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An oncologic emergency may be defined as any acute potentially morbid or life-threatening event directly or indirectly related to a patient's tumor or its treatment. The differential diagnosis for a patient with cancer who presents with acute conditions includes medical emergencies not related to the patient's diagnosis of cancer.
Neurologic EmergenciesCardiovascular EmergenciesRespiratory EmergenciesGenitourinary EmergenciesGastrointestinal EmergenciesMetabolic EmergenciesSIADHHematologic EmergenciesHemostatic EmergenciesChemotherapy-Induced EmergenciesReferences
An oncologic emergency may be defined as any acute potentially morbid or life-threatening event directly or indirectly related to a patient's tumor or its treatment. The differential diagnosis for a patient with cancer who presents with acute conditions includes medical emergencies not related to the patient's diagnosis of cancer. Occasionally, these emergent conditions may be the presenting symptom of a previously undiagnosed neoplasm.
Oncologic emergencies may be categorized by their system of origin, as metabolic, or as hematologic. The signs and symptoms of oncologic emergencies are often common problems experienced by individuals with cancer such as nausea, pain, headache, and fever. For prevention and early detection of oncologic emergencies, physicians must maintain a high degree of suspicion and must adequately educate patients about preventative measures and reporting of symptoms.
Spinal Cord Compression
Epidural spinal cord compression is devastating, and it is not an uncommon complication of malignancy. Spinal cord compression occurs in approximately 5% of patients with cancer, or 20,000 patients per year in the United States . Untreated spinal cord compression will invariably progress to produce paralysis, sensory loss, or loss of anal sphincter control.
The majority of cases of spinal cord compression in adults arise from metastatic breast, lung, or prostate cancer. In children, the tumors most commonly metastatic to the spine include neuroblastoma, Ewing's sarcoma, osteogenic sarcoma, and rhabdomyosarcoma . Other cancers that often cause spinal cord metastases include lymphoma, melanoma, renal cancer, sarcoma, and myeloma.
Compression usually results when an epidural tumor extends from an adjacent vertebral metastasis or from a pathologic vertebral compression fracture. In approximately 10% of cases, epidural compression results from direct paravertebral spread of tumor with epidural extension. Lymphoma and myeloma are the most common tumors of this type .
The compression occurs at the thoracic level of the spinal cord in 70% of patients as this is the portion of the cord that is narrowest, and the dorsal kyphosis can enhance symptoms. Tumors may cause compression at multiple noncontiguous sites in 10% to 38% of patients. The neurologic deficit is determined by the level of involvement of the cord. Cervical compression results in quadriplegia, thoracic compression in paraplegia, upper lumbar involvement in bowel and bladder dysfunction and extensor plantar reflexes, and cauda equina involvement in loss of bowel and bladder function and lower motor neuron weakness with normal plantar reflexes. The corticospinal tracts, posterior columns, and spinocerebellar tracts are most susceptible to compression. The Brown-Squard syndrome (a loss of vibratory and position senses on the side of compression and a contralateral loss of pain and temperature sensations) may be observed with lateral compression .
In 95% of patients, the initial symptom of epidural spinal cord compression is progressive pain in an axial or radicular distribution. Cancer patients who present with new back pain should be considered to have impending cord compression until proven otherwise. Similar to that of degenerative joint disease (DJD), pain from compression is often aggravated by movement, Valsalva's maneuver, straight leg raise, and neck flexion. However, certain characteristics of pain originating from spinal cord compression distinguish it from that of DJD. The pain of spinal cord compression is often burning or dysesthetic in nature and is exacerbated by palpation or percussion over the spine. The pain can occur at any level, whereas that of DJD is often felt in the low cervical or lumbar regions. Spinal cord compression pain is progressive and unrelenting, whereas pain from DJD is often characterized by remissions and exacerbations. The pain of cord compression often worsens when a patient lies down. Weakness, sensory loss, and incontinence are later findings. Once a neurologic symptom develops, it can evolve rapidly to paraplegia over a period of hours or days.
The differential diagnosis of epidural spinal cord compression includes epidural abscess, subdural abscess, hematoma, herniated disc, hypertrophic arthritic changes, intramedullary cord metastases, leptomeningeal disease, radiation myelopathy, myelopathy secondary to intrathecal chemotherapy, or vascular malformation . Evaluation often includes plain films of the spine, which may demonstrate lytic or blastic lesions or erosion of the pedicles. However, absence of these findings does not exclude cord compression.
Magnetic resonance imaging (MRI) has surpassed myelography as the diagnostic procedure of choice for cases of spinal cord compression. Myelography should be reserved for patients (such as those with cardiac pacemakers) unable to undergo MRI. Use of contrast enhancement with MRI increases the ability to detect leptomeningeal and intramedullary disease. Patients should undergo full spinal imaging prior to definitive therapy to exclude unexpected epidural disease at other levels that may later become symptomatic.
The most important factor determining prognosis is the level of neurologic function at the beginning of therapy. Once a serious neurologic deficit develops, fewer than 10% of patients regain function despite aggressive therapy . Immediate therapy involves the use of corticosteroids. Dexamethasone is the most commonly used steroid, but there is controversy regarding the optimal loading and maintenance doses. Commonly used doses of dexamethasone include a loading dose of 10 to 100 mg followed by 4 to 24 mg four times a day . Higher doses may be administered to patients with rapidly progressive symptoms. Steroids are then slowly tapered throughout definitive therapy.
Radiotherapy alone is the definitive treatment for most patients. The recommended radiation field is two normal vertebral bodies above and below the margins of the epidural tumor . There is no established optimal dose and fraction schedule .
Radiotherapy plus laminectomy is of no benefit, and laminectomy may increase morbidity by producing spinal cord instability. Anterior spinal decompression with stabilization is an option for patients who are physiologically able to tolerate the surgery. The following are indications for surgery: histopathology is unknown; neurologic deterioration develops during or after radiation; metastases are radiation resistant; pathologic fracture causes compression by bone; or there is instability of the spine. Rarely, chemotherapy can be used as primary therapy in chemosensitive tumors, but it is often inadequate as a single modality of treatment.
Increased Intracranial Pressure
Involvement of the brain parenchyma with mass lesions or obstruction of the flow of cerebrospinal fluid (CSF) by tumor tissue may lead to increased intracranial pressure. If the pressure increase is severe enough, herniation may result. Patients may present with headache, cranial nerve symptoms, nausea and vomiting, or the onset of seizures.
Normal intracranial pressure is less than 10 mm Hg; when it increases to greater than 20 mm Hg, injury is likely and symptoms may develop. This is associated with loss of brain autoregulation and development of ischemia or herniation.
Three herniation syndromes have been described. Central herniation is characterized by slow deterioration in the level of consciousness, with associated headache and focal neurologic deficits. Progression results in global neurologic changes, Cheyne-Stokes respiration, and small reactive pupils. Central herniation is often difficult to distinguish from metabolic encephalopathy and is usually the result of a hemispheric mass.
Uncal herniation is characterized by rapid loss of consciousness, lateral pupillary dilatation, and ipsilateral hemiparesis. It is usually the result of a mass in the temporal lobe or the lateral fossa of the frontal lobe.
Tonsillar herniation is characterized by occipital headache, vomiting, and hiccups followed by decreasing level of consciousness and respiratory compromise. It usually results from a posterior fossa mass .
Patients with early signs of increased intracranial pressure and herniation should be given intravenous corticosteroids. Usually, dexamethasone is given in doses similar to those used to relieve cord compression. Other temporizing measures include elevation of the patient's head to 30 degrees higher than the level of the heart, restriction of intravenous fluids, correction of hyperglycemia, and intubation with hyperventilation to maintain arterial PCO2 at 25 to 30 mm Hg .
Patients with impending herniation should also be treated with intravenous mannitol, 1 to 1.5 g/kg in a 20% solution. Mannitol can be repeated every 4 to 6 hours in doses adjusted to prevent excessive volume contraction and hypernatremia. Serum osmolality of greater than 320 mOsm/L should be avoided . Surgical intervention with decompression or shunting should proceed as soon as possible.
Seizures may be the presenting symptom in 15% to 30% of patients with brain metastases. Seizures can also be the result of complications of therapy, including infections, metabolic abnormalities, or medications.
Proper management of seizures acutely includes administration of diazepam (5 mg) or lorazepam for sustained seizures. Care must be taken to avoid injury to the patient and to maintain a patent airway. Patients should have a full diagnostic evaluation, including imaging, cultures, drug levels (if appropriate), and serum chemistries.
Patients with mass lesions should receive dexamethasone first and then definitive therapy. Sustained anticonvulsant therapy should then be initiated with phenytoin at a loading dose of 15 mg/kg and a maintenance dose of 300 mg/d.
Altered Mental Status
Altered mental status may take the form of confusion, decreased attentiveness, delirium, dementia, or coma. The condition may occur as a direct result of primary or metastatic lesions of the nervous system or secondarily from metabolic derangements, paraneoplastic syndromes, organ failure, infections, immune-mediated events, or iatrogenic causes. A full discussion of causes of altered mental status is beyond the scope of this chapter; however, several deserve mention.
Paraneoplastic neurologic syndromes can occur in the form of peripheral nervous system, muscular, neuromuscular, or central nervous system (CNS) disorders (Table 1) and can be seen in a variety of malignancies . Many of these syndromes are mediated by autoantibodies. For many, the etiology is still undefined. A paraneoplastic syndrome may be the initial presenting symptom of a malignancy or may occur at any time during the course of disease. These syndromes must be differentiated from the direct effects of cancer or therapy. The activity of the syndrome can parallel the course of the disease or exhibit an independent course. Specific therapy is often lacking and, therefore, is limited to treatment of the underlying malignancy.
|Paraneoplastic syndromes||Associated neoplasms|
|Subacute sensory neuropathy (PSN)||Small-cell lung cancer|
|Symmetric sensorimotor neuropathy||Carcinoma, lymphoma, myeloma|
|Motor neuropathy||Osteosclerotic myeloma|
|Guillain-Barre syndrome||Hodgkin's disease|
|Acquired amyloid neuropathy||Myeloma|
|Motorneuritis multiplex||Small-cell lung cancer|
|Intestinal pseudo-obstruction||Small-cell lung cancer|
|Lambert-Eaton myasthenic syndrome||Small-cell lung cancer|
|Polymyositis, dermatomyositis||Small-cell lung cancer, breast, ovary, lymphoma|
|Subacute necrotizing myopathy||Carcinoma, lymphoma|
|Encephalomyelitis (PEM)||Small-cell lung cancer, breast, ovary, lymphoma|
|Opsoclonus, myoclonus||Neuroblastoma, ovary, lung|
|Necrotizing myelopathy||Small-cell lung cancer, breast|
|Cancer-associated retinopathy and uveomeningitis||Small-cell lung cancer, breast|
Many chemotherapeutic agents produce neurologic toxicity. Among these are cytarabine, carmustine (BiCNU), etoposide (VePesid), fludarabine (Fludara), methotrexate, paclitaxel (Taxol), cisplatin (Platinol), ifosfamide (Ifex), vincristine (Oncovin), vinblastine, interleukin-2 (aldesleukin [Proleukin]), and interferon.
Leptomeningeal carcinomatosis is seen most commonly in the setting of advanced adenocarcinomas, with 4% to 15% of solid tumors demonstrating metastases to the leptomeninges. Lymphomas (7% to 15%) and leukemias (5% to 15%) as well as primary brain tumors (1% to 12%) also metastasize to the leptomeninges .
Clinical presentation varies but is generally referable to three areas: the cerebral hemispheres, the cranial nerves, and the spinal cord and roots. Patients can present with symptoms in unusual neurologic distributions. Symptoms and signs include headache, changes in mental status, nausea or vomiting, focal weakness of an extremity, seizures, pain in an axial or radicular distribution, dermatomal sensory loss, and bladder and bowel dysfunction. Cranial nerve findings can include diplopia, hearing loss, facial numbness, loss of visual acuity, and ophthalmoplegia.
Patients should undergo a lumbar puncture, as CSF cytology is the diagnostic procedure of choice. Increased protein, decreased glucose, and pleocytosis are suggestive of leptomeningeal disease, but only CSF cytology is diagnostic. Imaging can also suggest the diagnosis if studding of the leptomeninges or clumped nerve roots are seen. Gadolinium enhancement can improve the image.
Therapy includes whole neuraxis radiation for radiosensitive tumors or, for less sensitive tumors, intrathecal chemotherapy with thiotepa (Thioplex), cytarabine, or methotrexate, with or without radiotherapy .
Malignant pericardial effusions are the most common cause of pericardial tamponade. It is important for the physician to recognize this condition because it can lead to the early death of a patient who had an otherwise treatable malignancy and a good short-term prognosis. The median survival time for untreated patients is approximately 4 months; only 25% survive 1 year. However, it is estimated that patients with breast cancer who are successfully treated can survive approximately 10 to 13 months, and patients with other tumors can survive 6 months or longer .
Cardiac tamponade is rarely caused by primary tumors of the pericardium. Metastatic tumors including lung and breast tumors, lymphoma, leukemia, and melanoma are much more likely to cause the condition. Effusions and tamponade may also be caused by uremia, drugs, or radiation injury to the pericardium.
Presenting symptoms include dyspnea, cough, chest pain, fever, peripheral edema, hoarseness, hiccups, or nausea. Patients may also have no clinical symptoms. Physical examination will reveal hypotension, elevated jugular venous pressure, tachycardia, narrow arterial pulse pressure, and pulsus paradoxus greater than 10 mm Hg. A chest x-ray will show the characteristic large “water bottle” heart in slowly accumulating effusions; in rapidly accumulating effusions, the film may show a normal cardiac silhouette. Results of an electrocardiogram may demonstrate low electrical voltage with QRS complexes of less than 5 mV and electrical alternans.
The diagnostic test of choice is the echocardiogram. The functional significance of the effusion is demonstrated by the presence of collapse of the right atrium and right ventricle in diastole. Catheterization of the right side of the heart demonstrates increase and equalization of pressures of the right atrium, the right ventricle, the pulmonary artery in diastole, and the pulmonary capillary wedge pressure. The right atrial pressure tracing and the clinical jugular venous pulse demonstrate a prominent X descent .
Therapy is directed at relief of acute symptoms and prevention of reaccumulation. Temporizing measures include intravenous fluids, pressors, and oxygen, although positive pressure ventilation is contraindicated, as it decreases venous return to the heart.
Pericardiocentesis is the preferred procedure for immediate relief of symptoms. The fluid that is removed should be sent for chemical and cytologic analysis. Modalities to prevent reaccumulation of fluid include systemic chemotherapy, catheter drainage and sclerosis, radiation therapy, or surgical intervention. Sclerosis is achieved with tetracycline or bleomycin (Blenoxane); minimal experience is also reported with instillation of cisplatin, mechlorethamine (Mustargen), teniposide (Vumon), fluorouracil, thiotepa, quinacrine hydrochloride (Atabrine), and radioisotopes .
External beam radiation is often effective in leukemia- or lymphoma-induced effusions and may be administered in doses of 1 to 2 Gy/d over 3 to 4 weeks. A total dose of less than 35 to 40 Gy should prevent radiation pericarditis. Surgical procedures include pericardiectomy, pleuropericardial window, or subxiphoid pericardiotomy. Patients should be initiated on the appropriate systemic therapy concurrently if their performance status permits.
Superior Vena Cava Syndrome
Malignancy is also the most common cause of superior vena cava (SVC) thrombosis and the superior vena cava syndrome (SVCS). Lung cancer is the most common origin of the malignancy, leading to SVCS in 3% to 15% of patients. Other common causes include lymphoma and tumors metastatic to the mediastinum. A nonmalignant but cancer-associated cause of the syndrome is related to indwelling catheters for vascular access.
Superior vena cava syndrome develops as a result of diminished blood return to the heart. Clinical presentation varies, depending on the degree of obstruction of the SVC. Near total or complete obstruction results in the classic symptoms of the syndrome-facial edema, dyspnea, cough, orthopnea, and edema of the neck and upper extremities. Patients present less frequently with hoarseness, dysphagia, headache, dizziness, syncope, chest pain, lethargy, or alteration in mental status . If SVCS is left untreated, increased intracranial pressure, intracerebral bleeding, and airway compromise can develop.
Patients presenting with overt SVCS may be diagnosed by physical examination alone. However, more subtle presentations require diagnostic imaging. A chest x-ray may reveal a widened mediastinum or a mass in the right side of the chest. Computed tomography (CT) and MRI scans are useful in that they define anatomic relation of structures, document the nature of obstruction as intrinsic or extrinsic, and can document collateral circulation. Invasive contrast venography is the most conclusive diagnostic tool. It precisely defines the etiology of obstruction and provides catheter access for thrombolytic therapy.
If a patient has not previously been diagnosed with malignancy, establishing a tissue diagnosis is critical. The choice of therapy in cases where the patient's life is not at acute risk is governed by the type of tumor causing the obstruction. Tests such as sputum cytology, thoracentesis, bronchoscopy, needle aspiration of a peripheral lymph node, or mediastinoscopy can be performed safely and provide a diagnosis. Thoracotomy should be performed only if the other studies are non-diagnostic.
Therapy is guided by the urgency of the presentation and the type of malignancy. Patients rarely require urgent radiotherapy prior to obtaining a diagnosis. Temporizing measures include head elevation, supplemental oxygen, limited intravenous fluids, and limited use of diuretics. Corticosteroids should also be initiated for symptoms of respiratory or CNS compromise.
Definitive therapy includes radiotherapy with increased dose fractions (300 to 400 cGy) on the first 3 days followed by full course radiation at conventional dose fractions (180 to 200 cGy) and up to 3,000 to 5,000 cGy, depending on tumor type. Chemotherapy may be used alone for small-cell bronchogenic carcinoma or in conjunction with radiotherapy for lymphomas .
The role of thrombolytic therapy and invasive maneuvers involving stents and angioplasty are evolving. Thrombolytic therapy with streptokinase or urokinase may be useful if it is administered within 7 days of the onset of symptoms. Successful resolution of thrombosis is unlikely after 1 week. Suggested doses of urokinase and streptokinase, respectively, are a 4,400-U/kg bolus of urokinase followed by an infusion of 4,400 U/kg/h, and a 250,000-U bolus of streptokinase followed by an infusion of 100,000 U/h . Patients are at increased risk for another thrombosis, including deep venous thrombosis, and should continue to receive anticoagulant drugs such as heparin or warfarin. Warfarin in low doses can also decrease the incidence of catheter-related thrombosis. Selected patients may benefit from expandable stents, angioplasty, or surgical bypass.
Respiratory complications are commonly encountered in patients with cancer, either directly as a result of tumor growth and invasion (eg, obstruction, hemoptysis, lymphangitic spread, and leukostasis), or indirectly as a result of therapy (eg, infections, pulmonary edema, hypersensitivity reactions, and toxic injury from chemotherapy or radiation). Pulmonary infiltrates and infections are discussed elsewhere, in the sections on infections in patients with cancer, and will not be further delineated here.
Airway obstruction may occur as a result of endobronchial lesions or extrinsic compression from adjacent structures. Presentation may be acute or subacute. Patients present with complaints of cough, fullness in the neck, hemoptysis, dyspnea, dysphagia, or stridor. Common disease processes include bronchogenic cancer, head and neck cancers, lymphoma, thymoma, or thyroid malignancies.
Acute therapy for impending obstruction involves intubation or tracheostomy. Patients should receive supplemental oxygen and corticosteroids. Appropriate systemic or local therapy should be initiated, depending on tumor type. Subacute obstructing lesions may be palliated with neodymium-yttrium aluminum garnet (Nd:YAG) laser therapy or endobronchial stents or brachytherapy.
Massive hemoptysis, defined as expectoration of 400 to 600 mL of blood within 24 hours, is a rare event. Patients more commonly have non-life-threatening hemoptysis with blood-streaked sputum or smaller amounts of expectorated blood. These episodes should not be dismissed, however, as they may herald more serious bleeding.
Malignancy is second to infection as the most common cause of hemoptysis. Massive hemoptysis is most often seen with tuberculosis, aspergillosis, lung abscesses, bronchiectasis, and bronchogenic carcinoma. Contributing to the risk of hemoptysis are abnormal clotting parameters or thrombocytopenia, which may be seen with cancer chemotherapy.
The physical examination should be directed toward determining the site of hemorrhage. A head and neck examination should always be included to rule out nonpulmonary sites of bleeding. Bronchoscopy, if possible during hemoptysis, is the diagnostic procedure of choice and allows iced-saline lavage. Sites of bleeding can be identified in 85% to 90% of cases, and the patient should be positioned with the site of hemorrhage dependent.
Management includes bed rest in a semi-erect position, sedation, humidified oxygen, blood and fluid replacement, and transfusion of platelets and correction of abnormal clotting parameters. Endobronchial tamponade may be used acutely as a temporizing measure until definitive therapy can be initiated. Definitive therapies include surgical resection, Nd:YAG laser ablation, and bronchial artery catheterization and embolization.
Toxic Lung Injury
Chemotherapy: The lung is uniquely susceptible to chemotherapy-induced injury, as it contains the largest vascular and endothelial surface area. The lung is the first capillary bed reached by intravenously (IV) administered chemotherapy and, thus, is the area of the highest concentration of these drugs. The lung also has the highest tissue oxygen content, which can enhance the toxicity of mitomycin (Mutamycin), bleomycin, cyclophosphamide (Cytoxan, Neosar), and carmustine. The primary mechanism of injury is mediated by oxygen free radicals on capillary endothelium and necrosis of pneumonocytes. Some agents also cause hypersensitivity reactions with acute respiratory distress.
Clinically, toxic injuries may affect the pulmonary parenchyma, vasculature, airways, or pleura . Patients can present with a subacute process consisting of low-grade fevers, cough, and progressive dyspnea, or they can be acutely ill with high fevers, chills, and dyspnea suggestive of pneumonia. Physical examination demonstrates cyanosis, tachypnea, tachycardia, and use of accessory muscles of respiration. Depending on the etiology, auscultation may reveal diffuse crackles or clear lung fields.
Diagnostic evaluation is difficult, because symptoms and test results are often nonspecific. Toxic injury is a diagnosis of exclusion, and full evaluation is directed at excluding other common causes of respiratory decompensation including infection and parenchymal involvement by tumor. Patients should have arterial blood gas measurements, cultures, a chest x-ray, and ventilation/perfusion scans or angiography if such are clinically warranted. Bronchoscopy with samples for culture can increase the recovery of infectious agents. Occasionally, patients require open lung biopsy for definitive diagnosis.
Therapy involves stopping the toxic agent and administering corticosteroids. Supportive management with diuretics and mechanical ventilation may be required. Toxic injuries are reversible to varying degrees, and preventive measures should be routinely employed. Such measures include minimizing supplemental oxygen with bleomycin therapy and avoiding chest radiotherapy in these patients. Regular monitoring of gas exchange function with serial diffusion capacity of carbon dioxide (DLCO) measurements is recommended as an early index of toxic lung injury.
Radiation: The toxic effects of radiotherapy on the lung are also mediated by oxygen free radicals on vascular endothelium. Radiation toxicity to the lung may be acute or chronic. Radiation pneumonitis is an acute syndrome characterized by dyspnea, cough, and fever associated with an infiltrate on the chest x-ray corresponding to the radiotherapy port. Factors predisposing a patient to the development of the syndrome include a high total dose of irradiation (greater than 6,000 cGy), a large volume of irradiated tissue, the fractionation schedule, and chemotherapy with bleomycin, mitomycin, or doxorubicin (Adriamycin, Rubex). Age and presence of chronic obstructive pulmonary disease are not independent risk factors.
Therapy involves use of oxygen and corticosteroids (prednisone in doses of 1 to 1.5 mg/kg, initially). Treatment is continued with a slow tapering of the steroids. Most patients present within several weeks to 3 months after receiving radiation, although symptoms can develop as late as 6 months.
Patients may also present with late radiation fibrosis in a radiotherapy port approximately 6 months to 2 years after receiving radiation. Fibrosis is a fixed lung injury and thus is poorly responsive to therapy with steroids. Long-term supplemental oxygen is often required.
Hemorrhagic cystitis may be caused by certain chemotherapeutic agents (busulfan [Myleran], cyclophosphamide, ifosfamide, thiotepa), pelvic irradiation, some viruses, immune-acting agents (as in the penicillin family of antibiotics), and invasive urothelial tumors. The incidence of hemorrhagic cystitis, despite prophylactic measures with high-dose chemotherapy, can be as high as 40%, and mortality rates of 2% to 4% are reported with uncontrolled hemorrhage. Twenty percent of patients treated with pelvic irradiation also experience bladder complications .
The toxic effects of oxazaphosphorine drugs on the bladder is mediated by the aldehyde metabolite acrolein. Prophylactic measures are aimed at minimizing the formation of acrolein and its contact with urothelium. These measures include vigorous hydration to encourage frequent urination, continuous bladder irrigation, and administration of the uroprotective agent mesna (Mesnex). Mesna is a sulfhydryl compound that, unlike N-acetyl cysteine, neutralizes acrolein without reducing the therapeutic effect of the oxazaphosphorine parent drug. Mesna is oxidized to an inactive disulfide after parenteral administration and is then excreted almost exclusively by the kidney. In the urine, mesna neutralizes acrolein as well as slowing its production by slowing degradation of 4-hydroxy metabolites of alkylating agents .
The appropriate dose of mesna is controversial and recommended doses range from 60% to 160% of the cyclophosphamide dose . It can be administered parenterally or orally. The half-life of mesna is shorter than that of cyclophosphamide (1.5 vs 6 hours). Therefore, it must be administered in repeated doses or as a continuous infusion throughout administration of the alkylating agent. The optimal schedule is not well defined, but administration should begin prior to or concurrent with alkylating agent administration. Patients should have regular urinalyses to evaluate microscopic hematuria that may herald significant bleeding.
Once hemorrhagic cystitis develops, initial conservative therapies include clot evacuation, continuous bladder irrigation with saline or hydrocortisone, cessation of anticoagulant therapy, control of factors that predispose a patient to bleeding diatheses, or systemic therapy with aminocaproic acid . Second-line therapies include cystoscopy and fulguration, intravesical formalin administration , intravesical prostaglandin administration (carboprost tromethamine [Hemabate]), oral or parenteral conjugated estrogens , or intravesical administration of silver nitrate, phenol, or aluminum hydroxide. Intractable cases may require urinary diversion, internal iliac artery ligation or embolization, or cystectomy.
Urinary Tract Obstruction
Urinary tract obstruction most commonly occurs in the ureters or the bladder neck. An obstruction may be intrinsic or extrinsic in nature. Retroperitoneal primary or metastatic tumors that commonly cause this type of obstruction are outlined in Table 2 .
|Benign neoplasms||Malignant neoplasms|
|Lymphangioma||Lymphangiosarcoma Lymphosarcoma Hodgkin's disease Reticulum-cell sarcoma Non-Hodgkin's lymphoma|
|Benign pheochromocytoma||Malignant pheochromocytoma|
|Nephrogenic cysts||Urogenital ridge tumors|
Ureteral obstruction may be unilateral or bilateral, depending on the etiology. Bladder outlet obstruction typically produces bilateral hydronephrosis. Prostate and cervical cancers as well as radiation fibrosis are common causes of bladder outlet obstruction.
Evaluation is directed at determining the site of obstruction. Useful imaging modalities include intravenous urogram, renal ultrasound, and CT of the abdomen and pelvis. Occasionally, patients require invasive percutaneous procedures.
Therapies that relieve obstruction include percutaneous nephrostomy tubes, ureteral stents, suprapubic catheters, and transurethral resection of the prostate. Patients with obstruction also require antibiotic therapy to prevent pyelonephritis or systemic urosepsis.
Neutropenic enterocolitis (typhlitis) is a syndrome characterized by abdominal distension, tenderness on the right side of the abdomen, watery diarrhea, and fever observed in the setting of chemotherapy- or disease-induced neutropenia . The syndrome is most often associated with hematologic malignancies, aplastic anemia, myelodysplastic syndromes, and rarely, solid tumors (as with aggressive chemotherapy of breast cancer). The incidence of the syndrome is reported as 12% to 46% in autopsy studies . Differential diagnosis includes appendicitis, pseudomembranous enterocolitis, and diverticulitis. The cause of death in these patients is usually sepsis, and mortality rates range from 50% to 100% .
Pathologically, the syndrome is characterized by patchy inflammation involving the full thickness of the bowel wall. It is associated with well-demarcated ulcers and necrosis with minimal inflammatory infiltration of the ileum, cecum, or ascending colon. Factors that predispose a patient to this condition include prolonged ileus with bacterial invasion, direct damage to bowel mucosa, and hemorrhage into the bowel wall with necrosis. Nearly all patients presenting with this syndrome were treated previously with antibiotics that allowed the occurrence of fungal overgrowth and the selection of virulent organisms capable of invading the bowel wall .
Typhlitis is a clinical diagnosis; laboratory and x-ray findings are nonspecific. Plain films of the abdomen reveal the pattern of ileus with a distended cecum. A CT scan is the test of choice and may reveal thickening of the bowel wall with pneumatosis. Invasive studies such as endoscopy or a barium enema should be avoided as patients are at high risk for perforation.
Therapy is controversial. The literature reports a higher survival rate with surgical treatment than with medical treatment alone. However, these data are complicated by the fact that these patients are critically ill and often have comorbid conditions that adversely affect their prognosis. Medical management can be successful if the condition is recognized early.
Medical management consists of bowel rest; nasogastric suction; broad-spectrum antibiotics including agents effective against anaerobic, gram-negative, and Clostridium difficile organisms; use of hematopoietic growth factor support; and total parenteral nutrition. Surgery is indicated for perforation, bleeding, abscess formation, or failure of medical management. Necrotic bowel should be resected, and bowel diversion should be performed; primary anastamoses are unlikely to be successful in leukopenic patients.
Gastrointestinal Bleeding and Perforation
After hemorrhagic gastritis and peptic ulcer disease, malignancy is the third leading cause of gastrointestinal bleeding in patients with cancer. Lymphoma is the most likely tumor to directly cause bleeding . Perforation is a much less common complication with lymphomas, occurring in only 3% to 10% of cases. Patients with tumors likely to bleed when therapy is given (lymphomas, metastatic renal cell carcinomas) should have these resected prior to initiation of therapy, if possible.
Treatment modalities for hemorrhage include surgery and use of vasopressin, Nd:YAG laser, and arterial embolization for unresectable lesions. Evaluation should be vigilant to exclude other sites of bleeding.
Tumor Lysis Syndrome
Rapid destruction of malignant cells can result in the release of cellular breakdown products and intracellular ions causing potentially lethal metabolic derangements. Tumor lysis syndrome is observed in tumors with a rapid proliferation index including Burkitt's lymphoma, acute lymphocytic leukemia, acute nonlymphocytic leukemia, and less frequently, solid tumors of small-cell type, breast cancer, and medulloblastoma. The syndrome usually follows induction chemotherapy but can also be seen after treatment with radiotherapy, corticosteroids, hormonal agents (such as tamoxifen, biologic agents (such as interferon), or spontaneously in patients with a high tumor burden.
Metabolically, the syndrome is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. These can occur individually or in varying combinations. Unchecked, uric acid can precipitate in renal tubules and calcium-phosphate complexes can precipitate in the renal interstitium. These precipitates impair renal function, resulting in metabolic acidosis, which may worsen the syndrome. This constellation of metabolic findings can distinguish this syndrome from other causes of renal failure in patients with cancer (Table 3).
Severe volume depletion
High tumor burden, high serum lactate dehydrogenase (LDH), volume depletion, acid-concentrated urine, and excessive urinary uric acid excretion may predispose a patient to tumor lysis syndrome. Azotemia is often present before chemotherapy is initiated .
Patients may be clinically asymptomatic in the early stages of the syndrome. Advanced electrolyte abnormalities, however, may result in cardiac rhythm disturbances, seizures, carpopedal spasm, neuromuscular irritability, or disturbances in level of consciousness. Prophylactic measures including alkalinization of the urine, vigorous hydration, and administration of allopurinol should be initiated prior to initiation of systemic therapy. These measures can also be effective in the early stages of the syndrome. Unfortunately, prophylactic measures are not always successful in averting the syndrome.
Therapy includes regular monitoring of electrolytes, blood-urea-nitrogen (BUN), creatinine, uric acid, phosphorus, and calcium levels, often several times a day. Hydration should exceed 3,000 mL/m²/d (200 to 300 mL/h). Urinary flow can also be increased by use of a diuretic such as mannitol. Sodium bicarbonate can be added to IV fluids at 100 mEq/L for urinary alkalinization. Allopurinol should be administered in doses of 500 mg/m² on days 1 to 3, then reduced to 200 mg/m² throughout cytoreductive therapy. This regimen should be continued for at least 2 to 3 days after the completion of chemotherapy .
Patients with hyperkalemia should be monitored continuously for cardiac rhythm disturbances. Appropriate therapy with calcium and exchange resins should be initiated. Patients with persistently low calcium should be considered for calcitriol (Calcijex, Rocaltrol) therapy . Finally, these patients may also need empiric antibiotic therapy for opportunistic infections.
Hemodialysis may be required in situations wherein conservative management fails. Overt renal failure may develop with associated volume overload and life-threatening hyperkalemia. Hemodialysis is preferred over peritoneal dialysis because it is more effective in removing uric acid and phosphorus. Daily dialysis is usually required because cellular products accumulate rapidly. Renal insufficiency is usually reversible if treated early; late intervention may result in permanent renal insufficiency and dependence on dialysis.
The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is characterized by hyponatremia with inappropriately concentrated urine; it is observed in 1% to 2% of patients with cancer. Small-cell lung cancer is by far the most common cause; it is responsible for 60% of all cases of SIADH . The differential diagnosis of SIADH includes adverse effects of cytotoxic chemotherapy agents, notably cyclophosphamide and vincristine, and ectopic production of atrial natriuretic factor .
Clinical symptoms depend on the level of hyponatremia and the rapidity with which it has occurred. Patients with a slow onset or mild hyponatremia demonstrate subtle mental status and cognitive changes such as memory loss, apathy, impaired abstract thinking, fatigue, anorexia, myalgias, and headache. Severe hyponatremia (serum sodium less than 115 mEq/L) or rapid onset of hyponatremia is characterized by asterixis, altered mental status, confusion, lethargy, seizures, and ultimately, coma. The physical examination may demonstrate papilledema, pathologic reflexes, and focal findings.
The differential diagnosis of hyponatremia includes liver disease, congestive heart failure, renal failure, hypothyroidism, and adrenal insufficiency. Normal thyroid and adrenal function and establishment of euvolemia must be demonstrated prior to a diagnosis of SIADH . The volume status should be assessed by measurement of serum and urine electrolytes and osmolality. In SIADH, the urine sodium level is usually greater than 20 mmol/L and the urine osmolality commonly exceeds that of plasma.
Therapy involves treating the tumor producing the antidiuretic hormone or atrial natriuretic factor along with fluid management, usually fluid restriction or induced diuresis. Appropriate combination chemotherapy should be initiated, and brain metastases, if present, should be treated with radiotherapy.
Fluid intake should be limited to less than 1,000 mL/d and less than 500 mL/d if the patient responds poorly. Refractory cases of hyponatremia or patients who can be treated as outpatients can be managed with 600 to 1,200 mg/d of demeclocycline (Declomycin) in divided doses. Patients who are symptomatic with coma or seizures can be treated with 3% hypertonic saline by slow infusion at a rate sufficient to increase the serum sodium level by 0.5 to 1.0 mEq/L/h. Rapid correction (greater than 2 mEq/L/h) may be associated with central pontine myelinolysis. Normal saline with IV furosemide may also be effective [27,30].
Hypercalcemia of Malignancy
Hypercalcemia is the most common metabolic emergency seen in cancer patients. Between 10% to 20% of patients with known malignancies experience this complication during the course of their disease. The most common tumor types associated with hypercalcemia include those of the breast, lung, kidney, and esophagus, hematologic malignancies (notably multiple myeloma), and cancer of the head and neck . Hypercalcemia confers a grave prognosis; survival rate at 3 months is only 44% , with mean survival times of 1 to 6 months .
The serum calcium concentration is normally controlled by parathyroid hormone (PTH) and calcitonin. Vitamin D in the dihydroxylated form regulates intestinal absorption of calcium. PTH promotes calcium reabsorption in the distal nephron and enhances conversion of 25-hydroxycholecalciferol to calcitriol. PTH also activates both osteoblasts and osteoclasts, enhancing the rate of bony calcium turnover. Calcitonin counters these effects by suppressing osteoclast activity and stimulating deposition of calcium in the skeleton .
In contrast, hypercalcemia in malignancy is caused by the tumor's elaboration of systemically acting humoral factors, which alter calcium metabolism in the bones, kidney, or intestine (humoral hypercalcemia of malignancy) and by stimulation of bone resorption at sites of tumor metastases to bone. Both mechanisms may operate simultaneously in some patients.
Humoral hypercalcemia of malignancy mimics primary hyperparathyroidism in many aspects. It is characterized by increased bony reabsorption, hypercalciuria, increased renal absorption of calcium despite increased filtered calcium, increased nephrogenous cAMP, hypophosphatemia, and hyperphosphaturia. The similarity of this syndrome to primary hyperparathyroidism led to the discovery of parathyroid hormone-related protein, which plays a central role in mediating the syndrome. This protein can be detected in the circulation by radioimmunoassays. Other substances known to be involved in calcium homeostasis include calcitriol; interleukins 1, 4, and 6; tumor necrosis factor-alpha; transforming growth factors-alpha and -beta; leukemia inhibitory factor; and prostaglandins (PG), notably PGE2 .
Clinically, patients present with nonspecific symptoms, and the differential diagnosis is often difficult. Symptoms involve many bodily systems and are delineated in Table 4 .
Laboratory test findings include high serum calcium level (can be greater than 14 mg/dL), low serum chloride level, elevated or normal serum phosphate and bicarbonate levels, and elevated alkaline phosphatase levels. In contrast, only 25% of patients with primary hyperparathyroidism have a serum calcium level greater than 14 mg/dL, and the serum phosphate and bicarbonate levels are usually decreased while the serum chloride level is elevated to greater than 112 mmol/L .
Acute therapy begins with aggressive saline rehydration. Patients have large volume deficits, and replacement of 5 to 8 L of saline in the first 24 hours is recommended. Patients should then maintain a urine output of 3 to 4 L/d until chronic therapy becomes effective, usually over several days.
Serum electrolytes should be monitored closely and replaced as needed. Hypokalemia is common. Patients with severe hypercalcemia should undergo cardiac monitoring. Patients unable to tolerate large volume replacement can be treated with loop diuretics in doses of 20 to 100 mg every 1 to 2 hours, with the goal of generating a urine output of 300 to 500 mL/h. Thiazide diuretics are to be avoided as they can increase serum calcium levels. Also, vitamin preparations or parenteral nutrition formulas with vitamin D are to be avoided, and close monitoring is required with the use of hormonal agents such as tamoxifen.
Some of the numerous pharmacologic agents available for the chronic treatment of hypercalcemia are outlined in Table 5. Agents may be classified into those that strongly inhibit bone reabsorption (plicamycin [Mithracin], bisphosphonates, and gallium nitrate [Ganite]) and those that act by other mechanisms.
|Drug||Dosage||Onset of effect||Adverse effects||Comments|
|Saline||100-250 mL/h IV||Rapid||Volume overload, hypokalemia||More rapid initial infusion (250-500 mL/h) required to correct volume depletion|
|Furosemide||80-120 mg IV every 2-6 h||4 h||Volume depletion, hypokalemia, hypomagnesemia||Use only after correction of volume depletion|
|Calcitonin||4-8 U/kg IM or SC every 6-12 h||2-4 h||Nausea and vomiting, hypersensitivity||Test dose of 1 unit recommended before therapy; duration of effect only 2-3 days in many patients|
|Etidronate disodium||7.5 mg/kg IV qd for 3-7 d||24-72 h||Nephrotoxicity||Infuse over at least 2 hours to reduce toxicity; use with caution in patients with renal dysfunction|
|Pamidronate disodium||30-90 mg IV over 24 h; 4-h infusions can be used also||24-48 h||Fever||Doses up to 90 mg are recommended by manufacturer; use with caution in patients with renal dysfunction|
|Gallium nitrate||100-200 mg/m²/d by continuous infusion for 5 d||24-48 h||Nephrotoxicity||Avoid in patients whose serum creatinine > 2.5 mg/dL or who are receiving other nephrotoxic agents|
|Plicamycin||15-25 µg/kg IV over 4 h, every 48-72 h; 12.5 µg/kg in patients with renal or hepatic diseases||12-24 h||Hemorrhage, hepatotoxicity, nephrotoxicity, nausea, and vomiting||Avoid in patients with bleeding disorders; use with caution and reduce dosage in patients with renal or hepatic diseases; observe extravasation precautions|
Gallium Nitrate: Gallium acts to lower serum calcium levels by binding to bone and reducing the solubility of hydroxyapatite crystals. It does not alter the function of osteoclasts. The mean half-life of gallium is approximately 24 hours. The drug is not available for oral administration because it is poorly absorbed.
After the first dose, the serum calcium concentration in the patient's blood falls slowly, reaching a nadir at 7 to 10 days. Adverse effects include nephrotoxicity manifested as elevation in BUN and creatinine. The reported incidence is 8% to 15%. Other side effects of gallium include pulmonary effusions and infiltrates, optic neuritis, and reduced visual and auditory acuity [34,35]. Gallium has a direct antineoplastic effect on lymphoma and, thus, may be particularly effective against hypercalcemia resulting from this disease.
Plicamycin: Plicamycin is an antineoplastic antibiotic that induces hypocalcemia by directly inhibiting bone reabsorption and osteoclast function. It may also inhibit the function of vitamin D and PTH. Toxic effects occur with repeated doses and include hemorrhage, thrombocytopenia, qualitative platelet defects, renal insufficiency, hepatic injury, nausea, and vomiting. Plicamycin is contraindicated in patients with compromised renal function .
Calcitonin: Calcitonin is the drug of choice for rapid reduction of a patient's serum calcium level. It acts within minutes to decrease renal tubular calcium reabsorption. Calcitonin also inhibits osteoclast activity and decreases skeletal release of calcium.
Unlike other pharmacologic agents, calcitonin is used safely in patients with organ failure. Coadministration of glucocorticoids may prolong the action of calcitonin. Administration of calcitonin as a single agent rarely returns serum calcium levels completely to normal; tachyphylaxis develops within 72 hours of administration. Calcitonin is thus best given as temporizing therapy in cases of life-threatening hypercalcemia until longer-acting agents can take effect .
Bisphosphonates: Bisphosphonates are synthetic analogs of pyrophosphate; they inhibit osteoclast activity. Multiple agents have been developed, which differ in potency, activity, and side effects. Etidronate (Didronel) and pamidronate (Aredia) are the agents most commonly used in clinical practice.
Etidronate can be administered orally or parenterally, but its oral absorption is low. Adverse effects of etidronate include enhanced phosphate absorption by the kidney with hyperphosphatemia, metallic taste, bone demineralization after continued high doses, and nephrotoxicity. Use of etidronate is contraindicated in patients with a serum creatinine level of greater than 5 mg/dL .
Pamidronate is more potent than etidronate and lacks the unwanted side effect of bone demineralization. Adverse effects include fever in up to 25% of patients, hypocalcemia and hypophosphatemia in 10% to 20% of patients, lymphopenia, phlebitis at the infusion site, nausea, and renal dysfunction.
Hyperviscosity syndrome is characterized by sludging and decreased perfusion of the microvasculature and by vascular stasis brought on by markedly increased paraproteins or poorly deformable cells in the blood. Sludging is observed most frequently in retinal, cerebral, cardiac, and peripheral vessels. The syndrome is observed in conjunction with polycythemia vera, Waldenstrm's macroglobulinemia, multiple myeloma, chronic or acute leukemia with high cell counts, dysproteinemias, and very rarely with solid tumors. Waldenstrm's macroglobulinemia accounts for 85% to 90% of cases, and myeloma for 5% to 10% of cases . Hyperviscosity syndrome may also be observed in light chain disease where the light chain is highly polymerized .
Clinically, the syndrome is characterized by three symptoms: bleeding, visual signs and symptoms, and neurologic defects. Patients may also present with congestive heart failure. Bleeding diatheses are usually manifested by epistaxis, ecchymoses, and mucosal bleeding. Tortuous, distended, “sausage-like” retinal veins are pathognomonic findings of the syndrome. Hemorrhages, exudates, and papilledema can occur as hyperviscosity syndrome progresses .
Bleeding is multifactorial and is observed most commonly with IgM and IgA paraproteins . Laboratory test results may reveal thrombocytopenia and defects in platelet function manifested as prolonged bleeding time, abnormal clot retraction, and abnormal platelet aggregation studies. Coating of platelets by the paraprotein inhibits aggregation and the release of platelet factor 3 .
Paraproteins have also been reported to act as inhibitors of coagulation factors V, VII, and VIII and prothrombin complex. Reduced levels of coagulation factors are also observed. Amyloid can directly bind to factor X, causing neutralization of the protein. Finally, the paraprotein can inhibit fibrin monomer polymerization resulting in prolonged thrombin time.
Thrombosis may also occur with hyperviscosity syndrome; it primarily involves the limbs or central nervous system. Polycythemia vera is commonly associated with thrombosis. Large-vessel thrombosis is related to significantly elevated hematocrits, whereas small-vessel thrombosis is likely to result from platelet abnormalities.
Diagnosis is clinical and is confirmed by determination of the serum viscosity. The normal range for serum viscosity (compared with water) is 1.4 to 1.8. Most patients begin to develop symptoms at serum viscosities greater than 4.0 . Other laboratory test findings commonly observed include the presence of anemia and iron deficiency, an elevated red blood cell mass in relation to the blood volume, renal dysfunction with azotemia, rouleaux formation, high serum M protein measurements, and thrombocytopenia.
Plasmapheresis is the acute therapy of choice for symptomatic hyperviscosity. A plasma exchange of 3 to 4 L of plasma in 24 hours is recommended. Maintenance plasmapheresis of 1 to 2 L once or twice a week may be needed until definitive therapy is effective. Replacement is usually with fresh frozen plasma as it replaces immunoglobulins and clotting factors. Hypocalcemia related to citrate anticoagulants may be observed. Plasma exchange is more effective for IgM paraproteinemias as 80% of the protein is intravascular. Definitive cytoreductive chemotherapy should be initiated as soon as possible. The prognosis for a symptomatic patient depends on that for the underlying disease .
Patients with leukemia who have markedly elevated white blood cell (WBC) counts are at risk for end-organ damage related to leukemic infiltration and to the effects of leukemic cells on the vasculature. Intravascular sludging and leukostasis can develop along with white thrombus formation. Tissue damage occurs as a result of local hypoxia, hyperpermeability, and the release of lysosomes and procoagulants.
Diseases that predispose patients to leukostasis include acute myelogenous leukemia and chronic myelogenous leukemia in blast crisis with peripheral WBC counts greater than 100,000/mL or with rapidly increasing counts . It is less likely that symptomatic hyperleukocytosis will develop in patients with lymphoblastic malignancies. There is no absolute threshold WBC count above which this syndrome develops.
Pathogenetic mechanisms involve poor deformability of leukemic blasts with sludging in the microvasculature, local hypoxia caused by blast cell consumption of oxygen, affinity of neoplastic cells for the pulmonary epithelium, and blast cell invasiveness . Hyperviscosity usually does not occur as the hematocrit is reduced .
The pulmonary and neurologic systems are most frequently clinically involved. Neurologic symptoms include dizziness, blurred vision, tinnitus, ataxia, confusion, delirium, somnolence, papilledema, retinal vein distension, retinal hemorrhages, coma, and intracranial hemorrhage . Pulmonary symptoms include fever, tachypnea, dyspnea, hypoxia, pulmonary infiltrates, and respiratory failure. Hyperleukocytosis syndrome should be part of the differential diagnosis in all patients whose respiratory failure is associated with minimal findings on physical examination and chest x-ray . Other manifestations of the syndrome include congestive heart failure, priapism, and peripheral vascular occlusion .
Interpretation of laboratory test results is complicated by the fact that values may be spuriously altered by metabolically active WBCs. Platelet counts may be falsely elevated as automated counters may interpret WBC fragments as platelets. Manual platelet counts should be performed. The PO2 and serum glucose may be artificially lowered by oxygen consumption and glycolysis by the white cells in the blood sample . Pseudohyperkalemia may also be observed. Blood samples should be placed on ice immediately and kept cold until processed. Correlation should be obtained with pulse oximetry to assess the adequacy of oxygen replacement [41,44,46].
Management of the syndrome includes supplemental oxygen, allopurinol, urinary alkalinization, hydration, and immediate cytoreductive therapy [47,48]. Initial management should include leukapheresis because cytotoxic chemotherapy induces cell lysis and can temporarily worsen symptoms. If leukapheresis is not available, hydroxyurea in doses of 50 to 100 mg/kg/d (3 to 5 g/m²)  may be used to effect rapid cytoreduction. The goal is to reduce total WBC counts by 20% to 60% in the first few hours of treatment [41,43]. Whole brain irradiation in doses of 4 to 6 Gy is recommended for CNS involvement. Correction of hemoglobin concentration to greater than 10 g/dL is contraindicated as it may worsen symptoms . Definitive antileukemic chemotherapy can be given after initial therapy has reduced the risk to the patient.
The hemostatic system can be significantly altered by malignant disease and its treatment. A list of some of the causes of bleeding in patients with cancer is provided in Table 6. Abnormal hemostatic laboratory test values can be detected in 50% of patients with metastatic disease. Significant hemorrhage can occur in up to 10% of patients with cancer .
Disseminated intravascular coagulation
Decreased clotting factors/coagulation factor abnormalities
Overall, the most common cause of hemorrhage is thrombocytopenia (50%). Usually, thrombocytopenia is the result of chemotherapy or marrow involvement by a tumor, but it may also be caused by consumptive coagulopathy, immune-mediated mechanisms, infection, or sequestration .
Severe hemorrhage is uncommon with platelet counts higher than 10,000 to 20,000/mm³ or with slowly decreasing platelet counts. Use of prophylactic platelet infusions in such cases is controversial, as there are no prospective randomized studies that establish a threshold above which platelets should be maintained to avoid bleeding . However, because hemorrhage can be life threatening, platelet infusions of 6 to 8 units every 1 to 2 days are recommended until platelet counts consistently remain above 10,000/mm³ .
Patients who receive multiple transfusions often develop alloantibodies to human leukocyte antigen (HLA) class I determinants on platelets, which contribute to rapid clearance of transfused platelets. The incidence of alloimmunization in leukemic patients is 40% to 60% and approaches 80% to 90% in aplastic anemia patients . Patients in whom this condition develops should receive HLA-matched platelets from a family member or a single donor. Use of leukocyte-depleted platelets, leukocyte filters, single donor platelets, and UV-irradiated platelets can reduce the incidence of alloimmunization. These measures also reduce febrile transfusion reactions and the incidence of transfusion transmitted diseases such as cytomegalovirus (CMV). The use of IV immune globulin is controversial because the data on platelet response is inconclusive .
Abnormal platelet function also predisposes patients to bleeding. Platelet dysfunction is most commonly observed in myeloproliferative disorders such as chronic myelogenous leukemia (CML), essential thrombocythemia, myelofibrosis, and polycythemia vera as well as in diseases associated with paraproteins such as multiple myeloma, Waldenstrm's macroglobulinemia, and amyloidosis. Bleeding in these disorders is usually mucosal in nature and can be life threatening, as in gastrointestinal hemorrhage.
Platelet dysfunction associated with elevated platelet counts (greater than 700,000/mm³) can be corrected by platelet pheresis. The most common platelet functional defects noted include impaired aggregation to adenosine diphosphate (ADP) and epinephrine, deficiency of alpha granules, and defective platelet factor 3 release .
Paraproteins may be directed to platelet antigens and cause immune-mediated platelet destruction. Paraproteins may also interfere with platelet aggregation, fibrinogen binding, conversion of fibrinogen to fibrin (causing increased thrombin time), and inhibit clotting factor activity . The patients at greatest risk are those with kappa light chains and markedly increased serum protein and viscosity .
Malignancy involving the liver can cause defective or decreased synthesis of coagulation factors II, VII, IX, X, XI, XII, XIII, prekallikrein, high-molecular-weight kininogen, plasminogen, antithrombin III, protein S, and protein C. Bleeding can be corrected by replacement of vitamin K or the appropriate coagulation factors.
Acquired von Willebrand's disease also is seen in association with many hematologic malignancies. The disease usually improves with treatment of the underlying malignancy; other therapeutic measures include infusion of cryoprecipitate or desmopressin [51,55].
Primary fibrinolysis can be seen in solid tumors and in hematologic malignancies and is characterized by local or systemic activation of the fibrinolytic system resulting in plasmin degradation of fibrin, fibrinogen, factor V, and factor VIII. It is much less common than secondary fibrinolysis seen with disseminated intravascular coagulation, which should be excluded first. Solid tumors with tissues capable of inducing fibrinolytic activity include sarcomas and tumors of the breast, thyroid, colon, and stomach. Therapy involves giving tranexamic acid or epsilon-aminocaproic acid to inhibit fibrinolysis. The recommended dose of tranexamic acid is 500 mg orally or IV, every 8 to 12 hours; epsilon-aminocaproic acid can be given as a 5- to 10-g slow IV loading dose followed by 1 to 2 g/h for 24 hours. Patients may then receive oral therapy .
Many drugs can contribute to bleeding in cancer patients. Mechanisms of bleeding include defects in fibrin formation, platelet dysfunction, loss of vitamin K dependent factors, and development of coagulation factor inhibitors. Certain cephalosporins (for example, cefamandole [Mandol]) have an N-methylthiotetrazole side chain that induces a warfarin like gamma-decarboxylation of clotting factors. Many beta-lactam antibiotics impair aggregation of platelets by blocking ADP receptor activity. Amphotericin B (Fungizone), plicamycin, vincristine, and nitrofurantoin (Furadantin) also affect platelet function. Patients who are given antibiotic therapy should have regular monitoring of prothrombin time (PT), activated partial thromboplastin time (aPTT), and bleeding time, and vitamin K replacement should be considered. Bleeding can be treated with factor replacement or platelet infusions.
Asparaginase (Elspar) therapy for acute leukemia has been associated with bleeding and thrombotic events similar to those seen in disseminated intravascular coagulation (DIC). Bleeding is mediated by inhibition of hepatic protein synthesis with decreases in fibrinogen and factors V and VIII and increased fibrin degradation products. Thrombosis can result from acquired protein S and protein C deficiencies . Bleeding can be corrected by halting asparaginase therapy and administering cryoprecipitate and fresh frozen plasma . Other antineoplastic agents associated with bleeding include plicamycin, suramin, cyclosporine (Sandimmune), mitomycin, cisplatin, carboplatin (Paraplatin), and bleomycin .
Acute leukemias may be complicated by the development of DIC in up to 50% of patients. Myeloblasts, promyelocytes, monocytes, and lymphoblasts contain procoagulant materials capable of initiating DIC and fibrinolysis. This is well characterized in acute promyelocytic leukemia, the M3 variant of acute nonlymphocytic leukemia. Solid tumors and sepsis cause injury to tissues and vascular endothelium, which may initiate DIC by exposure of tissue factor. Some malignancies commonly associated with DIC are gastric, prostate, breast, and lung cancers .
Clinical manifestations of DIC may be varied and may include both bleeding and thrombosis. Mild bleeding can involve mucosal surfaces or skin with spontaneous bruising, petechiae, purpura, gingival bleeding, and bleeding from the sites of indwelling catheters. Fulminant DIC can be complicated by bleeding in multiple sites simultaneously and bleeding in pulmonary, CNS, gastrointestinal, or genitourinary sites. Thrombotic manifestations include deep venous thrombosis, pulmonary embolism, migratory thrombophlebitis (Trousseau's syndrome), or microangiopathic hemolytic anemia . Chemotherapy may trigger or worsen DIC; initiation of low-dose heparin therapy may ameliorate these effects .
Confirmation of DIC can be difficult; many laboratory tests show abnormal results only when applied to samples from cases of fulminant DIC. Low-grade or subacute DIC may be characterized by only subtly abnormal parameters or normal laboratory test results. Decreased quantities of platelets and fibrinogen and prolonged PT are together highly suggestive of the diagnosis . It must be recognized that sepsis and neoplasia both act to elevate fibrinogen levels, thus, a normal fibrinogen level may actually represent a relative decrease of fibrinogen by a consumptive process. An increase in the PT is due to decreased quantities of factors II, V, X, and fibrinogen. Other abnormal test results include prolonged aPTT and thrombin time, decreased antithrombin III levels, increased fibrin degradation products, elevated D-dimer assay, and the presence of fragmented cells or schistocytes in the peripheral blood.
Therapy must address initiating mechanisms and should also include treatment of the underlying malignancy or sepsis. Treatment of the clinical syndrome is governed by its manifestations and severity. Patients whose laboratory test results are abnormal but who have no clinical manifestations (such cases are common in cancers where antineoplastic therapy induces cell lysis, as in acute promyelocytic leukemia) should be treated with antineoplastic chemotherapy and antibiotics only. Close observation is necessary as these patients can clinically deteriorate. Heparin, in therapeutic doses of 1,000 U/h during induction chemotherapy, may decrease morbidity and mortality . Heparin should also be used in documented cases of thrombosis. Patients with thrombosis may also be given antiplatelet agents. Patients with Trousseau's syndrome often require chronic subcutaneous heparin.
Use of heparin in patients with bleeding in DIC is much more controversial. Heparin can interrupt the consumption of coagulation proteins and platelets by inhibiting thrombin formation but can cause bleeding by its own anticoagulant activity. No controlled trials have focused on heparin use in these patients, and heparin therapy must be individualized .
Patients with significant bleeding benefit from replacement of clotting factors and platelets. Cryoprecipitate and fresh frozen plasma are the replacement products of choice. Patients with fibrinogen levels of less than 125 mg/dL should receive cryoprecipitate.
Thromboembolic events occur in 5% to 10% of patients with cancer and are manifested as deep venous thrombosis, arterial thrombosis, migratory thrombophlebitis, pulmonary embolism, and nonbacterial thrombotic endocarditis . Thromboembolic events rank second to infections as a cause of death in patients with solid tumors. Some malignancies that are often associated with thrombotic events are colon, gallbladder, gastric, lung (any cell type), myeloproliferative syndromes, ovary, pancreas, and paraprotein disorders.
Nonbacterial thrombotic endocarditis can occur in patients with lung, pancreatic, and colon cancers. The aortic valve is most frequently involved, and the spleen is the most commonly infarcted organ.
Hypercoagulability is mediated by several mechanisms. Increased levels of clotting factors are described, including fibrinogen and factors I, V, VIII:C, IX, and XI, and are manifested as shortened aPTT and PT. Low-grade DIC is manifested by increased titers of fibrin degradation products and D-dimer. Decreases in coagulation inhibitors are also revealed by acquired protein C, protein S, and antithrombin III defects. Of the two expressions of DIC, thrombosis is more common than bleeding in patients who have solid tumors, with an incidence as high as 40% to 50% .
Solid tumors may cause tissue injury and elaboration of the tissue factor that initiates local thrombosis. Mucinous adenocarcinomas contain a sialic acid moiety that can nonenzymatically activate factor X.
Platelet abnormalities can also contribute to hypercoagulability with thrombocytosis and increased platelet adhesion. Thrombocytosis is most commonly associated with carcinoma of the pancreas, lung, gastrointestinal tract, ovary, and breast and with myeloproliferative syndromes.
Clinicians must carefully monitor patients for thrombotic complications. Appropriate testing includes impedance plethysmography, venography, arteriography, and ventilation/perfusion scanning. Full coagulation profiles should include PT, aPTT, platelet counts, D-dimer, fibrin split products, fibrinogen, antithrombin III, protein S, and protein C.
Therapy is directed at treating the acute event and reducing risk for subsequent events. All patients should receive antineoplastic therapy for the underlying malignancy. Asymptomatic patients may receive antiplatelet agents such as enteric-coated aspirin or dipyridamole.
Life-threatening thrombotic events can be treated with surgery (embolectomy or vena cava interruption) or thrombolytic therapy with streptokinase, urokinase, or plasminogen activators. Therapy for the acute condition should then be followed by anticoagulation with heparin.
Heparin and warfarin can be used to treat severe thrombosis and to minimize recurrent events. High doses of heparin are no more effective than low doses and are associated with increased risk of bleeding. Warfarin and heparin are generally contraindicated in patients with CNS disease. Heparin may be given for 7 to 10 days to maintain an aPTT of 1.5 to 2.0 times control. Oral warfarin can be started on day 5 and should overlap the heparin therapy for several days . Less intensive regimens of warfarin with an international normalized ratio (INR) of 2.0 remain effective against thromboembolism and confer less risk of bleeding. The recommended target range is an INR of 2.0 to 3.0 (equivalent to a PT of 1.3 to 1.5 times control) . The duration of oral anticoagulant therapy is controversial; patients should be treated for 3 months or for the duration of the time they are at risk .
Chemotherapeutic agents are classified as nonvesicants, irritants, or vesicants. By definition, vesicants can cause necrosis if extravasation occurs. If extravasation takes place, the drug should be immediately discontinued. The treatment for extravasation caused by daunorubicin (Cerubidine), doxorubicin, epirubicin (Farmorubicin), intravenous or intramuscular actinomycin, and mitomycin involves cooling the site with ice packs for approximately 24 hours and elevation of the limb. For the vinca alkaloids vincristine and vinblastine, the therapy consists of the application of warm compresses and local injection of hyaluronidase (Wydase). Immediate consultation with a plastic surgeon should be obtained because rapid debridement may minimize the overall injury.
1. Byrne TN: Spinal cord compression from epidural metastases. N Engl J Med 327:614â619, 1992.
2. Perrin RG: Metastatic tumors of the axial spine. Curr Opin Oncol 4:525â532, 1992.
3. Markman M: Common complications and emergencies associated with cancer and its therapy. Cleve Clin J Med 61:105â114, 1994.
4. Willson JKV, Masaryl TJ: Neurologic emergencies in the cancer patient. Semin Oncol 16:490â503, 1989.
5. Choucair AK: Myelopathies in the cancer patient: Incidence, presentation, diagnosis, and management. Oncology 5(6):71â80, 1991.
6. Boogerd W, van der Sande JJ: Diagnosis and treatment of spinal cord compression in malignant disease. Cancer Treat Rev 19:129â150, 1993.
7. Bates T: A review of local radiotherapy and cord compression. Int J Radiat Oncol Biol Phys 23:217â221, 1992.
8. Thomas CR, Edmondson EA: Common emergencies in cancer medicine: Cardiovascular and neurologic syndromes. J Natl Med Assoc 83:1001â1017, 1991.
9. Lyons MK, Meyer FB: Cerebrospinal fluid physiology and the management of increased intracranial pressure. Mayo Clin Proc 65:684â707, 1990.
10. Schiller JH, Jones JC: Paraneoplastic syndromes associated with lung cancer. Curr Opin Oncol 5:335â342, 1993.
11. Chamberlain MC:. Current concepts in leptomeningeal metastasis. Curr Opin Oncol 4:533â539, 1992.
12. Choucair AK: Myelopathies in the cancer patient: Incidence, presentation, diagnosis, and management. Oncology 5(7):25â37, 1991.
13. Vaitkus PT, Herrmann HC, LeWinter MM: Treatment of malignant pericardial effusion. JAMA 272:59â64, 1994.
14. Helms SR, Carlson MD: Cardiovascular emergencies. Semin Oncol 16:463â470, 1989.
15. Escalante CP: Causes and management of superior vena cava syndrome. Oncology 7(6):61â77, 1993.
16. Kreisman H, Wolkove N: Pulmonary toxicity of antineoplastic therapy, in Perry MC (ed): The Chemotherapy Source Book, pp 598â619. Baltimore, Williams & Wilkins, 1992.
17. DeVries CR, Freiha FS: Hemorrhagic cystitis: A review. J Urol 143:1â9, 1990.
18. Shepherd JD, Pringle LE, Barnett MJ, et al: Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation. J Clin Oncol 9:2016â2020, 1991.
19. Donahue LA, Frank IN: Intravesical formalin for hemorrhagic cystitis: Analysis of therapy. J Urol 141:809â812, 1989.
20. Levine LA, Jarrard DF: Treatment of cyclophosphamide-induced hemorrhagic cystitis with intravesical carboprost tromethamine. J Urol 149:719â723, 1993.
21. Liu YK, Harty JI, Steinbock GS, et al: Treatment of radiation or cyclophosphamide induced hemorrhagic cystitis using conjugated estrogen. J Urol 144:41â43, 1990.
22. Dosik GM, Luna M, Valdivieso M, et al: Necrotizing colitis in patients with cancer. Am J Med 67:646â656, 1979.
23. Pestalozzi BC, Sotos GA, Choyke PL, et al: Typhlitis resulting from treatment with taxol and doxorubicin in patients with metastatic breast cancer. Cancer 71:1797â1800, 1992.
24. Wade DS, Nava HR, Douglass HO: Neutropenic enterocolitis. Clinical diagnosis and treatment. Cancer 69:17â23, 1992.
25. Stellato TA, Shenk RR: Gastrointestinal emergencies in the oncology patient. Semin Oncol 16:521â531, 1989.
26. Arrambide K, Toto RD: Tumor lysis syndrome. Semin Nephrol 13:273â280, 1993.
27. Silverman P, Distelhorst CW: Metabolic emergencies in clinical oncology. Semin Oncol 16:504â515, 1989.
28. Dunlau RW, Camp MA, Allon M, et al: Calcitriol in prolonged hypocalcemia due to the tumor lysis syndrome. Ann Intern Med 110: 162â164, 1989.
29. Pierce ST. Paraendocrine syndromes. Curr Opin Oncol 5:639â645, 1993.
30. Moses AM, Scheinman SJ: Ectopic secretion of neurohypophyseal peptides in patients with malignancy. Endocrinol Metab Clin North Am 20:489â506, 1991.
31. Pimentel L: Medical complications of oncologic disease. Emerg Med Clin North Am 11:407â419, 1993.
32. Rosol TJ, Capen CC: Mechanisms of cancer-induced hypercalcemia. Lab Invest 67:680â702, 1992.
33. Thomas CR, Dodhia N: Common emergencies in cancer medicine: Metabolic syndromes. J Natl Med Assoc 83:809â818, 1991.
34. Kinirons MT: Newer agents for the treatment of malignant hypercalcemia. Am J Med Sci 305:403â406, 1993.
35. Hall TG, Burns Schaiff RA: Update on the medical treatment of hypercalcemia of malignancy. Clin Pharm 12:117â125, 1993.
36. Nussbaum SR: Pathophysiology and management of severe hypercalcemia. Endocrinol Metab Clin North Am 22:343â362, 1993.
37. Averbuch SD: New bisphosphonates in the treatment of bone metastases. Cancer 72:3443â3452, 1993.
38. Carter PW, Cohen HJ, Crawford J: Hyperviscosity syndrome in association with kappa light chain myeloma. Am J Med 86:591â595, 1989.
39. Geraci JM, Hansen RM, Kueck BD: Plasma cell leukemia and hyperviscosity syndrome. South Med J 83:800â805, 1990.
40. Patterson WP, Caldwell CW, Doll DC: Hyperviscosity syndromes and coagulopathies. Semin Oncol 17:210â216, 1990.
41. Baer MR: Management of unusual presentations of acute leukemia. Hematol Oncol Clin North Am 7:275â292, 1993.
42. Ringenberg QS, Doll DC: Acute nonlymphocytic leukemia: The first 48 hours. South Med J 83:931â940, 1990.
43. Soares FA, Landell GAM, Carduso MC: Pulmonary leukostasis without hyperleukocytosis: A clinicopathologic study of 16 cases. Am J Hematol 40:28â32, 1992.
44. Goenka P, Chait M, Hitti IF, et al: Acute leukostasis pulmonary distress syndrome. J Fam Pract 35:445â449, 1992.
45. Campbell J, Mitchell CA: Acute leg ischemia as a manifestation of the hyperleukocytosis syndrome in acute myeloid leukaemia. Am J Hematol 46:167, 1994.
46. Gartrell K, Rosenstrauch W: Hypoxaemia in patients with hyperleukocytosis: True or spurious, and clinical implications. Leuk Res 17:915â919, 1993.
47. Lascari AD: Improvement of leukemic hyperleukocytosis with only fluid and allopurinol therapy. Am J Dis Child 145:969â970, 1991.
48. Nelson SC, Bruggers CS, Kurtzberg J, et al: Management of leukemic hyperleukocytosis with hydration, urinary alkalinization, and allopurinol. Are cranial irradiation and invasive cytoreduction necessary? Am J Pediat Hematol Oncol 15: 351â355, 1993.
49. Dabrow MB and Wilkins JC: Management of hyperleukocytic syndrome, DIC, and thrombotic thrombocytopenic purpura. Postgrad Med 93:193â202, 1993.
50. Nand S, Messmore H: Hemostasis in malignancy. Am J Hematol 35: 45â55, 1990.
51. Bick RL: Coagulation abnormalities in malignancy: A review. Sem in Thromb and Hemost 18:353â372, 1992.
52. Heyman MR, Schiffer CA: Platelet transfusion therapy for the cancer patient. Semin Oncol 17:198â209, 1990.
53. Nugent DJ: Alloimmunization to platelet antigens. Semin Hematol 29:83â88, 1992.
54. Bensan K, Fields K, Hiemenz J, et al: The platelet-refractory bone marrow transplant patient: Prophylaxis and treatment of bleeding. Semin Oncol 20:102â109, 1993.
55. Ey FS, Goodnight SH: Bleeding disorders in cancer. Semin Oncol 17:187â197, 1990.
56. Rosen PJ: Bleeding problems in the cancer patient. Hematol Oncol Clin North Am 6:1315â1328, 1992.
57. Colman RW and Rubin RN: Disseminated intravascular coagulation due to malignancy. Semin Oncol 17:172â186, 1990.
58. Steingart RH: Coagulation disorders associated with neoplastic disease. Recent Resul Can Research 108:37â43, l988.
59. Levine M, Hirsh J: The diagnosis and treatment of thrombosis in the cancer patient. Semin Oncol 17:160â171, 1990.
60. Scates SM: Diagnosis and treatment of cancer-related thrombosis. Semin Thromb Hemost 18:373â379, 1992.