Life threatening toxicities of chemotherapies and immunomodulating medications

1. Description of the problem

What every clinician needs to know

Life threatening toxicities of chemotherapies and immunosuppressants can occur with varying frequency depending on the agent suspected and underlying patient risk factors. It is important for clinicians to remember that these medications can be the cause or contributor to many important complications that occur in the ICU.

Clinical features

Generalized tonic-clonic seizures, myoclonic epilepsy.

2. Emergency Management

When a life threatening toxicity of a chemotherapy agent or immunosuppressant agent is suspected or confirmed, initially the offending agent should be discontinued. The majority of therapies will require supportive care that can include mechanical ventilation, vasoactive medication support, fluid resuscitation and rarely hemodialysis. For nearly all medications in which these toxicities are suspected or confirmed, re-challenge with the offending agent is not recommended. For specific emergency management information, please refer the the individual medication information included in each section within.

3. Diagnosis

For diagnosis of specific toxicities, please see each specific agent or each organ system overview for details. It is important to remember that often the diagnosis of these toxicities is a diagnosis of exclusion after many other common or other life threatening disease processes have been ruled out.

4. Specific Treatment

Neurotoxicity associated with chemotherapy

Busulfan associated seizures

High dose busulfan is commonly used in conditioning regimens prior hematopoietic stem cell transplant. Seizures occurring due to busulfan are common, ranging with incidence ranging from 7.5-10%. These seizures usually present during therapy as generalized tonic-clonic or myoclonic epilepsy. Seizures can present as soon as the first dose and up to 24 hours after administration of the final dose. The severe nature of seizures associated with high dose busulfan has lead to widespread use of prophylactic antiepileptic drug administration.

The most common antiepileptic for prophylaxis has been phenytoin; however, the pharmacodynamic and pharmacokinetics of phenytoin are difficult to predict and therapeutic drug monitoring must be performed to ensure therapeutic drug levels and prevent toxicities. Additionally, busulfan has been reported to alter phenytoinpharmacokinetics, making it a less attractive option in these patients.

Other antiepileptic drugs such as valproic acid, phenobarbital and carbamazepine have undesirable side effects such as bone marrow suppression and sedation, as well as numerous drug interactions, making them less attractive options for seizure prophylaxis as well. However, prophylactic administration of benzodiazepines such as clonazepam and lorazepam have been used with success. Patients with any signs or symptoms of seizure activity should also be monitored with electroencephalogram. Long term changes in EEG can occur but are rare.

Focus on stabilizing the patient

Patients who present with busulfan induced seizure should be treated in the same manner as other seizure focuses. This includes stabilizing an airway and hemodynamic monitoring as well as measures to abort the seizure. Benzodiazepines are the drug of choice and should be administered immediately. Fortunately, these seizures as usually self-limiting, but additional antiepileptic drugs are necessary, with phenytoin being the drug of choice for treatment after failure of benzodiazepines.

Neurologic examinations and close monitoring for any signs of seizures should be conducted throughout busulfan conditioning. Once a seizure presents, electroencephalogram should be used to diagnose seizure activity. First line therapy is prophylaxis, which significantly decreases the risk for seizure. Prophylaxis with phenytoin and benzodiazepines lorazepam, clonazepam and diazepam has been effective for prevent seizures.

If patients do experience seizure, benzodiazepines should be used first line to abort seizure. If ineffective, anti-epileptic drug levels should be obtained to ensure therapeutic levels. In the meantime, patients may be managed with second line antiepileptic drugs such as valproic acid or levetirecetam with standard loading doses.

Prophylaxis

Lorazepam: 0.05 mg p.o. q6h beginning the evening before the first busulfan dose.

Clonazepam: Adults: 2-3 mg p.o. b.i.d., children: 1-1.5 mg p.o. b.i.d. beginning the day before first busulfan dose for 5 days.

Clonazepam and levetiracetam: 0.5 mg p.o. b.i.d., levetiracetam 500 or 250 mg p.o. b.i.d. (dose reduced to minimize somnolence and confusion) beginning the night before first busulfan dose until the morning after last dose of busulfan.

Diazepam: 5 mg p.o. q.d. on each of the 4 days that busulfan was administered.

Phenytoin: 5-6 mg/kg/day divided every 8-12 hours (dose adjusted based on pharmacokinetic parameters) Refractory cases are rare and should be managed similarly to patients with other seizure foci. Busulfan associated seizures are usually self-limiting and require no long term therapy. If patients have continued changes on EEG they should be managed with anti-epileptic drugs under the guidance of a neurologist.

Patients usually require no follow up and there are no long term neurologic sequelae. Busulfan is a bifunctional alkylating agent commonly used in conditioning regimens prior to hematopoietic stem cell transplant. Seizures and changes on EEG are common in both adults and children. Busulfan neurotoxicity is dose related, with higher doses conferring increased risk.

Posterior reversible encephalopathy syndrome

The calcineurin inhibitors tacrolimus and cyclosporine are cornerstones of immunosuppressive therapy in all solid transplant patients and are used commonly in the majority of patients following bone marrow transplant. Unfortunately, neurologic side effects of both medications are common. A serious but rare side neurologic side effect occurring in 1-3% of patients is posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukocencephalopathy syndrome (RPLS).

The syndrome consists of gradual onset of encephalopathy, confusion, mental status change, headache and commonly, severe hypertension (70-80% of patients). A small subset of patients may also present with or experience seizure. Drug concentrations in patients with PRES are typically elevated, but can occur with therapeutic levels. Additionally, PRES has been reported in all types of solid organ transplant as well as bone marrow transplant. There is no usual time period following transplant for the onset of PRES and cases as late as years following transplant have been reported.

Diagnosis is largely based on clinical findings of hypertension and encephalopathy, but clinical diagnosis should be confirmed with MRI. MRI of the brain shows edema in the cortex and subcortical white matter of the posterior brain. In conjunction with treatment, other causes for encephalopathy such as infection, stroke and seizure should be ruled out. Once diagnosis is established, treatment should begin promptly as delays may increase the risk for permanent deficit.

The primary treatment is removal of offending calcineurin inhibitor and rapid control of hypertension. No formal guidelines for rate of blood pressure reduction exist, but an initial reduction of 25% in the first hour with normalization over the subsequent 24 to 48 hours seems prudent. Intravenous blood pressure medications such as esmolol, labetalol or nicardipine should be used as continuous infusions to ensure rapid but controlled blood pressure reduction.

If calcineurin treatment cannot be avoided or discontinued, drug concentrations – in the case of supratherapeutic levels – should be reduced, or patients should switch to the alternative calcineurin inhibitor. Many cases describe successful resolution of neurologic deficits when patients are switched to the alternate calcineurin inhibitor. In patients whose deficits do not resolve with the above measures, sirolimus has been used with success in case reports (if appropriate for the type of organ transplant and there is no concern for wound healing).

In patients with clinical signs of seizure, an EEG should be obtained. These patients should be started on an anti-epileptic drug under the guidance of a neurologist. Phenytoin is the most common antiepileptic drug in acute seizure, but can decrease the levels of tacrolimus and cyclosporine, so therapeutic drug monitoring should occur in these patients. Additionally, patients with transplant may have renal insufficiency and/or hypoalbuminemia, which may increase the unbound phenytoin in these patients. Both free and total phenytoin levels should be monitored in these patients.

Some authors suggest careful monitoring of magnesium and avoidance of hypomagnesemia in patients with PRES, as this can exacerbate cerebral vasospasm and worsen clinical symptoms. Fortunately, PRES is usually reversible, as are the findings on imaging. In rare cases, permanent neurologic deficit has been reported.

Ifosfamide

Ifosfamide is a nitrogen mustard derivative that acts as a DNA alkylation agent. It is commonly used in solid and hematologic malignancies. Neurotoxicity with ifosfamide is common, occurring in 5-40% of patients, especially with higher doses. Neurotoxicity frequently occurs during the course of treatment and presents as encephalopathy, coma, seizure, delirium or hallucinations.

The onset of symptoms is acute, presenting within hours to days after administration, typically with the first or second dose of chemotherapy. Symptoms are usually transient and can resolve spontaneously within 48-72 hours; however, fatal cases and prolonged symptoms have been reported. The exact mechanism for neurotoxicity with ifosfamide is uncertain, but numerous theories exist including neurotoxic metabolites.

Once metabolite, chloroethylamine disturbs mitochondrial electron transfer chain and leads to accumulation of chloroacetaldehyde (CAA). CAA, which is similar in structure to chloral hydrate and acetaldehyde, leads to depletion of glutathione, which in turn leads to decreased detoxification of neurotoxic substances. Additionally, defective electron transfer leads to impaired hepatic gluconeogenesis which may also contribute to neurotoxicity.

Proposed risk factors for neurotoxicity with ifosfamide include low albumin, female gender, previous or current neurologic disease, renal insufficiency, hepatic disorders, concomitant treatment with CYP P450 3A4 inducers, poor performance status, bulky pelvic disease, previous cisplatin administration or high dose therapy (greater than 1.5gm/m2/day). In some studies infusion times of less than 6 hours have also been associated with increased risk of encephalopathy.

Diagnosis is based on clinical findings as CT scan of the head is normal. Also EEG abnormalities such as triphasic waves, and spike and wave abnormalities have been reported in patients receiving ifosfamide. Treatment of ifosfamide neurotoxicity primarily involves discontinuation of ifosfamide and supportive care including treatment of dehydration and electrolyte disturbances. Infusion of dextrose or glucose should also be utilized to combat possible impairment of gluconeogenesis.

Methylene blue has also been studied in severe cases or in patients with prolonged symptoms of ifofamide toxicity. Methylene blue acts to restore mitochondrial electron transfer by serving as an alternative electron acceptor. It also acts to restore hepatic gluconeogenesis and prevent the transformation of chloroethylamine into chloroacetaldehyde. Doses of methylene blue for ifosfamide toxicity range from 50-60 mg administered 4-6 times daily.

Adverse events of methylene blue are mild and include headache, confusion, dizziness, gastrointestinal disturbances and hypo- or hypertension. Serious adverse events such as arrhythmias, hemolytic anemia and methemoglobinemia are rare. Patients in whom continued ifosfamide is necessary may receive prophylaxis with a dextrose or glucose infusion and methylene blue at a dose of 50 mg administered every 6-8 hours during ifosfamide treatment. In some cases this has decreased or lessened the duration of neurotoxicity.

Additionally, there are case reports of ifosfamide rechallenge without prophylaxis and no subsequent development of neurotoxicity. If patients experience ifosfamide neurotoxicity, further courses of ifosfamide are not absolutely contraindicated.

Methotrexate

Methotrexate is a dihydrofolate reducatase inhibitor commonly used in hematologic malignancies as well as many rheumatologic diseases. Methotrexate can be administered orally, intravenously or intrathecally (IT). Low to moderate doses of intravenous methotrexate typically do not cause neurotoxicity, but intrathecal administration, commonly given for prophylaxis and treatment of meningeal diseases, can cause neurotoxicity. High does administered intravenously can also cause neurotoxicity. Neurotoxicity presentation is variable depending on route of administration.

A common neurotoxicity in patients receiving IT administration is aseptic meningitis, which occurs in 10-50% of patients. Signs and symptoms of meningitis present within hours of administration and are self-limiting, usually resolving within 2-3 days. If patients do experience aseptic meningitis, retreatment with methotrexate is not contraindicated as symptoms usually improve upon subsequent treatments. Additionally, pretreatment with corticosteroids during subsequent treatments may also prevent symptoms of aseptic meningitis.

A rare but serious complication of IT methotrexate is transverse myelopathy, which presents within hours to days of treatment but can be delayed for up to 1 week after administration. The syndrome initially presents with back pain and evolves to ascending paralysis, sensory loss and eventual loss of bowel and bladder control. Imaging with MRI may show cord edema, which may aid in diagnosis. There is no treatment of transverse myelopathy, but further courses of methotrexate are contraindicated. In case reports, administration of corticosteroids has shown no benefit. Recovery following transverse myelopathy is variable.

Another rate neurotoxicity with IT methotrexate is acute encephalopathy with tissue necrosis if there is a blockage of cerebrospinal fluid flow. There is no treatment and symptoms usually resolve. Encephalopathy with intravenous methotrexate is associated with high doses (greater than 1g/m2). Patients can present with encephalopathy manifested by somnolence and/or seizures.

Some patients may also experience focal neurologic deficits consistent with “stroke-like” symptoms. Evaluation of cerebrospinal fluid and head CT are unrevealing, but EEG changes consistent with encephalopathy may be seen. Encephalopathy typically presents days after treatment and resolves without intervention.

Cytarabine

Cytarabine is a pyramadine analog that inhibits DNA polymerase commonly used in hematologic malignancies. 10-20% of patients who receive high dose intravenous cytarabine (greater than 3gm/m2 administered every 12 hours) will experience neurotoxicity. Symptoms include cerebellar ataxia, somnolence and lethargy that present 3-8 days after an initial infusion.

Patients may experience neurotoxicity as early as the first course of therapy but can also present with symptoms upon subsequent courses. The elderly, patients with renal or hepatic insufficiency, and those receiving frequent drug administration or brain radiation, are at increased risk for experiencing these symptoms. Diagnosis consists of clinical manifestations as well as MRI, which may show white matter changes and cerebellar atrophy. EEG shows diffuse slowing consistent with encephalopathy.

Treatment should consist of immediate discontinuation of cytarabine, which leads to recovery in a few weeks in the majority of patients. 30% patients will not experience complete resolution of cerebellar symptoms. Once symptoms resolve, further cycles are not contraindicated, but neurotoxicity is likely to recur in patients with previous neurologic complications. The administration of IT cytarabine can also cause neurotoxicity, manifested as acute or subacute encephalopathy. Occasionally this is accompanied by seizures or aseptic meningitis. Seizures and meningitis are self-limiting and resolve upon discontinuation of therapy.

Fludarabine

Fludarabine is a purine analog that inhibits DNA synthesis commonly used in hematologic malignancies or as part of a conditioning regimen prior to bone marrow transplant. Patients receiving fludarabine may experience delayed progressive encephalopathy that occurs several weeks to months after treatment. Most commonly the presenting symptoms include visual disturbances resulting from cortical blindness, visual pathway demyelination and retinal bipolar cell loss.

Neurotoxicity progresses to severe lethargy, confusion, coma and death. Toxicity is progressive, occurring over the course of weeks to months. The most strongly associated predictor of neurotoxicity is dose and cases occur with doses approaching 40 mg/m2. Diagnosis is difficult as the drug was likely discontinued weeks ago and is no longer presenting as an active medication. As such, other causes of encephalopathy such as opportunistic infection, seizure and progressive multifocal leukoencephalopathy should be ruled out. Lumbar puncture, EEG and MRI can help to differentiate other causes of encephalopathy.

MRI changes include white matter changes, hyperintense lesions in the peri-ventricular and periatrial cerebral white matter on T2 and flair sequences. There is no treatment and most patients suffer irreversible and severe neurologic dysfunction. Mortality is high in these patients.

Interleukin

Interleukin-2 is a cytokine used primarily in metastatic melanoma and renal cell carcinoma. Mild neuropsychiatric symptoms are common, occurring in up to 30-50% in patients. Progressive neurologic decline is reported but rare (approximately 1% of patients). Other neurotoxicities with interleukin include vascular leak syndrome, which results in focal neurologic deficits due to increased intracranial pressure.

This may exacerbate other neurologic symptoms. Diagnosis is based on clinical symptoms, but MRI may show transient T2 hyperdensities. Symptoms of any neurologic deficit usually resolve upon discontinuation of interleukin, but fatal neurologic decline has been reported. Patients with minor neurologic symptoms may receive further courses, but patients who experience coma or psychosis lasting longer than 48 hours are contraindicated to receive additional treatment.

Cisplatin

Cisplatin is a bifunctional alkylating agent commonly utilized in many solid tumors, including breast, ovaries, head, neck and lung cancers. Neurotoxicity with cytarabine presents days following any course of therapy. The neurotoxicity presents as “stroke-like” and results from vascular occlusion with ischemic infarctions. Multiple possible causes for vascular toxicity with cisplatin have been proposed, including microembolism, thrombosis and vasculitis.

Transient hypercoagulability and increased blood viscosity may also contribute to thrombosis in these patients. Additionally, patients receiving cisplatin are commonly hypomagnesemic due to renal tubular injury from the cisplatin. This may contribute to cerebral vasospasm and exacerbate symptoms. Other causes for stroke should be sought in these patients, as this is a rare occurrence. Treatment includes discontinuation of the drug and, if possible, administration of standard therapy such as anticoagulation.

Hypersensitivity and anaphylactic reactions

Anaphylaxis and hypersensitivity reactions are among the most common side effects of chemotherapy. Reactions range from mild infusion reactions such as itching and hypertension to severe and potentially life-threatening. These reactions are graded 1 through 5, dependent on severity, in accordance with national guidelines proposed by the National Cancer Institute. (Table 1).

The immune mechanisms responsible for infusion reactions or hypersensitivity are also variable from Type I to Type 4 reactions depending on the chemotherapy. (Table 2).

In order to avoid or decrease infusion related reactions, skin testing prior to administration, premedication and desensitization strategies have been employed prior to treatment with chemotherapies highly likely to result in infusion reactions.

L-aspariginase

L-aspariginase is indicated for the treatment for acute lymphoblastic leukemia. Currently, two formulations of L-aspariginase are available, an Escherichia coli derivative and an Erwinia chrysanthemi derivative, the latter of which is not available in the United States. Peg-aspariginase, the E. coli derivative attached to polyethylene glycol, also is available. A 5-8% risk of hypersensitivity occurs per dose of L-aspariginase and the risk increases with subsequent doses. In fact, with repeated doses, up to 43% of patients develop hypersensitivity reactions including anaphylaxis. This risk increases with intermittent as opposed to daily administration. It is also more frequent with intravenous administration than with intramuscular or subcutaneous administration (45% vs 14%).

Treatment of hypersensitivity involves immediate discontinuation of medication and treatment of the reaction based on severity. In patients with 1 week or longer interval between treatments, skin testing is recommended. If patients have positive skin tests, treatment is not recommended. Patients who have experienced hypersensitivity with one formulation should switch to the alternate formulation, usually to the pegylated formulation in the United States.

Also, the Erwinia chrysanthemi formulation is available for compassionate use should the patient react to both forms of E. coli derivate. The switch from one formulation to the alternative may decrease reactions, but serious reactions may still occur. For these patients, a desensitization protocol available in the product labeling has been successful.

The taxanes

The taxanes are a class of is tubulin stabilizing drugs commonly used for ovarian, breast and non-small cell lung carcinoma. Paclitaxel is commonly associated with infusion related reactions, and prior to the advent of pre-medication, infusion related reactions occurred in up to 30% of patients. With the use of pre-medication including antihistamines and corticosteroids, the current incidence is 2-4%.

Although no standard pre-medication regimen exists, many patients receive dexamethasone (20 mgs, 12 and 6 hours before administration), and diphenhydramine and ranitidine (50 mg of each given intravenously 30-60 minutes before administration of paclitaxel). The recommended pre-medication prior to the administration of docataxel is 16 mg/day dexamthasone for 3 days prior to infusion. Despite pre-medication, most severe reactions occur during the first or second dose and within minutes of beginning drug infusion.

The mechanism for this reaction is likely due to direct mast degranulation and not IgE mediated, as the reaction occurs without prior exposure to drug. The exact cause of taxane mediated hypersensitivity is controversial. Some evidence exists that the diluent in paclitaxel, Cremophor EL, is responsible for the reaction, but animal models involving administration of paclitaxel alone still induce hypersensitivity. Additionally, docataxel does not contain Cremophor EL and hypersensitivity has still been reported.

If a patient does experience a reaction, the decision to interrupt therapy should be based on the severity of the reaction. Minor symptoms such as flushing or skin reactions do not require interruption. More serious reactions including hypotension or sign of anaphylaxis require discontinuation of the infusion. In patient with serious reactions, diphenhydramie 50 mg and hydrocortisone 100 mg IV should be given. Infusion should be withheld until symptoms abate, usually in less than 30 minutes.

Once symptoms resolve in mild to moderate cases, infusion can be re-initiated, as the initial reaction may deplete the mediators and further reaction is unlikely to occur. Upwards of 90% of patients will complete chemotherapy with rechallenge. If the initial reaction is severe, rechallenge is not recommended, but has been successfully accomplished in case reports. In these patients, switching to an alternative taxane is not recommended as cross reactivity does occur. If taxanes are essential to therapy, desensitization protocols do exist.

Platinums

Hypersensitivity reactions have been reported with all the platinum compounds (carboplatin, cisplatin and oxaliplatin). The total incidence of all reactions ranges from 10- 40%, depending on severity and specific platinum agent used. Reactions can occur within minutes of receiving an infusion but mild symptoms have been reported up to days after infusion. The cause of reaction is typically thought to be Type I or IgE mediated, although rare cases of Type II reactions have been reported.

Due to the IgE mediation, patients usually receive multiple courses of chemotherapy prior to reaction and the risk of hypersensitivity increases with each additional cycle. Unfortunately, pre-medication with steroids and antihistamine drugs are not useful in preventing reactions to platinum compounds. Instead, intradermal skin testing is commonly used to predict serious reactions.

Sensitivity of skin testing has been reported to be 75-100%. Patients with serious reactions should receive alternate chemotherapy, cautious rechallenge in a controlled setting, or desensitization. Cross reactivity is thought to be high between platinum compounds and administration with alternative platinum is not considered unless skin testing is negative. Negative skin testing has been used to switch between platinum therapies with success, but is not validated.

Etoposide

Etoposide is an antimitotic agent available in both intravenous or oral preparations that is commonly used for the treatment of solid and hematologic malignancies. Hypersensitivity reactions have been reported only with intravenous therapy, not oral. Serious infusion reactions occur in 1-2% of patients and mild reactions occur in 1-14% of patients. Most hypersensitivity reactions are reported with the first or second dose of etoposide, but have also been reported with subsequent doses. This pattern makes the immunologic basis for reaction uncertain.

Mild symptoms such as flushing and gastrointestinal complaints resolve immediately upon discontinuation of infusion; however, more serious reactions, such as bronchospams, may take hours to resolve. In patients who have mild to moderate reactions, rechallenge with premedication of corticosteroids and diphenhydramine results in successful completion of chemotherapy up to 65-78% of the time.

Slowing the rate of infusion by 50% has also resulted in decreased infusion reaction upon rechallenge. Additionally, a switch from etoposide to etoposide phosphate, a water soluble prodrug without polysorbate 80, has been successfully used in patients with severe hypersensitivity to etoposide. The lack of reaction to etoposide phosphate has led to the hypothesis that the polysorbate vehicle itself may be responsible for hypersensitivity reactions.

Monoclonal antibodies

Hypersensitivity reactions of all types and severity have been reported for all classes of biologic therapies including monoclonal antibodies. Currently, there are four main types of monoclonal antibodies classified on their relative humanization. In general, reactions occur more frequently with compounds that are less humanized. Table 3 presents classes of monoclonals and the relative humanization.

Alemtuzumab

Reactions with alemtuzumab are most common within the first week of treatment and decrease with subsequent infusions.

Cetuximab

Cetuximab causes severe infusion reactions in up to 4% of patients and occur within the first 30 minutes of the first infusion. In order to decrease infusion reactions, cetuximab should be infused slowly and premedication with diphenhydramine should be used. An IgE antibody that cross reacts with cetuximab has been found in cancer patients and healthy volunteers. This antibody may increase the risk of severe Type 1 reactions in patients without previous exposure to cetuximab.

Trastuzumab

Trastuzumab reactions frequently occur during the first dose and decrease with additional infusions. These reactions are usually mild to moderate, with severe reactions in only 1% of cases.

Panitumumab

Panitumumab infusion reactions occur in approximately 4% of patients. Only 1% are severe.

Rituximab

Infusion reactions are common in up to 80%, in patients receiving rituximab. They generally occur in the initial 30 minutes to 2 hours during the first infusion. The frequency of infusion related reactions decreases significantly with subsequent infusions. These reactions are most commonly fevers, chills and rigors, but serious reactions including urticaria, angioedema and hypotension affect up to 10% of patients. In order to decrease infusion reactions, premedication with acetaminophen and antihistamines is recommended. Also, a 50% reduction in the rate of infusion decreases the occurrence of infusion reactions. Glucocorticoids have shown no benefit in decreasing reactions. In patients unable to tolerate infusions, desensitization protocols do exist. (Table 4)

Denileukin difitox

Denileukin difitox, a fusion protein approved for the treatment of cutaneous T cell lymphoma, has been associated with a rare type of infusion reaction, capillary leak syndrome. The syndrome consists of hypotension, generalized edema and pulmonary edema, occasionally leading to respiratory distress. In clinical trials up to 27% of patients experienced capillary leak with 6% requiring hospitalization.

Most cases of vascular leak occur within 2 weeks of therapy and are self-limited; however, serious and fatal cases have been reported. In addition to pulmonary failure, vascular leak may cause increased compartment pressures leading to compartment syndrome or rhabdomyolysis. Capillary leak is more common in patients with low albumin and denileukin difitox is not recommended in patients with albumin lower than 3.0 g/dL. Discontinuation of medication may not resolve symptoms, which may in fact worsen.

In addition to capillary leak, serious infusion reactions have also been reported in 8% of patients treated with denileukin difitox. These infusion reactions are more common following the 3rd and 4th course of the drug. Limited data suggests that premedication with steroids may decrease the incidence of serious infusion reactions. Serious capillary leak and infusion reactions preclude further administration of denileukin difitox. Denileukin difitox should only be administered in centers with appropriate resuscitation equipment, including equipment for cardiac arrest.

With any infusion reaction, the medication should immediately be stopped and appropriate therapy such as epinephrine, corticosteroids, antihistamines, fluid administration, vasopressor therapy and cardiac resuscitation should be administered. Epinephrine should be administered subcutaneously at a dose of 0.3 mg in patients with life threatening symptoms such as respiratory distress, wheezing, stridor, hypotension, shock and unconsciousness.

Hepatic toxicity

Veno-occlusive disease or sinusoidal obstruction syndrome

Veno-occlusive disease or sinusoidal obstruction syndrome (SOS) is a life-threatening adverse event most commonly associated with high dose myoloablative chemotherapy and hematopoietic stem cell transplant. Although this patient population is at high risk, SOS has been described in patients in conjunction with multiple chemotherapy agents without bone marrow transplant.

SOS is characterized by hyperbilirubinemia, fluid overload and hepatomegaly, and occurs more commonly patients with allogeneic bone marrow transplant (BMT) as opposed to autologous BMT. Many BMT patients are conditioned with cyclophophamide and busulfan so, not surprisingly, these two agents are thought to present a higher risk of causing SOS than other chemotherapeutic agents.

If patients also receive total body irradiation, the risk is also higher. Preexisting liver disease, decreased albumin, older patients, those undergoing a second transplant and those receiving transplant from unrelated or unmatched donors are also at an increased risk for SOS. The gold standard for diagnosis is liver biopsy, but diagnosis is most commonly made on clinical exam and laboratory findings.

Diagnostic criteria include two or more of the following: bilirubin (usually direct) above 2 mg/dL, weight gain greater than 5%, painful hepatomegaly and ascites that cannot be attributed to other causes. The ascites in SOS is refractory to diuresis and up to 25% of patients may require dialysis.

The differential diagnosis of SOS includes graft versus host disease, fungal infection, viral hepatitis, sepsis induced organ dysfunction, drug toxicity and congestive heart failure. Imaging with ultrasound fails to show abnormality, but dopplers may show portal hypertension with reversal of flow. The signs and symptoms of SOS occur fairly soon after transplant, with most patients developing complications within the first 3 weeks after transplant, but late onset SOS (up to 50 days) has been reported. The prognosis is dependent on severity of disease with overall mortality between 3-80%. The level of bilirubin and the rate of bilirubin increase seem to be the factors most closely related to a worse prognosis.

Many treatments of SOS have been studied. In small series, tissue plasminogen activator (tPA) has led to symptom resolution but has an unacceptable rate of bleeding complications and is therefore not recommended. A promising treatment for SOS may be defibrotide, a novel drug that acts as a local anti-inflammatory, anti-ischemic and anti-thrombotic agent. Compassionate use and phase II studies have shown improved survival (up to 46% response) with the use of defibrotide. Currently defibrotide is not available outside of clinical studies.

Case reports using n-acetylcysteine, corticosteroids, hemofiltration with charcoal, portosystemic shunts and liver transplantation are available in the literature, but no conclusion regarding benefit of any of these modalities can be made due to the small sample sizes.

In the absence of other treatments, supportive care is the mainstay. This includes obtaining appropriate fluid balance to protect end organs while minimizing hepatic congestion. Standard treatments such as diuretics, paracentesis, hemodialysis and avoidance of nephrotoxicity medications are important to prevent end organ dysfunction. Even with these measures, severe SOS symptoms may take months to resolve.

L-aspariginase

L-aspariginase, indicated for the treatment for acute lymphoblastic leukemia, can cause pancreatitis, including severe cases, in 4-7% of patients. The cause of pancreatitis is likely multifactorial but may be due to severe hypertriglyceridemia caused by the drug or impairment of mitochondrial function. Treatment involves termination of the drug and supportive care, including volume resuscitation, antibiotic therapy if necrotizing, blood pressure support and, in severe cases, percutaneous decompression. In severe hypertriglyceridemia (levels 1000-2000 mg/dL), plasmapheresis has successfully been used to decrease serum triglycerides acutely. Rechallenge is not contraindicated and may be considered after complete resolution of symptoms.

Tyrosine kinase inhibitors

The tyrosine kinase inhibitors sunitinib, erlotinib and imatinib have all been associated with development of hepatotoxicity. Most cases are mild, but severe and life-threatening hepatotoxicity has also occurred. Reactions are idiosyncratic, not predictable or dose related. The most common presentations are lab abnormalities such as elevation of hepatic transaminases, bilirubin and INR. The incidence and time course for each tyroskine kinase inhibitor is different. Hepatotoxicity with imatinib occurs within 2-5 months but can occur as late as 18 months after beginning therapy.

Frequency of hepatotoxicity during clinical trials was 3-6%, including severe cases. The histologic findings with imatinib hepatotoxicity range from fatty necrosis, increased thrombosis and cytolytic hepatitis, including destruction of the bile ducts. Dependent on severity, hepatotoxicity can take weeks to months to resolve.

Erlotinib hepatotoxicity can occur days to weeks after beginning therapy. The exact incidence of serious toxicity is unknown, but 10% of patients in clinical trials experienced Grade 3 or higher hepatotoxicity. Hepatotoxicity with sunitinib therapy occurs in fewer than 1% of patients. In all cases of tyrosine kinase inhibitor hepatotoxicity, the offending medication should be discontinued immediately. Treatment is only supportive. Reintroduction of drug is possible after resolution of lab abnormalities, but in many cases, patients experience rapid recurrence of hepatotoxicity, even at reduced doses.

Before beginning therapy, liver function tests should be obtained and monitored monthly throughout therapy. Also, initial dose reduction for patients with hepatic impairment are stated in product labeling.

Nephrotoxicity

Hemorrhagic cystitis

Both the alkylating agents cyclophosphamide and ifosfamide can cause severe cases of hemorrhagic cystitis. The mechanism of hemorrhagic cystitis caused by cyclophosphamide is thought to be related to acrolein, a metabolite of cyclophosphamide that enters the uroepithelium and causes DNA damage resulting in tissue necrosis. 1-6% of patients receiving cyclophosphamide will develop gross hematuria with mortality rates for severe hemorrhagic cystitis ranging from 10-30%. The development is variable, as patients can develop signs and symptoms immediately to years after treatment. Symptoms may also persist for days to months despite intervention.

Prevention of hemorrhagic cystitis involves adequate hydration and forced diuresis with the goal of decreasing the time acrolein is in contact with the bladder. Hydration should begin 12-24 hours prior to cyclophosphamide administration, with a goal urine output of 100 ml/m2/hr. If urine output falls below target, diuretics should be given. The addition of mesna to cyclophosphamide and ifosfamide regimens has significantly decreased the risk of hemorrhagic cystitis. Mesna is given at 100-160% of the cyclophophamide dose as either a continuous infusion or intermittently 15-30 minutes before cyclophosphamide.

Treatment of severe hemorrhagic cystitis is varied from pharmacologic treatments such as aminocaproic acid and installation of intravesicular agents such as alum, silver nitrate and formalin, to clot evacuation, continuous bladder irrigation (CBI), hyperbaric oxygen and cystectomy. Prior to pharmacologic treatment, patients should be assessed for viuria, especially adenovirus and BK virus, which can contribute to hemorrhagic cystitis in immunosuppressed patients.

First line treatment is CBI with a large bore three-way Foley catheter. This will remove existing clots, making subsequent treatment more successful. If clots are not removed by CBI, manual removal may be necessary. If patients continue to bleed after CBI, intravesicular administration of alum, silver nitrate or prostaglandin may be necessary. Alum acts as a local astringent causing decreased edema and inflammation.

A 1% solution administered through a three-way Foley at a rate of 300-1000 ml/hr is common, although a 2-4% solution may achieve better results. Varying rates of success from 50-100% response have been demonstrated with alum therapy. Side effects are usually bladder spasm, suprapubic pain, urinary frequency or retention, and can be controlled with analgesics. Patients with renal dysfunction or those receiving prolonged alum irrigation should be monitoring for mental status changes as aluminum toxicity, although rare, can occur.

Carboprost tromethamine, a PGF2 prostaglandin, acts to repair the microvasculature and epithelium of the bladder. A solution of carboprost is instilled 3-4 times daily, allowed to dwell for 1-4 hours for 5-7 days. About half of patients respond, with a median response of 2-5 days. Side effects include bladder spasm and discomfort.

Silver nitrate acts to cauterize the bladder mucosa. A solution is instilled for 10-20 minutes, followed by bladder irrigation. The procedure is extremely painful and patients should anesthetized prior to treatment. The success of the procedure is variable and short lived. Systemic therapy with the antifibrinolytic aminocaproic acid has also been employed. The usual dose is a 5 gm loading dose followed by a continuous infusion of 1 gm/hr until bleeding stops. This will increase systemic clotting, thus decreasing hemorrhaging, but the risk that formed clots may be too large to pass through the foley does exist.

Formalin, also administered by direct instillation, acts as a local coagulant to bladder tissue. Administration causes significant pain and patients must be anesthetized. Although effective, this therapy should only be used in patients in whom other therapies have failed as repeated administration of formalin can cause reflux and hydronephrosis of the kidney. Cystoscopy to evaluate bladder anatomy should be performed prior to formalin installation.

Hyperbaric oxygen, investigated in case reports, should, in theory, increase oxygenation of tissues and promote healing. This therapy, usually delivered daily for multiple days, has decreased gross hematuria in case reports.

Invasive surgical therapies are reserved for patients who have failed less invasive measures discussed previously. Urinary diversion, arterial embolization and cystectomy have all been used for intractable hemorrhagic cystitis.

Pulmonary toxicity

The majority of chemotherapy or immunosuppressants have major to minor pulmonary toxicities as a consequence of therapy. Toxicities include interstitial pulmonary fibrosis (IPF), usual interstitial pneumonitis (UIP), pneumonitis, radiation recall-pneumonitis and alveolar hemorrhage. The incidence of these toxicities varies from case reports to up to 20% of patients exposed in the case of certain medications.

The majority of the toxicities seen are from direct cytotoxic injury to the cells (alveoli and pulmonary), which elicit release of cytokines from these cells and promotes other inflammatory cell recruitment to the lungs. Other chemotherapy agents that promote formulation of oxygen free radicals can promote oxidative injury or can systemically cause release of proinflammatory cytokines.

Bevacizumab

This chemotherapy that targets vascular endothelial growth factor (VEGF) is utilized in a number of different chemotherapy regimens including colorectal cancer, renal cell carcinoma and lung cancer. Along with thromboembolism, including pulmonary embolism, pulmonary hemorrhage is a potential complication of bevacizumab therapy. Pulmonary hemorrhage was seen in up to 31% of patients treated with bevacizumab for squamous cell NSCLC, and lower at 4% for non-squamous cell NSCLC. This complication is rarely reported when bevacizumab is utilized as chemotherapy for a site outside of the lung. Hemoptysis can also occur, or if a patient has recent history of hemoptysis with ½ teaspoon or greater, they should not receive bevacizumab.

Bleomycin

Bleomycin is one of the best known chemotherapy agents associated with pulmonary toxicity. This agent, which inhibits DNA synthesis and also causes some inhibition of some protein and RNA synthesis, is used for a number of solid tumors as well as lymphomas. Currently, the FDA labeling for bleomycin includes a black box warning regarding pulmonary toxicity. The warning is stated as follows: “Pulmonary fibrosis is the most severe toxicity associated with Bleomycin for Injection. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Its occurrence is higher in elderly patients and in those receiving greater than 400 units total dose, but pulmonary toxicity has been observed in young patients and those treated with low doses.”

Bleomycin pulmonary toxicity is potentially a combination of oxidative damage and lack of an enzyme in the lungs, bleomycin hydrolase. This enzyme breaks down bleomycin in all tissues in the body, but is not usually present or is present at very low levels in the lung. The cumulative bleomycin dosage administered is an important risk factor to the development of bleomycin pulmonary toxicity. Low doses of bleomycin (<270 units) have an estimated incidence of pulmonary toxicity of 1-2%, while higher doses of bleomycin (>360 units) are associated with an incidence of approximately 10%, though there are reports with higher rates up to 18%.

Other than cumulative dosage, age above 40 years old, use of other chemotherapies associated with pulmonary toxicity, radiation therapy, oxygen therapy, use of hematopoietic colony stimulating factors and renal function have all been identified as risk factors for bleomycin toxicity.

Signs and symptoms of bleomycin toxicity include non-productive cough, dyspnea, fever, tachypnea, and rales on chest auscultation that occur within 1-6 months after bleomycin treatment. The diagnosis of bleomycin-induced lung injury is usually made through a clinical diagnosis combining recent bleomycin therapy, exclusion of infectious or malignant causes of lung disease and clinical symptoms consistent with pneumonitis/interstitial lung disease (ILD).

Treatment of bleomycin-induced lung toxicity is to discontinue bleomycin therapy. Corticosteroids should be used in symptomatic cases as spontaneous recovery has occurred in non-symptomatic patients. The recommended dosing of prednisone is 60-100 mg/day for approximately 4 weeks based on patient response. This dose is then slowly tapered (e.g. 5 mg every week) over the next several weeks to months as the patient tolerates. Re-challenge with bleomycin is not recommended, especially with those patients who develop pulmonary fibrosis.

Busulfan

Busulfan is an alkylating agent predominately utilized in chemotherapy conditioning regimens prior to stem cell transplantation. Cases of bronchopulmonary dysplasia and pulmonary fibrosis occur, but are more common with long-term therapy (4 years). This is less commonly seen with pre-conditioning only regimens. Busulfan pulmonary toxicity may also be dose-related at a proposed dose threshold of 500 mg. The presentation is fever, progressive dyspnea, cough and possibly weight loss. Treatment includes drug discontinuation and supportive care. Re-challenge with further busulfan is not recommended and corticosteroids have sparse data to support their use but may be useful.

Carmustine

Carmustine is the representative agent of the nitrosourea class of DNA alkylating agents. These nitrogen mustards are used for a variety of cancers including solid tumors, lymphoma and as a part of conditioning regimens prior to stem cell transplantation. Pulmonary fibrosis is a known complication of nitrogen mustard chemotherapy administration, including carmustine. Carmustine pulmonary fibrosis can be divided into early onset (within 36 months) and late onset (2-3 years post treatment) fibrosis.

Early onset fibrosis is most common and 2-25% of patients treated with carmustine will develop pulmonary fibrosis. The incidence of pulmonary fibrosis from carmustine is likely dose-related. One study found the following incidence based on dose: less than 475 mg/m2 = 15% incidence; 475-525 mg/m2 = 32% incidence; greater than 525 mg/m2 = 47% incidence. Other than cumulative dosage the only other risk factor associated with pulmonary fibrosis is female gender. Patients with early-onset pulmonary fibrosis present with cough, shortness of breath and crackles on lung exam. Treatment includes drug discontinuation, supportive care and potentially corticosteroids.

One study demonstrated a potential benefit to a course of prednisone 1 mg/kg for 10 days then tapered. Late onset pulmonary fibrosis has only still been reported in case series or case reports to date. These cases begin to appear anywhere from 2-17 years post-carmustine exposure. Patients experience few to no symptoms for years until the onset of shortness of breath and cough. Unfortunately there is very little to treat late onset pulmonary fibrosis. Treatment focuses on supportive care and corticosteroids have shown little benefit.

Cyclophosphamide

Cyclophosphamide is an alkylating agent utilized in a number of chemotherapy regimens as well as for the treatment of several autoimmune disorders. Cyclophosphamide can cause pulmonary injury, including diffuse alveolar damage, BOOP and alveolar hemorrhage. This is typically defined as early onset pneumonitis within 1-6 months after the onset of cyclophosphamide therapy. The presentation during this time includes dyspnea, cough, fever and fatigue.

Onset of pneumonitis after 6 months after initiation of cyclophosphamide therapy is defined as late onset. This can occur months to years out from initiation of therapy. The symptom onset is slow and progresses slowly over time with worsening dyspnea and cough. Treatment of both early or late onset pneumonitis involves drug discontinuation, and re-challenge is not recommended. In early onset pneumonitis symptoms usually resolve gradually and corticosteroids can be used for symptom improvement. Late onset pneumonitis symptoms are typically irreversible and do not respond to drug discontinuation or corticosteroids.

Cytarabine

An antimetabolite chemotherapy utilized for a number of indications including AML, ALL and as part of conditioning regimens prior to stem cell transplantation. Pulmonary toxicity occurs as an adverse event of cytarabine therapy in 12-20% of treated patients. Patients have presented with pulmonary infiltrates and pulmonary edema requiring drug discontinuation approximately 1-2 weeks after treatment. In a review of 72 cases of cytarabine pulmonary toxicity, many occurred in relapsed leukemia patients, indicating an association between prior chemotherapy treatment and development of cytarabine pulmonary toxicity.

Patients present with mild fever, dyspnea, cough, hypoxia and crackles on physical exam. Treatment is drug discontinuation, supportive care and possibly corticosteroids, although to date the data to support corticosteroids remains sparse. Re-challenge is not recommended, as reoccurrence of symptoms is likely.

Dasatinib

A BCR-ABL tyrosine kinase inhibitor chemotherapy agent administered for CML and ALL. Severe fluid retention, which includes pulmonary edema and pleural effusions, can occur during dasatinib treatment in up to 10-23% of patients. Other lung changes can occur, such as parenchymal lung changes, ground-glass or alveolar lung opacities, or septal thickening. The time on onset of these lung changes or pleural effusions is wide-ranging, from 1 month to 500 days.

Permanent drug discontinuation is not typically required, as diuresis or thoracentesis can provide adequate treatment for the majority of pleural effusions. Instead, dasatinib may be reintroduced at a lower dosage (40 mg twice daily), often without recurrence of severe pulmonary side effects. Corticosteroids have been utilized in a small number of case reports of pulmonary changes (not pleural effusions) at doses of 40-60 mg/day of methylprednisolone with potentially positive results.

Erlotinib

An oral EGFR-TK inhibitor like geftinib, patients also develop ILD while on erlotinib. The current reported incidence of ILD is approximately 1%, based on an FDA review of over 500 cases, although this estimate may be low, given that the drug is utilized for advanced lung cancer and it may be challenging for the clinician to distinguish between erlotinib toxicity and advanced NSCLC complications.

The typical presentation for erlotinib pulmonary toxicity is acute cough and dyspnea with an average onset time of 39 days, though it can present as early as 5 days and as late as 9 months from drug initiation. Concurrent use of other chemotherapies and pre-existing pulmonary fibrosis are two potential risk factors for erlotinib-induced ILD. Treatment is primarily drug discontinuation and supportive care; drug re-challenge is not recommended. Corticosteroids can be considered but have little primary evidence to support their routine use.

Fludarabine

Fludarabine is a purine analog used mostly for refractory or relapsed hematologic malignancies including CLL. There is currently a black box warning regarding the use of fludarabine in combination with pentostatin in the treatment of patients with refractory CLL, as this has led to an unacceptably high incidence of fatal pulmonary toxicity. Currently the manufacturer does not recommend the combination of fludarabine and pentostatin due to this pulmonary toxicity.

Separately, fludarabine can cause interstitial pneumonitis. The largest series of 105 evaluated patients demonstrates an incidence rate of 8.6%. Pulmonary toxicity presents early into fludarabine therapy with signs and symptoms of dyspnea, fever, hypoxia and radiographic infiltrates. Treatment of fludarabine interstitial pneumonitis is to first ensure the patient does not have a concomitant infection, as fludarabine increases patient risk of bacterial and even some opportunistic infections, and then to discontinue fludarabine therapy and initiate corticosteroids, which will usually resolve symptoms. Re-challenge with fludarabine is not recommended, as reoccurrence is likely.

Geftinib

An oral epidermal growth factor (EGFR) tyrosine kinase (TK) inhibitor utilized in NSCLC patients. The potential mechanism for toxicity is due to the presence of EGFR expression on type II pneumocytes that are involved in alveolar wall repair. Administration of an EGFR-TK inhibitor potentially inhibits alveolar repair processes, which may directly or due to a second injury (such as infection, radiation or another pulmonary toxic medication) lead to pulmonary toxicity.

ILD has been reported with geftinib. The overall reported incidence is 1%, but this is lower at 0.3% in the predominately Caucasian evaluated U.S. population studied to date and higher at 2% in the Japanese population. Known risk factors that increase the incidence of ILD from geftinib include prior radiation (31% of cases) and prior chemotherapy (57% of cases) versus no prior chemotherapy (12% of cases). The Japanese patient cohort of nearly 2,000 patients also noted an increased association between ILD and smoking, male gender and co-incidence of interstitial pneumonia. Patients with potential geftinib ILD present with acute or worsening dyspnea, cough and fever.

The average time of onset is early at around 1 month and approximately one-third of all reported cases have been fatal. Treatment is primarily drug discontinuation and supportive care; drug re-challenge is not recommended. Corticosteroids can be considered but there is little primary evidence to support their routine use.

Gemcitabine

Gemcitabine is a pyrimidine analog used in the treatment of pancreatic cancer and non-small cell lung cancer. Retrospective analysis of gemcitabine pulmonary toxicity indicated a high rate (up to 13%). However, more recent assessments of patient cases and criteria for pulmonary toxicity indicate this estimate is around 1-2%. The toxicities range from interstitial pneumonitis, pleural effusions, eosinophilic pneumonia and diffuse alveolar damage.

Gemcitabine pulmonary toxicity presents with dyspnea, fever and cough, along with infiltrate on chest radiograph. The average time of onset is 1-2 months into treatment. Treatment of gemcitabine pulmonary toxicity is drug discontinuation, supportive care and corticosteroids or diuresis for certain types of toxicities. Generally, re-challenge with gemcitabine is not recommended as symptom recurrence is common and in cases where previous symptoms were severe re-challenge is likely to be associated with fatal pulmonary toxicity.

Imatinib

A BCR-ABL tyrosine kinase inhibitor chemotherapy agent used for CML, ALL and gastrointestinal stromal tumors (GIST). Fluid retention and edema can occur with imatinib treatment, including pulmonary edema, pericardial and pleural effusions. Severe fluid retention (defined as: pulmonary edema, pericardial/pleural effusion and ascites) occurred in 1.3% of newly diagnosed CML patients receiving imatinib. This increases to 2-6% with other CML patients receiving imatinib and 9-13.1% in patients with GIST.

There are cases of ILD with imatinib therapy, the largest being a case series of 27 patients. The average time to onset is 1.5 months and drug discontinuation is typically required. Symptom presentation is non-specific findings of drug cough, potentially fever, and dyspnea on exertion. Treatment is supportive care and corticosteroid treatment is usually also required for complete symptom resolution.

Methotrexate

Methotrexate a dihydrofolate reductase inhibitor, is utilized for a variety of hematologic malignancies as well as rheumatologic disorders. Among the toxicities of methotrexate include potential pulmonary toxicity, pneumonitis. Newer estimates of methotrexate-induced pneumonitis are between 2-5%. Methotrexate has been associated with causing bronchiolitis obliterans with organizing pneumonia (BOOP), pulmonary fibrosis, bronchitis, and acute lung injury (ALI) with pulmonary edema.

Some identified risk factors for methotrexate-induced pulmonary toxicity include: age above 60 years old, diabetes mellitus, hypoalbuminemia, rheumatoid pleuropulmonary involvement and previous use of disease-modifying antirheumatic drugs. There are criteria for the diagnosis of methotrexate-induced pulmonary toxicity originally developed for research purposes. These criteria have not been validated in clinical settings but can be helpful considerations for a clinician. They are divided into major and minor criteria:

Major criteria

• Hypersensitivity pneumonitis by histopathology without evidence of pathogenic organisms.

• Radiologic evidence of pulmonary interstitial or alveolar infiltrates.

• Blood cultures (if febrile) and initial sputum cultures (if sputum is produced) that are negative for pathogenic organisms.

Minor criteria

Shortness of breath for less than 8 weeks.

• Nonproductive cough.

• O₂ saturation below 90% at the time of initial evaluation on room air.

• DLCO below 70% that predicted for age.

• Leukocyte count below 15,000 cells/mm3.

Definite methotrexate pneumonitis is defined as major criteria 1 alone or major criteria 2 and 3 plus 3 of the 5 minor criteria. Probable methotrexate pneumonitis is defined as major criteria 2 and 3 plus 2 of the 5 minor criteria.

Methotrexate pneumonitis usually presents within the first year of therapy, but has presented years into treatment well after drug-discontinuation. Treatment is drug discontinuation, if not already discontinued, and re-challenge is not recommended. Symptoms should improve over several days to weeks after drug-discontinuation. There are case reports of treatment with corticosteroids. This is the primary treatment in cases where toxicity occurs well after drug discontinuaiton. When corticosteroids are being considered, infectious causes must be excluded prior to initiation.

Mitomycin

Mitomycin-C is an alkylating agent used for several different solid tumors including pancreatic, gastric and breast cancers. There are several pulmonary complications of mitomycin; however, the most serious and life threatening is mitomycin-associated thrombotic microangiopathy. This syndrome is characterized by the following: microangiopathic hemolytic anemia, thrombocytopenia, acute lung injury/ARDS and renal insufficiency due to thrombotic occlusion of glomerular capillaries.

The proposed risk factors for developing mitomycin-associated thrombotic microangiopathy are total drug dosage, receipt of 5-fluorouracil or blood transfusions prior to mitomycin therapy, and concomitant tamoxifen therapy. The onset of this syndrome occurs typically within 6-12 months after mitomycin initiation. The mortality associated with this syndrome is high (>70%).

There are strategies to reduce the incidence of mitomycin associated thrombotic microangiopathy. These include limiting total mitomycin dosage to 30 mg/m2, dosing mitomycin no more frequently than every 4-6 weeks and limiting high-inspired oxygen concentrations. Treatment has included plasmapheresis to improve renal function,, as this syndrome is similar to hemolytic-uremic syndrome. Other treatment options include hemodialysis and corticosteroids.

Rituximab

This anti-CD20 chemotherapy agent has been utilized for an increasing number of indications, including Non-Hodgkin’s lymphoma, CLL, rheumatoid arthritis and other hematologic disorders, and solid organ transplant. While rituximab infusion related reactions that can lead to dyspnea and other pulmonary symptoms will be discussed separately, ILD also can occur during rituximab therapy.

While the total case number reported remains low, the largest case series is nine patients in a cohort of 107 patients (8%) reviewed in China. These patients presented with dyspnea, non-productive cough and also potentially fever. Drug discontinuation is generally recommended, as are corticosteroids, for complete resolution of rituximab-induced ILD. Doses utilized have ranged from 20-40 mg/day of prednisone for several weeks. However, prior to initiation of corticosteroids infection must be ruled out or treated as patients treated with rituximab are at increased risk for infection, including some opportunistic pathogens (e.g. PCP).

Sirolimus

Sirolimus is a medication utilized in a number of solid organ transplant immunosuppressant regimens including kidney, liver and lung transplant. Pulmonary toxicity occurs in 5-10% of patients receiving sirolimus therapy, typically within 1-8 months from initiating sirolimus. Patients usually present with fever, dyspnea on exertion, fatigue, and less commonly weight loss or hemoptysis.

The diagnosis of sirolimus pneumonitis is based on patient symptoms, recent history of sirolimus therapy, and exclusion of infectious causes. This often includes bronchoalveolar lavage, which usually shows either predominately lymphocytic or eosinophilic alveolitis. 8-20% of patients with sirolimus-induced pulmonary toxicity will also present with diffuse alveolar hemorrhage. Currently the only risk factor identified for sirolimus-induced pneumonitis is severe renal impairment (SCr 1.9 or greater/hemodialysis). Sirolimus drug levels have not been associated with the development of pulmonary toxicity.

The treatment of choice is to discontinue sirolimus therapy. In the majority of cases symptoms will resolve without further intervention within 2-4 weeks. There is some case report data to suggest dose-reduction as an acceptable alternative to drug discontinuation; however, this decision must be weighed against potential organ rejection from lowering sirolimus dosage. Only a few cases to date have required corticosteroids for symptom resolution, which were initiated after ruling out infectious causes and waiting for spontaneous symptom resolution.

Taxanes

This class of chemotherapy that includes paclitaxel and docetaxel have been associated with pulmonary toxicity, including interstitial pneumonitis. This drug-induced pneumonitis occurs with both agents in 1-4% of drug recipients within days to weeks of drug initiation. Patients present with dyspnea on exertion, non-productive cough, fatigue and fever.

There are several proposed risk factors for taxane-induced pneumonitis. Concomitant cytotoxic therapy with gemcitabine, dosing interval weekly instead of every three weeks, and for docetaxel, doses of 100 mg/m2 as opposed to 60 mg/m2. Diagnosis is based on clinical symptoms, recent use of a taxane, and ruling out other infectious causes. Radiography and bronchoalveolar lavage are typically non-specific and best serve to rule out other differential diagnoses.

Treatment of taxane-induced pneumonitis is drug discontinuation until symptom resolution, and supportive care measures. Corticosteroids with prednisone 40-60 mg daily are used for more severe symptoms with a slow taper over one to two months.

5. Disease monitoring, follow-up and disposition

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Special considerations for nursing and allied health professionals.

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What's the evidence?

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