Chapter 72. Oncologic Emergencies

• Patients with malignancy are subject to life-threatening complications of the primary disease, its treatment, or coexisting medical diseases.
• Oncologic emergencies should be treated when they are associated with higher acute morbidity and mortality than the underlying malignancy.
• In patients who are terminally ill from their malignancy, restraint should be exercised in the diagnosis and management of oncologic complications.
• A high index of suspicion must be maintained for oncologic complications to be recognized because they often share features with other common medical illnesses.
• Frequent examination of critically ill patients is necessary because such patients (often intubated, bed-bound, hypotensive) are often unable to verbalize changes in their condition.

This chapter details the epidemiology, pathophysiology, clinical presentation, diagnostic approaches, and treatment modalities of the most common oncologic emergencies. Because of the systemic nature of cancer, these emergencies often affect organ systems remote from the original cancer, making diagnosis challenging. To recognize these disorders, it is important to develop a differential diagnosis for common signs and symptoms that occur in critically ill patients (Table 72-1). Given the long natural history of many advanced cancers, the successful diagnosis and management of these emergencies may be rewarded with prolonged survival. However, when cancer patients become end stage, the same invasive diagnostic procedures and aggressive treatments may be onerous. Decisions regarding management of these patients may be best made through discussions among the patient, the primary oncologist, the family, and the treating physician.

Superior Vena Cava Syndrome

Superior vena cava (SVC) syndrome is the clinical manifestation of SVC obstruction and occurs through external compression, thrombosis, or invasion of the vein. While previously in the realm of nonneoplastic entities such as syphilitic aortitis or histoplasmosis, SVC syndrome is now almost exclusively (>90%) secondary to malignancy.1 The syndrome complicates 2% to 8% of primary thoracic malignancies, most frequently small cell carcinoma of the lung, followed by other lung cancer histologies, non-Hodgkin's lymphoma, and mediastinal germ cell tumors.2–5 Studies estimate the risk of clinically evident subclavian vein thrombosis to be approximately 5%6,7 in cancer patients with indwelling central venous catheters, and some small percentage of these apparently evolve to SVC syndrome.8–10

To understand the clinical manifestations of the syndrome, an appreciation of the regional anatomy is necessary (Fig. 72-1). Because the venous drainage from the upper extremities, upper thorax, and head is obstructed, SVC syndrome presents with symptoms related to engorgement of these areas. Both the degree of SVC compromise and the extent of collateral veins determine the varied clinical presentation, which can be as mild as slight facial and upper extremity edema or as dire as intracranial swelling, seizures, hemodynamic instability, and tracheal obstruction. Table 72-2 lists the frequency of symptoms in 66 patients admitted with SVC obstruction.1 Because of the lore of the dire symptomatologies, physicians often react to suspected SVC syndrome with panicked urgency and are tempted to initiate treatment before a pathologic diagnosis can be made. However, some argue convincingly that the SVC syndrome is rarely so urgent as to preclude timely and methodical radiologic and pathologic evaluations prior to therapy.11

When a patient presents with suspected SVC syndrome, the first step is to obtain an imaging study to both confirm the diagnosis and assist in treatment decisions. Of the several imaging modalities available for diagnosing the syndrome, the best study is the one that can be obtained most expediently. Magnetic resonance imaging (MRI), contrast-enhanced computed tomographic (CT) scanning, radionuclide flow study, and traditional venography are all adequate modalities, but at most centers CT scan is the most readily available. CT scan and MRI also provide information regarding possible etiologies and thus can direct the approach to a tissue diagnosis. The approach to establishing a tissue diagnosis is defined by both the patient's clinical stability and the findings on examination and radiographic studies. Table 72-3 summarizes the diagnostic yields for several tests ranging from noninvasive approaches such as sputum cytology to the maximally invasive thoracotomy. Tissue diagnoses are important because they guide treatment; specifically, they identify patients for whom SVC syndrome should be treated with combination chemotherapy rather than with local measures such as radiation therapy or percutaneous vascular procedures. Patients with known thoracic malignancies clearly do not require a further tissue diagnosis.

Treatment of SVC syndrome is divided into supportive and definitive therapy. Acutely, patients should be supported with elevation of the head of their bed and supplemental oxygen. Although dexamethasone is sometimes used, its utility has never been supported by experimental data. The definitive treatment of SVC syndrome depends on the etiology. Studies of small cell lung cancer patients with SVC syndrome reveal systemic combination chemotherapy to be more efficacious than radiation therapy, with 73% to 100% of patients experiencing symptomatic relief within 7 days.5,12,13 Conversely, for non-small cell lung cancer and for solid tumors metastatic to the thorax, such as breast cancer, radiation therapy is the preferred treatment modality and is associated with a 56% to 70% success rate within 2 weeks.2 Finally, in patients with non- Hodgkin's lymphoma, single-modality chemotherapy and radiation therapy appear equally efficacious, with 100% of patients experiencing relief of symptoms within 2 weeks.3 For these patients, chemotherapy is argued to be the better modality because it also provides systemic therapy. Patients with recurrent or refractory symptoms may benefit from percutaneous stent placement. SVC stenting with thrombolytic therapy and/or systemic anticoagulation is associated with immediate relief of symptoms in more than 90% of patients and provides excellent palliation in most patients.14–20 Vascular bypass surgery is a treatment modality available for similar patients, but the even higher morbidity and mortality in such patients make it an infrequently employed therapy. Finally, for patients whose SVC syndrome is secondary to venous catheter thrombosis, thrombolytic therapy given within 5 days of the onset of symptoms is associated with a greater than 80% success rate.21,22 For thromboses of longer duration, catheter removal in the setting of systemic anticoagulation with heparin and warfarin may be a more successful approach.

Malignant Pericardial Disease

Pericardial disease in cancer patients can result from a variety of medical conditions, including radiation, uremia, infection, and malignancy. Autopsy series have shown that malignant involvement of the pericardium complicates 5% of cancers and is usually clinically silent.23,24 However, the series reveal that when malignant pericardial disease is symptomatic, it is often the direct or a supporting cause of death. Thoracic tumors are the most frequent tumors to invade the pericardium directly or hematogenously, with lung cancer first, followed by lymphoma and breast cancer.23,24

Malignant pericardial effusion leading to tamponade can be an immediately life-threatening complication of malignant pericardial disease and should be suspected in cancer patients with new cardiopulmonary complaints (see Chap. 28). Because the right-sided cardiac chambers are compressed by surrounding fluid, signs of both right-sided heart failure and left-sided heart insufficiency result. As Table 72-4 details, the presenting symptoms reflect these circulatory disruptions and are, in decreasing order of frequency, dyspnea, cough, orthopnea, chest pain, and pedal edema.25 Examination often reveals hypotension, tachycardia, distended jugular veins, and a paradoxical pulse of greater than 10 mm Hg. Chest radiographs reveal cardiomegaly in most and pleural effusions in approximately half of patients. However, patients with prior chest radiotherapy may not have radiographic evidence of cardiomegaly due to radiation-induced fibrosis of the pericardium. Electrocardiographic (ECG) abnormalities are protean, usually nonspecific, and commonly include sinus tachycardia and decreased voltage in the limb leads but rarely electrical alternans (i.e., alteration in the amplitude of the R wave, as shown in Fig. 72-2).24–26 Echocardiography confirms the diagnosis by revealing effusion associated with inspiratory increase in right ventricular dimensions and right atrial and/or right ventricular collapse. Classically, right-sided heart catheterization reveals equalization of intrapericardial, right atrial, right ventricular diastolic, and pulmonary capillary wedge pressures.27 Since not all pericardial effusions in cancer patients are malignant, both the clinical setting and the results of a diagnostic pericardiocentesis or pericardial biopsy are critical to determining the etiology and therefore the correct treatment for this condition.

Management of malignant pericardial effusions can be challenging and is divided into temporizing and definitive therapies. The immediate management of a hemodynamically significant pericardial effusion is echocardiography-guided pericardiocentesis. In 97% of patients, the fluid is removed successfully, and symptoms resolve immediately.28 Unfortunately, in approximately 50% of patients, the fluid reaccumulates, requiring subsequent pericardiocenteses. Several more definitive therapies targeted at decreasing the reaccumulation rate have been paired with pericardiocentesis, including radiation therapy, systemic chemotherapy, pericardial sclerotic therapies, and mechanical therapies. When administered following initial pericardiocentesis, these therapies have the following reaccumulation rates: radiation therapy 33%, systemic chemotherapy 30%, pericardial sclerosis with tetracycline 15% to 30%, and mechanical therapies (e.g., indwelling pericardial catheter placement, balloon pericardiotomy, thoracotomy with pericardiostomy) 0% to 15%.29–32

Of all the mechanical therapies, balloon pericardiotomy has the best reaccumulation profile, with 0% to 6% reaccumulation.29–32 The procedure includes a pericardiocentesis followed by balloon catheter dilation of the pericardial needle entrance site. Typically, a balloon catheter is placed across the pericardial entrance site and inflated two to three times, each for 1 to 2 minutes for a total procedure time of 20 to 40 minutes. Side effects have been limited to asymptomatic pleural effusions in most patients.29,30 Not only is balloon pericardiotomy more successful than other less invasive therapies, but it is also the most successful and least morbid of the other mechanical therapies, most of which require general anesthesia and thoracotomy. At centers with staff facile with this technique, patients requiring definitive management of malignant pericardial effusions should be evaluated for this therapy.

Even when fluid does not reaccumulate, cardiac function may not return to normal because of tumor infiltration of the epicardium. This causes diastolic dysfunction mimicking pericardial constriction. This combination of tamponade and cardiac restriction is termed effusive-constrictive pericarditis and may complicate as many as 50% of malignant effusions presenting with hemodynamic compromise. Diagnosis rests on measurement of right side of the heart and pericardial pressures both before and after draining the effusion.33 This complication may lead to critical hemodynamic deterioration in the days following pericardiocentesis, and while some patients may benefit from pericardiectomy, most will succumb.

Radiation-Related Pericardial Disease

Three well-described pericardial syndromes that can manifest in the months to years following radiation therapy to the mediastinum are acute pericarditis with or without tamponade, pericardial effusion with or without tamponade, and pericardial constriction.34 Such cardiac complications have been described in patients receiving radiation therapy for a variety of tumors within or adjacent to the thoracic cavity (e.g., breast cancer, Hodgkin's disease, esophageal cancer, lung cancer), and one study reported a 9% rate of pericardial effusion in patients receiving radiation therapy to esophageal tumors.35 The authors suggest that effusions may be predictable when considering elements of radiation administration, with fraction sizes of more than 2 Gy associated with increased risk. The symptoms associated with constrictive pericarditis typically develop insidiously over a period of months to years. Increasing abdominal girth and peripheral edema, along with progressive exertional dyspnea, are common complaints. As the disease progresses, symptoms suggestive of cardiac cachexia develop (e.g., weakness, dyspnea at rest, palpitations).

Patients generally have a normal or low blood pressure. Elevated venous pressure is demonstrated by jugular venous distention with a rapid y descent and rapid rebound. In contrast to cardiac tamponade, an inspiratory increase in jugular venous distention (Kussmaul's sign) occurs in constrictive pericarditis. The heart sounds are often distant. Hepatomegaly, pulmonary edema, and ascites are late clinical features of the syndrome. Chest radiographs show an enlarged cardiac silhouette in only slightly more than 50% of cases. Occasionally, intrapericardial calcifications are present; however, the absence of calcifications does not exclude constrictive pericarditis. ECG findings are nonspecific. Atrial fibrillation is observed in long-standing cases owing to elevated atrial pressure.

M-mode and two-dimensional echocardiography can demonstrate pericardial thickening, but most findings are nonspecific. Doppler echocardiography can demonstrate altered patterns of left ventricular filling that distinguish normal individuals from those with constrictive pericarditis. Patients with constrictive pericarditis typically have a rapid deceleration of filling velocity and a shortened filling period.

In constrictive pericarditis, cardiac catheterization will demonstrate equilibration of diastolic pressures in all four chambers. The ventricular pressure tracing will demonstrate the characteristic dip-and-plateau pattern, or square-root sign (Fig. 72-3). The early diastolic dip of ventricular pressure indicates abnormally rapid ventricular filling in constrictive pericarditis. The pulmonary artery pressure is slightly elevated, and the cardiac index is usually decreased. Angiography is able to demonstrate a thickened pericardium in most patients with constrictive pericarditis, and more recently, CT scan has been shown to effectively distinguish between restrictive myocardial disease and constrictive pericarditis by the presence of a thickened pericardium. Clinically significant pericardial effusions are managed with pericardial drainage as described earlier, and pericardial constriction is managed with cardiac surgery (e.g., pericardial stripping, pericardial resection).

Spinal Cord Compression

Malignant compression of the spinal cord complicates between 5% and 10% of all malignancies and requires emergent initiation of therapy to stop what is often rapid and irreversible neurologic deterioration.36 In 85% of patients, the condition results from the hematogenous spread of a previously diagnosed cancer to the vertebral body that then compresses the cord directly or causes vertebral body collapse, compressing the cord.37 In a small number of patients (10%), the condition results from paraspinal malignancies such as lymphoma that compress neural structures traversing the foramina. The most common vertebral levels of spinal cord compression (SCC) are thoracic (70%), lumbosacral (15%), and cervical (15%), and up to 50% of patients have tumor in more than one, often noncontiguous vertebra.37,38 Clinical series have shown that the tumors most likely to cause SCC are, in decreasing order of frequency, breast carcinoma, lung carcinoma, lymphoma, prostate carcinoma, renal cell carcinoma, and myeloma, together accounting for nearly 70% of histologies.37

The presenting symptoms and signs of malignant SCC in 130 patients are detailed in Table 72-5.37 While back pain is the presenting complaint in almost all patients (96%), the pain can be either localized or radicular, and it can be challenging to distinguish SCC from benign conditions such as degenerative joint disease or disk disease. Characteristics suggestive of SCC include a history of pain worsening with Valsalva maneuver, cough, or recumbency. Subsequent examination reveals clear, objective weakness (usually bilateral and symmetric) in 87% of patients. Sensory deficits are noted in 78% and autonomic dysfunction (like urinary retention or incontinence) in 57% of patients. Patients with autonomic dysfunction at the time of diagnosis form an important poor-prognosis subgroup in which 66% lose ambulation.

After the suspicion of malignant SCC is raised by history and/or physical examination, dexamethasone should be administered (see details of dosing below), and radiologic evaluation must be obtained quickly. The absence of objective neurologic signs of SCC should not dissuade the clinician from the appropriate diagnostic evaluation. Nearly all patients (>80%) with SCC will have abnormal plain radiographs.36,38,39 The anteroposterior (AP) view can reveal pedicle pathology such as erosion or displacement; the lateral view can reveal vertebral body pathology such as collapse; and the oblique view can reveal foramina pathology such as encroachment or enlargement. Since plain films are both highly sensitive and specific for malignant SCC, they are preferable to bone scans, which, although quite sensitive for malignant bony disease, are less sensitive for SCC.40 An important exception to this rule occurs in lymphoma patients, 60% of whom will have no abnormalities on plain films.41 Subsequent imaging with gadolinium-enhanced MRI will both confirm the diagnosis and determine the extent of disease for radiation planning.42,43 Of note, an MRI examination of the entire spine is often necessary, irrespective of the site of pain, because multilevel disease is often present, particularly in patients with prostate cancer and myeloma. If MRI is unavailable or contraindicated, the more invasive metrizamide myelography with or without CT scan can confirm the diagnosis.

In most cases, pretreatment neurologic function portends posttreatment function, with most ambulatory patients (approximately 80%), fewer paretic patients (<50%), and even fewer paraplegic patients (<10%) ambulatory after therapy.37,38,40 Therapy for SCC is divided into temporizing therapy and definitive therapy. Acutely, patients should be given dexamethasone 10 mg intravenously, followed by 4 mg every 6 hours to continue until the completion of definitive therapy. The steroid will decrease cord edema and thereby transiently improve neurologic signs and symptoms in some patients. Radiation therapy and surgical decompression via laminectomy are the two definitive treatment modalities. Series examining the effect of laminectomy followed by radiation therapy compared with radiation therapy alone reveal radiation therapy alone to be equally efficacious and far less morbid than the more invasive therapy in most patients.37–44 However, there are several instances in which surgery with radiation therapy is preferable to radiation therapy alone, including patients in whom a tissue diagnosis is needed, in whom the tumor is radio-refractory such as sarcoma or melanoma, in whom there is spinal instability requiring surgical stabilization, and in whom disease occurs in a previously irradiated field. Finally, for those patients whose SCC results from bony metastases, regular bisphosphonate therapy is an appropriate approach to decreasing the risk of subsequent skeletal complications of the malignancy. Ninety milligrams of intravenous pamidronate infused over 2 hours every 4 weeks has been found in placebo-controlled, randomized trials to reduce skeletal complications in patients with myeloma and patients with breast cancer metastatic to the bone.45,46 Zolendronic acid, a newer bisphosphonate that can be infused more rapidly, appears to offer equivalent protection against skeletal events.47

Cerebral Herniation Syndromes

In cancer patients, cerebral herniation syndromes result from space-occupying brain tumors that increase intracranial pressure and thereby compress the brain against rigid cranial elements (see Chap. 65). Herniation can result from primary central nervous system (CNS) tumors or from those metastatic to the CNS, with lung cancer, breast cancer, melanoma, renal cell carcinoma, and lymphoma the most common.48 With increased intracranial pressure, patients initially experience intermittent bilateral frontal or occipital headaches. The headaches often awaken patients from sleep or are present on awakening in the morning. They can be accompanied by signs of elevated intracranial pressure, such as projectile vomiting, unsteady gait, and papilledema. As intracranial pressure increases further, cerebral function decreases, leading to inattention, apathy, psychomotor retardation, and somnolence. Because the brain is compartmentalized by the falx cerebri and tentorium, increased pressure in one compartment is equalized into the other compartments through characteristic herniations. MRI may reveal the herniation, as well as the causative tumor and edema (Fig. 72-4).

Management of malignant cerebral herniation syndromes centers around decreasing intracranial pressure through several simultaneous interventions and then initiating definitive antitumor therapy. First, the patient should be loaded with dexamethasone 10 mg intravenously, followed by 4 mg every 6 hours, to mitigate cerebral edema and thereby reduce intracranial pressure. The patient then should be intubated for both airway protection and hyperventilation to a PaCO2 of roughly 30 mm Hg. Hypocapnia to this level results in cerebral vasoconstriction, which will decrease intracranial volume and thereby reduce intracranial pressure. The effect, however, is of a short duration (48 to 72 hours) because renal bicarbonate wasting will act to normalize cerebral pH and thereby normalize cerebral blood flow.49 Finally, a loading dose of the osmotic diuretic mannitol 100 g, followed by 25 g as needed, may further reduce intracranial edema. The patient should be evaluated emergently by a radiation oncologist for more definitive therapy with cranial radiation therapy.

Carcinomatous Meningitis

Carcinomatous meningitis results from the direct or hematogenous seeding of the meninges by tumor cells and should be suspected in cancer patients presenting with deficits in multiple areas of the neuraxis. Autopsy studies suggest that malignant involvement of the meninges is common, occurring in 8% of cancer patients. These studies reveal that patients with acute leukemias have the highest rates of leptomeningeal disease, followed by patients with non-Hodgkin's lymphoma, small cell lung cancer, and breast cancer.48

The diagnosis of carcinomatous meningitis is often elusive, with symptoms that can be both diffuse and localized. Diffuse symptoms result from decreased brain metabolism that is seen with malignant CNS disease, from cerebral spinal fluid (CSF) obstruction causing hydrocephalus and increased intracranial pressure, or from diffuse meningeal irritation. These patients present most frequently with headache and have signs of altered mental status on examination. Localized signs result from spinal and/or cranial nerve root invasion. In cases of spinal nerve root involvement, the most frequent presenting complaint is lower motor neuron weakness, and the most frequent examination findings are reflex asymmetry and weakness. Spinal sensory nerves also can be affected, resulting in complaints of paresthesias and findings of sensory loss. Cranial nerves damaged by tumor deposits result in cranial nerve palsies. Among those with cranial nerve involvement, the most frequent presenting complaint is double vision, and the most frequent examination finding is ocular muscle paresis due to compromise of cranial nerves III, IV, and VI.50

Carcinomatous meningitis is diagnosed most reliably through examination of the CSF, not through neuroimaging. Once a head CT scan excludes a concomitant mass lesion that could cause herniation during lumbar puncture, the patient should undergo a lumbar puncture, followed by CSF examination. Table 72-6 details the initial CSF results of 90 patients with leptomeningeal metastases. It reveals that 97 percent of patients with carcinomatous meningitis have CSF abnormalities with the following distribution: elevated protein 81%, elevated white blood cell count 57%, positive cytology 54%, elevated opening pressure 50%, and depressed glucose 31%. The cytology yield increases to 86% if three lumbar punctures are performed.50 MRI with gadolinium can identify leptomeningeal deposits as areas of enhancement but is positive in only 33% to 66% of cases.51,52

Successful treatment of carcinomatous meningitis can arrest or sometimes reverse neurologic loss, extending patient survival from weeks to months.50 The treatment modalities are intrathecal chemotherapy and/or radiation therapy. Because the blood-brain barrier hinders the passage of systemic chemotherapeutic agents into the brain, chemotherapy must be administered intrathecally through a ventricular reservoir (e.g., Ommaya shunt) or through a lumbar puncture. Standard regimens are methotrexate 10 mg twice weekly (with systemic leucovorin to prevent bone marrow suppression), thiotepa 5 to 10 mg twice weekly, or cytarabine 90 mg twice weekly until clinical neurologic improvement occurs or until CSF cytology clears of malignant cells. The interval between doses is then increased to weekly or monthly. While acute side effects are transient nausea and vomiting, the late side effects are myelosuppression and mucositis from systemic absorption of the chemotherapeutic agent. Radiation therapy is a second treatment option for established cranial or cauda equina neuropathies and may be given either singly or in association with intrathecal chemotherapy. Focal areas of disease are irradiated rather than the entire neuraxis because the latter is associated with substantial myelosuppression. The acute side effect is transient nausea. A rare complication of concomitant methotrexate and radiation therapy is leukoencephalopathy.50 With these therapies, approximately 50% of patients will experience either improvement or stabilization of their disease.50 Since carcinomatous meningitis is often a late finding in the course of a patient's malignancy, and since treatment often has limited success, the decision of whether to treat needs to be considered carefully, taking into account the patient's performance status and the state of his or her systemic cancer. It is not unusual for patients with carcinomatous meningitis to be at such a point in their illness (i.e., have widespread and refractory cancer) that the complication is managed with supportive care alone and not chemotherapy or radiation.

Lactic Acidosis

Tumor-induced lactic acidosis is an extremely rare condition that occurs in malignancies with exceptionally high proliferative indices, such as Burkitt's lymphoma; small noncleaved, non-Burkitt's lymphoma; or acute lymphoblastic leukemia. Although the mechanism has not been established definitively, it is likely a function of tumor cell hypoxia leading to anaerobic metabolism (glycolysis) that generates lactate. Concomitant hepatic impairment by the malignancy may reduce the patient's ability to metabolize the lactate produced. The diagnosis of lactic acidosis should be suspected in cancer patients with large tumor burdens who have anion-gap acidoses and no history of toxic ingestion or clinical or laboratory evidence of diabetic ketoacidosis or uremia. Such patients usually have high levels of serum lactate dehydrogenase (LDH), indicating high tumor cell turnover. The mainstay of treatment of this condition is treatment of the malignant cause of the acidosis with urgent chemotherapy. The role of exogenous sodium bicarbonate in the management is controversial, with several animal and human studies reporting increased cellular acidosis, increased serum lactate concentration, and higher mortality in subjects treated with bicarbonate.53–56 Although standard texts recommend supplemental bicarbonate therapy in patients with a blood pH of less than 7.1, it is not clear that this improves clinical outcome in this patient population.

Tumor Lysis Syndrome

Tumor lysis syndrome is another complication of rapidly proliferating tumors. Tumor lysis syndrome is a life-threatening condition caused by the rapid release into the plasma of large quantities of cytoplasmic solutes, most notably potassium, uric acid, and inorganic phosphate, liberated by tumors with high proliferative indices (e.g., Burkitt's lymphoma) either because of rapid cell turnover or because of cell lysis by cytotoxic chemotherapy. Uric acid nephropathy may result from intrarenal precipitation of massive amounts of uric acid. Uric acid crystals in the renal collecting system obstruct urine flow, raising intrarenal pressure and thereby decreasing vascular perfusion. The end result is acute oliguric renal failure. Patients may develop lethargy, seizures, nausea, and vomiting and eventually symptoms and signs of volume overload. Laboratory evaluation typically reveals elevated potassium, uric acid, and inorganic phosphate levels and often creatinine. Urine evaluation can reveal uric acid concentrations of 150 to 200 mg/dL and both uric acid and sodium monourate crystals.57

The management of tumor lysis syndrome is primarily preventive, with the goal to decrease uric acid production and increase its urine solubility. Decreased production is achieved through the use of allopurinol, a xanthine oxidase inhibitor. Treatment with allopurinol should precede chemotherapy by 2 to 3 days, if possible. The initial dose of between 300 and 800 mg daily should reflect tumor burden. The dose eventually may be decreased to between 100 and 300 mg daily and should continue through the period of cytoreduction. The dose should be reduced for renal insufficiency. Increased uric acid solubility can be achieved by maximizing urine output and by making the urine alkaline through the use of sodium bicarbonate or acetazolamide.58,59 Urinary output of 3 L/d (125 mL/h) and a urinary pH of 7 or greater often are recommended. The use of recombinant urate oxidase (rasburicase), a catalyst in the oxidation of uric acid to allantoin, in the prophylaxis or treatment of patients with hyperuricemia in the setting of leukemia and lymphoma shows promising results.60 The drug has the advantage over allopurinol of both blocking uric acid formation and increasing its solubility and requiring administration only hours prior to chemotherapy administration. For patients in whom uric acid nephropathy develops despite these measures, hemodialysis can both acutely decrease serum uric acid and correct the volume and electrolyte effects of acute renal failure.61

Hypercalcemia

Hypercalcemia is the most common life-threatening metabolic disorder associated with malignancy. It has been estimated that between 10% and 20% of cancer patients become hypercalcemic during the course of their disease.62 Cancers commonly associated with hypercalcemia include both solid tumors, in particular squamous cell histologies, and hematologic malignancies, in particular multiple myeloma.

Dysregulation of bone resorption is the principal factor implicated in the hypercalcemia of malignancy, although defects in renal clearance and intestinal absorption also have been described. Current evidence suggests that this disorder is most often due to increased bone resorption secondary to diffusible factors produced in excess by cancer cells or direct malignant bone invasion. The best characterized of the diffusable factors is parathyroid hormone–related peptide (PTHrP). In cancers metastatic to bone, the bony destruction that was originally attributed to the tumor cells themselves in most cases may be secondary to high local concentrations of PTHrP resulting in osteoclast activation. Other diffusible factors also have been implicated in tumor-related osteolysis and subsequent hypercalcemia, notably tumor necrosis factor and interleukin 6 in multiple myeloma.63,64

The clinical manifestations of hypercalcemia of malignancy are protean and depend on both the rate of increase of serum calcium concentration and the absolute value. A slow rise to 14 mg/dL may be imperceptible, whereas a rapid elevation to 12 mg/dL could result in coma. The typical presentation is with nausea, vomiting, anorexia, fatigue, weight loss, and dehydration. Table 72-7 lists many of the common signs and symptoms. Serum calcium has diuretic properties, leading in the hypercalcemic state to volume contraction and eventually dehydration. In the setting of volume contraction, the kidney actively resorbs sodium at the distal tubule under the stimulation of antidiuretic hormone. In addition to resorbing sodium, the Na+, K+ pump resorbs calcium and wastes potassium. This action leads to further increases in total body calcium and deficiency of potassium. The increased calcium, in turn, causes more volume loss, resulting in further resorption of sodium and calcium and loss of potassium. Therefore, when patients become hypercalcemic, they enter a self-perpetuating physiologic cycle of increasing hypercalcemia.

Treatment is focused on reversing the physiologic progression of hypercalcemia, as well as on attenuating the underlying pathologic process that initiated the elevation. To interrupt the physiologic progression acutely, one should rehydrate patients with intravenous fluids and correct hypokalemia. Treatment of the underlying pathology consists of both anticancer therapies and initiation of bisphosphonate therapy to attenuate release of calcium from the bone. Since the randomized trial showing pamidronate to be superior over saline alone, bisphosphonates, like pamidronate, became the cornerstone of the treatment for hypercalcemia of malignancy through their inhibition of osteoclast activity.65 A newer bisphosphonate, zoledronic acid, has the advantage over pamidronate of both more rapid administration and more rapid resolution of hypercalcemia. A large randomized study comparing zoledronic acid with pamidronate revealed that a single 4-mg dose of zoledronic acid infused over 5 minutes was superior to a single 90-mg dose of pamidronate infused over 2 hours in normalizing serum calcium concentration within 10 days (88% versus 70%) and in the duration of response (32 versus 18 days).66 Other therapeutic measures may be required in acute, symptomatic hypercalcemia resistant to hydration. For example, calcitonin given at the dose of 200 to 400 MRC units intramuscularly or subcutaneously every 12 hours will rapidly lower serum calcium concentration and, although its effects are short-lived, may be useful in the period before bisphosphonate therapy takes effect.

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was first described in the 1950s by investigators who reported the finding of hyponatremia associated with renal sodium loss and high urine osmolality in two lung cancer patients.67 The authors correctly theorized that cancer-produced antidiuretic hormone (arginine vasopressin) was responsible for the syndrome.68 The tumor most frequently associated with SIADH is small cell lung cancer, although many other cancers have been reported to cause the syndrome. Up to 15% of small cell lung cancer is complicated by SIADH.69 However, as shown in Table 72-8, a host of other mechanisms can be responsible for SIADH in cancer patients, including infections, drugs, pulmonary processes, and CNS processes.

Antidiuretic hormone is normally synthesized in the posterior pituitary and functions as a critical physiologic regulator of water balance. It acts primarily on the collecting tubules of the nephron to stimulate upregulation of water channels, permitting increased free water resorption. It is controlled by a complex network of signals derived from volume and osmoreceptors in the hypothalamus, left atrium, and pulmonary veins and from circulating angiotensin II. Excessive autonomous secretion of ADH leads to excess water resorption out of proportion to sodium, resulting in progressive water intoxication and hyponatremia. The hyponatremia can lead to CNS toxicity, with headaches and fatigue ultimately progressing to confusion, seizures, coma, and death.

The mainstay of treatment of SIADH caused by tumors is therapy for the underlying malignancy. When this is not sufficient, or when the serum sodium concentration is less than 130 mEq/L, fluid restriction is the next step. For relatively mild cases, restriction of free water to 1 L/d may be adequate to correct the serum sodium concentration. Greater fluid restriction occasionally may be required, although it is difficult to accomplish, especially in the outpatient setting. Another approach is serum sodium correction with 3% saline in patients with acute (<48 hours), symptomatic hyponatremia. Care needs to be taken to avoid too rapid correction of the serum sodium concentration, however, because central pontine myelinolysis70 and volume overload may occur because patients with SIADH are euvolemic. Specifically, the rate of change in the serum sodium concentration should not exceed 1 to 2 mEq/L per hour, and an absolute change of greater than 20 mEq/L in 24 hours should be avoided. After the serum sodium concentration reaches 120 to 125 mEq/L, therapy should be shifted to free water restriction. For chronic cases of hyponatremia, in which free water restriction is not feasible, pharmacologic therapy with demeclocycline has proven to be effective. Demeclocycline inhibits the renal effects of antidiuretic hormone and, when used in doses of 600 to 1200 mg/d, usually restores the serum sodium concentration to normal in 5 to 14 days.71

Hemorrhagic Cystitis

Hemorrhagic cystitis results from inflammation of the bladder and presents with dysuria, hematuria, and urinary frequency. In cancer patients, the condition can result from chemotherapy, radiation therapy, or viral infections. Cyclophosphamide and ifosfamide are the most frequent chemotherapeutic agents implicated in hemorrhagic cystitis and act through their metabolite acrolein to damage the bladder mucosa. While previously complicating greater than 40% of bone marrow transplants, hemorrhagic cystitis now occurs in less than 5% due to preventive management with hydration and the drug mesna.72–76 Vigorous intravenous hydration generates a high urine output that limits bladder exposure to acrolein. Mesna is a thiol that is activated in the kidney and inactivates acrolein in the bladder. Because its half-life is shorter than that of cyclophosphamide, it must be started prior to cyclophosphamide and continued after the completion of the cyclophosphamide infusion. For patients in whom hemorrhagic cystitis develops despite these measures, emergent urologic consultation must be obtained regarding possible bladder irrigation, cystoscopy with clot extraction and fulguration, or chemical hemostasis with formalin. In refractory cases, vascular ligation or even cystectomy may be required.

Hyperviscosity syndrome (HVS) and leukostasis are disorders resulting from a malignant excess of blood components and requiring rapid evaluation for possible emergent apheresis, chemotherapy, and radiotherapy.

Hyperviscosity Syndrome

HVS results from high levels of serum paraprotein often elaborated by Waldenstrom's macroglobulinemia (IgM) or multiple myeloma (IgG, IgA, and very rarely light-chain disease). HVS is characterized by a clinical triad of visual changes, bleeding, and neurologic changes, with patients often presenting with blurred vision, “dizzy headache,” and mucosal oozing.77,78 The visual and neurologic symptoms result from sludging of blood through end arterioles, and the bleeding results from paraprotein-induced platelet dysfunction, clotting factor inhibition, and fibrin inhibition. Funduscopic examination can reveal tortuous vessels with a sausage-like appearance termed fundus paraproteinaemicus, as well as retinal hemorrhage and papilledema. The diagnosis is made by observing a serum paraprotein concentration in the setting of an elevated blood viscosity (usually >4.0 cP). Treatment is plasmapheresis to decrease the paraprotein acutely, followed by chemotherapy to decrease production of the paraprotein. Of note, some IgM paraproteins are cold-reactive, making plasmapheresis with a room-temperature cell separator problematic. These patients should undergo plasmapheresis with prewarmed equipment in a warm room.

Leukostasis

Leukostasis is a rare condition that results from an excess of the blood's cellular elements. The signs and symptoms result from end-organ ischemia, infarction, and hemorrhage due to microvascular thrombi from leukocyte aggregates. Patients may present with visual changes, confusion, and dyspnea. Evaluation may reveal mental status changes, papilledema, cardiogenic or noncardiogenic pulmonary edema, liver dysfunction, renal failure, and priapism. Blood rheology studies and clinical reports reveal the risk of leukostasis to be a complex function of white blood cell type, maturity, and number, as well as hematocrit and platelet count (see Chap. 71). Patients with acute leukemias or the accelerated phase of chronic myelogenous leukemia (CML) with blast counts greater than 50,000/μ L are at a far greater risk for leukostasis than patients with chronic lymphocytic leukemia (CLL) with lymphocyte counts of even 500,000/μ L.79,80 Leukemia patients who present with leukostasis should not receive blood product transfusions until their white blood cell count has been decreased substantially through leukapheresis, chemotherapy, or both because additional blood products will exacerbate their condition through increasing blood viscosity. Patients with pulmonary or CNS leukostasis may require emergent local radiation therapy to arrest organ compromise.

Financial support was provided by a grant from the National Institutes of Health (EBL, Grant No. K07 CA93892).