Pulmonary Medicine

Chemotherapy-Related Drug-Induced Lung Injury

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What every physician needs to know

While the term “chemotherapy” may apply to any drug, it usually refers to drugs used in cancer treatment. The first chemotherapeutic agent, nitrogen mustard, is historically associated with the notorious use of sulfur mustards (mustard gas) as agents of chemical warfare. In that context, mustard gas was known to cause depression of white blood cell counts, leading to its investigation as a treatment for lymphoma. Notably, when mustard gas was inhaled in high concentration as a chemical warfare agent, severe pulmonary edema developed, an effect shared by many related chemotherapeutic compounds, including carmustine and cyclophosphamide.

The differential diagnosis of patients with cancer receiving chemotherapy who develop pulmonary complaints or chest radiographic abnormalities may be particularly challenging ( Table 1).

When patients with cancer develop pulmonary problems, distinguishing between the malignancy itself and complications of therapy can be difficult. Such patients are often immunosuppressed and physically stressed from the underlying disease, as well as from treatment with chemotherapy, radiation, and surgery. They are more susceptible to usual and unusual or opportunistic infections, particularly respiratory infections.

Relapse or spread of neoplastic disease in the lung often complicates pulmonary evaluation. In addition, chemotherapeutic agents are often given in combinations, further complicating assessment. In nearly all clinical situations, the diagnosis of drug-induced lung disease is one of exclusion, as diagnostic tests, including radiographic and pathologic examinations, are typically nonspecific.

Finally, chemotherapeutic agents may also be used in the treatment of patients with non-malignant inflammatory disorders. In these situations, as with cancer, the underlying disorder and its treatment often render the patient susceptible to infection, and the same diagnostic challenges exist as noted previously. In both neoplastic and inflammatory disorders, pulmonary complications of treatment may be rapidly progressive, severe, and even fatal. A working knowledge of the spectrum of such complications is essential. The physician must also consider consequences beyond the immediate clinical situation. The decision concerning whether a drug can be given safely again may have significant impact on the patient’s future cancer treatment.

Classification

Individual agents within pharmacologic groups of drugs may be associated with idiosyncratic and distinctive toxicities; however, within a given group, drug toxicity is usually stereotypical. It may be difficult to tease out the toxicity that arises from the use of anti-neoplastic agents from complications related to progression of the malignancy itself or to other treatment side effects, including toxicity of other chemotherapeutic agents, radiation, oxygen therapy, surgery, and immunosuppressive medications. The major classes of chemotherapeutic agents and their toxicities include the following:

Cytotoxic Antibiotics (Table 2)

Bleomycin

Pulmonary toxicity that is due to bleomycin has been studied extensively. The drug is concentrated in the lung and skin, so the major toxicities occur in these organs. Up to 20 percent of patients treated with bleomycin develop clinical pulmonary disease, and the toxicity is fatal in an estimated 1 percent. In research settings, bleomycin is used to induce pulmonary fibrosis in animal models. Pathologically, these models demonstrate Type I pneumocyte destruction and Type II pneumocyte hyperplasia and dysplasia, with fibroblast activation, collagen deposition, and eventually fibrosis.

In the acute setting, lung biopsy may show changes consistent with diffuse alveolar damage. However, the pathologic findings are not diagnostic of bleomycin toxicity, as they may be seen in clinical scenarios common to cancer patients who are receiving chemotherapy, including sepsis, adult respiratory distress syndrome (ARDS), and tumor lysis syndrome.

Overall, the incidence of significant bleomycin-associated pulmonary toxicity is approximately 10 percent, and fatal toxicity occurs in about 1 percent of all bleomycin-treated patients. Identified risk factors include: (1) a cumulative dose greater than 400 units (although toxicity has been reported with administration of much lower doses); (2) older age; (3) concurrent, prior, or post-treatment thoracic irradiation; (4) renal insufficiency (since the drug is excreted by the kidneys); (5) concomitant treatment with other cytotoxic agents; and (6) exposure to high concentrations of inspired oxygen (typically in the setting of surgery with general anesthesia).

In addition, genetic factors may play a role in development of pulmonary injury, as suggested by patient variability to bleomycin-induced injury and strain-specific susceptibility to toxicity in mouse models. Bleomycin is degraded by bleomycin hydrolase, an enzyme heterogeneously distributed in the lung; in animal models, development of pulmonary fibrosis is associated with a decrease in bleomycin hydrolase activity.

Several syndromes are associated with bleomycin pulmonary toxicity, each characterized by a different time course:

  • Interstitial lung disease is the most common syndrome; it may progress to end-stage pulmonary fibrosis (Figure 1). The clinical presentation is typically subacute, with symptoms of dry cough and dyspnea accompanied by interstitial changes on radiographs occurring within a few weeks to six months of treatment. Patients who develop interstitial lung disease that is due to bleomycin should have the drug withheld. Withdrawal of the drug in mild cases may result in improvement. The role of corticosteroids is less clear, although they are probably of little benefit in patients with advanced fibrosis. Corticosteroid doses reported in case series typically start at an initial dose of 60 to100 mg/day with slow tapering over a period of months, guided by clinical assessment of the patient.

Figure 1.

Bleomycin-associated acute or chronic interstitial pneumonitis may also appear many months or years after treatment. This clinical scenario may be seen in patients who receive thoracic irradiation and in those exposed to high inspired concentrations of oxygen (e.g., patients who undergo general anesthesia for a surgical procedure). Patients should be counseled about the latter possibility, and a recommendation should be made to avoid exposures to unnecessarily high concentrations of oxygen if possible.

  • Acute pneumonitis that is due to bleomycin is associated with fever and peripheral eospinophilia or an elevation in eosinophils in bronchoalveolar lavage (BAL) fluid. The syndrome typically resolves with discontinuation of drug and administration of corticosteroids. While rechallenge with bleomycin in patients who demonstrate hypersensitivity-type reactions (as evidenced by peripheral or BAL eosinophilia, suggestive radiographic changes, or compatible histologic findings) is widely described as feasible, a reasonable alternative treatment should be strongly considered if one is available.

  • Chest pain associated with bleomycin infusion occurs in approximately 3 percent of patients. The syndrome, which typically resolves with discontinuation of the infusion, is not a contraindication to further treatment with the drug.

The role of pulmonary function testing during treatment with bleomycin is controversial:

  • Since a significant number of bleomycin-treated patients are expected to develop drug-related lung injury, routine pulmonary function testing is often performed despite a lack of evidence supporting its use.

  • The typical abnormalities seen with bleomycin toxicity include declines in the diffusion capacity for carbon monoxide (DLCO) and lung volumes. The findings, which are not specific for drug toxicity, may reflect pulmonary changes related to infection, malignancy, or even physical debilitation from treatment.

  • In case of abnormal test results, consideration is usually given to discontinuing the drug, a decision that may have significant clinical consequences.

Mitomycin-C

Mitomycin-related pulmonary toxicity, which occurs in approximately 3-12 percent of patients, is associated with a wide variety of syndromes:

  • Acute interstitial pneumonitis is the most common syndrome. It occurs primarily in patients treated with mitomycin in combination with vinca alkaloids. Onset may be abrupt, occurring several hours after administration of the vinca alkaloid, and clinical manifestations may be severe.

  • Noncardiogenic pulmonary edema has been described in the setting of mitomycin given in combination with vinblastine.

  • Chronic interstitial disease with pulmonary fibrosis appears to be dose-related; a cumulative dose of 20 mg/m2 or more is associated with a higher likelihood of toxicity. Case reports suggest that glucocorticoid treatment for interstitial pneumonitis may be of benefit. In one case series of five patients with mitomycin-induced pnemonitis, the authors concluded that premature withdrawal of glucocorticoids may result in relapse of symptoms and radiographic infiltrates.

  • Bronchospasm may be seen during mitomycin infusion.

  • Mitomycin is among the chemotherapeutic causes of pulmonary hypertension related to pulmonary veno-occlusive disease.

  • Microangiopathic hemolytic anemia and renal failure, with or without pulmonary hemorrhage, have been reported; the syndrome may occur within months after initiation of mitomycin or up to several months after cessation of treatment.

Actinomycin-D

Like bleomycin and mitomycin, Actinomycin D may cause pulmonary toxicity in the form of acute or subacute interstitial lung disease. The drug has been implicated in exacerbations of lung injury related to thoracic irradiation. The radio-sensitizing effect may persist over long periods of time.

Alkylating Agents (Table 3)

Busulfan

Busulfan has been in clinical use for decades--long enough to enable recognition of both long-term and acute pulmonary toxicities.

  • Less than 5 percent of patients treated with busulfan develop significant pulmonary toxicity.

  • The pathophysiologic mechanism of lung injury is unknown.

  • Busulfan and the nitrosoureas are exceptions to the typical pattern that pulmonary toxicity related to chemotherapy generally occurs within weeks or a few months of initiation of treatment. Symptoms of busulfan-associated pulmonary fibrosis tend to present insidiously over weeks or years after treatment.

  • In a group of patients followed prospectively after a bone marrow transplant-conditioning regimen using a busulfan-cyclophosphamide combination, at one year of follow-up, 20 percent demonstrated a decrease in transfer factor (diffusion capacity). The decrease was accentuated in smokers. While this degree of depression of pulmonary function may be clinically silent, a small percentage of patients may present with significant severe and progressive interstitial lung disease and fibrosis up to ten years after treatment. This finding emphasizes that obtaining a thorough history of past medications is important in evaluating patients with unexplained interstitial lung disease. In such cases, pulmonary fibrosis may be progressive, severe, or fatal (Figure 2).

  • Busulfan should be withdrawn, if possible, in managing pulmonary toxicity; however, since many cases will be delayed until after therapy has been completed, usually little can be done to limit exposure. Anecdotal reports of response, along with a lack of other reasonable treatment options, support a trial of corticosteroids (e.g., prednisone at 1 mg/kg/day) for patients with progressive symptoms and loss of pulmonary function in whom infection has been excluded.

Figure 2.

Cyclophosphamide

Pulmonary toxicity related to cyclophosphamide is rare, occurring in only 1 percent or less of patients. Despite the low incidence, physicians in both oncologic and non-oncologic practices will encounter patients in whom potential drug-related pulmonary injury is a real consideration. Cyclophosphamide is used commonly in combination cancer therapies and as immunosuppressive therapy in autoimmune diseases. With regard to the latter, cyclophosphamide may be used to treat interstitial lung disease, so worsening of the patient’s pulmonary status will necessarily raise concern for superimposed drug toxicity, and distinction between progression of the underlying primary interstitial process and drug-related pulmonary toxicity may be difficult.

Published reports describing large numbers of patients with cyclophosphamide pulmonary toxicity are lacking. Based on individual case studies and small case series, two syndromes have been described: acute pneumonitis and late-onset pneumonitis with progressive pulmonary fibrosis.

  • Acute pneumonitis, which appears within several months of initiation of therapy, is associated with cough, dyspnea, and development of interstitial infiltrates. The disorder appears to respond to discontinuation of the drug and, perhaps, to administration of corticosteroids, although evidence for the latter is anecdotal. Case reports that describe acute, rapidly progressive interstitial disease in patients concurrently receiving cyclophosphamide and other potential pulmonary toxins reinforce the recommendation that such combinations should be carefully considered before initiation.

  • Late-onset progressive pulmonary fibrosis is more common in patients treated with low doses of the drug over long periods of time (months to years). In one series reporting late-onset toxicity, symptoms included progressive dyspnea and cough. Pulmonary function testing demonstrated abnormalities in DLCO, and chest imaging showed parenchymal infiltrates with bilateral pleural thickening; three of the five patients reported died of progressive respiratory failure. No improvement was seen with corticosteroid therapy.

Other Alkylating Agents

Chlorambucil is a nitrogen mustard derivative that uncommonly causes interstitial pneumonitis and pulmonary fibrosis. The drug is typically used over long durations in management of chronic lymphoreticular malignancies or inflammatory conditions. While the cumulative dose is not clearly a risk factor, the potential for pulmonary toxicity well into the course of treatment should be appreciated.

Ifosfamide is structurally similar to cyclophosphamide. Its principal toxicity is usually related to the bladder; pulmonary toxicity is rare.

Melphalan is used in a variety of oncologic disorders, including treatment of solid tumors, a setting in which pulmonary toxicity is rare. However, the drug has been used more recently as part of high-dose conditioning regimens prior to stem cell transplantation; the potential for pulmonary toxicity with high-dose therapy is unknown.

Antimetabolites (Table 4)

Methotrexate

Methotrexate is a folate antagonist used broadly as a chemotherapeutic agent and as an immunomodulator in patients with non-neoplastic inflammatory diseases. Up to 30 percent of patients treated with methotrexate over long periods of time for inflammatory illnesses have toxicity in one or multiple organs sufficient to warrant discontinuation of the drug. Pulmonary toxicity from methotrexate occurs in 2-7 percent of patients with rheumatoid arthritis.

The syndromes, risk factors, and time course for methotrexate-induced lung injury vary, perhaps reflecting the diverse situations in which the drug is used. Patients treated for inflammatory disorders, of which rheumatoid arthritis is the most common, typically receive relatively small doses over long periods of time (e.g., 2.5 - 25 mg per week over years). In contrast, patients treated for malignancy receive much higher doses over relatively shorter time intervals (weeks to months).

Several pulmonary toxicity syndromes have been described with methotrexate use:

  • Hypersensitivity pneumonitis, the most common, is variably accompanied by fever, peripheral eosinophilia, skin rash, or lymphocytic alveolitis noted in BAL fluid. If a lung biopsy is performed, granulomatous inflammation or mononuclear cell infiltration may be seen. The syndrome may resolve spontaneously, even with continuation or rechallenge with the drug, similar to what has been observed with bleomycin. However, in the absence of a firm indication to expose the patient to continued toxicity because of specific anticipated benefit, continuation of the drug is generally not recommended.

  • Methotrexate pulmonary toxicity may also present as a more insidious subacute syndrome of interstitial pneumonitis, leading to chronic fibrosis.

  • Bronchiolitis obliterans organizing pneumonia (BOOP) in the setting of rheumatoid arthritis treated with methotrexate has been reported.

  • Acute lung injury with noncardiogenic pulmonary edema (ARDS) has been described in the setting of intrathecal administration of drug.

A number of risk factors for pulmonary toxicity with methotrexate have been identified:

  • The drug is primarily excreted by the kidneys; the risk of toxicity is higher in older patients and in the setting of renal insufficiency.

  • 50-80 percent of methotrexate is protein-bound; diseases resulting in hypoalbuminemia and higher dosing regimens may predispose to toxicity.

  • In patients with rheumatoid arthritis, prior use of disease-modifying drugs, underlying rheumatoid pleuropulmonary involvement, and diabetes also appear to increase pulmonary risk.

  • There are conflicting reports regarding the influence on the risk of pulmonsty toxicity of dose intensity, route of drug administration, and dosing intervals.

  • The risk of toxicity may be increased by concomitant use of drugs that decrease renal excretion of methotrexate (e.g., salicylates, phenylbutazone, penicillin, and sulfonamides) or decrease its protein binding (e.g., salicylates, barbiturates, phenytoin, phenylbutazone, and nonsteroidal anti-inflammatory drugs).

As with all chemotherapeutic drugs, no controlled trials evaluating treatment strategies for pulmonary toxicity related to methotrexate are available. Withdrawal of the drug is the initial approach in management. In patients with hypersensitivity pneumonitis, withdrawal may be sufficient, with improvement evident within a relatively short period of time (e.g., days to weeks). Many anecdotal reports and small case series suggest a role for corticosteroids (e.g., prednisone at a dose of 1 mg/kg/day, followed by slow tapering based on clinical response).

Cytosine Arabinoside (Ara-C)

Cytosine arabinoside (Ara-C), a pyrimidine nucleoside analog that rapidly inhibits DNA synthesis, is used in high-dose chemotherapy regimens, typically to induce remission in acute hematologic malignancies. Pulmonary toxicity appears to parallel the intensity of treatment.

Ara-C may induce acute or subacute noncardiogenic pulmonary edema, occurring during drug infusion or up to several weeks after treatment. Although an incidence of up to 13 percent has been reported, a large trial of over 1000 patients with acute myeloid leukemia treated with high-dose Ara-C and daunorubicin (for induction), followed by monthly maintenance with Ara-C, did not reflect significant pulmonary toxicity, suggesting the complication is relatively uncommon. Treatment is supportive.

Less commonly, Ara-C is associated with bronchiolitis obliterans organizing pneumonia (BOOP), usually when administered with anthracyclines or interferon-alpha. In most, but not all, patients, clinical and radiographic resolution is seen within days to weeks, with or without administration of corticosteroids.

Gemcitabine

Gemcitabine is a pyrimidine analog that is structurally similar to Ara-C. Patterns of gemcitabine-associated lung injury are poorly defined; they include noncardiogenic pulmonary edema, interstitial pneumonitis, pleural effusion, and pulmonary fibrosis.

In a review of pulmonary toxicity in the clinical trial and safety databases performed for its parent pharmaceutical company, the incidence of serious gemcitabine-related pulmonary toxicity was estimated at less than 1% percent; however, in Phase II and III clinical trials evaluating patients treated with gemcitabine in combination with other cytotoxic therapy or chest irradiation, an incidence of over 10 percent has been reported.

A review performed by the Research on Adverse Drug Events and Reports (RADAR) project of the National Cancer Institute evaluated all pulmonary injury cases reported to the Food and Drug Administration’s Adverse Event Reporting System (AERS), as well as cases reported in the medical literature, The median interval of presentation with pulmonary injury was 48 days after initiation of gemcitabine. In the RADAR series, gemcitabine-induced pulmonary toxicity was severe, with a third of patients dying. However, mild cases of drug toxicity are unlikely to be reported to the FDA or to appear in publications.

Risk factors associated with pulmonary toxicity include coadministration of bleomycin and concurrent administration of agents (including the taxanes and vinorelbine), which, like gemcitabine, result in the release of inflammatory cytokines. Gemcitabine is known to be a potent radiosensitizer, and the possibility of severe radiation-associated pneumonitis should be considered with prior, concurrent, or post-treatment thoracic irradiation. Treatment consists of withdrawal of drug and supportive care; anecdotal reports suggest improvement in severe cases with administration of corticosteroids.

Fludarabine

Fludarabine, a purine analog, is usually used for treatment of chronic lymphoproliferative disorders and, in that context, may be administered over long periods of time. The largest reported series describes pulmonary toxicity occurring in approximately 9 percent of patients treated at a single institution. Evidence of interstitial pneumonitis developed 3-6 days after treatment. Toxicity did not correlate with age, prior chemotherapy, or underlying lung disease; however, toxicity was more common in patients with chronic lymphocytic leukemia than in those with other disorders. Other reports describe a more delayed onset of toxicity, occurring within weeks or months of treatment.

The presence of interstitial inflammation and granulomata in lung biopsies suggests an underlying hypersensitivity mechanism, a consideration further supported by the observation that improvement is often seen with administration of corticosteroids.

Fludarabine is also associated with profound immunosuppression, which places patients at increased risk of opportunistic infections (e.g., Pneumocystis jiroveci). This effect may persist for months after treatment, warranting a high clinical suspicion for infection in appropriate clinical circumstances.

Nitrosoureas (Table 5)

Carmustine (BCNU)

Pulmonary toxicity is among the most common side effects of the nitrosourea compounds. Carmustine is the most widely used of these drugs and is the one most strongly associated with pulmonary complications. Like bleomycin, carmustine is used in the laboratory setting as a model for pulmonary fibrosis.

While interstitial lung disease that is due to carmustine may be fulminant and may be observed within days or weeks after treatment, although the more common presentation is subacute and occurs over months or years. Most patients who develop pulmonary fibrosis do so within three years of treatment. However, the risk of developing severe pulmonary fibrosis persists over many years. In a 25-year follow-up of seventeen survivors of childhood brain tumors who were treated with high-dose (more than 700 mg/m2) carmustine, 53 percent died of complications related to pulmonary fibrosis, including two within the first three years, four between six and thirteen years, and two between thirteen and twenty-five years after chemotherapy.

Pulmonary toxicity is dose-related; a third of patients who receive a cumulative dose of greater than 525 mg/m2 develop severe, progressive interstitial disease, while less than15 percent of those who receive a cumulative dose under 475 mg/m2 develop toxicity. Median time to presentation after chemotherapy is 93 days. Additional risk factors include female sex, concurrent or previous treatment with other chemotherapeutic agents, underlying pre-existing lung disease, chest radiotherapy, oxygen therapy, and young age (under age six years) at the time of treatment.

The cardinal pathologic finding is interstitial fibrosis with Type II pneumocyte hyperplasia, dysplasia, fibroblast proliferation, and a relative paucity of inflammation. Radiographic evaluation in patients with delayed pulmonary toxicity demonstrates progressive interstitial abnormalities that are typically basilar, although upper lobe predominance has been described.

Pneumothorax appears to be more commonly associated with carmustine toxicity than with other chemotherapies.

Given the typical insidious, late onset of findings, the role of pulmonary function test monitoring has been raised, but little information is available for guidance. In a study of patients undergoing high-dose chemotherapy with carmustine in combination with cyclophosphamide and cisplatin (as a conditioning regimen prior to autologous stem cell transplantation for breast cancer), high-dose inhaled fluticasone during the initial twelve weeks of treatment was associated with a significantly smaller decline in DLCO at three months than that seen in historical controls. In general, corticosteroid treatment for late-onset pulmonary fibrosis related to carmustine or to any other chemotherapeutic agent is ineffective.

Other Nitrosoureas

The other members of the nitrosourea family--lomustine (CCNU), semustine (methyl CCNU), and chloroethyl nitrosourea--have not been used or studied as extensively as carmustine has. Reports of pulmonary infiltrates or fibrosis related to these agents are relatively few, but based on the agents' chemical relationship with carmustine, their potential for causing pulmonary toxicity should be considered.

Biologic Response Modifiers (Table 6)

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Gefitinib and erlotinib are orally active, small-molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase. Gefitinib is not available in the United States, but it has been used widely in Asia. Interstitial lung disease has been well recognized as a complication of both gefitinib and erlotinib.

The incidence of interstitial lung disease related to gefitinib appears to vary by race; rates are higher in Asians. In one reported Japanese series, pre-existing interstitial lung disease, concurrent cardiac disease, older age, poor performance status, and smoking were associated with increased risk for development interstitial lung disease. Pulmonary toxicity with erlotinib, including fatal cases of progressive interstitial lung disease, has also been described; it appears to occur at a lower frequency than with gefitinib. Other EGFR inhibitors, including cetuximab, may also be associated with pulmonary toxicity, although no large series have been reported.

Pulmonary toxicity occurs early, usually within days to one or two months of initiation of treatment. Although the incidence of pulmonary toxicity is fairly low, when it occurs, it may be rapidly progressive and is fatal in up to 45 percent of cases.

Patients typically present with dyspnea and cough. Radiographs demonstrate progressive ground-glass opacities and infiltrates, consolidation, and bronchiectasis. Distinguishing these findings from worsening pulmonary findings that are due to progression of underlying cancer may be challenging. Furthermore, since use of these agents is usually based on the identification of patients who have a mutational tumor analysis that suggests potential drug responsiveness, the decision to stop treatment is particularly difficult.

Glucocorticoids are often given, but they are of unproved incremental benefit beyond supportive care and removal of the offending agent.

All-trans Retinoic Acid

All-trans retinoic acid (ATRA) is a vitamin A derivative used in patients with promyelocytic leukemia. The mechanism of action is induction of maturation of leukemic cells to normal neutrophils. Its use has been associated with the "retinoic acid syndrome," which is characterized by fever, generalized edema, interstitial pulmonary infiltrates, pleural and pericardial effusions, and, in its most severe form, by diffuse alveolar hemorrhage and renal insufficiency. The syndrome typically occurs within several weeks of drug initiation and is frequently accompanied by a pronounced leukocytosis.

The incidence appears to be mitigated by the preventive use of corticosteroids. In contrast to other agents that cause acute pulmonary injury, continued use of ATRA is often justifiable, as the syndrome tends to resolve with corticosteroids; it may not recur with appropriate pretreatment and is associated with a good outcome in properly selected patient populations.

Vascular Endothelial Growth Factor Inhibitors

Bevacizumab

Bevacizumab is a monoclonal antibody that binds circulating vascular endothelial growth factor (VEGF). Since VEGF appears to be a critical modulator of tumor angiogenesis, it is not surprising that VEGF inhibition in patients with lung cancer is associated with complications of pulmonary hemorrhage and hemoptysis. This complication appears to be particularly problematic in patients with squamous cell lung cancer, although hemoptysis and tumor cavitation in the setting of treatment with bevacizumab is described in non-squamous lung cancers as well. Pre-existing hemoptysis and squamous cell lung cancer histology are relative contraindications to treatment with bevacizumab.

Rituximab

Rituximab is an anti-CD 20 monoclonal antibody developed for use in patients with B-cell lymphoma. The drug is now increasingly used in patients with severe rheumatologic conditions and in solid organ transplants.

Rituximab causes an immediate infusion reaction in over half of patients after receiving the initial dose; findings include headache, fever, rash, nausea, pruritus (with or without urticaria), and possibly angioedema and bronchospasm. Premedication may abrogate symptoms, and subsequent infusions are less likely to cause adverse reactions.

Reports of rituximab-associated interstitial lung disease have increased in frequency. In a series of more than one hundred patients receiving rituximab for non-Hodgkins lymphoma, 8 percent developed interstitial lung disease, usually accompanied by fever, cough, and dyspnea.

Treatment consists of withdrawal of the drug and initiation of corticosteroids; in some cases, progression to fatal pulmonary complications occurs. Since rituximab exerts its effect through B-cell depletion, infection is a common complication. Distinguishing pulmonary infection from drug-related toxicity may be a challenge.

Interleukin-2

Interleukin-2 (IL-2) is sometimes used for treatment of metastatic renal cell carcinoma or melanoma. IL-2 may be highly toxic, and drug administration predictably results in noncardiogenic pulmonary edema, hemodynamic instability, cardiac arrhythmias, and renal insufficiency. Protocols for administration of high-dose IL-2 counter-intuitively call for continuation of the agent (up to a point), despite development of severe adverse effects. Consequently, drug administration requires a monitored setting, such as that available in an intensive care unit.

Taxanes (Table 7)

Taxanes

The taxane family of drugs exerts chemotherapeutic effects through inhibition of microtubule disassembly and disruption of the G2 and M phases of the cell cycle. The two most commonly used taxanes are paclitaxel and docetaxel.

When it was first introduced into clinical practice, paclitaxel was associated with up to a 30 percent incidence of acute infusion reactions, consisting of bronchospasm, urticaria, and hypotension. These findings are consistent with a hypersensitivity or allergic reaction. Pretreatment with antihistamines and glucocorticoids is now routine, and the incidence of severe infusion reactions has decreased substantially.

Both paclitaxel and docetaxel are associated with acute and chronic progressive interstitial pneumonitis, which may develop during or following a course of treatment. Respiratory failure has also been reported. In some cases, the proposed mechanism of injury has been a hypersensitivity reaction, although supporting evidence is limited. Long-term follow-up studies on the clinical course are sparse. The combination of a taxane and other cytotoxic therapies appears to increase the risk of interstitial pneumonitis. In particular, use of paclitaxel or docetaxel with gemcitabine appears to predispose to severe or life-threatening pneumonitis. Taxanes are radiosensitizers; indeed, the incidence of pulmonary toxicity appears increased when concomitant thoracic irradiation is given.

Docetaxel has been associated with a fluid retention syndrome characterized by capillary leak, peripheral edema, pleural effusions, ascites, and, in severe cases, pulmonary edema. Pretreatment with glucocorticoids appears to decrease the frequency of this complication. Treatment for taxane-associated pulmonary toxicity consists of withdrawal of the drug and supportive care. Use of glucocorticoids may be reasonable if hypersensitivity is suspected as the underlying mechanism of injury. (However, clinical data establishing an immunologic cause may be lacking.) In addition, a course of corticosteroids may be reasonable if underlying infection and progressive malignancy are excluded.

Are you sure your patient has chemotherapy-related drug-induced lung injury? What should you expect to find?

Important Considerations in the Evaluation of Patients for Chemotherapy-Related Pulmonary Toxicity

The clinical manifestations of drug-induced pulmonary toxicity are nonspecific. The time course of toxicity is variable, but in most cases, it occurs relatively early, such as within the first weeks or months after initiation of therapy. Notable exceptions include drugs associated with chronic pulmonary fibrosis, including bleomycin, busulfan, and the nitrosoureas, with which progressive fibrosis may occur over the course of many years.

Symptoms of pulmonary toxicity, such as cough, dyspnea, and chest discomfort, as well as systemic symptoms, including weight loss and fatigue, are nonspecific. They may be difficult to distinguish from symptoms related to infection or the underlying cancer. Failure to consider drug-related pulmonary toxicity as a cause of symptoms may result in progression of adverse effects.

Physical examination in early disease may be completely normal, with progressive disease accompanied by signs related to the type of pulmonary involvement, such as inspiratory crackles in patients with interstitial pneumonitis, wheezing in patients with bronchoconstriction or hypersensitivity syndromes, and dullness to percussion and diminished breath sounds in patients with pleural effusion. These signs are also nonspecific.

The presence of persistent pulmonary symptoms, even mild persistent dyspnea, particularly in the presence of a suggestive lung examination and radiographic abnormalities, should raise the possibility of drug toxicity. Evaluation of a patient with possible chemotherapy-related toxicity is facilitated by asking two questions: Is the drug administered known to cause pulmonary complications when used alone or in combination with other drugs? Is the patient’s pulmonary syndrome consistent with drug-related toxicity? Implicit in the evaluation is exclusion of other common causes of pulmonary decompensation, including progression of malignancy and infection.

Syndromes of Chemotherapy-Related Pulmonary Toxicity (Table 8)

Interstitial Pneumonitis/ Pulmonary Fibrosis

Acute pneumonitis is characterized by dry cough, dyspnea, and basilar crackles. A rapid course may mimic noncardiogenic pulmonary edema, while a more subacute course presents insidiously over weeks or months. Progressive pneumonitis may result in pulmonary fibrosis developing over months or many years after cessation of drug use; in some cases, respiratory failure may develop. In one study of long-term survivors of childhood and adolescent malignancies, pulmonary fibrosis developed many years after exposure to some chemotherapeutic agents, particularly the nitrosoureas (carmustine and lomustine), bleomycin, cyclophosphamide, and busulfan.

Chest radiographs show reticular infiltrates, which reflect irreversible fibrosis in severe cases; traction bronchiectasis may be seen. Pulmonary function tests demonstrate abnormalities in DLCO and a restrictive ventilatory defect. Lung biopsies characteristically demonstrate proliferation of atypical Type II pneumocytes; organizing pneumonia, and, in some cases, bronchiolitis obliterans organizing pneumonia (BOOP) may be seen, a finding which may not enable differentiation between drug-induced pneumonitis and infection.

Noncardiogenic Pulmonary Edema

Noncardiogenic pulmonary edema usually presents abruptly with rapidly progressive respiratory distress developing over hours. Diffuse crackles are noted on lung examination, and arterial blood gases show hypoxemia. The chest radiograph demonstrates diffuse alveolar or reticular infiltrates without cardiomegaly or pleural effusions. BAL findings are nonspecific. In severe cases, diffuse alveolar damage (DAD) may be seen on lung biopsy; however, DAD is a nonspecific finding and may be seen with infection, shock, transfusion reactions, and tumor lysis syndrome, as well as with drug toxicity. Withdrawal of the offending drug and supportive care usually are associated with a good prognosis.

Hypersensitivity Pneumonitis

Pulmonary eosinophilic syndromes typically occur acutely during the time the patient is exposed to the drug. Several syndromes that are likely pathophysiologically distinct tend to be lumped under in the “hypersensitivity” category, all of which result in cough and dyspnea; some are accompanied by fever and fatigue, and less commonly, myalgias, arthralgias, or skin eruption.

Drug toxicity presenting as a Loeffler’s-like syndrome or "simple pulmonary eosinophilia" has been described. Symptoms are usually mild, and chest radiographs demonstrate patchy pulmonary infiltrates that may be migratory; peripheral eosinophilia is typically seen. Symptoms usually resolve with withdrawal of the drug, and rechallenge will result in relapse.

Chronic eosinophilic pneumonia associated with drug toxicity follows a subacute course over weeks to months and is often accompanied by systemic symptoms, peripheral eosinophilia, and radiographic infiltrates that may be migratory. Patients usually respond well to corticosteroids, as do patients with idiopathic chronic eosinophilic pneumonia; however, unlike in patients with idiopathic chronic eosinophilic pneumonia, the course is usually not relapsing as long as the patient is not rechallenged with the drug. BAL in drug-induced eosinophilic lung disease in many, but not all, cases demonstrates increased eosinophils (more than 20%) and lymphocytes.

True hypersensitivity pneumonitis that is due to a cell-mediated (Type IV), delayed reaction also appears to occur in some cases of drug toxicity, with symptoms and radiographic changes occurring within hours or days after drug exposure, a situation that may be difficult to distinguish from acute noncardiogenic pulmonary edema.

Pulmonary Vascular Disease

Pulmonary veno-occlusive disease (PVOD), characterized by fibrotic occlusion of pulmonary veins and eventual development of pulmonary hypertension, is an uncommon complication of chemotherapy. The usual symptom is progressive dyspnea. PVOD may be associated with interstitial abnormalities; pleural effusions are commonly seen, which is unusual in patients with idiopathic pulmonary arterial hypertension. Evaluation for PVOD may be difficult; a definitive diagnosis requires a surgical lung biopsy.

Hepatic veno-occlusive disease in the context of treatment for hematopoietic malignancies is more common than PVOD and is thought to result from injury to hepatic venules from toxic drug metabolites.

Pleural Disease

Pleural disease related to drug toxicity usually occurs in conjunction with pulmonary parenchymal toxicity. An isolated pleural effusion or pleuritis without parenchymal lung disease has been described with methotrexate, procarbazine, and docetaxel, and, in isolated case reports, with other chemotherapeutic agents. In contrast to non-chemotherapeutic agents, drug-induced lupus has not been described in cancer therapies.

Infusion Reactions

Chemotherapeutic agents may produce reactions during their infusion that do not necessarily correlate with the drug’s known toxicities. The reactions usually occur during or within a few hours of termination of the infusion. Pulmonary symptoms may be as mild as dyspnea or chest tightness, or as severe as anaphylaxis or hypoxia. Systemic symptoms include pruritus, tachycardia, fever, chills, gastrointestinal complaints, and skin rash.

In general, the severity of infusion reactions may be mitigated by premedication with corticosteroids or by slowing the infusion rate. The exception to this rule is anaphylaxis, the most severe and most dangerous form of infusion reaction. In cancer treatment, anaphylaxis is most commonly observed with platinum drugs and taxanes, although it has the potential to occur with any drug.

Radiation Sensitization

Many chemotherapeutic agents increase the risk of radiation injury to the lung; particularly noteworthy are bleomycin, dactinomycin, cyclophosphamide, vincristine, doxorubicin (adriamycin), mitomycin, taxanes, gemcitabine, and interferon-alpha. While this increased risk of lung toxicity may be advantageous in use of combined modality therapy, adverse consequences related to development of radiation lung injury may arise.

Pulmonary toxicity should be of particular concern in patients treated with combined modality therapy, which includes thoracic irradiation, such as in patients with lung cancer, breast cancer, or mediastinal tumors, including lymphoma.

Beware: there are other diseases that can mimic chemotherapy-related drug-induced lung injury.

Not applicable.

How and/or why did the patient develop chemotherapy-related drug-induced lung injury?

Not applicable.

Which individuals are at greatest risk for developing chemotherapy-related drug-induced lung injury?

Not applicable.

What laboratory tests should you order to help make the diagnosis, and how should you interpret the results?

The diagnosis of pulmonary toxicity related to drug exposure must be made clinically. No laboratory tests are diagnostic. Laboratory evaluation should be performed primarily to exclude other causes of progressive pulmonary symptoms and abnormal radiographs, including infection, volume overload, or progressive malignancy.

Often, the first evidence of a new pulmonary process may be an abnormal chest radiograph, with or without pulmonary symptoms. In many cases, chest computed tomography (CT) will be better at characterizing the pattern and extent of the abnormality. As with routine laboratory studies, radiographic findings are nonspecific. Radiographic patterns that may be useful in determining the basis for clinical findings include that of radiation pneumonitis, which typically follows the distribution of the thoracic irradiation portal, or the discovery of mediastinal or hilar adenopathy, findings which would be uncommon with drug toxicity and more suggestive of progressive tumor .

What imaging studies will be helpful in making or excluding the diagnosis of chemotherapy-related drug-induced lung injury?

See discussion of individual agents.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of chemotherapy-related drug-induced lung injury?

Pulmonary function tests (PFTs) provide an objective measurement of physiologic lung function at the time of initial concern about drug toxicity and may be useful in patient follow-up. The use of PFTs in evaluating patients with various drug toxicities has been widely reported for nearly all the drugs noted as causes lung injury; however, as for laboratory and radiographic evaluation, PFT abnormalities are nonspecific.

PFTs may be influenced by a multitude of factors, including muscular weakness, general fatigue, and pain. Reproducibility can be problematic. Anemia impacts the DLCO. PFTs performed to evaluate patients with suspected or known drug toxicity should include measurements of DLCO and lung volumes; DLCO impairment and a restrictive pattern are the most common abnormalities observed. There are no routine recommendations currently regarding performance of PFTs before, during, or after chemotherapeutic regimens.

What diagnostic procedures will be helpful in making or excluding the diagnosis of chemotherapy-related drug-induced lung injury?

The differential diagnosis for pulmonary findings in oncology patients who are receiving chemotherapy is broad, and it includes progression of the underlying malignancy, infection, and drug toxicity (Figure 3). The consequences of misdiagnosis may be severe. Since symptoms, physical examination findings, laboratory evaluation, pulmonary function tests, and imaging studies are nonspecific, consideration should be given to the potential benefit of a diagnostic procedure, including bronchoscopy and surgical lung biopsy.

Bronchoscopic findings are not diagnostic for drug toxicity. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies is performed primarily to identify or exclude recurrent malignancy or infection. Performed in sequential fashion, BAL may be useful in identifying patients with alveolar hemorrhage syndrome, which may occur as an uncommon manifestation of drug-induced pulmonary injury. BAL fluid analysis usually demonstrates a nonspecific elevation in cell counts in patients with drug toxicity, although an elevation in eosinophils may be seen in hypersensitivity reactions.

Surgical lung biopsy, including video-assisted thoracoscopic surgery (VATS) and open thoracotomy, allows larger portions of lung tissue to be sampled than are possible with bronchoscopically obtained transbronchial biopsies, but the procedure is more invasive. Surgical biopsy may be safer in patients with bleeding dyscrasias or thrombocytopenia, and like bronchoscopy, it may be valuable in definitively identifying recurrent malignancy or infection. Reliable pathologic recognition of patterns of interstitial pneumonitis, organizing pneumonia, hypersensitivity reactions, diffuse alveolar damage, and other potential manifestations of drug toxicity is much more likely with surgical, rather than bronchoscopic, lung biopsy. While the findings may not definitively establish a diagnosis of drug toxicity, the exclusion of malignancy and infection, along with consistent histopathologic findings, supports the diagnosis.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of chemotherapy-related drug-induced lung injury?

Cytologic studies and tissue biopsies obtained from bronchoscopy or surgical lung biopsy may be useful in distinguishing drug toxicity from underlying tumor.

If you decide the patient has chemotherapy-related drug-induced lung injury, how should the patient be managed?

The cardinal rule of management in patients suspected of having pulmonary disease related to drug toxicity is drug withdrawal; few situations justify continuing an injurious exposure. (However, see the discussion of all-trans retinoic acid and interleukin-2.) Since the impact of discontinuing a chemotherapeutic agent beneficial to cancer treatment is potentially enormous, the decision should be made only if other causes of the findings--most importantly, infection or cancer progression--are reasonably excluded; concurrence by the patient’s treating oncologist is key.

Withdrawal of a drug may be adequate to reverse toxicity, particularly in the case of infusion reactions. Patients with acute or subacute interstitial pneumonitis or hypersensitivity syndromes should be considered for glucocorticoid treatment (e.g., prednisone,1 mg/kg/day, tapered over the course over weeks to months). Patients who are unlikely to respond to glucocorticoids include those with a chronic pulmonary fibrosis that presents months or years after treatment, those with noncardiogenic pulmonary edema, and those with pulmonary vascular disease.

All patients should receive supportive care, including alleviation of dyspnea, supplemental oxygen (if indicated), and adequate pain management.

What is the prognosis for patients managed in the recommended ways?

See discussion under individual agents.

What other considerations exist for patients with chemotherapy-related drug-induced lung injury?

Not applicable.

What's the evidence?

Alarcon, GS, Kremer, JM, Macaluso, M. "Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis.". Ann Intern Med. vol. 127. 1997. pp. 356-64.

This multicenter study identifies predictors of lung injury related to the use of methotrexate in patients with rheumatoid arthritis (older age, diabetes, rheumatoid pleuropulmonary involvement, prior use of disease-modifying anti-rheumatic drugs, and hypoalbuminemia).

Allen, J, Camus, P, Rosenow, EI. "Drug-induced eosinophlic lung disease". Clinics in Chest Medicine. WB Saunders. 2004. pp. 77-88.

The various drug-induced pulmonary eosinophilic clinical syndromes are summarized in this review.

Andersson, BS, Luna, MA, Yee, C, Hui, KK, Keating, MJ, McCredie, KB. "Fatal pulmonary failure complicating high-dose cytosine arabinoside therapy in acute leukemia.". Cancer. vol. 65. 1990. pp. 1079-84.

In this series of 103 relapsed acute leukemia patients treated with high dose Ara-C, 13 developed an acute capillary leak syndrome associated with a high mortality rate.

Belknap, SM, Kuzel, TM, Yarnold, PR. "Clinical features and correlates of gemcitabine-associated lung injury: findings from the RADAR project.". Cancer. vol. 106. 2006. pp. 2051-7.

Gemcitabine lung injury is uncommon, but it can be severe, and it appears more likely to occur when the drug is given in combination with other medications associated with pulmonary toxicity.

Cooper, JA, White, DA, Matthay, RA. "Drug-induced pulmonary disease. Part 1: Cytotoxic drugs". Am Rev Respir Dis. vol. 133. 1986. pp. 321-40.

This classic paper is a seminal work on cytotoxic drug-associated pulmonary disease and still provides a useful overview of this area of pulmonary medicine.

Flieder, D, Travis, W, Camus, P, Rosenow, EC. "Pathologic characteristics of drug-induced lung disease". Clinics in Chest Medicine. vol. 37. WB Saunders. 2004. pp. 45.

This comprehensive overview of the pathologic patterns and findings associated with drug-associated lung disease provides an important foundation for correlating clinical, pathologic, and radiographic findings.

Huggins, J, Sahn, S, Camus, P, Rosenow, EI. "Drug-induced Pleural Disease". Clinics in Chest Medicine. WB Saunders. 2004.

Pleural disease as a manifestation of chemotherapy-associated toxicity is relatively uncommon in the absence of parenchymal pulmonary toxicity but is described with a number of drugs, which are reviewed here.

Jules-Elysee, K, White, D. "Bleomycin-induced pulmonary toxicity.". Clinics in Chest Medicine. vol. 11. 1990. pp. 1-20.

Bleomycin has been used in clinical cancer care for several decades. This article reviews the evidence related to risk factors for pulmonary toxicity, and the clinical presentation, evaluation, and approach to patients suspected of having bleomycin-induced lung injury.

Kremer, JM, Alarcon, GS, Weinblatt, ME. "Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review.". Arthritis Rheum. vol. 40. 1997. pp. 1829-37.

This multicenter study identifies the symptoms and radiographic and histopathologic features of methotrexate-associated lung injury in a retrospective cohort of patients with rheumatoid arthritis.

Kudoh, S, Kato, H, Nishiwaki, Y. "Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study.". Am J Respir Crit Care Med. vol. 177. 2008. pp. 1348-57.

In a large cohort of Japanese patients treated with gefitinib for non-small cell lung cancer, a 4 percent incidence of interstitial lung disease over twelve weeks of treatment was observed. Mortality related to interstitial lung disease in this group was 31.6 percent. Risk factors included older age, poor performance status, smoking, and pre-existing interstitial lung disease.

Linette, DC, McGee, KH, McFarland, JA. "Mitomycin-induced pulmonary toxicity: case report and review of the literature.". Ann Pharmacother. vol. 26. 1992. pp. 481-4.

This article includes a discussion of the medical literature related to mitomycin-associated pulmonary toxicity syndromes reported from 1966-1991.

Liu, X, Hong, XN, Gu, YJ, Wang, BY, Luo, ZG, Cao, J. "Interstitial pneumonitis during rituximab-containing chemotherapy for non-Hodgkin lymphoma.". Leuk Lymphoma. vol. 49. 2008. pp. 1778-83.

In this series of 107 patients treated with rituxan for non-Hodgkins lymphoma, the incidence of interstitial lung disease was 8 percent. Most patients improved with glucocorticoid treatment, but one fatal case ,as well as recurrences of interstitial disease with rituxan rechallenge, were observed.

Lohani, S, O' Driscoll, BR, Woodcock, AA. "25-year study of lung fibrosis following carmustine therapy for brain tumor in childhood.". Chest. vol. 126. 2004. pp. 1007.

Carmustine is associated with pulmonary fibrosis, which may occur acutely or subacutely over months to many years. This study reports a 53 percent mortality rate related to pulmonary fibrosis up to 25 years after high-dose carmustine treatment.

Lund, MB, Kongerud, J, Brinch, L, Evensen, SA, Boe, J. "Decreased lung function in one-year survivors of allogeneic bone marrow transplantation conditioned with high-dose busulphan and cyclophosphamide.". Eur Respir J. vol. 8. 1995. pp. 1269-74.

This prospective study identified transient decreases in lung volumes and persistent reduction in gas transfer one year after bone marrow transplantation, presumed related to conditioning with busulphan and cyclophosphamide. The findings emphasize the potential for long-term effects of cytotoxic drugs on lung function, even in asymptomatic patients.

Movsas, B, Raffin, TA, Epstein, AH, Link, CJ. "Pulmonary radiation injury". Chest. vol. 111. 1997. pp. 1061-76.

This article is a thorough review of pulmonary radiation injury that covers clinical syndromes and radiographic features, risk factors, histopathology and mechanisms of injury, and preventive strategies.

Phillips, TL, Wharam, MD, Margolis, LW. "Modification of radiation injury to normal tissues by chemotherapeutic agents.". Cancer. vol. 35. 1975. pp. 1678-84.

Many chemotherapeutic agents are radiosensitizers that will potentiate the therapeutic effect as well as the toxicity of therapeutic radiation, as described in this article.

Reck, M, van Zandwijk, N, Gridelli, C. "Erlotinib in advanced non-small cell lung cancer: efficacy and safety findings of the global phase IV Tarceva Lung Cancer Survival Treatment study". J Thorac Oncol. vol. 5. pp. 1616-22.

In this safety and efficacy report in a heterogeneous group of over five thousand patients treated worldwide with erlotinib, interstitial lung disease was rare, occurring in less than 1 percent of patients.

Sandler, A, Gray, R, Perry, MC. "Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.". N Engl J Med. vol. 355. 2006. pp. 2542-50.

Bevacizumab binds circulating vascular endothelial growth factor; pulmonary hemorrhage occurs more frequently in patients with squamous cell lung cancer and/or pre-existing hemoptysis than in those with other tumor types and without hemoptysis - clinical features which constitute relative contraindications to treatment.

Tallman, MS, Andersen, JW, Schiffer, CA. "Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome.". Blood. vol. 95. 2000. pp. 90-5.

In this series of 167 patients receiving all-trans retinoic acid for acute promyelocytic leukemia, the incidence of the retinoic acid syndrome was 26 percent, emphasizing the importance of appropriate pretreatment.
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