family of peroxisome proliferator-activated receptors that are upregulated by the binding of bexarotene to a receptor on the nucleus. This upregulation not only regulates lipid metabolism but also affects thyroid hormone synthesis (18). Hypothyroidism contributes to lipid disorders in patients receiving bexarotene. Because bexarotene causes hypertriglyceridemia in approximately 40% of patients, lipid levels and thyroid functions should be checked before bexarotene therapy. If triglyceride levels are 200 to 400 mg/dL, dietary modifications are recommended. If triglyceride levels are 400 to 1,000 mg/dL, omega-3 fatty acids with fibrates or nicotinic acid should be started. Lipid levels should be checked after initiation of therapy, because triglyceride levels over 1,000 mg/dL increase the risk of acute pancreatitis (19).
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Hypercholesterolemia is the second most common side effect of bexarotene, having been reported in 48% of treated patients (20). The long-term significance of drug-induced hypercholesterolemia is unclear; however, atorvastatin has been successfully used to treat bexarotene-associated hypercholesterolemia in patients at the University of Texas MD Anderson Cancer Center (MDACC).
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Mitotane, an analog of the insecticide dichlorodiphenyltrichloroethane, is used in patients with adrenocortical carcinoma as adjuvant therapy. The potential side effects of this therapy include hypercholesterolemia. Although the exact mechanisms of hypercholesterolemia remain unclear, mitotane stimulates hydroxymethylglutarate–coenzyme A reductase. A study from MDACC showed that mitotane increases high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels (21). Patients with adrenocortical carcinoma usually have a poor prognosis, making the clinical significance of mild to moderate elevation of cholesterol uncertain. However, in long-term survivors on adjuvant mitotane therapy, hyperlipidemia can lead to early development of atherosclerotic disease. The benefits of treating mitotane-induced lipid abnormalities in long-term survivors have not been established.
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Mammalian target of rapamycin inhibitors have metabolic side effects that include hypercholesterolemia and hypertriglyceridemia (see Table 52-1). Although the mechanisms of these side effects are unclear, hypercholesterolemia can be caused by dysregulation of sterol regulatory element binding proteins in the mTOR pathway (22). Another possible mechanism is reduction in lipid clearance from the bloodstream (23).
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Before starting mTOR inhibitor therapy, baseline fasting glucose, LDL cholesterol, and triglyceride levels should be checked. The lipid profile should be monitored for every cycle. The goals of lipid-reducing therapy are to keep fasting LDL cholesterol at or below 190 mg/dL and triglycerides at or below 300 mg/dL, if life expectancy is >1 year. Therapeutic lifestyle changes are the first appropriate approach for patients with hyperlipidemia. If such lifestyle changes fail to reduce LDL cholesterol to ≤190 mg/dL, statin therapy should be started. The goals of LDL cholesterol reduction vary with patients’ cardiovascular risk factors. Patients with triglyceride levels above 1,000 mg/dL have an increased risk for acute pancreatitis. Fibrate, omega-3 acid esters, niacin, and combination therapy are the treatment options for hypertriglyceridemia (5).
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Water and Electrolyte Disorders
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Serum osmolality is tightly regulated, primarily by interaction between the hypothalamic osmoreceptors that regulate secretion of antidiuretic hormone from cells in the paraventricular and supraoptic nuclei, the hypothalamic thirst center, and the kidneys. Disruption of any of these regulators may lead to a disturbance in free water clearance and subsequent abnormalities in serum sodium levels.
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Syndrome of Inappropriate Antidiuretic Hormone Secretion and Hyponatremia
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Hyponatremia is a relatively common electrolyte abnormality in patients with cancer. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the most common underlying causes for hyponatremia in this patient population. In addition to its association with hyponatremia, SIADH is characterized by low serum osmolality and an inappropriately high urine osmolality with elevated urine sodium. SIADH is a diagnosis of exclusion after ruling out hypovolemia, heart failure, renal insufficiency, cirrhosis, adrenal insufficiency, hypothyroidism, salt-wasting syndrome, and the use of diuretics. In patients with cancer, SIADH may be caused by ectopic antidiuretic hormone production by a variety of tumors. Syndrome of inappropriate antidiuretic hormone secretion is most commonly seen in patients with small cell lung cancer. Other tumors described (less commonly) in association with SIADH include malignant thymoma, oral squamous cell carcinoma, prostate carcinoma, and pancreatic carcinoma. Chemotherapy-induced lysis of antidiuretic hormone–containing cancer cells may lead to severe hyponatremia at the time of chemotherapy induction.
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Other factors that may increase antidiuretic hormone secretion include nausea, pain, narcotics, and nicotine. Antineoplastic agents such as high-dose intravenous cyclophosphamide, vincristine, vinblastine, and cisplatin can also increase antidiuretic hormone secretion.
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In cases of hyponatremia secondary to SIADH, urine osmolality is higher than plasma osmolality, and urine sodium is determined by sodium intake. In patients with SIADH, urine sodium is usually higher than 40 mEq/L. Fluid restriction (usually 500-1,500 mL of free water a day), an increase in salt intake, and occasionally, loop diuretics are attempted first in most cases of SIADH when the patient is asymptomatic or has mild symptoms. In the presence of severe symptoms (seizures or obtundation), hypertonic saline infusions might be needed with close and frequent monitoring of sodium levels to avoid rapid correction and possible osmotic demyelination syndrome (previously called central pontine myelinolysis). Demeclocycline (600-1,200 mg/d) can be used in cases in which hyponatremia does not respond to more fluid restriction. Vasopressin receptor (V2) antagonists (tolvaptan and conivaptan) have been approved by the US Food and Drug Administration for treatment of clinically significant hypervolemic or euvolemic hyponatremia associated with heart failure or SIADH (24).
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Diabetes Insipidus and Hypernatremia
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Central diabetes insipidus can occur after surgery for brain tumors and occasionally in cases of tumors near the sella or the hypothalamus that invade the neurohypophysis or disrupt the pituitary stalk. These cases are often recognized by a clinical presentation of polyuria or polydipsia and are usually treated with 1-deamino-8-D-arginine vasopressin (subcutaneously, intranasally, or orally) to control the symptoms and correct the associated hypernatremia.
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Nephrogenic diabetes insipidus can also occur in patients with cancer, and multiple antineoplastic agents have been described in association with this syndrome. Ifosfamide is well known to induce damage to the proximal renal tubule and, to a lesser extent, the distal renal tubule, and thereby induce nephrogenic diabetes insipidus. Streptozocin has also been reported to cause nephrogenic diabetes insipidus.
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In addition to being associated with diabetes insipidus, hypernatremia in patients with cancer is commonly caused by insufficiency of free water, especially when patients are on parenteral or tube feeding regimens or are too debilitated to obtain water for themselves.