30 - Oncology Emergencies and Critical Care Issues | Handbook of Cancer Chemotherapy

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

> Table of Contents > Section IV - Selected Aspects of Supportive Care of Patients with Cancer > Chapter 30 - Oncology Emergencies and Critical Care Issues Anaphylaxis, Spinal Cord Compression, Cerebral Edema, Superior Vena Cava Syndrome, Hypercalcemia, Tumor Lysis Syndrome, and Respiratory Failure

Chapter 30

Oncology Emergencies and Critical Care Issues Anaphylaxis, Spinal Cord Compression, Cerebral Edema, Superior Vena Cava Syndrome, Hypercalcemia, Tumor Lysis Syndrome, and Respiratory Failure

Roland T. Skeel

Spinal cord compression, cerebral edema, superior vena cava syndrome (SVCS), anaphylaxis, respiratory failure, tumor lysis syndrome, and bone metastasis can be major causes of morbidity and, in some cases, potential mortality in patients with cancer. Because of the critical nature of these complications of cancer and its treatment, oncologists, oncology nurses, and other oncology health professionals must be prepared to recognize the signs and symptoms of these disorders promptly, so that appropriate therapy can be instituted without delay.

I. Spinal cord compression

A. Tumors

The common tumors resulting in spinal cord compression are breast cancer, lung cancer, prostate cancer, and renal cancer, although it may also occur with sarcoma, multiple myeloma, and lymphoma. Purely intradural or epidural lesions are uncommon because more than three-fourths of cases arise from either metastasis to a vertebral body or other bony parts of the vertebra or, less commonly, direct extension from a paravertebral soft tissue mass. Seventy percent of the bone lesions are osteolytic, 10% osteoblastic, and 20% mixed. More than 85% of patients with metastases to the vertebra have lesions that involve more than one vertebral body.

B. Symptoms and signs

The most common early symptoms seen in patients with spinal cord compression are localized vertebral or radicular pain. These are not from the cord compression per se but rather from involvement of the vertebral structures and nerve roots at the level of the compression. Localized tenderness to pressure or percussion over the involved vertebrae is often found on physical examination. Because pain is seen initially in up to 90% of patients, localized back pain, radicular pain, or spinal tenderness in a patient with cancer should evoke the clinical suspicion of the physician and prompt further evaluation to determine whether the patient has potential or early cord compression. Muscle weakness, evidenced by subjective symptoms or objective physical findings,

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is present in 75% of patients by the time of diagnosis. The clinician must be aware that progression of this symptom can vary from a gradual increase in weakness over several days to a precipitous loss of function over several hours that may worsen rapidly to the point of paraplegia. If muscle weakness is present, it is incumbent on the physician to act urgently to obtain consultation with the neurosurgeon and the radiation oncologist. It is not appropriate to wait until the next morning! By the time there is muscle weakness, most patients also have sensory deficits below the level of the compression and often have changes in bladder and bowel sphincter function. When compression is diagnosed late or if treatment is not started emergently, only 25% of patients who are unable to walk when treatment is started will regain full ambulation.

C. Diagnosis

Magnetic resonance imaging (MRI) is the diagnostic modality of choice, although high-resolution computed tomography (CT) with myelography is an alternative. Plain radiographs and bone scans give evidence of metastases to vertebrae, but, in and of themselves, they are not diagnostic of spinal cord involvement.

When there is evidence of bony involvement of the spine on a plain radiograph, CT scan, or bone scan, our approach is to obtain an MRI for those patients who have subjective or objective evidence of weakness, radicular pain, paresthesia, or sphincter dysfunction because these patients are at the highest risk of spinal cord compression. Routine MRIs in patients who have completely asymptomatic bony spine metastases (without pain, tenderness, or neurologic findings on a comprehensive clinical examination) are not cost effective. In patients with only localized pain or tenderness to correspond with the bone scan or radiographic findings, the yield of additional tests is also low. Thus, the clinical determination of whether to obtain additional invasive or costly diagnostic tests is more difficult and requires a careful assessment of all clinical features of the patient. All patients with metastasis to the spine require close follow-up, and they and their families must be urged to report relevant symptoms immediately.

D. Treatment

As noted in the preceding text, immediate consultation with radiation oncology and neurosurgery is imperative. Because of potentially precipitous deterioration when neurologic deficits have developed, treatment should be started immediately.

Corticosteroids. When a radiologic study identifies the level of cord compression or a neurologic deficit is detected on physical examination, dexamethasone should be started to reduce spinal cord edema. The recommended dose is 10 to 20 mg IV as a loading dose and then 4 to 6 mg PO or IV every 6 hours, to be continued through the initial weeks of radiation therapy. Some recommend higher doses up to 96 mg daily, but whether there is any real benefit is not established and toxicity of the steroids is clearly greater. At completion of radiotherapy, the dexamethasone therapy may be tapered.
Radiotherapy
- Although the preferences of individual centers vary, we generally recommend the immediate initiation
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  of radiotherapy once cord compression is diagnosed. This is based on both randomized and nonrandomized studies showing no significant improvement in outcome for patients treated with surgery plus radiation as compared with those treated with radiation alone. Secondly, metastatic disease to the spine is often not totally resectable, so that follow-up radiation therapy is frequently required. Thirdly, because patients with evidence of spinal metastases frequently have either overt or microscopic evidence of metastases elsewhere that would likely grow during the postoperative recuperation period after surgery, the use of radiotherapy instead allows the initiation of some form of systemic therapy concurrently.
- Dose and Schedule. Radiation therapy is most frequently given to a total dose of 40 to 45 Gy with daily dose fractions of 200 to 250 cGy. Alternatively, 400 cGy daily may be given initially for the first 3 days of therapy and then subsequently decreased to standard-dose levels for the completion of the radiation course. Short-course therapies with higher dose fractions have also been used. These appear to have similar functional outcome in patients with a short prognosis, but local control is maintained for a longer time when long course (standard) therapy is used. The longer course is thus recommended for patients with better prognosis from their overall disease. In selected cases, stereotactic radiosurgery, which is more commonly used in brain metastases, may be effective.
- The clinical response to radiation is dependent not only on the degree of cord involvement and the duration of symptoms but also on the underlying cell type. In general, patients with severe deficits such as complete paraplegia or a long duration of neurologic deficit are unlikely to have returned to normal function. This underscores the need to diagnose and treat these patients rapidly. Lymphoma, myeloma, and other hematologic malignancies, along with breast and prostate cancers and small cell lung carcinoma, tend to be more responsive than adenocarcinomas of the gastrointestinal tract, non small cell lung cancer, renal cancer, and others.
Surgery. Surgery still plays a crucial role for some patients. Traditional approaches include decompressive laminectomy for posterior lesions or anterior approaches for other lesions. Newer treatment options include minimally invasive vertebroplasty and kyphoplasty, which may effectively maintain function and reduce pain in appropriately selected patients and have a shorter recovery time than other procedures. Indications for surgery include worsening of neurologic signs or symptoms or the appearance of new neurologic findings during the course of radiation treatment, vertebral collapse at presentation, a question of spinal stability, and disease recurrence within an earlier radiation port. In select patients, the use of surgery to remove disease in the vertebral bodies followed
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by stabilization can result in dramatic improvement in pain and function.

II. Cerebral edema

A. Clinical evaluation

Neurologic signs and symptoms. Intracranial metastases commonly manifest as a variety of neurologic symptoms and signs, including headache, change inmentation, visual disturbances, cranial nerve deficits, focal motor or sensory abnormalities, difficulty with coordination, and seizures. In the more critical condition of brain stem herniation, there may be gradual to rapid loss of consciousness, neck stiffness, unilateral or bilateral pupillary abnormalities, ipsilateral hemiparesis, or respiratory dysfunction; the specific findings depend on whether there is uncal, central, or tonsillar herniation. Any new neurologic complaint from a patient with cancer should be viewed by members of the oncology team with a high index of suspicion that it represents metastasis, especially if metastasis to the brain is commonly associated with the patient's tumor type.

The history and physical examination provide the first clue to the presence of a metastatic lesion or associated cerebral edema. In general, a history of gradual progression of neurologic symptoms before the development of a significant deficit is more consistent with a metastatic lesion, whereas the absence of symptoms followed by the abrupt onset of a severe deficit is suggestive of a cerebrovascular event.
Radiologic studies. MRI is the imaging modality of choice because it has greater sensitivity than CT in detecting the presence of metastatic lesions, evaluating the posterior fossa, and determining the extent of cerebral edema. CT is substituted for MRI in many institutions because of availability, ease of administration, shorter test time and less cost. However, although CT is sufficient to detect the presence of cerebral edema in most patients, it is necessary to realize that CT fails to diagnose some lesions and may underestimate cerebral edema. If CT of the brain reveals no definite abnormality in the presence of persistent neurologic findings, MRI is the recommended next step. Delay of appropriate imaging studies (either CT or MRI) to examine plain skull radiographs or to obtain radionuclide studies in patients experiencing neurologic difficulties is not warranted.

Warning: In a patient with cancer who has focal neurologic signs or symptoms, headache, or alteration in consciousness, a lumbar puncture to evaluate for possible neoplastic meningeal spread should not be done until a CT scan or MRI shows no evidence of mass, midline shift, or increased intracranial pressure. To do the lumbar puncture without this assurance could precipitate brain stem herniation, which is often rapidly fatal.

B. Treatment

Symptomatic therapy. Once the presence of cerebral edema is established, dexamethasone 10 to 20 mg IV to load, followed by 6 mg IV or PO four times daily should be started. The rationale for the use of steroids
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centers around the etiology of cerebral edema. It appears that the invasion of malignant cells releases leukotrienes and other soluble mediators responsible for vasodilation, increased capillary permeability, and subsequent edema. Dexamethasone inhibits the conversion of arachidonic acid to leukotrienes, thereby decreasing vascular permeability. Additionally, steroids appear to have a direct stabilizing effect on brain capillaries. There is some evidence to suggest that patients who do not have lessening of cerebral edema with the dexamethasone dose just described may respond to higher doses (50 to 100 mg/day). Because of the risk of gastrointestinal bleeding and other side effects of doses higher than 32 mg/day, higher doses are usually not given for more than 48 to 72 hours.

Patients with severe cerebral edema leading to a lifethreatening rise in intracranial pressure or brain stem herniation should also receive mannitol 50 to 100 g (in a 20% to 25% solution) infused IV over approximately 30 minutes. This may be repeated every 6 hours if needed, although serum electrolytes and urine output must be monitored closely. Patients with severe cerebral edema should be intubated to allow for mechanical hyperventilation to reduce the carbon dioxide pressure to 25 to 30 mm Hg in order to decrease intracranial pressure.
Therapy of the intracerebral tumor. Once the patient has been stabilized, appropriate therapy for the cause underlying the cerebral edema should be implemented. Radiation is the usual modality for most metastases, but surgery may be considered in addition for suitable candidates with easily accessible lesions; combined surgery and radiotherapy may result in a longer disease-free and total survival if there are only one or two metastatic lesions and the systemic disease is controlled. Stereotactic radiosurgery combined with whole brain radiation is an effective and equivalent alternative to surgery plus whole brain radiation, provided the lesions are not too large and limited in number.
Nonmalignant causes of cerebral edema, such as subdural hematoma in thrombocytopenic patients and brain abscess, toxoplasmosis, or other infections in immunocompromised patients, must always be considered.

III. Superior vena cava syndrome (SVCS)

The superior vena cava is a thin-walled vessel located to the right of the midline just anterior to the right main-stem bronchus. It is ultimately responsible for the venous drainage of the head, neck, and arms. Its location places it near lymph nodes that are commonly involved by malignant cells from primary lung tumors and from lymphomas. Lymph node distention or the presence of a mediastinal tumor mass may compress the adjacent superior vena cava, leading to superior vena cava syndrome (SVCS). Similarly, the presence of a thrombus due to a hypercoagulable state secondary to underlying malignancy or a thrombus developing around an indwelling central venous catheter may also lead to the development of this syndrome.

A. Symptoms and signs

Patients who develop SVCS commonly complain of dyspnea, orthopnea, paroxysmal nocturnal

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dyspnea, and facial, neck, and upper-extremity swelling. Associated symptoms may include cough, hoarseness, and chest or neck pain. Headache and mental status changes may also be seen. A patient's symptoms may be gradual and progressive, with only mild facial swelling being present early in the course of this disorder. These early changes may be so subtle that the patient is unaware of them. Alternatively, if a clot develops in the superior vena cava in association with narrowing of the vessel, the signs and symptoms may appear suddenly. Physical examination may reveal a spectrum of findings from facial edema to marked respiratory distress. Neck vein distention, facial edema or cyanosis, and tachypnea are commonly seen. Other potential physical findings include the presence of prominent collateral vessels on the thorax, upper-extremity edema, paralysis of the vocal cords, and mental status changes.

B. Radiologic evaluation

Patients may often be diagnosed by physical findings plus the presence of a mediastinal mass on chest radiographs. Although it was thought previously that the superior venacavogram was required to establish the diagnosis and delineate the extent of obstruction, current opinion now appears to favor the use of CT instead. CT permits a more detailed examination of surrounding anatomy, including adjacent lymphadenopathy; may differentiate between extrinsic compression and an intrinsic lesion (primary thrombus); poses less risk to the patient; aids in treatment planning for radiation therapy; and allows for possible percutaneous biopsy of a compressing mass.

SVCS may occur in patients with subclavian or internal jugular IV catheters. The injection of contrast material into these catheters is useful to determine the presence of a thrombus. However, a thrombus forms in the venous vasculature distal to the caval obstruction in most patients with SVCS secondary to external compression. Thus, a clot may be primary or secondary; determination of the cause and the appropriate treatment depends on both the clinical situation and the radiologic findings.

C. Tissue diagnosis

Although some patients present with such severe respiratory compromise as to require emergent treatment, most patients are clinically stable and may undergo biopsy for a tissue diagnosis if they are not previously known to have cancer. Tissue may be acquired through multiple methods including bronchoscopy, CT-guided biopsy, mediastinoscopy, mediastinotomy, and thoracoscopy. Thoracotomy is the most invasive option and is rarely needed. Because of increased venous pressure and dilated veins distal to the obstruction, extreme care must be taken to ensure adequate hemostasis after any biopsy procedure.

D. Treatment

Initially, patients with SVCS may be treated with oxygen for dyspnea, furosemide 20 to 40 mg IV to reduce edema, and dexamethasone 16 mg IV or PO daily in divided doses. The benefit of dexamethasone is not clear. In patients with lymphoma, there is probably a lympholytic effect with resultant decrease in tumor mass; in patients with most other tumors, the effect is probably limited to decreasing any local inflammatory reaction from the tumor and from subsequent initial radiotherapy.

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Neoplasms. Therapy for SVCS ultimately involves radiation therapy formost tumors but possibly chemotherapy as a single modality for particularly sensitive tumor types such as small cell lung cancer, lymphomas, and germ cell cancers. Radiation therapy may be given in relatively high-dose fractions (e.g., 4 Gy) for several days, followed by a reversion to standard doses thereafter. Dexamethasone is continued for approximately 1 week after the start of radiation treatment.
Thrombi. SVCS secondary to vascular thrombi has been treated in the past with thrombolytic therapy, though this treatment is less commonly used now. It is particularly important to avoid thrombolytic therapy in patients with a tumor that might bleed, and when thrombi are secondary to external SVC pressure from neoplasms, thrombolytics are not needed. A newer highly effective treatment for the relief of signs and symptoms is percutaneous stent placement in the superior vena cava. Anticoagulation with heparin after thrombolytic therapy or stent placement is recommended, because clot formation is common, even when external pressure was the primary cause of the obstruction. Depending on the situation, therapeutic doses of warfarin may be indicated to prevent propagation of the clot (see Chapter 29).

IV. Anaphylaxis

A. Causes

Anaphylaxis, although infrequent, is one of the most catastrophic potential side effects of biologic and chemotherapy. Anaphylaxis is a hyperimmune reaction mediated by the release of immunoglobulin E. This emergency situation may arise in oncology patients who are exposed to serum products, bacterial products such as L-asparaginase, certain cytotoxic agents (such as paclitaxel [Taxol] or the Cremophor component of paclitaxel), antibiotics such as penicillin, iodine-based contrast material, latex, and monoclonal antibodies (which have murine components). However, virtually any drug can lead to a hyperimmune response resulting in anaphylaxis.

B. Clinical manifestations

Patients may display anxiety, dyspnea, and presyncopal symptoms. Urticaria, generalized itching, and evidence of bronchospasm and upper-airway angioedema may occur. Peripheral vasodilation may manifest as facial flushing or pallor, can result in significant hypotension, and may lead to syncope.

C. Management

Prompt recognition and treatment can be invaluable in blunting an adverse response and may prevent a reaction from becoming life threatening. Patients must be assessed rapidly to ensure that an open airway is present and maintained. Supplemental oxygen should be given for respiratory symptoms. Endotracheal intubation may be necessary. If severe laryngeal edema rather than bronchospasm is the cause of respiratory distress, tracheostomy or cricothyrotomy is necessary.

Epinephrine 0. 3 to 0.5 mg (0.3 to 0.5 mL of 1:1,000 epinephrine or 3 to 5 mL of a 1:10,000 solution) IV is given every 10 minutes for severe reactions with laryngeal stridor, major bronchospasm, or severe hypotension, for
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a maximum of three doses (1 mg) or until the episode resolves, whichever occurs first. For milder reactions, a dose of 0.2 to 0.3 mL of 1:1,000 epinephrine may be given SC and repeated every 15 minutes for two additional doses if needed. In the event of life-threatening anaphylaxis, 0.5mg (5 mL of a 1:10,000 solution) should be given IV; this dose may be repeated once in 10 minutes if needed. Because of the cardiovascular stress associated with epinephrine, its use in relatively minor allergic reactions, such as pruritus alone, should be avoided. Alternatively, epinephrine may be administered through the endotracheal tube if IV access is unavailable.
Intravenous fluids (either normal saline or lactated Ringer's solution) may be given for hypotension. Hypotension unresponsive to these measures requires the use of vasopressors such as dopamine.
Albuterol or metaproterenol aerosol treatments can be used to treat bronchospasm.
Diphenhydramine 25 mg IV may be followed by a second dose, if necessary. Blood pressure must be monitored because hypotension can result.
Corticosteroids have a slow onset of action measured in hours. Although their administration may be reasonable for their later effects, they do not have a primary role in the acute management of this emergent condition. Hydrocortisone 100 to 500 mg IV or methylprednisolone 125 mg IV may be given for their later effects.
Cimetidine 300 mg IV or any other H2-blocker may be given for urticaria; it has no significant role in acute, severe episodes, although it has a preventive role in averting reactions from paclitaxel along with dexamethasone and diphenhydramine.

V. Respiratory failure

A. Causes

Respiratory failure in patients with cancer may have many potential causes:

Bacterial or other pneumonias, especially in patients who are neutropenic due to therapy
Sepsis (and other causes of the systemic inflammatory response syndrome)
Interstitial pulmonary spread of cancer
Overwhelming parenchymal pulmonary metastases
Radiation injury
Lung damage from agents (such as bleomycin, mitomycin, high-dose cyclophosphamide, or methotrexate)
Pulmonary edema secondary to cardiac damage from cytotoxic agents (such as doxorubicin), or capillary leak syndrome from biologic agents (such as IL-2)
Retinoic acid syndrome from tretinoin (all-trans-retinoic acid) therapy of acute promyelocytic leukemia
Pulmonary emboli, either multiple small or single large

B. Management

The management of severe respiratory failure requires intubation and mechanical ventilation, which is usually managed by pulmonologists or critical care specialists.

However, because the prognosis of most patients with advanced solid tumors who develop respiratory failure is poor,

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careful consideration of a patient's entire medical situation must be made. Relevant factors include the patient's underlying medical illnesses, such as concurrent cardiopulmonary disease, and their particular tumor type and potential for response to antineoplastic therapy. It is prudent some would say imperative to ascertain well in advance of the emergency the goals of the patients and the wishes of patients and their families regarding intensive care unit support and full resuscitative measures.

C. Prevention

If possible, progressive steps to prevent or lessen the possibility of the development of respiratory failure should be undertaken. These include the following:

Careful monitoring of granulocyte counts to be aware of patients at risk for bacterial infection.
Routine lung auscultation of patients receiving agents with potential pulmonary toxicity followed by appropriate action in the event of pulmonary findings. This may include giving furosemide if indicated and discontinuing offending agents (such as bleomycin before the development of serious symptoms. Reasons for discontinuing bleomycin therapy include unexplained exertional dyspnea, fine bibasilar rales, fine bibasilar reticular shadows on chest radiograph, and significant fall in pulmonary function tests from pretreatment levels.
Ensuring that patients are ambulatory or that antithrombotic precautions are taken for hospitalized patients who are bedridden.
Consideration of underlying cardiopulmonary disease, prior chest irradiation, and so forth before patients are considered for systemic therapy is most important. Concurrent illnesses may proscribe the selection of or modify the dosing of cytotoxic agents (such as cisplatin, which requires substantial IV hydration) and biologic agents (such as IL-2, before which patients' cardiac and pulmonary function should be tested).

VI. Tumor lysis syndrome

This syndrome may be seen with any tumor that is undergoing rapid cell turnover as a result of high growth fraction or high cell death due to therapy. In general, acute leukemia, high- and intermediate-grade lymphoma, and, less commonly, solid tumors such as small cell lung cancer and germ cell cancers undergoing therapy are the most commonly associated tumor types. Tumor lysis syndrome is characterized by the metabolic abnormalities of hyperuricemia, hyperkalemia, and hyperphosphatemia leading to hypocalcemia. Patients with underlying chronic renal insufficiency are more susceptible to developing tumor lysis syndrome because of their limited capacity to excrete the products of rapid tumor cell destruction. Severe clinical situations, including acute renal failure, and serious cardiac dysrhythmia, including ventricular tachycardia and ventricular fibrillation, may develop. It is therefore important for physicians to be aware of which patients might be at risk for this syndrome, attempt to prevent its onset, monitor patients' blood chemistry values carefully, and initiate treatment promptly.

A. Prevention

It is useful to start all patients who have tumor types or therapy that predispose to this complication on allopurinol 600 to 1,200 mg/day PO in divided doses for

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1 or 2 days at least 24 hours before initiating chemotherapy, and continuing with 300 mg PO b.i.d. for 2 to 3 days after the start of therapy. Thereafter, patients may receive allopurinol 300 mg/day PO.

For patients who must be treated immediately, allopurinol is started at the same dose just described, urine should be alkalinized (pH 7), and IV fluid hydration with a brisk diuresis of approximately 100 to 150 mL/hour of urine maintained. This can be achieved through the use of IV crystalloid, with 1 ampule (44.6 mEq) of sodium bicarbonate in each liter of IV solution. If the desired urine output is not reached after adequate hydration, furosemide 20 mg IV may be given to facilitate diuresis. If routine monitoring of urine shows pH less than 7.0, an additional ampule of sodium bicarbonate may be added to each liter of infused fluid. Acetazolamide 250 mg PO q.i.d. may also be added to keep the urine alkaline.

Recombinant urate oxidase, rasburicase, is a safe and effective alternative to allopurinol. The recommended dose of rasburicase is 0.15 to 0.2 mg/kg/day for 5 days, but excellent control of hyperuricemia may be achieved with a lower dose of 3 mg/day.

B. Monitoring

During the course of chemotherapy for patients at risk of tumor lysis syndrome, serum electrolytes, phosphate, calcium, uric acid, and creatinine levels should be checked before therapy and at least daily thereafter. Patients at high risk (e.g., high-grade lymphoma with large bulk) should have these parameters checked every 6 hours for the first 24 to 48 hours. In addition, patients who show any initial or subsequent abnormality in any of these parameters should have appropriate therapy initiated and have measurements of abnormal parameters repeated every 6 to 12 hours until completion of chemotherapy and normalization of laboratory values.

C. Treatment

Patients who have evidence of tumor lysis syndrome must have adequate hydration with half-normal saline solution. Oral aluminum hydroxide can be used to treat hyperphosphatemia.

Hyperkalemia may be treated in multiple ways. However, the clinician must differentiate between methods that reduce serum potassium by driving this ion intracellularly (as is done with dextrose and insulin or sodium bicarbonate) and methods that lead to actual potassium loss out of the body (as with furosemide through the urine and with sodium polystyrene sulfonate resin [Kayexalate] through the gut). If hyperkalemia or hypocalcemia occurs, an electrocardiogram should be obtained, with continuous monitoring of the cardiac rhythm until these abnormalities are corrected. In addition, because of the potential cardiac arrhythmias secondary to hyperkalemia with hypocalcemia, cardioprotection could be achieved through the use of IV calcium.

We recommend the following:

For patients with mild elevation of potassium (serum potassium no higher than 5. 5 mEq/ L), increasing IV hydration using normal saline solution with a single dose (20 mg) of IV furosemide is often sufficient. An alternative to normal saline is the use of 2 ampules of sodium
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bicarbonate (89 mEq) in 1 L of 5% dextrose/water, although alkalinization per se is probably not beneficial.
For patients with serum potassium levels between 5.5 and 6.0 mEq/ L, increased IV fluids, furosemide, and oral sodium polystyrene sulfonate resin 30 g with sorbitol may be used.
For patients with serum potassium levels of more than 6.0 mEq/L or evidence of cardiac arrhythmia, several options may be combined. IV calcium gluconate, 10 mL of a 10% solution or 1 ampule, is given first, followed by increased IV fluids, furosemide, plus 1 ampule of 50% dextrose and 10 U of regular insulin IV. Albuterol may be used to augment the effect of the insulin. Oral sodium polystyrene sulfonate resin with sorbitol also may be used except in patients with a history of congestive heart failure or reduced left ventricular function. Dialysis may be necessary for refractory hyperkalemia.

VII. Hypercalcemia

A. Causes of tumor hypercalcemia

Associated tumors. Hypercalcemia is relatively common in patients with malignancy. In one study, it was shown that the most common cause of hypercalcemia in hospitalized patients is malignancy. Hypercalcemia of malignancy can be associated with bone metastasis, or it may occur in the absence of any direct bone involvement by the tumor. On the basis of the findings of a study on 433 patients with hypercalcemia of cancer, 86%of the patients had identifiable bone metastasis. More than one-half (n = 225) of the cases were accounted for by patients with breast carcinoma, and cancer of the lung and kidneys accounted for a smaller proportion. Patients with hematologic malignancies accounted for approximately 15% of the cases. These patients usually had hypercalcemia in the presence of diffuse tumor involvement of bone, although in a small percentage there was no evidence of bone involvement.
Humoral mediators. In approximately 10% of the cases with malignancy, hypercalcemia develops in the absence of radiographic or scintigraphic evidence of bone involvement. In this group of patients, the pathogenesis of hypercalcemia appears to be secondary to humoral mediators, dominant of which is parathyroid hormone (PTH) related protein (PTHrP), as well as other osteoclast-activating factors (OAFs). A number of other cytokines, with potential bone-resorbing activities, including IL-6 and tumor necrosis factor (TNF- ), have been identified. These cytokines may account for the previously designated OAF. There is evidence indicating that prostaglandins (PGs) play a role in the hypercalcemia of malignancy. PGs are potent stimulators of bone resorption. There may also be the coexistence of tumor with primary hyperparathyroidism or other cause of hypercalcemia (e.g., vitamin D intoxication, sarcoidosis).

B. Symptoms, signs, and laboratory findings

Hypercalcemia often produces symptoms in patients with cancer and, in fact, may be the patients' major problem. Polyuria and nocturia, resulting from the impaired ability of the kidneys to

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concentrate the urine, occur early. Anorexia, nausea, constipation, muscle weakness, and fatigue are common. As the hypercalcemia progresses, severe dehydration, azotemia, mental obtundation, coma, and cardiovascular collapse may appear. In addition to hypercalcemia, the laboratory studies may reveal hypokalemia and increased blood urea nitrogen (BUN) and creatinine levels. Patients with hypercalcemia of malignancy frequently have hypochloremic metabolic alkalosis, whereas with primary hyperparathyroidism, metabolic acidosis is more common. The concentration of serum phosphorus is variable. PTH levels may be normal, low, or high, but marked elevations are rarely seen. Bone involvement is best evaluated by a bone scan, which is often positive in the absence of radiographic evidence of bone involvement.

C. Treatment

The management of hypercalcemia of malignancy has two objectives: reducing elevated levels of serum calcium and treating the underlying cause. When hypercalcemia is mild to moderate (corrected [for albumin concentration] serum calcium <12 to 13 mg/dL) and the patient is not symptomatic, adequate hydration and measures directed against the tumor (e.g., surgery, chemotherapy, or radiation therapy) may suffice. Severe hypercalcemia, on the other hand, is a life-threatening condition requiring emergency treatment. Therefore, for more severe degrees of hypercalcemia, other measures must be taken, including enhancement of calcium excretion by the kidney in patients with adequate renal function and the use of agents that decrease bone resorption.

The agents used for treatment of hypercalcemia have differences in the time of onset and duration of action as well as in their potency. Therefore, effective treatment of severe hypercalcemia requires the use of more than one modality of therapy.

A suggested approach to the treatment of severe hypercalcemia is as follows:

Rehydration with 0.9% sodium chloride
Bisphosphonate therapy either pamidronate or zoledronic acid
Continuing saline diuresis (0.9% sodium chloride + furosemide)

Rehydration. Rehydration and restoration of intravascular volume comprise the most important initial step in the therapy of hypercalcemia. Rehydration should be accomplished using 0.9% sodium chloride (normal saline) and often requires the administration of 4 to 6 L over the first 24 hours. Rehydration alone causes only a mild decrease of the serum calcium levels (about 10%). However, rehydration improves renal function, facilitating urinary calcium excretion.
Saline diuresis. After adequate restoration of intravascular volume, forced saline diuresis may be used. Sodium competitively inhibits the tubular resorption of calcium. Therefore, the IV infusion of saline causes a significant increase in calcium clearance. Because of the large amounts of saline that may be required to correct hypercalcemia, it is advisable to monitor the central venous pressure
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continuously. The infusion of normal saline (0.9% sodium chloride) at a rate of 250 to 500 mL/hour, accompanied by the IV administration of 20 to 80 mg of furosemide every 2 to 4 hours, results in significant calcium diuresis and mild lowering of the serum calcium inmost patients. This type of therapy requires strict monitoring of cardiopulmonary status to avoid fluid overload. Also, it requires ready access to the laboratory to prevent electrolyte imbalance, because the urinary losses of sodium, potassium, magnesium, and water must be replaced to maintain metabolic balance. In some cases, the infusion of saline at rates of 125 to 150 mL/hour plus the addition of furosemide 40 to 80 mg IV once or twice a day may reduce the serum calcium until other measures aimed at inhibiting bone resorption take effect.
Bisphosphonates
- Mechanism of action. The bisphosphonates are potent inhibitors of normal and abnormal osteoclastic bone resorption. They bind to the surface of calcium phosphate crystals and inhibit crystal growth and dissolution. In addition, they may directly inhibit osteoclast resorptive activity.
- Pamidronate and zoledronic acid. Pamidronate and zoledronic acid are very potent inhibitors of bone resorption and highly effective agents for the treatment of hypercalcemia of malignancy. Pamidronate was the treatment of choice for hypercalcemia of malignancy for several years, but zoledronic acid, is at least as effective in the treatment of hypercalcemia and can be given over a shorter period of time.
  - Dosage and administration. For symptomatic, moderate hypercalcemia (corrected serum calcium 12 to 13.5 mg/dL), the recommended dose of pamidronate is 60 to 90 mg given IV as a single dose over 4 to 24 hours. The maximum recommended dose of zoledronic acid in hypercalcemia of malignancy is 4 mg, given as a single dose IV infusion over no less than 15 minutes. Doses may be repeated in 3 to 4 days if inadequate response has been seen.
  - Side effects. Pamidronate and zoledronic acid are usually well tolerated, and no serious acute side effects have been reported. Mild fever with temperature elevations of 1C have been noted occasionally in patients after drug administration. The transient fever is presumed to be due to release of cytokines from osteoclasts. Pain, redness, swelling, and induration at the site of infusion occur in approximately 20% of patients. Hypocalcemia, hypophosphatemia, or hypomagnesemia may be seen in 15% of the patients. Both should be used with caution in patients with decreased renal function. Osteonecrosis of the jaw in association with dental procedures and conditions can be a debilitating side effect of the bisphosphonates and requires the skill of an experienced dentist or oral surgeon.
Glucocorticoids. Large initial doses of hydrocortisone 250 to 500 mg IV q8 hour (or its equivalent) can be effective
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in the treatment of hypercalcemia associated with lymphoproliferative diseases such as non Hodgkin's lymphoma and multiple myeloma and in patients with breast cancer metastatic to bone. However, it may take several days for glucocorticoids to lower the serum calcium level. Maintenance therapy should be started with prednisone 10 to 30 mg/day PO. The mechanisms by which glucocorticoids lower the serum calcium are multiple and involved.
Oral phosphate supplements (Neutra-Phos or Fleet Phospho-soda). Oral phosphate therapy is an adjunct for the chronic treatment of hypercalcemia of malignancy. Oral phosphate decreases the intestinal absorption of calcium and enhances the deposition of insoluble calcium salts in bone and tissue. Oral phosphate supplements at dosages of 1.5 to 3.0 g/day of elemental phosphorus can result in mild lowering of the serum calcium levels as well as a reduction in urinary calcium excretion. Diarrhea usually limits the amount of phosphate that can be given. Phosphate supplements should never be given to patients with renal failure or when hyperphosphatemia is present, as soft tissue calcification may occur. Monitoring of the level of calcium and phosphorus as well as the calcium times phosphorus ion product is important to prevent metastatic calcifications.
Other agents. Mithramycin is no longer used or recommended for hypercalcemia of malignancy. Salmon calcitonin use is uncommon, because of the requirement for frequent administration and the rapid development of therapeutic refractoriness. However, it does have a rapid duration of action and may be administered to patients with congestive heart failure and hypercalcemia. Calcitonin Salmon is given at 4 IU/kg every 12 hours SC or IM. The dose may be increased to 8 IU/kg every 12 hours after 24 to 48 hours if response is unsatisfactory.

VIII. Bone metastasis

Metastases to bone occur frequently from many types of tumors and have great potential for morbidity. Bone involvement can be a source of constant pain, limiting a patient's activity and quality of life. The consequences of spinal involvement have been discussed already. The occurrence of a pathologic fracture in a weight-bearing bone has catastrophic implications: patients who are consequently immobilized or bedridden are predisposed to a variety of complications including deep venous thrombi, pulmonary emboli, aspiration pneumonia, and decubitus ulcers as well as psychosocial consequences, including depression.

A. Clinical findings

Bone involvement with metastatic disease manifests as a spectrum of clinical presentations. This can vary from constant aching pain through nocturnal exacerbations of pain to sharp pains brought on by pressure, weight bearing, other use, or range of motion of the affected site. Tenderness of an affected bone area may or may not be present. Tenderness or sharp pain with weight bearing often implies a greater degree of disruption of the bony architecture and therefore a greater potential for fracture, particularly in a weight-bearing area.

B. Radiologic findings

These often depend on the type of malignancy involved as well as the extent of the metastases.

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Multiple myeloma is a prime example of a malignancy that leads to pure osteolytic lesions. Consequently, radionuclide bone scans are rarely useful in the evaluation of patients with this disease. Rather, a metastatic skeletal survey (plain radiographs) is preferable. In contrast, prostate cancer most commonly has purely osteoblastic lesions. Therefore, a radionuclide bone scan would be the diagnostic test of choice. In general, most tumor types have the potential to yield either type of bone lesion or both. A radionuclide bone scan may be done to permit a global view in these patients. Although [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (FDG-PET) can also pick up bone metastasis, unless there is a reason to look at nonbony areas for other sites of disease it is not necessary to use it, and it is considerably more expensive.

The presence of hot spots in the spine, in weight-bearing bones such as the femur, or in other major long bones such as the humerus should lead the clinician to assess the patient further with plain radiographs of these bones. Patients who display significant cortical thinning of long bones or large lytic bone metastases are at high risk of developing pathologic fractures with great morbidity. These patients should be evaluated both by orthopedic surgery for consideration of prophylactic surgery to stabilize the affected bone and by radiation oncology for treatment of the tumor to permit regeneration of normal bone.

C. Treatment

Surgery. Because rapid return of the patient to as normal a life as possible is an overriding concern when treating patients with metastatic disease, surgical stabilization is most often the initial step in treating pathologic fractures of long bones. If the fracture is the initial manifestation of tumor relapse, biopsy confirmation can also be obtained. Whereas fractures at sites of significant residual bony architecture can be satisfactorily stabilized with an intramedullary rod or pin, marked lytic destruction may necessitate additional structural support such as methylmethacrylate cement to fill the intramedullary canal and cortical defects. Pathologic fractures of non weight-bearing bones can be managed by splinting (ribs) or sling immobilization (humerus or clavicle) while delivering radiotherapy to promote healing. Fixation may also be used in the upper extremities to speed recovery of function, particularly of the humerus. Surgical stabilization of the spine may also be used in selected circumstances (provided the patient has an anticipated survival time of more than 3 months) with open or minimally invasive procedures such as kyphoplasty and vertebroplasty, and can result in significant pain relief and reduction in risk of cord and nerve root compression.
External-beam therapy. Radiation doses of 15 to 20 Gy in three to five fractions lead to complete relief of pain in approximately 50% of patients, with an additional 30% of patients having some decrease in pain, whereas 80% to 90% show significant improvement with 30 to 40 Gy. The alleviation of symptoms can be expected within 2 to 3 weeks. For patients who may be expected to have more
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prolonged survival, higher doses over a larger number of fractions may be used. Most patients receive optimal results from courses of 30 Gy in 10 fractions (2 weeks) or 40 Gy in 15 fractions (3 weeks).

Radiotherapy fields should include the area of evident bone involvement, as shown on radiograph and bone scan, with a sufficient extension to prevent relapse at the portal margin. It is seldom necessary to treat an entire long bone unless the entire bone is involved because encroachment on marrow reserve may compromise any systemic chemotherapy that might also be indicated.
Strontium 89 (⁸⁹Sr) therapy. A different approach to the therapy of symptomatic bone metastases is through the use of radioisotopes, such as ⁸⁹Sr, which is given by IV injection. This isotope is highly selective for bone, is an emitter of -radiation, and has low penetration into surrounding tissue. Strontium's affinity to metastatic bone disease is reported to be 2 to 25 times greater than its affinity to normal bone. This therapy is especially useful in patients with breast or prostate cancer who have many metastatic bone sites or who have received maximal external-beam irradiation to a specific site. Palliative effects may be seen in other types of tumors as well. Pain relief may occur as early as 1 to 2 weeks after the first injection. Multiple studies indicate that 10% to 20% of patients experience complete pain relief, whereas another 50% to 60% have at least a moderate reduction in symptoms. Responses last for 3 to 6 months. Patients who experience some relief of symptoms may receive multiple doses at 3-month intervals if there has been adequate hematologic recovery.

The toxicity of ⁸⁹Sr is primarily hematologic, involving both leukocytes and platelets. Approximately 10% of patients may experience a transient flare of their bone pain, similar to what is seen with tamoxifen therapy in breast cancer. This flare reaction often foreshadows a response to treatment. Other radioisotopes for the palliation of painful bone metastases include samarium 153 and rhenium 186.
Biphosphonates. Pamidronate and zoledronic acid are specific inhibitors of osteoclastic activity. They are not only effective for the treatment of hypercalcemia associated with malignancy but can reduce bone pain and reduce fractures, especially in multiple myeloma, breast cancer, and prostate cancer. Zoledronic acid appears to be more effective than pamidronate in reducing the risk of skeletal system related events. Some improvement in survival may be seen in multiple myeloma.