Tumor Lysis Syndrome

Case reports of metabolic and electrolyte abnormalities after chemotherapy for rapidly growing tumors such as Burkitt’s lymphoma and leukemias were first published in the 1950s.⁹ Cadman and his colleagues in the 1970s proposed a mechanism that linked these metabolic observations.¹⁰ More recently, TLS has been observed in patients with solid tumors and has been observed in patients receiving immunotherapy, such as IL-2, sunitinib, imatinib, and rituximab.^11–14 TLS after treatment for solid tumors is relatively rare.

TLS is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.¹⁰ Electrolyte abnormalities can appear as soon as 6 hours after chemotherapy administration and can persist for 5 to 7 days after treatment. The hyperuricemia comes from the massive release of intracellular nucleic acids and their metabolism by xanthine oxidase into uric acid. Urate crystals can form in the renal collecting ducts and result in oliguric and anuric renal failure. Similarly, potassium and phosphate are released from lysing tumor cells, and renal excretion of these intracellular ions is impaired by hyperuricemia. Serum calcium levels drop from ectopic calcium deposition; this becomes more likely as the calcium-phosphorus product increases. Calcium deposition is favored by a calcium-phosphorus product greater than 60 mg²/dL² and becomes severe when the product is more than 75 mg²/dL². The clinical manifestations of TLS depend on which electrolyte derangement predominates. Tetany, confusion, hypotension, dysrhythmias, and sudden death have been reported with TLS. The most effective management approach for this syndrome is to anticipate its occurrence and intervene prospectively. Patients at greatest risk for TLS are those with a diagnosis of a rapidly growing lymphoma or leukemia with high blast counts, and pretreatment levels of lactate dehydrogenase greater than 1500 U/dL and uric acid greater than 10 mg/dL. Pretreatment azotemia is also a poor prognostic sign. Azotemia may be exacerbated by uric acid nephropathy, which is more common with uric acid levels exceeding 20 mg/dL. It is unlikely that TLS will occur in patients at risk who do not develop metabolic changes within 48 hours after receiving chemotherapy. Guidelines for prophylaxis and treatment of TLS are given in Box 80.1. It is important to note that rasburicase poses an oxidative stress and can induce hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Hypercalcemia

Hypercalcemia is the most common metabolic abnormality occurring in cancer patients. Approximately 10% to 20% of all cancer patients have hypercalcemia at some point in their course. The clinical symptoms of hypercalcemia are nonspecific and include lethargy, confusion, nausea, and anorexia. Often the clinical symptoms in cancer patients may be subtle because the onset of hypercalcemia is gradual. The mechanism that underlies all cases of cancer-related hypercalcemia is increased calcium resorption from bone due to enhanced osteoclast activity mediated through receptor activator for nuclear factor κB ligand (RANKL).¹⁵ This resorption increase can be due to local action of tumor in bone or to the production of bone-resorbing hormones and cytokines by tumor cells remote from bone. Normally, increased circulating calcium results in decreased parathyroid hormone (PTH) production. When PTH levels decrease, bone resorption and renal tubular reabsorption of calcium decline. Low PTH levels cause a decrease in vitamin D production; thus, gut absorption of calcium is lowered. Although PTH levels are suppressed in cancer patients with hypercalcemia, the destructive action of tumor deposits in bone or the action of tumor-produced hormones on bone maintains high calcium resorption rates. This is accomplished through osteoclast activation and proliferation from factors produced by the tumor, such as interleukin 1 (IL-1), tumor necrosis factor (TNF), prostaglandin E₂, granulocyte-macrophage colony-stimulating factor (GM-CSF), transforming growth factor-α, platelet-derived growth factor, and PTH-related peptides.^16–20 Malignancies that commonly cause hypercalcemia include multiple myeloma, breast carcinoma, epidermoid lung carcinoma, and renal cell carcinoma. Hypercalcemia in lymphoma and leukemia is probably not associated with PTH-related peptide, but rather with the overproduction of activated vitamin D.^20,21

Cardiac complications and renal dysfunction are the most serious end-organ effects of hypercalcemia. Electrocardiogram (ECG) changes include prolongation of the PR and QRS intervals and shortening of the QT interval. Bradydysrhythmias and bundle branch blocks become more frequent with serum calcium levels greater than 16 mg/dL. These may progress to complete heart block and asystole. Renal dysfunction may also occur because increased serum calcium induces a diuretic effect, which can cause moderate to severe dehydration and prerenal azotemia. This process can result in acute tubular necrosis if untreated.

Management for any symptomatic hypercalcemic patient should begin with intravenous hydration, which may increase renal blood flow and enhance calciuresis.²² Renal excretion of calcium can be enhanced with furosemide diuresis, although no randomized trials exist to support its use in hypercalcemia. These measures should be viewed as temporizing steps until definitive treatment has been implemented. The bisphosphonates zoledronic acid, pamidronate, alendronate, etidronate, and clodronate have been shown to be highly effective in the long-term treatment of hypercalcemia of malignancy. These agents work by binding to the hydroxyapatite in bone and preventing calcium resorption, although they may also have much more complicated effects on the cell cycle and bone turnover.^23,24 A commonly used bisphosphonate regimen is a single dose of pamidronate (60-90 mg intravenously over 2 to 4 hours) or zoledronic acid (4 mg intravenously over 15 minutes). Doses may be repeated in 3 to 4 days if the calcium does not decline. In addition, therapy directed at controlling the tumor should be implemented. RANKL inhibitors are now available for clinical use (denosumab) that inhibit osteoclast activity induced by malignancy and may be more potent in inhibiting bone resorption compared to bisphosphonates.^25,26 Gallium nitrate can be tried in patients with hypercalcemia unresponsive to bisphosphonates.²⁷ Calcitonin, glucocorticoids, or mithramycin can also be tried in patients unresponsive to first-line therapies, although these therapies are no longer commonly used owing to potential renal injury. Dialysis may be necessary if renal compromise is severe. Treatment recommendations are summarized in Table 80.1.

Oncogenic Osteomalacia

Oncogenic osteomalacia is a rare syndrome characterized by severe hypophosphatemia, high serum alkaline phosphatase, aminoaciduria, glycosuria, low levels of 1,25-dihydroxyvitamin D, and normal serum calcium. The syndrome is the result of humoral inhibition of activation of 25-hydroxyvitamin D. Patients present with bone pain and muscle weakness. Hemolysis from hypophosphatemia is a possible sequela of this syndrome. The tumors that give rise to oncogenic osteomalacia are usually vascular mesenchymal tumors, such as hemangiopericytoma. Treatment involves surgical removal of the tumor and phosphate supplementation.

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

SIADH is associated with carcinoid tumors, myeloma, lymphoma, and carcinomas originating in the lung, prostate, esophagus, head and neck, adrenal gland, and pancreas. Cerebral metastasis from any tumor can also give rise to SIADH. Clinical findings are mainly neurologic, often do not correspond precisely to serum sodium levels, and range from mild confusion to coma and seizures. Because the clinical findings are secondary to water intoxication and hyponatremia, treatment involves water restriction (500 mL/day) and control of the primary tumor. More aggressive treatment should be started with 0.9% or 3% saline solution and furosemide diuresis for patients with neurologic deficits from hyponatremia. The rate of intravenous fluid supplementation should be adjusted based on the urinary excretion of sodium and potassium. Correction of severe hyponatremia (sodium less than 125 mEq/L) should take place over 7 to 10 days. Too rapid a correction can lead to serious neurologic sequelae such as central pontine myelinosis. Patients who fail to respond to water restriction can be treated with demeclocycline (600 to 1200 mg daily), which blocks the peripheral action of antidiuretic hormone (ADH). There is also a new class of selective vasopressin V₂-receptor antagonists that compete with native vasopressin, resulting in an increase of free water clearance. Tolvaptan (15-60 mg daily) can be used in patients who do not respond to demeclocycline.

Adrenal Failure

Cancers of the lung, breast, kidney, stomach, and pancreas and melanoma are the tumors that metastasize most often to the adrenal glands. It is estimated that more than 90% of adrenal tissue must be destroyed before clinical manifestations of adrenal insufficiency appear. The clinical signs and symptoms of hypoadrenalism include weakness, gastrointestinal complaints, postural hypotension, dehydration, and electrolyte disturbances. The typical electrolyte profile is hyponatremia, hyperkalemia, and a mild anion gap acidosis.

Adrenal failure has also been observed in patients receiving ipilimumab, an antibody that blocks the effects of an inhibitory protein in T cells known as CTLA-4 (cytotoxic T-lymphocyte antigen 4) and is used in the treatment of advanced melanoma.⁴ Hypoadrenalism from ipilimumab is usually secondary to panhypopituitarism induced by T-cell–mediated hypophysitis.²⁸ These patients can present with headache and visual changes from pituitary swelling in addition to the clinical findings of hypoadrenalism as reviewed earlier. Evaluation of these patients should include a contrast-enhanced brain magnetic resonance imaging (MRI), and measurement of serum levels of cortisol, adrenocorticotropic hormone (ACTH), and thyroid-stimulating hormone (TSH).

The diagnosis of hypoadrenalism can be made with a cosyntropin stimulation test. Plasma cortisol levels are obtained before cosyntropin injection (0.25 mg intravenously) and 30 and 60 minutes after injection. A normal response is an increase in plasma cortisol of at least 7.0 mg/dL in 60 minutes. If the cortisol response to cosyntropin stimulation is suboptimal, physiologic doses of glucocorticoids should be administered twice a day (cortisone acetate, 25 mg every morning and 12.5 mg every evening). Mineralocorticoid supplementation is required in some patients (fludrocortisone, 0.05-0.1 mg daily). If the diagnosis of adrenal insufficiency is highly suspected, treatment should begin immediately after completion of the cosyntropin test. For patients in adrenal crisis with circulatory collapse, hydrocortisone should be given at stress doses (100 mg intravenously every 8 hours). This dose of hydrocortisone should also be adequate to supplement mineralocorticoid-deficient patients. Patients receiving glucocorticoids as part of their chemotherapy regimen (usually lymphoma or myeloma patients) or for treatment of brain tumors or metastases, may already have adrenal suppression and require stress-dose glucocorticoid replacement during episodes of neutropenic sepsis or elective surgery.

Pheochromocytoma

Pheochromocytoma is most commonly associated with the multiple endocrine neoplasia syndrome. The clinical features of this tumor are related to episodic catecholamine release and include hypertension, severe headache, cardiac dysrhythmias, pallor, perspiration, and rarely, hypotension. Patients can also present with a multisystem crisis characterized by encephalopathy, hyperpyrexia, and hemodynamic instability.²⁹ Diagnosis is made by measuring urinary catecholamine metabolites. An elevated vanillylmandelic acid is accurate approximately 90% of the time in making the diagnosis.³⁰ Patients with borderline catecholamine levels can often be diagnosed with the clonidine suppression test.³¹ Localization of pheochromocytomas can be difficult because the tumors can arise anywhere between the base of the brain and the scrotum and can be multicentric. MRI and computed tomography (CT) are helpful in visualizing adrenal abnormalities. Nuclear medicine studies with m-[¹¹¹I]iodobenzylguanidine (MIBG) can be used if the CT scan is negative. MIBG scans are sensitive and specific for detecting ectopic adrenal medullary tissue.³² Positron emission tomography (PET) imaging and diffusion-weighted MRI can detect sites of disease not apparent on CT or MIBG and can aid in surgical planning.^33–35 Surgical extirpation of the tumor is the only effective treatment. Preoperative control of catechol secretion is necessary and can be attained with long- or short-acting α-adrenergic blockade (phenoxybenzamine 10 mg orally two or three times daily or doxazosin 2-16 mg orally daily). A comparison of preoperative management strategies using long- versus short-acting α-antagonists showed no difference in long-term outcome after surgery, although the incidence of intraoperative hypertension was greater with short-acting medications like doxazosin, terazosin, and prazosin.³⁶ Tachycardia can be controlled with beta blockers, but these should be started only after phenoxybenzamine. Patients in hypertensive crisis can be managed with α-methyltyrosine or calcium channel blockers such as nifedipine or nicardipine.^37–39

Tumor-Induced Hypoglycemia

Functional endocrine tumors can give rise to a variety of clinical syndromes. Most of these problems can be managed outside the ICU; however, tumor-induced hypoglycemia can cause serious consequences including coma, seizures, and focal neurologic deficits. A number of different mechanisms can give rise to hypoglycemia. Autonomous insulin production is most commonly associated with islet cell tumors, whereas production of insulin-like growth factors (IGF-1 or IGF-2) is seen with non–islet cell tumors.⁴⁰ Slow-growing mesenchymal tumors such as leiomyosarcoma, mesothelioma, and fibrosarcoma are the most common non–islet cell tumors that cause hypoglycemia.

Treatment should be focused on control of the tumor. Insulinomas are often benign and can be cured by surgical removal. For unresectable malignancies, hypoglycemic episodes can often be reduced with supportive measures such as dietary modification with frequent meals. Insulinomas may respond to diazoxide, an inhibitor of insulin secretion. Glucagon infusions may be beneficial in some patients.⁴¹

Chemotherapy-Induced Metabolic Disturbances

A number of chemotherapy drugs can cause potentially severe electrolyte disturbances. Cyclophosphamide is associated with hyponatremia from SIADH. Vinca alkaloids such as vinorelbine and vinblastine also cause SIADH. Cisplatin and carboplatin can cause renal tubular defects resulting in hypokalemia and hypomagnesemia, which can be severe enough to require intravenous replacement. Mithramycin lowers serum calcium by a mechanism that is thought to involve inhibition of the effect of PTH on osteoclasts. Although mithramycin can be used for the treatment of hypercalcemia, it can also cause hypocalcemia in patients with normal serum calcium. Cetuximab, a humanized murine antibody directed against the epidermal growth factor receptor (EGFR) and used to treat colon carcinoma and head and neck cancer is associated with severe and symptomatic hypomagnesemia from inappropriate urinary excretion.⁴² Cetuximab may interact with EGFR in the loop of Henle blocking resorption of magnesium and causing secondary hypokalemia and hypocalcemia. Abiraterone, a CYP17 inhibitor of androgen biosynthesis used in men with advanced prostate cancer, also increases adrenal mineralocorticoid synthesis resulting in clinically significant hypokalemia and decreases glucocorticoid synthesis necessitating concurrent administration of prednisone. Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), used in the management of advanced renal cancer and neuroendocrine tumors, can induce severe hyperglycemia requiring insulin.^43,44 The mechanism through which mTOR inhibitors cause hyperglycemia is not fully understood but may involve decreased insulin secretion, direct toxicity to pancreatic β-cells, or impaired suppression of hepatic glucose production.⁴⁵

Superior Vena Cava Syndrome

Obstruction of blood flow through the superior vena cava (SVC) can be caused by fibrosis, thrombosis, external compression, or invasion of the vessel by tumor. SVC syndrome can also be caused by thrombus secondary to a central venous access device, which is now a common fixture of oncologic care. Malignancies that involve the mediastinum, such as lung carcinoma and lymphoma, are the most common causes of this syndrome. Facial and upper extremity edema, facial plethora, headache, and tachypnea are the most common clinical presentations. Collateral venous channels may be found on the chest or abdomen. Death from SVC syndrome is rare, but life-threatening respiratory compromise and elevated intracranial pressure can occur. Therapy for SVC syndrome depends on the underlying malignancy; thus, a biopsy is mandatory for optimal management of these patients. If lymphoma or small cell lung carcinoma is the cause of SVC syndrome, initiation of the appropriate chemotherapy regimen can rapidly shrink the mediastinal mass and is the treatment of choice. For tumors not responsive to chemotherapy, radiation therapy given with high initial fractions (3 to 4 Gy/day) can provide symptomatic relief in more than 80% of patients.⁴⁶ Thrombolysis has only been studied in catheter-associated SVC syndrome and is effective in this setting.⁴⁷ Endovascular stents can restore patency of the SVC in approximately 50% of patients and can result in significant palliation.⁴⁸ Improvement is often evident within 72 hours and the patency of occluded endovascular stents can sometimes be restored with angioplasty.

Cardiac Tamponade

Although primary or metastatic tumors of the heart can decrease cardiac output by impairing ventricular outflow, the most frequent causes of cardiac tamponade in cancer patients are metastatic tumors of the breast and lung, and melanoma, lymphomas, and leukemias. Tamponade may occur through either encasement of the heart by tumor or production of a malignant pericardial effusion. The clinical manifestations of tamponade include decreased exercise tolerance, shortness of breath, and cough. Voltage may be decreased on ECG with a pulsus alternans pattern present. Muffled heart tones, a pericardial rub, or an increased paradoxical pulse (i.e., decrease in systolic blood pressure on inspiration exceeds 10 mm Hg) may be present on physical examination. Echocardiography is extremely useful in confirming the diagnosis of tamponade if it is suspected on physical examination. Diastolic collapse of the right atrium or right ventricle on echocardiogram is an indicator of hemodynamic compromise.49,50 Swan-Ganz catheterization may be helpful to confirm the presence of significant tamponade.

Pericardiocentesis for relief of tamponade is indicated emergently when echocardiographic or clinical evidence of hemodynamic compromise is present. Intravenous infusions of normal saline at high flow rates (100 to 500 mL/hour) may be required to support the patient until a drainage procedure is performed. Although rapid reversal of cardiac filling problems can be accomplished by this procedure, a long-term solution is required. Creation of a pericardial window can prevent the reaccumulation of fluid in more than 90% of patients.⁵¹ Sclerosing agents such as tetracycline and bleomycin have also been used to prevent reaccumulation of pericardial fluid.⁵² Sclerosants may be instilled into the pericardial space after adequate drainage has been accomplished and appear to have a success rate comparable to pericardial window procedures. Some centers also perform pericardial windows using video-assisted thoracoscopy, but there have been no prospective randomized studies showing superior clinical outcomes for subxiphoid versus video-assisted thoracoscopy approaches.⁵³

Treatment-Induced Cardiac Dysfunction

A number of chemotherapy medicines have cardiac toxicities that can be life threatening. Cumulative doses of doxorubicin greater than 450 mg/m² are associated with an increased risk for congestive heart failure (CHF). Heart damage from this drug is thought to be from an iron-dependent generation of free radicals, which secondarily cause oxidative damage to lipid membranes and intracellular organelles.⁵² This toxicity can present acutely or months after drug administration. It is more prevalent in older patients and those with a history of coronary artery disease, hypertension, tobacco abuse, or chest radiation therapy. Initial management with diuretics, digoxin, and angiotensin blockers is usually of benefit, but heart failure can be progressive. Liposomal encapsulation of doxorubicin or the use of dexrazoxane to prevent oxygen-derived free radical formation, may diminish the cardiac toxicities of this agent.^54–56 Other anthracyclines, such as mitoxantrone and epirubicin, may have a lower incidence of CHF. Furthermore, weekly low-dose boluses or continuous-infusion methods of doxorubicin administration appear to reduce the incidence of clinically significant heart damage. Although anthracycline-induced cardiac damage has generally been considered irreversible, some studies suggest that some improvement in cardiac function may occur with aggressive medical management.⁵⁷ Paclitaxel, which is commonly used in ovarian, breast, and lung carcinomas, is associated with bradydysrhythmias.^57,58 Ventricular tachycardia, myocardial infarction, and cardiac ischemia have also been reported. Cyclophosphamide, which is commonly used in breast cancer, lymphoma, and stem cell transplant conditioning regimens, is associated with sporadic instances of CHF, which may be severe and occurs within a few days of cyclophosphamide administration, especially at high doses. Hemorrhagic myocarditis with myonecrosis was seen on autopsy specimens from these patients. These events appear unrelated to cumulative dose or method of administration. CHF from ifosfamide has also been reported.⁵⁹ CHF is usually seen approximately 2 weeks after high doses of the drug and appears more frequently in patients with concurrent renal insufficiency. Medical management successfully reverses the heart failure in most patients. CHF is also associated with trastuzumab, an anti-HER2 (human epidermal growth factor receptor 2) antibody used commonly in the management of certain forms of breast carcinoma. The incidence of CHF after trastuzumab in a large randomized trial was between 3% and 4%, and was more common in patients with antecedent cardiac disease, older patients, and those having diminished ejection fraction (EF) after anthracycline-containing chemotherapy.⁶⁰ Most patients with trastuzumab-induced cardiac dysfunction have improved symptoms with appropriate medical management for CHF and discontinuation of trastuzumab.

Serial echocardiography studies have been used to assess cardiac toxicities in patients receiving chemotherapy for many years, but subtle alterations in myocardial function can be missed with standard assessment of EF. A decrease in longitudinal strain assessed by Doppler measurements of tissue velocity at baseline and repeated at 3 months after starting anthracyclines or trastuzumab is a more sensitive predictor of cardiac dysfunction than EF61,62 and may be useful in identifying patients in need of medical management before significant symptoms occur.

Radiation therapy delivered to the chest for the treatment of Hodgkin’s disease, lung malignancies, breast cancer, or other neoplasms can result in a number of cardiac toxicities, including radiation pericarditis with tamponade, myocardial fibrosis, and premature coronary artery disease. The toxic effects of radiation therapy are secondary to microvessel fibrosis and may take up to 20 years to appear.⁶³ After mantle-field radiation therapy, the risk of fatal myocardial infarction is more than three times greater than in age-matched control subjects, although mantle-fields are rarely used currently to treat patients with lymphoma. Nervertheless, it is difficult to treat the mediastinum without also treating the heart.

Lymphangitic Tumor Involvement

Interstitial lung processes in cancer patients may be due to a variety of infectious insults but can also be caused by direct lymphangitic spread of the tumor. The symptoms of lymphangitic involvement are nonspecific and include dyspnea, nonproductive cough, and hypoxemia. Pulmonary hypertension and cor pulmonale can also be present. The diagnosis can be established by video-assisted thoracoscopic biopsy or transbronchial biopsy. Pulmonary microvascular cytologic specimens obtained with a wedged pulmonary artery catheter may be a less invasive way to make the diagnosis of lymphangitic carcinomatosis.⁶⁴ The prognosis of this condition is generally poor, with a life expectancy of 1 to 6 months. Appropriate systemic treatment should be implemented when the site of the primary malignancy is diagnosed.

Treatment-Induced Pulmonary Dysfunction

A number of chemotherapy agents and radiation therapy can cause pneumonitis leading to chronic pulmonary fibrosis. The chemotherapeutic agents most likely to cause this problem are bleomycin and mitomycin, but other alkylators, nitrosoureas, antimetabolites, gemcitabine, taxanes, and vinca alkaloids can cause pulmonary dysfunction. Inhibitors of the mTOR pathway such as everolimus and temsirolimus used in the treatment of advanced renal cancer can also induce severe pneumonitis.44,65 Erlotinib, an inhibitor of the phosphorylation of EGFR used in the treatment of advanced lung cancer, can also induce severe and irreversible pneumonitis.⁶⁶ The underlying mechanisms for lung injury induced by these agents are not fully understood, but likely involves oxygen-derived free radical toxicity⁶⁷ and dysregulation of leukocyte apoptosis regulated by TNF-receptor family members. TRAIL (TNF-related apoptosis-inducing ligand) has shown promise in preclinical models of bleomycin lung injury and may also have antitumor properties.⁶⁸ We advocate that cancer patients in need of supplemental oxygen should receive the lowest possible fractional concentration of oxygen that produces a hemoglobin oxygen saturation of greater than 90%. Irreversible lung damage can occur if excessive oxygen is administered to patients receiving bleomycin or radiation therapy. Clinical assessment is crucial to patient management because there are no sensitive or accurate tests to predict the onset or course of bleomycin-induced pulmonary toxicity. The resting diffusion capacity has been used, but is suboptimal to follow patients.⁶⁹ Treatment recommendations are based on the recognition of three distinct clinical entities:

Diffuse Interstitial Pneumonitis

The differential diagnosis of diffuse pulmonary infiltrates in cancer patients is large. Infectious causes include bacterial, viral, fungal, and protozoal pathogens. Noninfectious causes for diffuse pulmonary infiltrates are neoplasm, autoimmune disease, cardiac failure, leukostasis, pulmonary hemorrhage, and radiation- or chemotherapy-induced pneumonitis. Making a diagnosis on clinical grounds is difficult because the radiographic and physical examination findings are virtually indistinguishable among these diverse causative entities. Performing an open-lung biopsy is often the only way to confirm a diagnosis; however, empiric treatment may result in equally good patient outcomes. A randomized study compared immediate open-lung biopsy followed by therapy directed at the diagnosis versus empiric antibiotics alone without biopsy to treat diffuse pulmonary infiltrates in cancer patients.⁷⁰ The antibiotic regimen included trimethoprim-sulfamethoxazole (20 mg/kg/day intravenously) and erythromycin (30 mg/kg/day intravenously, divided into four daily doses). A broad-spectrum antibiotic was added if the patient was neutropenic at the time of diagnosis. There was no significant difference in the outcome for these patients; however, those who received an open lung biopsy had a greater complication rate. Empiric antibiotics are appropriate initial management for diffuse interstitial infiltrates, but patients who do not improve after 4 days of empiric therapy should receive open-lung biopsy.

The decision to place a patient with a cancer diagnosis on ventilator support is often controversial for medical staff and families. It is generally recognized that such patients have a poor prognosis, with a mortality rate approaching 80%. A large multicenter trial prospectively examined prognostic variables for cancer patients requiring ventilatory support.⁷¹ Factors having a statistically significant negative influence on survival were a diagnosis of leukemia, allogeneic stem cell transplantation, progressive cancer, cardiac dysrhythmia, presence of disseminated intravascular coagulation (DIC), and need for vasopressor support. Prior surgery with curative intent was protective and probably relates to a selection bias for patients with physiologic reserve sufficient to tolerate surgery. Although this model is similar to other prognostic models used in the ICU setting, it differs in its emphasis on cancer-specific factors. There also appears to be a positive association between recovery from neutropenia, pneumonia, and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation and an inverse relation to survival in patients with hematologic malignancy.⁷² The mortality rate of patients with ARDS during neutropenic recovery was 86.8% versus 51.5% in patients without ARDS in this single institution study. In general, the assessment of the potential reversibility of the organ dysfunction is the critical variable. Most iatrogenic toxicities are reversible, and patients having toxicity from treatment can generally be supported to recovery. Similarly, organ dysfunction from treatable malignancies should be assumed to be reversible. However, when more than three organ systems are failing, the chances of recovery are very small. The decision to place a cancer patient on ventilator support is highly individualized, but such models can assist in counseling families about level-of-care issues.

Hemoptysis

Hemoptysis can be a presenting sign of cancer, especially endobronchial lesions of non–small cell lung cancer. Patients presenting with significant hemoptysis and airway compromise can be palliated with a variety of bronchoscopic techniques including argon or neodymium:yttrium-aluminum-garnet (Nd:YAG) laser, photodynamic therapy, stent placement, endoluminal brachytherapy, or combinations of these techniques.⁷³ External beam radiation, pulmonary artery embolization, and blood pressure control can also be effective in controlling hemoptysis.

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been used with chemotherapy agents to increase overall response and time-to-progression in lung cancer. Bevacizumab can also cause significant and life-threatening hemoptysis; especially in patients with squamous cell histologic lung cancer.⁷⁴ The mechanism of hemoptysis after bevacizumab is collapse of the tumor vasculature resulting in tumor cavitation in proximity to major blood vessels. Because cancer outcomes can be improved with bevacizumab, we endorse an aggressive approach in supporting patients who experience hemoptysis as a result of this or other vascular-targeting agents.

Febrile Neutropenia and Septic Shock

Despite appropriate broad-spectrum antibiotics, approximately 10% of febrile neutropenic patients progress to septic shock. Fluid resuscitation and pressor agents such as phenylephrine, dopamine, dobutamine, and norepinephrine remain standard treatment for the hemodynamic consequences of shock despite advances in understanding the physiology and immunologic sequelae of shock and a growing number of drugs that may influence the pathophysiology of this clinical entity. Treatments aimed at modifying the host reaction to sepsis other than hemodynamic support have not been shown to improve outcomes.

Spinal Cord Compression

The tumors that most often cause spinal cord compression from epidural metastases or bony destruction are carcinomas of the lung, breast, and prostate and multiple myeloma. The level of the spinal cord involvement determines the clinical neurologic deficit. Cervical cord compression can cause quadriplegia or respiratory arrest; thoracic, paraplegia, and lumbar involvement can give rise to loss of bladder and bowel function. If the problem is detected when local or radicular pain is the only symptom, treatment with glucocorticoids, radiation therapy using conventional or conformal techniques, or laminectomy can be highly effective. If the patient presents with a neurologic deficit, such as the inability to walk, the chance of significant improvement is less than 10%.⁷⁸ MRI is the diagnostic test of choice for diagnosing epidural metastases. Glucocorticoids should be started emergently for patients who present with myelopathy (dexamethasone 10 mg followed by 4 mg every 6 hours) and imaging obtained as soon as possible. The maximal effect of dexamethasone on alleviating symptoms may not be achieved at total doses of 24 mg/day. If clinical improvement from glucocorticoids is suboptimal, doubling the dose each day up to a maximum of 200 mg/day total dose may improve symptom control until definitive therapy is implemented.⁷⁹ The standard of care for cord compression had been glucocorticoids and radiation; however, a randomized trial has shown benefit for decompressive surgery followed by radiation.⁸⁰ Eighty-four percent of patients randomized to receive surgery and radiation maintained the ability to walk compared to 57% in the radiation alone group. Better palliation of pain and the duration of ambulation were maintained better in the surgery group. A meta-analysis of 1595 articles describing 2495 patients supports better functional improvement and pain control using surgery with or without postsurgical radiation in the management of malignant spinal cord compression.⁸¹

Brain Metastases and Hemorrhage

Tumor metastatic to the brain may be a localized problem, amenable to surgical resection with good results.⁸² Patients who present with significant peritumoral edema and increased intracranial pressure may suffer brain herniation if acute measures are not taken. Therapy includes high-dose glucocorticoids (dexamethasone 10 mg, followed by 4 mg intravenously every 6 hours), intubation and mechanical hyperventilation to maintain partial pressure of carbon dioxide in arterial blood (PaCO₂) between 25 and 30 mm Hg, and mannitol diuresis (1.0 to 1.5 g/kg intravenously as a 20% solution). Patients who do not respond may benefit from higher glucocorticoid doses (dexamethasone 25 to 50 mg every 6 hours). After stabilizing the patient with these acute interventions, definitive radiation therapy or surgery can be started. Prophylactic anticonvulsants are often administered; however, this intervention has scant supportive data and should be held in most patients until a seizure has occurred.^83,84 Frontal lobe tumor deposits and brain metastases from melanoma are two situations in which prophylactic antiseizure medication should be considered. Newer radiation techniques such as stereotactic or gamma knife radiosurgery can also be effective in controlling or eradicating brain metastatic disease, although this modality is more appropriate for patients with good functional status and a total volume of metastatic disease less than 12 cm³.⁸⁵

Dose-intensive therapy for acute leukemia is associated with prolonged thrombocytopenia and the possibility of intracranial hemorrhage. It was previously thought that such events were highly associated with platelet counts less than 20,000 cells/µL⁸⁶; however, the threshold for platelet transfusion used in most medical centers is now 10,000/µL, based on a randomized trial that showed no difference in patient outcome with the more stringent threshold.⁸⁷ Other events, such as sepsis and fever, contribute to the likelihood of bleeding with thrombocytopenia. Patients with solid tumors are also less likely than those with leukemia to bleed as a consequence of thrombocytopenia. In cancer patients with suspected intracranial bleeding and thrombocytopenia, the platelet count should be maintained above 50,000 cells/µL. The best strategy to maintain adequate hemostatic function with platelet transfusion support is controversial because platelet kinetics are complex.^88,89 We advocate frequent dosing or continuous infusion of platelets in actively bleeding thrombocytopenic patients who have poor increments in platelet count after transfusion resulting from platelet sensitization. The blood bank should identify human leukocyte antigen (HLA)-matched platelet donors for such patients and maintain an adequate supply of the HLA-matched platelets. Single-donor platelets are often more effective than pooled platelets in this setting.

Uncontrolled Seizures

In 15% to 30% of patients who develop brain metastases, the initial sign is a generalized seizure.⁹⁰ Metabolic disturbances, such as hyponatremia from SIADH, may also cause seizures in cancer patients. Acute control can be obtained with intravenous diazepam (5 mg intravenously every 5 to 10 minutes up to 30 mg). Standard measures to protect the airway, prevent aspiration, and avoid limb injury should also be implemented. After acute control has been attained, phenytoin should be started (15 mg/kg intravenously at a maximum rate of 50 mg/minute, then maintenance doses of 300 mg/day). Phenytoin up-regulates the P-450 system in the liver, which may accelerate the metabolism of certain chemotherapy agents, such as paclitaxel and docetaxel.^91,92 Levetiracetam (1000 mg daily) is also highly effective in the acute and chronic management of seizures induced by brain malignancy.⁹³ Antiseizure agents that do not influence P-450 cytochromes, like gabapentin, should be used in patients requiring taxane-based chemotherapy. Serum levels of phenytoin and levetiracetam should be monitored.

Seizures, coma, and other neurologic complications can occur with a variety of chemotherapeutic and biologic agents. Most of these toxicities improve with cessation of the causative agent and supportive care. Ifosfamide-induced neurotoxicity has a unique mechanism related to changes in mitochondrial fatty acid oxidation and the accumulation of glutaric acid metabolites.⁹⁴ Treatment with methylene blue (200-300 mg orally or intravenously daily), an electron-accepting drug, can reverse and prevent neurologic toxicity during ifosfamide infusion.⁹⁵

Tumor-Induced Emergencies

For most tumor types, obstruction may be related to a localized lesion that is readily amenable to surgical correction. In women with ovarian cancer, the obstruction is often related to loss of peristalsis in long segments of bowel because of diffuse wall invasion by malignancy. Little can be done with surgical intervention in such circumstances. Improvement hinges on the availability of effective chemotherapy. Bowel obstruction or perforation can occur from primary or metastatic tumors. If the patient presents with peritoneal signs of an acute abdomen, then emergent exploratory surgery is indicated.⁹⁷ For less clear-cut presentations, abdominal radiographs, CT scans, and endoscopy may be helpful. These patients can be managed initially with bowel rest, nasogastric suction, and anaerobic antibiotic coverage until a diagnosis is made. Somatostatin can provide palliation in some patients, probably by increasing intestinal water resorption.⁹⁸

Biliary obstruction can occur from primary tumors of the pancreas, bile ducts, or gallbladder but more commonly is from tumors metastatic to the porta hepatis, such as breast carcinoma, melanoma, or lymphoma. Ascending cholangitis and sepsis are possible sequelae if bile drainage is not accomplished. A percutaneous or endoscopic approach can be used to decompress the bile ducts emergently. Effective treatment of the primary tumor should be implemented when possible. If the tumor is unlikely to respond to chemotherapy or radiation therapy, palliation with an internal stent or an operative biliary diversion procedure is indicated.

Hemorrhage of an abdominal viscus can occur from chemotherapy or progressing tumor. Identifying the source of the bleeding can be accomplished with endoscopy, CT scan, angiography, or labeled red blood cell studies. Bleeding from ulcers or mucosal irritation from chemotherapy can usually be managed medically or with endoscopic control via heater probe or Nd:YAG laser. If a tumor deposit is the cause, surgical control of the site should be considered. If the patient is not a surgical candidate, an angiographic embolization procedure may provide effective palliation.

Chemotherapy-Induced Gastrointestinal Dysfunction

Typhlitis (ileocecal syndrome) is seen most often in patients with leukemia receiving induction chemotherapy. It presents usually after more than 7 days of neutropenia with watery diarrhea, abdominal distention, and right-sided abdominal tenderness. Bowel rest and antibiotics may be successful in treating this condition, but surgery is required for repeated sepsis, bowel necrosis, or perforation. This syndrome can occur on subsequent cycles of chemotherapy; thus, a colonic diversion procedure may be needed in order to complete chemotherapy.

Colitis can occur in up to 40% of patients who have received ipilimumab of whom 5% experience severe symptoms including high-output diarrhea and intestinal perforation.4,99 Neutrophilic and lymphocytic infiltrates are evident on biopsy consistent with the idea that ipilimumab elicits autoimmune tissue damage by breaking self-tolerance. Intervention early when symptoms are mild or moderate (e.g., 4-6 stools per day over baseline) is key to avoiding severe or life-threatening colitis. Initial management is to withhold ipilimumab and administer loperamide. If symptoms persist, then a course of glucocorticoids should be started (e.g., prednisone 0.5 mg/kg/day). For patients who have seven or more stools per day, abdominal pain, melena, or hematochezia, then glucocorticoids (e.g., prednisone 1-2 mg/kg/day) should begin promptly with a slow taper when symptoms resolve. Endoscopic evaluation may be helpful. Emergent surgery for perforation is appropriate. TNF inhibitors (e.g., infliximab) can be effective in managing diarrhea from ipilimumab unresponsive to glucocorticoids.⁹⁹ Figure 80.1A and B depicts the biopsy findings in ipilimumab colitis and an associated tumor response.

A number of chemotherapy agents can decrease bowel motility resulting in ileus. Examples of such medications are paclitaxel, vincristine, and cytosine arabinoside. Supportive care of the ileus is usually successful, but toxic megacolon can occur and is an indication for surgical management.

A particularly difficult management problem is the severe constipation that can accompany the use of opioid analgesics in patients with advanced cancer. Prophylactic measures are very important, including the use of stool softeners and osmotic laxatives and maintaining patient activity as much as possible. Even with optimal prophylaxis, results are often unsatisfactory. Methylnaltrexone, a µ-opioid receptor antagonist that does not cross the blood-brain barrier, can significantly improve constipation, usually within 4 hours of dosing, without reducing the analgesic effect of narcotics.¹⁰⁰

Gastrointestinal Lymphomas

Lymphoma presenting as a gastric or intestinal mass is common in AIDS patients and in patients with B-cell lymphomas arising in mucosal-associated lymphatic tissue (MALT) secondary to Helicobacter pylori infection. This situation warrants extreme caution because perforation of an abdominal viscus is a potentially life-threatening complication of potentially curative chemotherapy. Because perforation is a major concern in these patients, initial surgical resection is advocated by some authors.101,102 Others have noted low rates of abdominal catastrophe in patients treated with chemotherapy and radiation therapy alone.¹⁰³ Data from patients with gastric MALT lymphoma treated with antibiotics or radiation therapy suggest that perforation is rare in patients achieving a tumor response.¹⁰⁴ Patients with extensive gastric involvement by lymphoma should start chemotherapy in the hospital with surgical consultation to monitor for possible perforation or obstruction. Perforation is more common in patients with small intestinal involvement with aggressive histologic lymphomas compared to gastric or colon involvement by lymphoma.

Tumor-Induced Genitourinary Dysfunction

Obstructive uropathy resulting in hydronephrosis can occur at the bladder outlet or anywhere along the path of the ureter. Bladder outlet problems are most commonly caused by local tumor invasion from prostate, bladder, rectosigmoid, cervical, or ovarian neoplasms. Metastatic deposits from gastric, breast, or pancreatic malignancies can also obstruct the bladder outlet. Tumors that arise from retroperitoneal structures or metastasize to the retroperitoneum can cause ureteral obstruction. Examples of tumors that commonly have a retroperitoneal presentation are Hodgkin’s and non-Hodgkin’s lymphoma, germ cell tumors that metastasize to retroperitoneal lymph nodes, and axial sarcomas. Primary tumors of the ureter can also cause obstruction. If the obstruction and the resulting hydronephrosis are of short duration, percutaneous drainage and decompression are recommended. If there is a concurrent infection, decompression is mandatory and constitutes an oncologic emergency. After a period of 48 to 72 hours, a ureteral stent can be placed using the anterograde or retrograde approach. Furosemide-renal scanning can be used to confirm the presence of kidney function if there is a question about the reversibility of the functional impairment of the obstructed kidney.¹⁰⁵ After stenting, appropriate radiation therapy, chemotherapy, or hormonal treatment should be implemented for control of the malignancy.

Renal function can also be compromised indirectly by malignancies. The nephrotic syndrome is seen in association with several solid tumors, such as colon, gastric, ovarian, and breast carcinomas. Lymphomas, especially those of T-cell origin, and chronic lymphocytic leukemia can also cause nephrotic syndrome and other glomerulopathies. Multiple myeloma and Waldenström’s macroglobulinemia can produce amyloid and cryoglobulin deposits in the kidneys, resulting in acute tubular necrosis or interstitial nephritis. Recurrent and chronic pyelonephritis is common in patients with myeloma. Dialysis may be necessary to support the patient until effective antitumor therapy is given.

Chemotherapy-Induced Genitourinary Complications

Hemorrhagic cystitis can be caused by acrolein, a metabolite of cyclophosphamide and ifosfamide. This problem can usually be prevented with adequate hydration, bladder irrigation, or the use of thiol-based chemoprotectants, such as mesna. Mesna administration is mandatory for ifosfamide treatment. If the hemorrhagic cystitis is severe and unresponsive to supportive measures and saline bladder irrigation, formalin bladder instillation can be performed under general anesthesia.¹⁰⁶ A 1% formalin solution should be used, but bladder fibrosis and strictures may occur despite this low concentration. Care must be taken to avoid reflux of the formalin up the ureters. Urinary diversion and cystectomy may be required for uncontrolled bleeding.

Methotrexate, an antifolate chemotherapy agent, can precipitate in renal tubules and cause acute tubular necrosis if adequate hydration and urinary alkalinization are not achieved before therapy. If renal toxicity occurs, leucovorin rescue should be started, based on serum levels of methotrexate (Table 80.2 provides details of methotrexate toxicity prevention or reversal). Intravenous fluids containing bicarbonate, furosemide, and mannitol may be helpful in preventing oliguric renal failure.

Hyperleukocytosis

Large numbers of leukemic blasts may be present in acute leukemias or in the late stages of chronic leukemias. When the number of circulating myeloblasts is greater than 100,000 cells/µL, the viscosity of the blood increases because white blood cells are much less deformable than red blood cells. Patients with chronic lymphocytic leukemia can tolerate higher circulating numbers of malignant cells (e.g., 100,000-300,000 cells/µL) without consequence. In acute leukemia, the blasts may invade and weaken the vessel wall, leading to hemorrhage. Hyperleukocytosis chiefly affects the microvasculature in the lungs and the central nervous system. Symptoms can range from mild shortness of breath and blurred vision to pulmonary congestion, hypoxia, intracranial hemorrhage, and TLS (tumor lysis syndrome). Rapid institution of leukapheresis can often decrease leukocyte counts by 20% to 50%.¹⁰⁷ Although the improvement may be transient, chemotherapy treatments for the underlying leukemia can be accomplished with greater safety, and perhaps a lesser degree of TLS.

All-trans-retinoic acid (ATRA), used in the treatment of acute promyelocytic leukemia (APL), induces differentiation of leukemic cells.¹⁰⁸ ATRA is associated with a leukocytosis syndrome characterized by fever, dyspnea, and interstitial lung infiltrates on chest radiograph, which can progress to ARDS.¹⁰⁹ ARDS may be secondary to accumulation of differentiated leukemic blasts and their release of cytokines, such as IL-2, in the lung. Leukapheresis is ineffective in this setting; however, the early implementation of glucocorticoids is beneficial (dexamethasone 10-20 mg/day in divided doses).

Disseminated Intravascular Coagulation

DIC can be associated with a variety of solid tumors, including carcinoma of the prostate, lung, breast, and gastrointestinal tract, and melanomas. However, DIC is the hallmark of the clinical presentation for APL. The leukemic blasts in APL manufacture procoagulants, which are released into the circulation, particularly after cytotoxic chemotherapy.¹¹⁰ The use of ATRA for treating APL has lessened the severity of DIC in this illness, but a new complication has been added (discussed in the previous paragraph). To manage DIC in APL, serial determinations of fibrin split products and fibrinogen levels should be made. Replacement of fibrinogen can be accomplished with cryoprecipitate (1 bag/2 kg of body weight initially, followed by 1 bag/10-15 kg of body weight daily). If DIC worsens after cryoprecipitate, intravenous heparin can be started but should be used cautiously. Antifibrinolytic agents, such as epsilon-aminocaproic acid, should be avoided because they can block the normal dissolution of thrombi and increase organ damage.

The most effective approach to DIC is prevention. Given the reciprocal serious complications associated with using ATRA alone or cytotoxic chemotherapy in the treatment of APL, the DIC and ATRA syndromes are best prevented by using ATRA and combination chemotherapy together so that the mass of cells differentiating in response to ATRA can be reduced to levels by the cytotoxic chemotherapy that do not result in sticking and sludging in the lungs.

Interleukin 2

IL-2-induced capillary leak is the chief underlying cause for most of its end-organ toxicity. The capillary leak is associated with endothelial relaxation caused by nitric oxide.111,112 Clinical data also support the notion that nitrate levels are greatly elevated in patients treated with IL-2.¹¹³ In addition, the adhesion of activated lymphocytes to vascular endothelium after IL-2 administration has been shown to cause vascular leak in a rabbit model.¹¹⁴

The most common serious manifestation of IL-2–induced capillary leak is hypotension with essentially the same hemodynamic findings of warm shock¹¹⁵; thus, effective support for these patients requires the use of parenteral α-adrenergic agonists, such as phenylephrine or dopamine.^116,117 Recommendations for treating cytokine-induced hypotension are given in Table 80.3. Fluid administration, though of transient benefit, often exacerbates the pulmonary capillary leak seen with IL-2. IL-2 infusions can be continued, despite hypotension, with appropriate pressor management. In our clinical experience, phenylephrine doses of up to 500 µg/minute can be tolerated to reverse IL-2–induced hypotension in this selected group of patients who have normal cardiopulmonary function before treatment. IL-2 doses are held until capillary leak has improved sufficiently to warrant a decrease in phenylephrine to less than 100 µg/minute and can be resumed thereafter in the absence of other dose-limiting toxicities.

Allergic and Anaphylactic Reactions to Monoclonal Antibodies

Allergic reactions to monoclonal antibodies occur in 10% to 15% of patients, probably because some agents are chimeric mouse proteins. However, even humanized antibodies can produce shortness of breath, tachycardia, and hypotension, especially with the first infusion. The symptoms may result from complement activation by the antibody and can often be safely managed by slowing or temporarily stopping the antibody infusion. When symptoms abate, the antibody infusion can be resumed at half the initial rate. Mild allergic manifestations, such as urticaria and pruritus, can be managed with oral antihistamines. We advocate a stepwise approach, starting with H₁ blockers (diphenhydramine, 50 mg every 4 hours alternating with hydroxyzine, 50 mg). H₂ blockers (ranitidine 150 mg every 12 hours) may be added if urticaria worsens. Pharyngeal and laryngeal edema can occur, with or without bronchospasm. Clinical manifestations of upper airway edema include drooling, phonation changes, and a sensation of throat pain or tightness. For these more severe presentations, stopping the antibody and a period of observation in the ICU setting is recommended. Parenteral antihistamines should be started, along with inhaled β₁-agonists if bronchospasm is present. Fiberoptic endoscopic examination of the hypopharynx should be performed to determine the extent of the edema. If repeat fiberoptic examination after 4 to 6 hours shows resolution of the edema, resumption of the antibody at the lower dose or reduced flow rate can be considered. If laryngeal edema worsens, intubation may be necessary to protect the airway.

There are rare patients who experience an anaphylactic reaction with circulatory collapse after monoclonal antibody treatment or other immunotherapy. This response is not always predicted by test doses of the antibody. The prognosis for these individuals in our clinical experience is poor, with a mortality rate approaching 100% despite the prompt implementation of intensive care support.

Immune-Mediated Toxicities from T-Cell–Directed Therapy

A new class of monoclonal antibodies directed at the regulatory pathways of T cells is being developed, and has shown great promise in inducing durable antitumor effects in a variety of solid tumors, myeloma, and leukemia. The four T-cell pathways under investigation are CTLA-4, PD-1, OX40, and 41BB. Thus far, ipilimumab, a monoclonal antibody antagonizing the inhibitory function of CTLA-4, is the only one of these T-cell–targeted antibodies that has been approved by the Food and Drug Administration (FDA) for the treatment of advanced melanoma, but it is likely that more T-cell–directed agents will enter oncologic practice in the future.

The toxicities of ipilimumab have been extensively reviewed¹²⁵ and include rash, diarrhea, colitis with perforation, endocrinopathies, hepatocellular injury, fatigue, and pyrexia. The toxicities are presumed due to T-cell activation induced by CTLA-4 blockade by ipilimumab, although the precise mechanism is not well understood. Of these toxicities, immune-mediated colitis has the greatest potential to induce critical illness, as discussed earlier.

Acute and Chronic Graft-Versus-Host Disease

Graft-versus-host (GVH) disease is most commonly seen in the setting of allogeneic transplants but can be observed after syngeneic and autologous transplants. It is well documented that GVH disease can reduce recurrence rates in leukemia¹²⁶; it also lowers overall survival after transplant. The prerequisites for GVH disease are that the graft must include a population of immunologically competent T cells, the graft recipient must be unable to destroy these cells, and tissue antigens must be present in the recipient that are not present in the donor.¹²⁷ Studies of the immunobiology of GVH disease suggest that dysregulation of T-cell subsets (CD4⁺, CD25⁺, Foxp3⁺, Treg, and T_H17) are instrumental in the clinical manifestations of GVH disease and represent potential therapeutic targets.^128,129

The clinical manifestations of GVH include skin rash (maculopapular or diffusely erythematous), liver function abnormalities, and gastrointestinal symptoms including diarrhea, nausea, vomiting, and ileus.¹²⁶ These toxicities are graded (I to IV) on a semiquantitative basis. Grade I or II GVH disease has relatively little morbidity, but grade IV GVH disease carries a 100% mortality rate. Treatment of established GVH disease requires suppression of the immune system. The drugs used most commonly to suppress GVH disease are glucocorticoids, cyclosporine, tacrolimus, and methotrexate, which are usually used in combination. Gamma globulin infusions may also be beneficial in the prophylaxis of GVH disease.¹³⁰ The mechanism of action of gamma globulin is unknown but may involve binding to Fc receptors, which may prevent T cells from recognizing target tissues.

Veno-occlusive Disease

Hepatic veno-occlusive disease (VOD) is a clinical syndrome characterized by weight gain (fluid), tender hepatomegaly, and elevations of hepatocellular enzymes and bilirubin. The syndrome is the result of endothelial toxicity from high-dose chemotherapy, and results in a local hypercoagulable state with tissue factor synthesis, down-regulation of thrombomodulin, and release of von Willebrand factor with the resultant formation of blood clots in hepatic veins.¹³¹ The incidence of VOD has diminished with the prophylactic use of heparin.¹³² Agents used in the treatment of established VOD include tissue plasminogen activator,¹³³ antithrombin III,¹³⁴ antioxidant therapy,¹³⁵ and transjugular intrahepatic portosystemic stent-shunt.¹³⁶ Clinical trials using a polydisperse oligonucleotide known as defibrotide¹³⁷ are showing activity and defibrotide may be helpful in both the prevention and treatment of VOD. Intensive support is often needed for patients with VOD. Despite aggressive treatment, the mortality rate for severe established VOD approaches 100%.¹³⁸ Patients with milder disease may recover with supportive measures. Early recognition and intervention are key factors influencing outcome.

Infectious Complications of Stem Cell Transplantation

Different facets of immune function return at varying intervals after bone marrow transplant.¹³⁹ Integumentary and mucosal barriers are disrupted in the period immediately after myeloablative chemotherapy. For this reason, aerobic bacteria and Candida organisms are the most likely pathogens early after transplant. There are decreased neutrophil numbers for the first 2 to 4 weeks after transplant, although the use of colony-stimulating factors shortens the neutrophil recovery period. Until neutrophil numbers increase, herpes simplex virus, Candida, Aspergillus, and bacterial infections are common. It should be noted that the full chemotactic function of neutrophils does not return for 100 days after transplant. Cellular and humoral immunity defects persist for 1 to 3 months after transplant and may lengthen if GVH disease occurs. Fungal and cytomegalovirus (CMV) infections predominate in this period.^140,141 From 3 months to 1 year after transplant, T cells remain dysfunctional and disordered immunoregulation may occur. Varicella zoster, hepatitis C, Pneumocystis jiroveci pneumonia, and pneumococcal pneumonia are the most common infections until T-cell function has recovered. Immune deficits may be moderated by antigen-specific immunity conferred by the transplanted marrow and the use of gamma globulin infusions, which are now routinely given after allogeneic transplant. Antibiotic recommendations in bone marrow transplant are similar to those for other febrile neutropenic cancer patients. Individual recommendations should take into account the frequency of specific microorganisms isolated at a given institution. Trimethoprim-sulfamethoxazole and fluoroquinolone antibiotics (e.g., ciprofloxacin) are routinely used for the prophylaxis of Pneumocystis organisms and gram-positive infections, respectively. Invasive fungal infections can be a significant cause of morbidity and death after transplant, but voraconazole prophylaxis or secondary therapy can be effective. CMV responds poorly to single-agent therapy, but the combination of ganciclovir and gamma globulin infusions improves outcome in these patients. Death rates from CMV pneumonitis approached 80% before use of the combination regimen. The use of CMV-negative donors and the elimination of CMV-contaminated leukocytes from platelet and red blood cell transfusions with leukocyte filters have reduced the mortality rate from CMV infection.

There has been ongoing work in using cytotoxic T-lymphocyte (CTL) clones to treat specific opportunistic infections including those from CMV, Epstein-Barr virus (EBV), and adenovirus.142–144 Augmentation of antiviral activity was conferred with these infusions in most patients.¹⁴⁵ This strategy may prove useful in reducing the number of life-threatening infections in bone marrow transplant, human immunodeficiency virus, and other immunodeficiency states.¹⁴²

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