Fluids and Diuretics

The initial intervention in the treatment of hypercalcemia is the administration of isotonic saline at a rate of 200 to 500 mL/hr based on the degree of hypovolemia and renal and cardiovascular dysfunction to maintain urine output of 150 to 200 mL/hr (5). Once the fluid deficit is replaced, the infusion rate should be decreased to 100 to 200 mL/hr in patients without cardiac or renal impairment (20). The patient must be carefully monitored to prevent fluid overload. Saline hydration reduces serum calcium level by increasing the glomerular filtration rate and increasing calcium delivery to the proximal tubule where urinary calcium excretion is augmented by the calciuric effects of saline (5).

Loop diuretics inhibit calcium reabsorption at the loop of Henle, increasing calciuresis. These agents should be used judiciously and only after euvolemia is achieved in hypovolemic patients or in patients who present with volume overload (5,9,18). Because of ensuing complications such as hypokalemia, hypomagnesemia, and volume depletion, and because of the availability of bisphosphonates, loop diuretics are used less favorably in clinical practice (24).

TABLE 147.2 Treatment of Hypercalcemia of Malignancy

Bisphosphonate Therapy

Bisphosphonates inhibit osteoclastic bone resorption and are the principal agents used in the management of hypercalcemia of malignancy (25,26). When compared to saline and diuretics alone, and other antiresorptive agents including calcitonin, bisphosphonates are superior in treating hypercalcemia of malignancy (5). Because only 1% to 2% of oral bisphosphonates are absorbed, these drugs are administered intravenously (7). Pamidronate and zoledronate are the most commonly used bisphosphonates for the treatment of hypercalcemia of malignancy. Patients respond to bisphosphonate therapy within 2 to 4 days, with a nadir in serum calcium occurring within 4 to 7 days; normocalcemia may persist for 2 to 4 weeks (5,16). Zoledronate is 850 times more potent than pamidronate and is considered first-line therapy (9,27). In a pooled analysis of two randomized controlled trials comparing a single 4-mg dose of zoledronic acid to a 90-mg dose of pamidronate, serum calcium concentrations normalized within 10 days in 88% versus 70% of patients, respectively, and the duration of response was 32 days versus 18 days, respectively, within the two groups (27). Both zoledronate and pamidronate have been associated with acute and chronic renal failure, with more adverse events reported with zoledronate. Dose reduction of zoledronate is recommended in patients with a creatinine clearance between 30 and 60 mL/min. Other complications of bisphosphonates include acute systemic inflammatory reactions such as fever and arthralgias, ocular inflammation, electrolyte imbalances, and osteonecrosis of the jaw (28).

Other Agents

Calcitonin is a well-tolerated synthetic polypeptide analog of salmon calcitonin, which reduces serum calcium levels by inhibiting bone resorption. When administered subcutaneously or intramuscularly, it produces a rapid but transient decrease in serum calcium levels within 12 to 24 hours (5,9). This agent is useful in patients with congestive heart failure (CHF) or renal failure where saline, diuresis, and bisphosphonates may be contraindicated. Tachyphylaxis may occur with continued use (7). Glucocorticoids are effective in decreasing serum calcium in hypercalcemia of malignancy associated with some lymphomas, particularly Hodgkin lymphoma (HL). These agents have limited utility in the acute setting because a reduction in serum calcium may not be observed for 1 to 2 weeks (11).

Denosumab is a human monoclonal antibody that inhibits osteoclast formation by preventing human receptor activator of nuclear factor kappa-β ligand (RANKL) from binding with its receptor. It is metabolized and excreted by the liver and considered safe to give to patients with renal insufficiency although optimal dosing is uncertain. In patients with multiple myeloma, hypercalcemia, and severe renal impairment (serum creatinine 2.5 to 5.7 mg/dL), denosumab improved serum calcium and was associated with improved in renal function (29). In patients with breast cancer metastatic to bone, denosumab proved superior to zoledronic acid in preventing skeletal-related events such as pathologic fractures (30). It has also proved efficacious in patients with persistent hypercalcemia despite bisphosphonate therapy (31,32).

Dialysis may be necessary for patients with severe malignancy-associated hypercalcemia and concomitant renal insufficiency or heart failure, who will not tolerate the therapies outlined above (5,16).

Pathophysiology

Rapid dissolution of cells with aggressive cytotoxic therapy results in an increase in plasma uric acid, potassium, and phosphorus levels. Hyperphosphatemia then leads to secondary hypocalcemia; hyperkalemia occurs 6 to 72 hours after the administration of chemotherapy (39). Associated manifestations include lethargy, nausea, vomiting, diarrhea, muscle weakness, paresthesias, and electrocardiographic abnormalities such as peaked T waves, PR-interval prolongation, and QRS-complex widening. Ventricular arrhythmias may lead to sudden death (7,34). Hyperphosphatemia is seen 24 to 48 hours following chemotherapy (39). Malignant cells may contain up to four times more phosphorous than nonneoplastic cells and, as plasma phosphorous increases with cell lysis, the normal renal mechanism that excretes excess phosphate and prevents distal tubular reabsorption becomes overwhelmed, leading to hyperphosphatemia (42). Acute hyperphosphatemia manifests as secondary hypocalcemia with a range of signs and symptoms including anorexia, vomiting, confusion, neuromuscular irritability, tetany, carpopedal spasm, seizures, dysrhythmias, and cardiac arrest (7,34). Secondary hypocalcemia occurs in association with hyperphosphatemia when the calcium phosphate product exceeds 60. Calcium phosphate then precipitates into tissues, including the renal interstitium and tubules, resulting in nephrocalcinosis (35). However, hypocalcemia may persist even after correction of hyperphosphatemia when an inappropriately low plasma calcitriol level is present (43). Hypocalcemia itself causes a rise in serum parathyroid hormone, which, in turn, increases phosphate resorption in the proximal tubule, leading to nephrocalcinosis and acute renal failure (ARF) (7).

Hyperuricemia occurs 48 to 72 hours after chemotherapy (39). Patients may exhibit nonspecific symptoms such as nausea, vomiting, anorexia, and lethargy. ARF with associated oliguria, edema, hypertension, and altered sensorium will be seen in untreated patients (36). Uric acid is generated from purine metabolism in the liver. Adenosine and guanosine nucleotides are degraded to hypoxanthine and xanthine, respectively, and xanthine oxidase converts these products to uric acid (7). Rapidly proliferating neoplastic cells have high turnover rates with accelerated purine catabolism from DNA and RNA degradation (44), and these cells contain large amounts of purine nucleotides; consequently, with cytotoxic therapy, there is a rapid rise in plasma uric acid (36). Uric acid is excreted by the kidneys through the processes of glomerular filtration, partial proximal tubular reabsorption, and distal tubular secretion (35). The clearance of uric acid is independently proportional to intravascular volume status (34) and the urinary flow rate (35), and may be significantly reduced in the presence of dehydration or tubular obstruction from acute nephrocalcinosis or uric acid nephropathy. Uric acid nephropathy develops when uric acid crystals deposit in the renal tubules and collecting ducts under acidic conditions. The urinary pKa of uric acid is 5.4, and the luminal pH of the distal tubules and collecting ducts is 5.0, resulting in the poor solubility of uric acid in acidic urine (7). This poor solubility, coupled with the marked hyperuricosuria present in ATLS, leads to uric acid precipitation, intraluminal obstruction, oliguria, and ARF (7,45). ARF in ATLS may also be caused by renal calculi from phosphate and uric acid precipitation (34), as well as ischemic acute tubular necrosis caused by renal hypoperfusion (36). Drug toxicity, sepsis, and tumor-associated obstructive uropathy or renal parenchymal infiltration may exacerbate ATLS-induced ARF (42).

Diagnosis and Classification

Hande and Garrow (38) first classified ATLS into laboratory TLS and clinical TLS. Cairo and Bishop (42) have modified and further developed this classification system into the Cairo–Bishop definition, which uses laboratory and clinical data in conjunction with a grading scale to assess the severity of ATLS. Laboratory TLS (LTLS) is defined as two or more of the following metabolic abnormalities occurring 3 days before or 7 days after chemotherapy: uric acid 8 mg/dL or greater, potassium 6 mEq/dL or greater, phosphorous 6.5 mg/dL or greater, or a 25% increase in baseline levels of these metabolites, and calcium up to 7 mg/dL, or a 25% decrease from baseline level. Clinical tumor lysis syndrome is defined as LTLS in addition to one or more of the following findings: serum creatinine at least 1.5 times the upper limit of normal, cardiac dysrhythmia/sudden death, or seizure. The grading of ATLS from 0 through 5 is determined by the presence or absence of LTLS, the degree of serum creatinine elevation, and the presence and severity of the cardiac arrhythmia and seizure (42).

Prevention and Treatment

Early recognition of patients at high risk for ATLS is an essential component of the management strategy so that appropriate prophylactic interventions can be instituted.

Controversies

• Administration of urine alkalinizing agent such as sodium bicarbonate or acetazolamide can only be recommended in patients with metabolic acidosis and high levels of uric acid. It should be discontinued when serum phosphate levels begin to rise (47).
  
• The preferred regimen for lowering serum uric oxide remains unclear. Although rasburicase is a more effective hypouricemic agent than allopurinol, it is unknown if its use results in improved clinical outcomes such as reduced AKI and mortality.

Pathophysiology

The severity of signs and symptoms depends on the extent, location, and rapidity of onset of the SVC occlusion (62). In general, obstruction within or below the azygos vein results in more pronounced symptoms. Normally, azygos venous capacity increases from 11% to 35% to augment drainage of the head and neck (52), but impedance of flow from obstruction precludes this auxiliary function (52,61,66). With slowly developing SVCS, collateral vessels in the chest wall and upper extremities are recruited as a diversion for the existing SVC engorgement; hence, SVCS in this population is of insidious onset, as in fibrosing mediastinitis (62). The most commonly reported symptom in SVCS is dyspnea followed by head and facial swelling (53,57). Other cardiopulmonary symptoms include cough, orthopnea, and chest pain. Associated signs are neck and arm vein distention, plethora or cyanosis of the head and neck (53), venous collateralization in the arms and upper chest wall (61), and chronic pleural effusions (61,62). More extensive airway or vascular obstruction is predicted when positional maneuvers such as lying supine or leaning forward exacerbate respiratory or cardiac symptoms; for example, respiratory insufficiency in the supine position worsens as the weight of the mediastinal structures impinges on the tracheobronchial tree. In the substantially compromised patient with SVCS, cardiopulmonary arrest may ensue simply with the administration of sedatives and general anesthesia (61). Other head and neck signs and symptoms range from conjunctival and periorbital edema, nasal congestion, dysphagia, and hoarseness due to laryngeal nerve compression (67) to proptosis, glossal edema, stridor secondary to laryngeal edema, and tracheal obstruction (61,62). Patients with central nervous system (CNS) manifestations may exhibit mild headaches, dizziness, and lethargy with progression to syncope in rapidly developing or complete SVC obstruction, seizures, or coma from cerebral edema and increased intracranial pressure (52,61). Bleeding complications such as epistaxis, hemoptysis, and GI hemorrhage from esophageal varices in long-standing SVC may occur (61).

Diagnosis

Once the clinical diagnosis of SVC syndrome is suspected, confirmation can be obtained using radiologic techniques. Chest radiography reveals widening of the superior mediastinum in approximately 60% of patients (60,61,63) and pleural effusions, most frequently right-sided, in up to 25% of patients (53,61). A normal chest radiograph, however, does not exclude the diagnosis. Contrast-enhanced helical computed tomography (CT) accurately delineates the site, extent, and cause of the occlusion (63,66), as well as any associated thrombus and collateral vessel development (66). The radiologic diagnosis of SVCS is made by demonstrating both decreased or absent venous opacification below the level of obstruction and prominent collateral vessel opacification (63). MRI is an alternative imaging method in patients with iodinated contrast allergy or without adequate venous access for contrast administration, but offers no distinct advantage over CT (52,61,68). Venography is most useful when planning bypass or stenting procedures (52,66). Although venography is superior to CT in identifying the site and extent of obstruction and in mapping the collateral circulation, it does not elucidate the underlying cause of the SVCS (68), unless SVC thrombosis alone is the causative factor (58,63,66).

Treatment

The primary goals of treatment are symptom relief and eradication or palliation of the underlying malignancy. Initial symptomatic management involves bed rest, head elevation to reduce venous pressure, and supplemental oxygen administration. Diuretics and sodium restriction may decrease edema, but reports are anecdotal. Use of glucocorticoids to minimize inflammatory responses to tumor or radiotherapy (XRT) is controversial (64), but steroids are a mainstay of treatment in NHL (61,63). Urgency of treatment is guided by the severity of symptoms (58,69–72). The American College of Chest Physicians (ACCP) and the National Comprehensive Cancer Network (NCCN) recommend expedited stent placement or radiotherapy for patients with symptomatic SVCS (73,74). Patients with evidence of cerebral or laryngeal edema or those with hemodynamic compromise require an emergent intervention.

Controversies

The need for long-term anticoagulation following SVC stent placement remains unclear. Given the poor prognosis of many of these patients, there is little data to guide choice of anticoagulant and duration of therapy. Most practitioners favor a short course (4 to 12 weeks) of dual antiplatelet therapy. Anticoagulation with low–molecular-weight heparin is indicated when SVC occurs in the presence of an upper extremity DVT.

Oropharyngeal and Tracheal Obstruction

Sudden upper airway obstruction (UAO) of the larynx, pharynx, or extrathoracic trachea is uncommon with cancers of the head and neck. Tumors of the larynx, pharynx, base of tongue, and thyroid are primarily slow growing and, as they progressively enlarge, obvious signs and symptoms of airway compromise are usually evident prior to the development of acute obstruction (85); tracheal masses, which take years to be discovered, first become symptomatic when the airway lumen is narrowed by 75% (86). Mechanisms of UAO include direct tracheal invasion as well as extrinsic tracheal compression (87).

In the head and neck, direct tracheal invasion is seen with locally advanced oropharyngeal tumors, laryngeal neoplasms associated with bulky or supraglottic lesions, and rarely, thyroid cancer and primary tracheal tumors (85). In thyroid cancer, tracheal invasion develops in 1% to 6.5% of patients, and UAO is the most common cause of death in this group (88). Direct tumor extension into the trachea from adjacent structures by malignancies of the lung, esophagus, and mediastinum occurs more frequently than metastatic disease spread (89).

Tracheal impingement in lung cancer occurs when there is tracheal ingrowth of the primary tumor originating in a mainstem bronchus or from enlarging paratracheal or subcarinal lymph nodes. Bilateral vocal cord paralysis with recurrent laryngeal nerve paralysis may also be associated with lung malignancies (85,90). Extrathoracic malignancies may metastasize to mediastinal and endobronchial lymph nodes, causing airway obstruction. Renal cell carcinoma, sarcomas, breast cancer, and colon cancer are most commonly involved (91). Melanoma may arise as a primary tracheal tumor but more often is a metastatic lesion (89).

Tracheal compression, which is usually attributable to benign disease, is a secondary mechanism of UAO in neoplastic disease and is often the initial presentation of mediastinal tumors and extensive lymphoma (92).

Intrathoracic Obstruction

Pathophysiology

The mechanisms by which MSCC occurs include vertebral body invasion by tumor with possible vertebral collapse causing encroachment on the anterior spinal cord (85%); direct extension into the intervertebral space by paraspinal lymphoma, sarcoma, or lung cancer, seen in 10% to 15% of cases; and epidural or intramedullary space invasion, seen in less than 5% of cases (102). The mechanism of injury to the spinal cord is mediated by white matter vasogenic edema and axonal swelling that result from cord compression. Venous hypertension, decreased spinal cord blood flow, and cord infarction ensue, resulting in ischemic hypoxic neuronal injury.

Pain, which may be characterized as localized, radicular, or referred, is the primary presenting symptom in MSCC, occurring in 83% to 95% (106,108,111) of patients for a median of 8 weeks prior to diagnosis (106,108). Focal bony pain is typically localized, dull or aching, and constant. Direct tenderness of the involved vertebral body may be evident with periosteal destruction (112). With time, radicular pain occurs in the dermatome of the affected nerve root and is severe, deep, and lancinating. Radicular symptoms occur most often in the lumbosacral spine and may be unilateral or bilateral, the latter more frequent with thoracic spine involvement (107,113). Referred pain does not radiate, but appears in a region distal to the area of pathology; for example, sacroiliac pain may result from L1 compression (113). The pain of MSCC is typified by worsening with recumbency secondary to distention of the epidural venous plexus (106,107); coughing, sneezing, or Valsalva maneuvers will also exacerbate the pain (102). Straight-leg raising identifies a lumbosacral radiculopathy, and neck flexion reproduces symptoms of thoracic radiculopathy (107,111,113).

Motor weakness is present in 60% to 85% of patients on diagnosis of MSCC. Although only one-third of patients complain of lower extremity weakness on initial presentation (107), two-thirds are not ambulatory at the time of diagnosis (106,107). Motor deficits at the level of the conus medullaris or above generally have a symmetric distribution. Paresis is usually seen in the extensors of the upper extremities or the flexors of the lower extremities, depending on the location of the lesion in the spine. Upper motor neuron signs such as spasticity, hyperreflexia, and Babinski responses, may be present. Cervical lesions may lead to quadriplegia and respiratory collapse (112).

Sensory deficits, reported as varying degrees of paresthesias, are less common than motor deficits but can still be found in 40% to 90% of patients. The level of hyperesthesia on examination occurs one to five levels below the actual anatomic level of cord compression (106). The sensation of an electric shock radiating through the spine and extremities with neck flexion, termed the Lhermitte sign, is seen infrequently with cervical or thoracic neoplasms. Perineal paresthesias may occur with cauda equina lesions. Gait ataxia may follow sensory loss impairment, but in the absence of sensory findings, impairment of the spinocerebellar tract should be considered.

Bowel and bladder dysfunction reflects autonomic dysfunction and is a late manifestation of MSCC (113). Patients report urinary hesitancy and frequency, and both incontinence of urine, from poor sphincter tone or overflow of urine, and urinary retention may ensue. At the time of diagnosis, 50% of patients are incontinent or catheter-dependent (114); patients may also exhibit erectile dysfunction and impotence. Constipation and incontinence of stool with diminished sphincter tone may be present (113).

Diagnosis

The imaging study of choice in evaluating MSCC is magnetic resonance imaging (MRI); this noninvasive test provides high resolution of the soft tissues, including bony metastases and intramedullary pathology. One study found that MRI had a sensitivity, specificity, and overall accuracy of 93%, 97%, and 95%, respectively, in detecting MSCC in patients with known malignancies, excluding primary CNS tumors (114). When the entire spine is imaged beyond the area of clinically determined cord compression, multiple epidural metastases (MEMs) are found in 30% of patients. Because the presence of MEMs may alter treatment strategy, several studies have purported using whole-spine MRI in all patients undergoing imaging (104,109,114,115). Myelography, with or without CT myelogram, is a more invasive tool than MRI and is used in imaging MSCC when MRI is contraindicated. CT alone does not adequately define the soft tissues and spinal cord, and plain radiographs and radionuclide testing have low sensitivity and specificity for demonstrating MSCC. Plain films detect vertebral metastases at the site of known cord compression only 80% of the time, and many metastases are missed because the ability to visualize these lesions requires that 30% to 40% of the bone be eroded (116).

Delay in diagnosis may be attributed to the patient’s failure to identify symptoms and diagnostic delays by the generalist and hospital practitioner, leading to potentially avoidable deterioration in motor or bladder function (117).

Treatment

The goals of therapy are pain control and preservation of neurologic function. Treatment options include narcotics, corticosteroids, radiation, and surgery. Pretreatment neurologic function is the most important predictor of posttreatment outcome (118,119).

Controversies

The role of high-dose steroids remains unclear. As noted above, only one of three studies demonstrated improved motor function at higher doses of dexamethasone (with an increased incidence of side effects). Current practice favors the use of high-dose steroids only for patients with severe myelopathy upon presentation.

Pathophysiology

The pericardium is a fibroserous sac, composed of two layers that surround the heart. The outer layer is the fibrous pericardium, which attaches to the diaphragm and securely anchors the heart within the thoracic cavity. The serous pericardium is a single layer of mesothelial cells and its underlying connective tissue, which lines the fibrous pericardium. During embryonic development, the heart invaginates the walls of the serous pericardium, creating a potential space between an inner serous layer that is adherent to the heart (visceral pericardium) and an outer serous layer that lines the fibrous pericardium (parietal pericardium). The pericardial space is formed between the two serous layers, and it normally contains 15 to 50 mL of fluid for lubrication. The fluid is drained from the right pleural space into the right lymphatic duct, and from the parietal pericardium into the thoracic duct (130,131); any interruption in this flow will result in accumulation of fluid and pericardial effusion. The mechanisms by which malignant disease generates MPCEs include direct invasion of the pericardium or myocardium, and disruption of lymphatic flow from lymph node metastases or from prior radiotherapy to the chest or mediastinum (126,128). The tumors that invade the pericardium directly or hematogenously are most often lung cancer, followed by lymphoma and breast cancer (52,126).

With either of the aforementioned mechanisms, pericardial fluid accumulates and inhibits passive diastolic filling of the normally low-pressure right heart structures, producing jugular and abdominal venous hypertension (126). As the pericardial effusion expands, the heart is further compressed, leading to reduced diastolic compliance, decreased diastolic filling, and, ultimately, decreased stroke volume, cardiac output, and blood pressure. Right atrial and right ventricular collapse ensues, resulting in frank tamponade, which, untreated, will lead to shock (133). Pericardial reserve volume, defined as the volume that will just distend the pericardium, is approximately 10 to 20 mL. As the pericardial effusion enlarges, capacity for stretch is exceeded. Therefore, when fluid accumulates rapidly, the pericardium cannot stretch rapidly enough to accommodate the added volume, and the heart becomes compressed (131). Under these circumstances, acute tamponade may occur with as little as 50 mL of fluid (132). When effusions develop chronically, the pericardium is able to compensate by stretching slowly over time—the phenomenon of stretch relaxation (131–133). In cancer patients, the MPCE develops slowly, and as much as 2 L of pericardial fluid may be present before critical symptoms occur (132).

Patients may be asymptomatic with small pericardial effusions (9,124) and, in general, symptoms correlate with the compressive effect of the effusion on surrounding structures, including the lung, trachea, and esophagus. Symptoms include dyspnea, cough, chest pain, hoarseness, hiccups, and dysphagia (131). The most commonly reported physical sign is distension of the jugular veins. The classic finding of the Beck triad of hypotension, increased jugular venous pressure, and quiet heart sounds may be present, in addition to the Kussmaul sign, which is paradoxical jugular venous distention and increased jugular venous pressure on inspiration. Sinus tachycardia, hepatomegaly, and peripheral edema may all be apparent. On cardiac examination, dullness beyond the apical impulse and râles can be detected, and in patients with inflammatory effusions, a pericardial rub is often heard. A narrow pulse pressure is frequently noted, and pulsus paradoxus, a decrease in systolic blood pressure greater than 10 mmHg, is observed in 77% of patients with acute tamponade; patients may report a feeling of uneasiness (132). When low-output shock results from failure of compensatory mechanisms to maintain cardiac output, the patient exhibits cold, clammy skin, cyanosis, oliguria, and altered mental status (133).

Diagnosis

Chest radiograph reveals a water bottle–shaped heart with widening of the cardiac silhouette and, occasionally, pericardial calcifications (132); pleural effusions will be present in one-third of cases (126). The ECG may demonstrate a low-voltage QRS or nonspecific ST-T wave changes (9). Electrical alternans in the P wave and QRS complex is a rare finding, noted in 0% to 10% of patients (131), in which every other QRS complex has a lower-voltage and/or reversed polarity (132). The echocardiogram precisely localizes the pericardial fluid, discerns the quality of the effusion (homogeneous vs. heterogeneous), determines whether loculations or bulky tumor are present, assesses right and left ventricular function, and ascertains whether right atrial and right ventricular diastolic collapse are present. On echocardiography, the heart may be seen to swing in a pendular fashion within the pericardial fluid. Right heart catheterization is the definitive standard for further defining the pericardial effusion. Classically, there will be equalization of diastolic pressures across all cardiac chambers (126).

Treatment

There are no randomized control trials to guide the management of malignant pericardial effusions. Treatment strategy should be individualized to each patient based on age, comorbid conditions, malignancy type, and overall prognosis (125). Although temporizing measures such as volume repletion and inotropic support may provide some benefit, definitive treatment requires removal of fluid from the pericardial space. The initial emergent intervention in malignant cardiac tamponade is to drain the effusion, usually with echocardiographic guidance (124). Fluid should be sent for chemical analysis, microbiology, and cytology; the effusion is removed successfully in 97% of patients (134). In the absence of tamponade, systemic chemotherapy is administered as baseline treatment (124), thereby precluding recurrences in 67% of cases (134). Systemic chemotherapy is effective in controlling malignant effusions when the tumors are chemosensitive, as in lymphoma, leukemia, and breast cancer. Notably, XRT is highly effective (93%) in controlling malignant pericardial effusions in patients with lymphoma and leukemia, although radiation myocarditis or pericarditis is, in itself, a complication of radiotherapy (134). Pericardiocentesis should be performed in MPCE, especially when these are large, for symptomatic relief and to establish a cause. Because fluid reaccumulates within 48 hours of the initial pericardiocentesis (135), intrapericardial sclerosing or cytostatic agents, selected according to tumor type, should be administered to prevent recurrence. The mechanism of action of sclerosing agents is to effect symphysis of the visceral and parietal pericardia (124). A surgical approach to MPCE management is subxiphoid pericardiotomy to create a pericardial window. An advantage of this technique is that it is performed using local anesthesia and has a low recurrence rate. Additionally, tissue can be obtained for pathologic review. However, there is a small risk of myocardial laceration, pneumothorax, and mortality with this procedure. One study showed a 12% recurrence at 1 year and a 4% reoperation rate for subxiphoid pericardiotomy (125). Pleuropericardiotomy and pericardiectomy, which require general anesthesia, have higher morbidity and mortality rates, and are rarely used in MPCE management (124). Percutaneous balloon pericardiotomy is a treatment option for patients with large recurrent neoplastic pericardial effusions. Requiring only local anesthesia, it facilitates passage of pericardial fluid into the left pleural or peritoneal spaces, which have greater resorptive capacity. The major side effect is asymptomatic pleural effusion in most patients (52,136). Percutaneous balloon pericardiotomy appears to be a safe and effective technique in patients with large MPCEs and recurrent tamponade (90 to 97%) (136,137). Reaccumulation rates with this method are 0% to 6%. Reaccumulation rates for other therapies that are administered after initial pericardiocentesis is performed are radiotherapy, 33%; systemic chemotherapy, 30%; sclerotherapy with tetracycline, 15% to 30%; and mechanical therapies, including indwelling pericardial catheter placement, balloon pericardiotomy, and thoracotomy with pericardiostomy, 0% to 15% (52).

Even if there is no reaccumulation of fluid, cardiac function may remain impaired in the presence of epicardial infiltration by tumor. Diastolic dysfunction occurs because of the constrictive effect of a diseased epicardium surrounding the heart. Effusive-constrictive pericarditis results in a combination of tamponade and cardiac restriction. This entity must be considered in the differential diagnosis when a patient develops hemodynamic collapse a few days after pericardiocentesis. Pericardiectomy may be useful in alleviating the constrictive component; irrespective of this procedure, mortality is extremely high (52,138–140).

Pathophysiology

NE has a predilection for the terminal ileum, cecum, and appendix (160). One factor that may explain this predisposition is the overall decreased blood supply to the colon (145). Also, inherent to the cecum is decreased vascularity and increased distensibility compared to other colonic segments (151,161), and progressive distention in the cecum may cause increasing intraluminal pressure and exacerbation of submucosal edema (151). The pathogenesis of NE is multifactorial and remains unclear (141,145). Drug-induced cytotoxic mucosal injury (141,142,151) initiates the process by limiting cellular proliferation and generating glandular epithelial atypia and necrosis (cytosine arabinoside), and by producing myenteric plexus degeneration (vincristine) (151). Subsequently, mucosal barrier integrity is breached because cells cannot rapidly regenerate to repair the damaged surface (151). Once mucosal damage develops, bacterial translocation occurs, resulting in microbial infection and sepsis (141,151). Marked neutropenia impairs host defense and promotes further microbial invasion; bowel flora becomes altered (145). Blood cultures are often positive for Clostridium septicum, C. difficile, Escherichia coli, Pseudomonas, Klebsiella, Enterobacter, and Staphylococcus (144,151). Candidiasis, primarily Candida albicans, which colonizes mucosal surfaces, is the most common fungal infection in neutropenic patients and is associated with a high morbidity and mortality (162). These microbial infections lead to inflammation and edema. With sustained profound neutropenia, bacterial invasion is unconstrained, resulting in transmural necrosis, hemorrhage, ulceration, and perforation (144,145,151,163). In addition to drug-induced mucosal injury, infiltration of mucosa with leukemic and lymphoproliferative cells and mucosal ischemia from sepsis-related hypotension may also participate in initiating and perpetuating mucosal injury (151,160).

Diagnosis

The onset of NE is 7 to 10 days after treatment when neutropenia is evident. The clinical presentation includes fever, occurring in 90% of all hospitalized neutropenic patients at any time (163), nausea and vomiting, abdominal pain, and watery or bloody diarrhea. Physical examination may reveal stomatitis with diffuse mucositis, abdominal tenderness, abdominal distention, and peritoneal signs suggestive of bowel perforation (151,152,164). In 60% to 80% of patients, right lower quadrant (RLQ) tenderness is elicited. Palpation of a mass in the RLQ usually indicates a thickened, dilated, fluid-filled cecum (151).

On laboratory analysis, in addition to neutropenia, thrombocytopenia may be seen. Blood cultures are positive in 50% to 82% of cases for bowel organisms as described above (144). Stool studies may be notable for absence of C. difficile toxin A because C. difficile is not the primary pathogen in NE (143,161).

Plain radiographs of the abdomen are usually normal or nonspecific. Findings may include a decrease in RLQ gas with dilated small bowel loops and air–fluid levels consistent with a distal bowel obstruction. Free intraperitoneal air after perforation, pneumatosis coli, or localized or diffuse “thumb-printing” characteristic of mucosal edema may be exhibited (141,151). Sonography assists in confirming the diagnosis of NE and in excluding other differential diagnoses by detecting bowel wall thickening. Additionally, ultrasound is useful in following the clinical course of the disease (145,165). Sonographic manifestations of NE include a rounded mass with dense central echoes and a wider hyperechoic periphery (141), pseudopolypoid changes of the cecal mucosa, and pericolic fluid collections (151). CT is a more accurate modality for assessing cecal wall thickening and evaluating the extent of the colitis (141,145). It also has utility in differentiating NE from appendicitis, appendiceal abscess, or pseudomembranous colitis (167). CT findings include diffuse submucosal thickening and edema of the terminal ileum and ascending colon, mural hemorrhage, pericolic fluid collections, abscess formation, pneumatosis coli, and intraperitoneal free air (145). The false-negative rates in identifying NE for CT, ultrasound, and plain radiographs are 15%, 23%, and 48%, respectively (149).

Barium enema is unsafe because it may result in bowel perforation in the presence of severely damaged, necrotic bowel (142,167). Endoscopic evaluation is generally avoided because it involves a high risk of perforation in addition to hemorrhagic and infectious complications, and it may precipitate fulminant mural necrosis (141). Colonoscopy has been performed in a small number of patients and shows irregular nodular mucosa, ulcerations, hemorrhagic friability, and a masslike lesion resembling carcinoma (142).

Management

Prospective trials or case-control studies evaluating therapeutic interventions in NE are lacking (143). Conservative management of NE is indicated for patients without overt perforation, peritonitis, or bleeding; this includes bowel rest, intravenous fluid and blood product resuscitation, broad-spectrum antibiotics, granulocyte colony-stimulating factor (G-CSF), and nasogastric decompression. Medications that inhibit bowel motility, such as antidiarrheal and narcotic agents should be avoided because they perpetuate ileus and promote bacterial overgrowth (152). Patients with chemotherapy-induced NE may suffer from repeated episodes with future treatment; therefore, further chemotherapy should be withheld until NE has completely resolved. Bowel decontamination may be helpful before subsequent chemotherapy (142). Empiric antibiotic therapy with a carbapenem, piperacillin–tazobactam, or cefepime plus metronidazole should be initiated immediately (143,151,168). Empiric antifungal therapy with voriconazole or amphotericin B therapy should be considered in profoundly neutropenic patients whose fevers persist beyond 3 days of appropriately dosed broad-spectrum antibiotics (146).

G-CSF increases cell division in myeloid precursor cells, decreases bone marrow transit time, and modulates activity and function of developing and mature neutrophils (163). As clinical improvement in NE patients is usually seen after normalization of the neutrophil count, G-CSF is often given as part of initial management of this condition; it should be noted that there are no data to support its use. Furthermore, there is a theoretical risk that bowel inflammation during immune recovery may lead to further inflammation and perforation (142).

There are no standard recommendations, but rather, general guidelines in the literature regarding surgical intervention in NE. Most patients are unlikely to be surgical candidates. Early reports recommended aggressive and early surgical resection of involved bowel, anticipating that in the natural history of NE, bowel perforation is inevitable (143). Subsequent series demonstrate successful nonsurgical management (143,169,170). More recent publications support surgery with laparotomy alone for patients with perforation and ileus (143). Some advocate that patients who fail to improve or develop bowel perforation and peritonitis after 2 or 3 days of conservative therapy warrant consideration for surgery (161,171). Several authors recommend surgery for severe complications such as abscess, necrotic bowel, and obstruction (145). In general, definitive indications for surgery include intraperitoneal free air/perforation, generalized peritonitis, and persistent bleeding in spite of correction of coagulopathy (141,151). Important considerations that must influence the decision to surgically intervene are the patient’s prognosis and comorbidities (151). If surgery is warranted, the procedure of choice is colectomy with ileostomy and mucous fistula; a primary anastomosis is used in very few patients (172). Of note, the extent of mucosal necrosis may be underestimated by the appearance of the serosa. A surgeon must ensure complete resection of edematous bowel, even in the absence of necrosis and inflammation, to preclude a fatal outcome (151).

Controversies

The management of NE is not based on prospective studies of medical versus surgical intervention. Treatment is usually individualized and based on past experience. Although it appears reasonable to treat patients with early NE conservatively, there are no data to support superior outcomes with this approach.

Pulmonary Toxicities

Pulmonary toxicity, both acute and chronic, is seen increasingly with numerous antineoplastic agents (176). Chemotherapy-induced lung disease describes lung injury with multiple etiologic agents and varying pathophysiologic mechanisms. These major mechanisms include direct lung toxicity, immunologic response, and increased capillary permeability. The corresponding clinical presentations are interstitial pneumonitis/fibrosis, hypersensitivity syndrome, and capillary leak syndrome, respectively, and each may eventuate in fulminant respiratory failure. Symptoms can appear immediately or months after termination of therapy (177).

Antitumor Antibiotics

Alkylating Agents

Microtubule-Targeting Agents

Antimetabolites

Differentiation Agents

Cardiac Toxicities

Small Molecule Kinase Inhibitors

The drugs sunitinib, sorafenib, dasatanib, and lapatinib belong to the family of small molecule tyrosine kinase inhibitors (TKI). These agents interfere with VEGF, FLT, and PDGF-mediated pathways and have activity across a wide spectrum of malignancies.

Gastrointestinal Toxicities

Immunomodulatory Agents

The successful use of immunomodulatory antibodies in the treatment of melanoma and other malignancies heralds a new front in the treatment of cancer. The anti–cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibodies ipilimumab and tremelimumab (currently under development) as well as the anti–programmed cell death-1 receptor antibodies nivolumab and pembrolizumab carry a unique set immune–related toxicities affecting the skin, GI tract, liver, and endocrine system. These adverse events are triggered by a release of natural immunologic inhibition and are often successfully managed with a course of immunosuppressive therapy such as corticosteroids, tumor necrosis factor-alpha antagonists, or mycophenolate mofetil. The approach to treatment of these adverse events is based upon clinical experience, as there no prospective trials to guide therapy.