Hypercalcemia of malignancy (HCM) is defined as a serum calcium level greater than 10.5 mg/dl (Gullatte et al., 2005; Kaplow & Reid, in press).

The reported incidence of HCM is 10% to 40% of patients (Crossno, 2004; Gullatte et al., 2005; National Coalition for Cancer Survivorship [NCCS], 2005; Solimando, 2001).

Etiologic factors of HCM include specific cancers, treatment modalities, and nonmalignant causes. HCM is most often associated with primary tumors of the breast, lung, head and neck, kidney, esophagus, gastrointestinal (GI) tract, and cervix; lymphomas; leukemia; multiple myeloma; and melanomas (Gullatte et al., 2005; Kaplow & Reid, in press; National Cancer Institute [NCI], 2005).

Cancer treatment modalities such as estrogen, antiestrogen agents, and all- trans retinoic acid are associated with the development of HCM (Gullatte et al., 2005).

Non–cancer-related factors associated with HCM development include immobility dehydration, excessive intake of calcium and vitamin D, decreased parathyroid hormone levels, vitamin A intoxication, hyperparathyroidism, and thiazide diuretic or lithium use (Carroll & Schade, 2003; Crossno, 2004; Gullatte et al., 2005; Kaplow, in press; NCI, 2005).

HCM most often results from bone metastasis. This causes osteoclastic bone resorption and release of calcium. Calcium is released from the bone faster than the kidneys can excrete it (Gullatte et al., 2005; Kaplow & Reid, in press). The types of HCM are osteolytic (results from direct bone destruction by a tumor or metastasis) and humoral (results from circulating factors secreted by cancer cells) (Carroll & Schade, 2003; Inzucchi, 2004; Kaplow, in press; NCI, 2005; Solimando, 2001).

Clinical manifestations of HCM vary depending on effects of calcium on the neurologic, GI, renal, and cardiovascular systems; rate of the rise of calcium levels; and patient’s stage of disease and overall condition, renal function, and degree of HCM. They are usually related to the effects of calcium on smooth, skeletal, and cardiac muscle (Gullatte et al., 2005). Neurologic symptoms include mental status changes, hallucinations, jumbled speech, depression, and fatigue. Patients may report visual changes. Diminished deep tendon reflexes may be noted (Beckles, Spiro, Colice et al., 2003; Carroll & Schade, 2003; Crossno, 2004; Inzucchi, 2004; Kaplow & Reid, in press; NCI, 2005; NCCS, 2005; Shuey & Brant, 2004; Solimando, 2001).

Several cardiovascular symptoms exist. These include potential electrocardiographic changes such as prolonged PR interval, widened QRS complex, shortened QT interval, shortened or absent ST segments, and widened QT intervals. Patients may present with atrioventricular block bradycardia, bundle-branch block, or cardiac arrest, depending on severity. Hypertension and myocardial irritability may be observed (Beckles et al., 2003; Carroll & Schade, 2003; Crossno, 2004; Inzucchi, 2004; Kaplow & Reid, in press; NCI, 2005; NCCS, 2005; Shuey & Brant, 2004).

GI manifestations may include nausea, vomiting, anorexia, abdominal pain, ileus, constipation, abdominal distention, dry mouth, increased gastric acid production, pancreatitis, or peptic ulcer disease (Beckles et al., 2003; Carroll & Schade, 2003; Crossno, 2004; Inzucchi, 2004; NCI, 2005; NCCS, 2005; Shuey & Brant, 2004; Solimando, 2001).

Renal effects are polyuria, polydipsia, nocturia, renal failure, dehydration, and nephrogenic diabetes insipidus. Calcium phosphate crystals may be present in the renal tubules (Beckles et al., 2003; Carroll & Schade, 2003; Crossno, 2004; Inzucchi, 2004; Kaplow & Reid, in press; NCI, 2005; NCCS, 2005; Shuey & Brant, 2004; Solimando, 2001).

Other symptoms that may manifest in a patient with HCM include osteoporosis, arthritis, pathologic fractures, and pruritus (Beckles et al., 2003; Carroll & Schade, 2003; Crossno, 2004; Inzucchi, 2004; Kaplow & Reid, in press; NCI, 2005; Shuey & Brant, 2004; Solimando, 2001).

Laboratory findings linked with HCM are abnormal serum creatinine, calcium, electrolytes, magnesium, phosphorus, and possibly elevated alkaline phosphatase (Crossno, 2004; Kaplow & Reid, in press; Shuey & Brant, 2004). The degree of HCM is determined by laboratory measurement of serum calcium in relation to serum albumin levels. Calcium levels should be corrected based on albumin levels, since 40% of calcium is bound to albumin (Gullatte et al., 2005; Kaplow & Reid, in press).

The primary treatment of HCM is treatment of the causal malignancy. This may require chemotherapy, radiation therapy (RT), hormonal therapy, and/or surgical resection (Gullatte et al., 2005; Kaplow & Reid, in press). Irrespective of severity, management should include treatment of any underlying non–disease-related causes.

Patients with a corrected calcium level less than 12 mg/dl may require only monitoring. Patients with moderate to severe HCM (more than 13 mg/dl) require aggressive treatment (Kaplow & Reid, in press).

The degree of monitoring required will depend on the patient’s condition and overall goals of care. Many side effects of treatment can be prevented or managed. Since serum sodium, potassium, calcium, phosphorus, and magnesium levels may decrease, levels should be monitored at least daily. Serum calcium levels will require monitoring, especially during bisphosphonate therapy. The management of symptoms and side effects is essential (NCI, 2005).

Patients treated for HCM will require close follow-up once normal calcium levels have been attained. The underlying malignancy, following its trajectory, may worsen and ongoing HCM management may be required (NCI, 2005; Shuey & Brant, 2004). Frequency of follow-up is also based on the anticipated lasting effect of the treatment modalities used (NCI, 2005).

Patients and families require education regarding what symptoms to observe and the importance of reporting symptoms early. Measures can include preventing dehydration, weight-bearing activities, managing pain, and avoiding thiazide diuretics (Gullatte et al., 2005).

Patients and families should have the sequelae of untreated HCM explained to them; these include loss of consciousness and coma, which may be acceptable outcomes for patients at end-of-life who are suffering or have uncontrollable symptoms or when treatment of the underlying malignancy is no longer feasible (NCI, 2005).

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a condition of water intoxication. It is depicted by inappropriate production and secretion of antidiuretic hormone (ADH). This causes increased tubular water reabsorption with subsequent water retention, dilutional hyponatremia, a decreased serum osmolality, and increased urine osmolality (Flounders, 2003; Kaplow & Reid, in press; Shirland, 2001). The secretion of ADH occurs despite adequate circulating fluid volume and urinary sodium excretion and (Beckles et al., 2003; Gullatte et al., 2005).

SIADH occurs in 1% to 14% of patients with malignancy. Patients with small-cell lung cancer (SCLC) have an incidence of up to 10% (Hemphill & Ismach, 2001; Kaplow, 2005; Kaplow & Reid, in press).

The causes of SIADH are (1) cancer, (2) neurologic disorders, (3) benign lung disease, and (4) drugs (Baylis, 2003; Gullatte et al., 2005). SCLC is the most common cancer associated with the development of SIADH. Other associated malignancies are non–small-cell lung cancer (NSCLC); carcinoid tumors; squamous cell carcinoma of the head and neck; breast, brain, prostate, esophagus, pancreas, colon, thymus, uterus, bladder, ovarian, or duodenal tumors; neuroblastoma; mesothelioma; Hodgkin’s and non-Hodgkin’s lymphomas; and leukemia. It can also be caused by metastasis to the central nervous system (CNS) (Flounders, 2003; Gullatte et al., 2005; Kaplow & Reid, in press).

Some chemotherapeutic agents place patients at risk to develop SIADH. These include vincristine, vinblastine, cyclophosphamide, ifosfamide, cisplatin, and melphalan. Each of these agents can cause hyponatremia and elevated ADH levels (Gucalp & Dutcher, 2001; Gullatte et al., 2005; Kaplow & Reid, in press; Tan, 2002).

Non–cancer-related etiologic factors for SIADH include medications (e.g., opioids, antidepressants, NSAIDs, thiazide diuretics, barbiturates, and anesthetic agents), CNS disorders (e.g., brain abscess or herniation, hemorrhage, head trauma), and pulmonary disorders (e.g., infection, pneumonia, lung abscess, tuberculosis). Pain, stress, and nicotine have also been identified as causative factors (Flounders, 2003; Kaplow & Reid, in press; Tan, 2002).

The symptoms depend on the degree and speed at which hyponatremia develops (Baylis, 2003). The hallmark signs of SIADH are hyponatremia, serum hypo-osmolality, and inappropriately concentrated urine for serum osmolality (Gullatte et al., 2005).

Patients present with a variety of symptoms that may be due to dilutional hyponatremia, hypocalcemia, or hypokalemia. SIADH affects the CNS, GI, renal, musculoskeletal, cardiac, and respiratory systems. CNS symptoms include mental status changes, headache, ataxia hallucinations, agitation, fatigue, malaise, tremors, hyporeflexia, myoclonus, and unexplained seizures (Gullatte et al., 2005). GI symptoms may include nausea, vomiting, diarrhea, anorexia, and abdominal cramping. If the renal system is affected, the patient may manifest thirst, weight gain without edema, and oliguria. Musculoskeletal symptoms are muscle cramps and weakness. Patients may have hypotension or normal blood pressure and heart rate as well as fluid retention. Possible respiratory symptoms include inability to maintain a patent airway and inability to mobilize secretions (Baylis, 2003; Beckles et al., 2003; Flounders, 2003; Gullatte et al., 2005; Kaplow & Reid, in press; Tan, 2002). If a serum sodium level is less than 120 mmol/L and develops acutely, the patient is at risk for the development of cerebral edema (Gullatte et al., 2005; Langfeldt & Cooley, 2003).

Diagnosis of SIADH is based on laboratory data and through the exclusion of other contributing factors of hyponatremia. The clinician should have a high index of suspicion based on the presence of risk factors in a hyponatremic patient (Gullatte et al., 2005; Janicic & Verbalis, 2003). Laboratory data consistent with a diagnosis of SIADH are a urinary sodium level of greater than 40 mEq/L, urinary osmolality greater than 1000 mOsm/kg, serum hypo-osmolality, and hyponatremia (Kaplow & Reid, in press).

Continuous monitoring of the patient is important to identify changes in clinical status. Assessment of fluid and electrolyte status and for side effects of treatment is equally essential. Collaboration among the physician, pharmacist, and nurse to manage anxiety and depression will help optimize patient outcomes, as many medications will need to be avoided (Flounders, 2003; Kaplow & Reid, in press).

Treatment of the underlying cause of SIADH may be implemented. Treatment modalities include chemotherapy, RT, and/or corticosteroids (Kaplow & Reid, in press). The foundation of management is fluid restriction to less than 800 to 1000 ml/day until serum sodium improves (Kaplow & Reid, in press; Flounders, 2003). Demeclocycline administration is recommended if fluid restriction alone is not effective (Gullatte et al., 2005; Kaplow & Reid, in press; Flounders, 2003; Tan, 2002).

Patients with acute hyponatremia and severe neurologic symptoms should receive 3% saline at a rate of 300 to 500 ml over 4 to 6 hours until a serum sodium of 125 mg/dl is attained (Crook, 2002). Serum sodium should be corrected at a rate of 0.5 to 2 mEq/h to prevent complications of therapy (Flounders, 2003; Gucalp & Dutcher, 2001; Gullatte et al., 2005; Kaplow & Reid, in press; Kozniewska, Podlecka, & Rafalowska, 2003). Loop diuretics are recommended to decrease urine concentration and promote urinary free water excretion (Gucalp & Dutcher, 2001; Gullatte et al., 2005).

The key to managing SIADH is early detection to prevent complications. Monitoring fluid status may require urine specific gravity, daily weights, serum and urine electrolytes, and strict intake and output (I/O). Patients receiving hypertonic saline require ongoing assessment for overcorrection and/or fluid overload. Neurologic assessment is essential as rapid changes in mental status may signify worsening hyponatremia and rapid changes in sodium (Gullatte et al., 2005).

SIADH resolves in less than 3 weeks when treatment of the underlying cause has been successful. Symptoms often recur if there is tumor progression (Beckles et al., 2003; Flounders, 2003; Kaplow & Reid, in press). While patients are being treated, serum chemistries may be monitored on a periodic basis (Tan, 2002).

Patients and family members should be taught signs and symptoms to observe for, actions to take, and when to seek medical attention. While the patient is receiving treatment of SIADH, comfort measures such as mouth care and administration of small amounts of ice chips may be given to combat the discomfort of thirst. Family members should also be taught to observe for changes in mental status (Flounders, 2003; Gullatte et al., 2005).

Superior vena cava syndrome (SVCS) results from obstruction of the superior vena cava (SVC). The blockage may be above or below the azygous vein from an intravascular clot, tumor in the right main upper lobe bronchus, or significant mediastinal lymphadenopathy. The obstruction impairs blood flow to the right atrium and venous drainage above the upper thorax. This results in a decreased venous return (Gullatte et al., 2005; Hemann, 2001; Kaplow & Reid, in press; Rowell & Gleeson, 2005; Wudel & Nesbitt, 2001).

An incidence of 2.4% to 21.1% of SVCS in lung cancer patients has been reported (Rowell & Gleeson, 2005).

Most cases of SVCS are due to malignancy. Of these, 80% are due to NSCLC and non-Hodgkin’s lymphoma (Beckles et al., 2003; Kaplow & Reid, in press; Thirlwell & Brock, 2003). In patients with lung cancer, SVCS is usually due to direct extension or lymph node metastasis (Beckles et al., 2003; Kvale, Simoff, & Prakash, 2003). Some cases are due to breast or testicular cancer metastasis. T-cell leukemia causes mediastinal adenopathy and enlargement of the thymus, which can compress the SVC. Rare cases of SVCS are attributed to Kaposi’s sarcoma, esophageal cancer, thymoma, mesothelioma, and Hodgkin’s disease (Kaplow & Reid, in press).

Nonmalignant causes of SVCS include tuberculosis, indwelling central venous catheters or pacemaker wires, Silastic or dialysis catheters, aneurysm of the aortic arch, or constrictive pericarditis (Gullatte et al., 2005; Kaplow & Reid, in press).

Because of the location of the SVC (it is surrounded by structures that do not compress), the SVC’s thin walls, and the low presssure of blood flow in the SVC, when regional lymph nodes or the aorta enlarge, the SVC constricts effortlessly, and thus blood flow becomes sluggish and occlusion frequently occurs (Gullatte et al., 2005).

The signs and symptoms of SVCS are related to severity and location of the obstruction. It is usually not until the obstruction is complete that clinical manifestations become obvious. This makes the diagnosis of SVCS more challenging.

Symptoms tend to be more severe when the obstruction is below the azygous vein (Rowell & Gleeson, 2005). The respiratory, cardiac, and CNS systems are affected. CNS manifestations include mental status changes, headache, dizziness (especially when leaning forward), blurred vision, and syncope. Respiratory symptoms are shortness of breath, dyspnea, hoarseness, cyanosis, cough, dysphagia, and stridor. Cardiac symptoms may include edema of the face, arm, and upper chest; dilated veins in the upper torso, shoulders, and arms; jugular venous distention; tachycardia; chest pain; and hypotension. Patients may present with erythema of the eyelids, tightness of the neck (Stokes sign), or periorbital edema (Beckles et al., 2003; Gucalp & Dutcher, 2001; Gullatte et al., 2005; Kaplow & Reid, in press).

Management of SVCS is designed for symptom management and treatment of the underlying cause. If the patient has adequate collateral circulation and symptoms are minimal, treatment may not be required (Hemann, 2001; Wudel & Nesbitt, 2001).

Patients with SVCS should be maintained with the head of the bed elevated. Oxygen therapy may be needed for dyspnea (Thirlwell & Brock, 2003). The patient should be protected from fluid overload. Upper extremity venous catheters should be avoided (Gullatte et al., 2005).

Routinely, management consists of steroids and either chemotherapy or RT. Steroids are usually given to patients receiving RT due to potential radiation-induced edema. If used, high-dose steroids should be given for a limited time period (Kaplow & Reid, in press; Rowell & Gleeson, 2005).