Introduction
Adverse drug reactions have been the object of intense scrutiny since the early 1990s and have been recognized as a top safety priority by health care quality improvement organizations across the United States. A groundbreaking report published in 1999 by the Institute of Medicine only intensified this attention by suggesting that medical errors, including medication errors, may be responsible for 98,000 patient deaths per year in the United States. Specifically, medication errors and preventable adverse drug events may injure 1.5 million people and cost billions of dollars annually. Up to 2% to 5% of hospitalized patients may have nonpreventable adverse drug reactions. The classification of drug reactions includes allergic or hypersensitivity reactions, overdosage, intolerance, idiosyncratic reaction, side effects, and secondary effects.
We know relatively little about the pharmacokinetic properties of drugs in individual patients. Many drug-related injuries are not reproducible in animals and therefore cannot be studied in depth. Moreover, if a drug administered in the therapeutic dose range caused an adverse reaction in most of the patients who received it, the drug would not be usable. Indeed, only a small percentage of the population develops pulmonary toxicities to otherwise successful drugs. Nevertheless, drug-induced pulmonary diseases represent a significant problem and are likely underrecognized. It is estimated that less than 5% of all adverse drug-induced pulmonary diseases and overall less than 1% of serious and unexpected events are formally reported to the U.S. Food and Drug Administration (FDA). The number of drugs associated with pulmonary toxicity is steadily increasing. By 2009, more than 350 drugs have been identified to cause adverse pulmonary reactions. These reports are of various nature and quality, ranging from clear toxicities established in large series to isolated case reports. Some of these medications are listed in Table 71-1 . To minimize mortality and significant morbidity, it is incumbent on the clinician to keep in mind at least the more common drugs that may induce pulmonary disease.
| CHEMOTHERAPEUTIC |
| Cytotoxic |
|
| Noncytotoxic |
| ANTIBIOTIC |
| ANTI-INFLAMMATORY |
| ANALGESIC |
| CARDIOVASCULAR |
| ILLICIT |
| INHALANT |
|
| INTRAVENOUS |
| MISCELLANEOUS |
* Typically present as acute or subacute respiratory insufficiency.
Four mechanisms of drug injury to the lungs are recognized: (1) oxidant injury, such as during chronic nitrofurantoin ingestion; (2) direct cytotoxic effects (and these effects may be aggravated by oxidant injuries); (3) deposition of phospholipids within cells, such as those produced by cationic amphophilic drugs such as amiodarone; and (4) immune-mediated injury through drug-induced systemic lupus erythematosus (SLE). Although extensive investigation has been undertaken to look for other forms of immune system–mediated injury, only the SLE induced by drugs has been proven.
Chemotherapeutic Agents
Chemotherapeutic agents are extensively used in solid and hematologic malignancies but are also increasingly employed for their immunosuppressive properties in the management of various inflammatory disorders. Because of the severity of the diseases in which they are employed, higher risks for potential adverse lung reactions are typically tolerated, and as such, pulmonary complications of chemotherapy are common in this clinical setting. It is, however, a diagnostic challenge for the clinician who must determine the responsibility of the chemotherapeutic agent, usually on the basis of a diagnosis of exclusion, and decide whether or not to discontinue it, with the risk of depriving his or her patient of a potentially life-saving therapy.
Oncology patients are prone to a number of pulmonary complications irrespective of their chemotherapy regimen, including opportunistic infections, atypical presentations of common lung infections, radiation-induced lung injury, cardiogenic or noncardiogenic pulmonary edema, and, of course, metastatic lung involvement. The various presentations of drug-induced pulmonary disease must be rapidly differentiated from these other etiologies whose clinical presentations, including fever and diffuse radiographic abnormalities, may be extremely similar to chemotherapy-induced pulmonary reactions. As combination regimens are generally the rule, it can become difficult to incriminate one agent over the other. Chemotherapy-associated pulmonary reactions have become a major problem, particularly in relation to therapeutic regimens containing bleomycin, methotrexate, cyclophosphamide, and a host of newer agents ( Table 71-2 ).
| ANTIBIOTIC-DERIVED AGENTS |
|
| ALKYLATING AGENTS |
|
| ANTIMETABOLITES |
|
| NITROSOUREAS |
|
| PODOPHYLLOTOXINS |
|
| NOVEL ANTITUMOR AGENTS |
|
| IMMUNE MODULATORY AGENTS USED IN MALIGNANCY |
|
| OTHER MISCELLANEOUS CHEMOTHERAPY AGENTS |
|
Consistent criteria for drug-induced lung disease have not been officially established. Uncertainty that a given respiratory complication is linked to a particular drug is generally present. Confirmation with rechallenge is to be avoided because it is often neither practical nor generally ethical. Hence the diagnosis of cytotoxic lung damage rests on an appropriate history of drug exposure, histologic evidence of lung injury, and the exclusion of other causes of the lung damage. There is no single diagnostic test or tissue biopsy that can definitively confirm the diagnosis of chemotherapy-associated lung disease. Thus a careful and thorough evaluation to eliminate the possibilities of other conditions producing these effects, particularly infection, is warranted. It is estimated that 10% to 20% of patients undergoing some type of chemotherapy will develop respiratory symptoms directly related to their treatment. Thus the clinician should maintain a high index of suspicion and carefully screen for other competing causes of pulmonary injury that may affect these immune-compromised patients.
The clinical presentation of many chemotherapy drug effects is quite similar, with the exception that some present more acutely, whereas others tend to be more insidious in their onset. In general, nonproductive cough, dyspnea, and often fever begin weeks to years after the agent is first administered. Occasionally, symptoms may present acutely, as in the case of hypersensitivity reactions or infusion reactions. Symptoms may also manifest years after discontinuation of the drug, perhaps reactivated by radiotherapy, a process called “radiation recall.” Fever is common with most chemotherapeutic drug-induced pulmonary injury, but it may not be consistently present, and chills are usually absent. Weight loss may be present. The chest radiograph in cases of chemotherapy-induced lung disease may be unremarkable for days or weeks before showing typical changes of a diffuse interstitial infiltrative pattern. Alternatively, there may be a diffuse mixed alveolar-interstitial pattern, which may occasionally be useful in recognizing early drug effects ( Fig. 71-1 ). Auscultation of the lungs will frequently reveal crackles, which are also nonspecific. In some instances, pleural effusions may be present during adverse drug reactions, but not consistently.
Pulmonary function studies are abnormal in almost all patients with cytotoxic drug–induced lung disease when compared with pretreatment testing. The carbon monoxide diffusing capacity (D l CO ) may decrease before reduced volumes are detected. In addition, this decrease in D l CO may precede the onset of symptoms and radiographic changes by days or weeks. In several prospective investigations, diffusing capacity has been used to detect early onset of pulmonary reactions, at which time the agents are discontinued to minimize progression into overt clinical disease. Bronchoalveolar lavage (BAL) may be another means of assessing early lung damage from these drugs; however, the results are often variable. In general, the greatest utility of BAL is to exclude infection.
Antibiotic-Derived Agents
Bleomycin
Bleomycin is an antibiotic chemotherapeutic agent that was isolated in 1966 from Streptomyces verticillus. Its pulmonary toxicity was recognized early and has since been one of the main factors limiting its use in the clinical setting. The incidence of bleomycin lung toxicity ranges anywhere from 0% to 46%; pulmonary function testing and chest radiographs reveal that 20% of patients treated with bleomycin develop overt pulmonary disease, and up to 3% die from pulmonary consequences of bleomycin therapy.
The mechanisms by which bleomycin exerts its antineoplastic effects are diverse. Direct cytotoxic effect, prevention of neoangiogenesis by the tumor, stimulation of the production of various cytokines, and free radical generation via formation of a complex between ferrous iron and oxygen are likely the most important. The latter effect may explain increased bleomycin toxicity with high fractions of inspired oxygen. This is often a problem during anesthesia and in the postoperative recovery period. This sensitivity to supplemental oxygen may persist for months and, perhaps, years after discontinuation of the drug. Perhaps one of the most consistent features of bleomycin-induced lung disease is the concept of cumulative toxicity. The incidence of pulmonary toxicity is significantly greater in those who have received a cumulative dose of greater than 450 units, with a 10% death rate in those having received a total dose greater than 550 units of bleomycin. However, doses as little as 50 units may occasionally be enough, especially when other synergic factors are present. Rapid rates of delivery by the intravenous route may also play a role, and slower infusion rates, as well as intramuscular injections, have been recommended.
Bleomycin is metabolized primarily by the kidneys. Hence renal failure predisposes to impaired metabolism of the drug and increased toxicity. It is also inactivated by an enzyme, bleomycin hydrolase, present in most tissues except for the lungs and skin. The lack of a detoxifying enzyme in the skin may explain the scleroderma-like skin changes occasionally observed with bleomycin. Radiotherapy is itself a common cause of pulmonary complications and is also thought to promote the generation of free radicals, toxic to both the tumor cells and surrounding tissues. The concomitant use of bleomycin and radiotherapy may be synergistic. Treatment with bleomycin may reactivate prior radiation-induced lung disease, a process called radiation recall, as mentioned earlier as an example of a delayed drug reaction. Pulmonary toxicity is also increased in patients older than 70 and in those with preexisting lung disease. There is good evidence that pediatric patients may also be at increased risk, with 70% of children treated with bleomycin for rhabdomyosarcoma developing pulmonary toxicity in one study. Impaired or immature ability to process free radicals and inadequate kidney function may explain these differences. Finally, bleomycin toxicity may be synergistically increased by several other chemotherapeutic agents.
Although of uncertain value, determination of pretreatment D l CO and its frequent monitoring have been suggested in an attempt to predict subsequent clinical deterioration. A progressive fall in the D l CO should prompt withdrawal of further bleomycin administration. Vital capacity and pulmonary capillary blood flow may be better predictors of lung toxicity. In addition, the enhanced sensitivity of computed tomography (CT) scanning may also be useful in establishing an early diagnosis of bleomycin pneumonitis. In one series of 100 patients receiving bleomycin, chest CT scans were abnormal in 38%, whereas the chest radiographs were abnormal in only 15%. Serial imaging studies are not recommended in the absence of specific symptoms.
Other forms of bleomycin-induced lung disease have been described, albeit less commonly. Hypersensitivity reactions ( eFig. 71-1 ) are possible with an association of fever and peripheral blood or BAL eosinophilia. Discontinuation of bleomycin and initiating corticosteroids usually bring about rapid reversal of this hypersensitivity variant of bleomycin pneumonitis.
An additional rare, but clinically important, presentation of bleomycin pneumonitis is that of nodular pulmonary lesions mimicking tumor metastasis ( Fig. 71-2 ). These reactions to bleomycin have been described in the setting of lymphoma or seminoma, requiring surgical biopsy to differentiate bleomycin-associated lung injury from recurrence of the primary malignancy. Although bleomycin pulmonary toxicity may reflect diffuse alveolar damage ( eFig. 71-2A ), these nodular lesions from bleomycin often exhibit the histologic pattern of organizing pneumonia (see eFig. 71-2B ). Pneumothorax and pneumomediastinum have also been described.
In suspected cases of bleomycin lung toxicity, discontinuation of the drug is warranted. Administration of corticosteroids is often recommended. It would seem prudent to pay particular attention to avoid high fractions of inspired oxygen and concomitant radiotherapy and to monitor the kidney function carefully during the duration of treatment. One study demonstrated that, if the patient survives the acute injury from bleomycin, pulmonary findings might improve substantially over time (see eFig. 71-1 ). However, if significant fibrosis is present, the process may progress insidiously despite the administration of corticosteroids. Histologic, end-stage bleomycin pneumonitis may appear similar to the usual interstitial pneumonia pattern.
Mitomycin C
Mitomycin C is another antibiotic chemotherapeutic agent associated with pulmonary toxicity, which shares features similar to those induced by bleomycin. It has been employed in the management of bladder tumors, lung cancer, anal cancer, metastatic breast carcinoma, metastatic liver tumors, and esophageal malignancies. One series estimated the incidence of mitomycin-induced pneumonitis to be approximately 8%, with two additional series suggesting the incidence ranged from 12% to as high as 39%. Similar to bleomycin-induced lung toxicity, the cumulative dose appears associated with the incidence of pulmonary manifestations in a linear fashion, with pulmonary fibrosis unlikely at doses less than 30 mg/m 2 . Again, high fraction of inspired oxygen and radiotherapy may exacerbate this phenomenon. Concomitant administration of other chemotherapeutic agents such as bleomycin, doxorubicin, or cyclophosphamide may enhance pulmonary toxicity.
The symptomatology, imaging abnormalities, and histologic findings of mitomycin-induced pneumonitis are similar to those of other alkylating drug toxicities. However, it has been suggested that the D l CO may not fall before the onset of clinical symptoms, making it an unreliable predictor of overt lung disease. In addition, a favorable response to corticosteroid therapy has also been quite dramatic in many of these patients, possibly greater than in other forms of chemotherapy-associated lung injury.
In addition to mitomycin-induced pneumonitis, there are reports of an unusual reaction to mitomycin C consisting of microangiopathic hemolytic anemia with associated noncardiogenic pulmonary edema and renal failure, in particular when associated with 5-fluorouracil. This may be associated with pulmonary hypertension. Most of these patients developed side effects between 6 and 12 months after beginning mitomycin C chemotherapy. Up to one half of these patients evolve into the acute respiratory distress syndrome (ARDS), with mortality as high as 95% in some series. The mortality in patients with mitomycin C–associated hemolytic uremic syndrome who do not develop acute respiratory distress syndrome is still in the range of 50%. In some instances, this unusual drug reaction appears to be precipitated by blood transfusions. Microangiopathic changes are present in the lungs and kidneys with intimal hyperplasia of the arterioles, along with prominent nuclear atypia of the capillary cells and capillary fibrin thrombi. Treatment is essentially supportive, with initiation of plasma exchange with or without dialysis and corticosteroids when deemed appropriate.
Pulmonary veno-occlusive disease (PVOD) has also been rarely reported in patients receiving mitomycin C. In one case report, PVOD was confirmed on autopsy.
Other Antibiotic Chemotherapeutic Agents
A variety of other antibiotic chemotherapeutic agents have been associated with respiratory complications, although the nature of combined chemotherapeutic regimens makes it difficult to attribute the responsibility to one drug instead of another. Doxorubicin is an anthracycline agent notorious for causing cumulative cardiotoxicity with possible cardiogenic pulmonary edema. Rare cases of interstitial pneumonias have also been described, usually in combination with other drugs, typically with mitomycin C. Organizing pneumonia has rarely been reported. Infusion reactions with dyspnea may be observed in 5% to 10% of patients treated with pegylated liposomal doxorubicin. Epirubicin is a similar compound with fewer side effects. Pulmonary complications are rare but may be seen in conjunction with other chemotherapeutic agents. Mitoxantrone is an anthracenedione inhibitor of topoisomerase II used in the treatment of multiple sclerosis, acute lymphoid leukemia, acute myeloid leukemia, breast cancer, liver cancer, non-Hodgkin lymphoma, and prostate cancer. Rare cases of subacute interstitial pneumonias have been described. Actinomycin D has also been associated with reactivation of prior radiation pneumonitis.
Alkylating Agents
Busulfan
Busulfan has been used for the management of chronic myeloproliferative disorders. It was discovered in 1961 and found to be responsible for significant pulmonary toxicity shortly after. The average duration from the initiation of therapy to the onset of respiratory symptoms is roughly 3.5 years, ranging between 8 months and as late as 10 years. However, busulfan pulmonary toxicity can develop as soon as 6 weeks following initiation of therapy. The incidence of busulfan pulmonary toxicity is estimated to be 6%, with a reported range of 2.5% to 43%. The mortality rate is extremely high, in the range of 80%. No effective therapy has been identified, and discontinuation of the drug with or without initiation of corticosteroid therapy, although recommended, is of unclear value. No obvious aggravating factors have been identified, except perhaps the concomitant administration of other chemotherapeutic agents or radiotherapy. Age and cumulative dose do not seem to play any important role.
Dyspnea, fever, and cough begin in a more insidious fashion with busulfan than with many other chemotherapy lung toxicities. Such symptoms have even been reported to begin months after busulfan therapy has been discontinued. The chest radiograph in busulfan toxicity reveals a combined alveolar and interstitial process to a greater degree than in other chemotherapy reactions. This is likely due to a high degree of desquamation of injured epithelial cells into the alveolar spaces. This alveolar debris may be so extensive as to suggest pulmonary alveolar proteinosis in some patients receiving busulfan. This form of alveolar proteinosis is more refractory to therapeutic lavage than is idiopathic pulmonary alveolar proteinosis. Busulfan-induced pulmonary toxicity is characterized by the presence of acute lung injury with associated atypical type II pneumocytes with markedly enlarged pleomorphic nuclei and prominent nucleoli ( eFig. 71-3 ).
Cyclophosphamide
Cyclophosphamide is widely included in combination chemotherapy for hematologic malignancies and solid tumors. It is also used in the treatment of granulomatous polyangiitis. The incidence of pulmonary toxicity is estimated at around 1%, although accumulating evidence suggests that it may be much more common. A case series from a large tertiary referral center only identified six patients older than 20 in whom cyclophosphamide was the only factor contributing toward pulmonary injury. Clinical features of cyclophosphamide-associated pulmonary toxicity include fever, dyspnea, cough, gas-exchange abnormalities, parenchymal opacities, and pleural thickening. Two patterns of cyclophosphamide-induced lung toxicity have been described. First, there can be an early-onset pneumonitis within the first 1 to 6 months after institution of therapy. This form generally responds to withdrawal of cyclophosphamide. In contrast, there may also be a late-onset pneumonitis that may develop after months or even years of therapy and result in progressive lung fibrosis and bilateral pleural thickening. This late-onset variety unfortunately has minimal response to withdrawal of cyclophosphamide or to corticosteroid therapy. The dose of cyclophosphamide and development of lung disease are not clearly related. Supplemental oxygen and radiotherapy may increase the likelihood of lung manifestations. Likewise, concomitant administration of other agents such as bleomycin, and perhaps carmustine, in preparation before bone marrow transplantation seems to accentuate the phenomenon. There have also been rare reports of rechallenge with cyclophosphamide without subsequent recurrence of the pulmonary toxicity. For obvious reasons, this is generally not recommended.
Chlorambucil
This agent has been prescribed primarily for chronic lymphocytic disorders. The clinical presentation, chest radiographic abnormalities, and histologic features of chlorambucil-associated pneumonitis are remarkably similar to those described in other alkylating agent–induced pulmonary toxicities. Cumulative doses in excess of 2 g seem to increase the risk significantly. The presentation is usually insidious, happening 6 months to a year or more after the start of therapy. Surveillance of lung function, particularly D l CO , may be of benefit in anticipating which patients will deteriorate and require discontinuation of the agent. Few data are available on the efficacy of corticosteroid therapy in chlorambucil-related lung toxicity.
Melphalan
Melphalan has been enlisted in the treatment of multiple myeloma. There have been relatively few well-documented cases of pulmonary toxicity associated with melphalan. The course of melphalan-associated pulmonary injury varies from acute to more subacute in tempo. Patients present with insidious to abrupt onset of dyspnea, cough, and frequently fever. There are no particular clues for predicting which patients will develop side effects. The incidence of pulmonary side effects from melphalan must be generally low, in view of the fact that this agent has been widely employed in the long-term management of myeloma.
Ifosfamide
Ifosfamide is structurally related to cyclophosphamide and has been used in the treatment of a variety of solid tumors, including lung, testicular, and breast cancer. Case reports of subacute interstitial pneumonias can be found in the literature, although the responsibility of ifosfamide remains unclear, as it was used in combination with other chemotherapeutic agents such as docetaxel. One case of fatal acute pneumonitis primarily due to ifosfamide has been reported. A case of methemoglobinemia has also been described, presumably secondary to the interaction between 4-thioifosfamide, a metabolite of ifosfamide, and glutathione and resultant oxidative stress.
Other Alkylating Agents
Procarbazine is primarily used in the treatment of Hodgkin lymphoma and glioblastoma multiforme. Rare cases of interstitial pneumonias have been reported, sometimes characterized by significant eosinophilia suggesting a hypersensitivity reaction. Progression to widespread and irreversible fibrosis seems rare.
Oxaliplatin has been associated with laryngeal dysesthesia and was thought to be responsible for the development of diffuse alveolar damage, often in association with 5-fluorouracil. More typically, there can be severe anaphylactic reactions during infusion of the drug in about 1.3% of the cases. Eosinophilic pneumonia has also been rarely reported.
Temozolomide is a second-generation alkylating agent now considered standard of care as an adjuvant therapy for glioblastoma in association with radiotherapy. It is also used in the treatment of metastatic melanoma. Few respiratory side effects have been described, mainly pharyngitis, sinusitis, cough, upper respiratory tract infection, and dyspnea. Pneumonitis was found in up to 4.8% of patients in Phase II trials. One case of organizing pneumonia that resolved after discontinuation of treatment was described.
Chlorozotocin, an alkylating agent used in the treatment of neuroendocrine tumors, has been associated with several cases of mild pneumonitis. All cases resolved with discontinuation of the drug and administration of corticosteroids.
Antimetabolites
Methotrexate
Methotrexate is present in many combination regimens for malignancies and is also used extensively for nonmalignant conditions, including psoriasis and rheumatoid arthritis. It interferes with the metabolism of folic acid, hence specifically targeting replicating cells and leading to a variety of well-described adverse effects, including bone marrow suppression, mucositis, alopecia, and gastrointestinal manifestations. Pulmonary toxicity is thought to develop in about 10% of all patients treated but is fortunately rarely fatal. Dyspnea, nonproductive cough, and fever usually commence a few days to several weeks after initiation of therapy. However, in rare cases, symptoms may be observed a few months or years after onset of therapy.
Methotrexate-associated pneumonitis ( eFig. 71-4 ) is almost always reversible with or without the addition of corticosteroids. Eosinophilia is seen in at least half of the cases, and the disease is therefore believed to represent a hypersensitivity reaction. The intriguing feature of this reaction is that the drug may be reinstituted following resolution of methotrexate pneumonitis without necessarily triggering a subsequent recurrence of symptoms or findings. In about one third of the patients, weakly formed granulomas are identified in lung biopsy, which is unusual in other forms of chemotherapy-associated lung disease ( eFig. 71-5 ). Hilar lymphadenopathy is occasionally present, and this might mimic the manifestations of sarcoidosis. There is no cellular atypia, such as is seen in many other cytotoxic drug toxicities.
The chest radiograph tends to reveal a homogeneous opacity throughout all lung fields. Hilar adenopathy or pleural effusion is seen in at least 10% to 15% of patients with methotrexate lung toxicity. In distinct contrast to most of the other chemotherapy-induced pulmonary toxicities, prospective investigations of patients receiving methotrexate have not demonstrated a diminished D l CO that might predate subclinical toxicity. In addition, pulmonary toxicity in response to methotrexate does not appear to be dose related. There have been a few reports of fatal reactions either from intrathecal methotrexate or from oral ingestion after previous intrathecal injections. Two other important manifestations associated with methotrexate should be mentioned. Opportunistic infections related to T-cell deficiency need to be excluded, in particular Pneumocystis pneumonia, which has been reported in a number of patients receiving methotrexate, either alone or in combination with corticosteroids. Peculiar Epstein-Barr virus–related lymphomas that typically resolve after discontinuation of treatment have also been reported and may be directly related to an alteration in immune surveillance induced by methotrexate (as seen in posttransplantation lymphoproliferative disorders). The clinical presentation, chest radiography, and other clinical features can be quite similar to methotrexate lung.
Azathioprine and 6-Mercaptopurine
More than two dozen case reports of azathioprine-associated pneumonitis have been reported. However, the net overall incidence must be low, considering the widespread use of this agent for neoplastic and non-neoplastic conditions. Nevertheless, the possibility of an azathioprine pneumonitis must be considered in any individual receiving this agent. Azathioprine is metabolized to 6-mercaptopurine, and there have been a handful of reports detailing cytotoxic interstitial pneumonitis in association with this metabolite. However, most of these patients have also received other agents that potentially could be implicated in the lung injury described.
Cytosine Arabinoside
Cytosine arabinoside (ara-C) is a cytotoxic agent used to induce remission in acute leukemia and other hematologic malignancies before bone marrow transplantation. Intensive ara-C treatment regimens have been associated with rapidly fatal noncardiac pulmonary edema ( Fig. 71-3 ). Histologic examination of lung tissue during ara-C pulmonary toxicity reveals substantial accumulation of intra-alveolar proteinaceous material without the cellular atypia and mononuclear infiltration described with other cytotoxic drugs. In two large series, 13% to 28% of the patients with toxicity developed respiratory distress during the administration of the drug, and nearly one half developed symptoms within a month of completing drug administration. The mechanism underlying this reaction is unknown, and the associated mortality is high. Treatment for ara-C pulmonary toxicity is largely supportive, with mechanical ventilation, careful management of fluid status, and surveillance for superimposed infectious complications.
Gemcitabine
Gemcitabine is a pyrimidine analogue, with structure and activities similar to ara-C. It is highly active against non–small cell lung cancer, as well as breast, pancreatic, and ovarian cancers. It is usually well tolerated, with the most prevalent toxicity being bone marrow suppression, as well as nausea, rash, transaminase elevation, and edema in some cases. The incidence has probably been underestimated. Dyspnea has been reported in 10% of treated patients, with severe dyspnea reported in up to 5%. Noncardiogenic pulmonary edema is thought to develop in 0.1% to 7% of all patients treated. There are three major patterns of respiratory involvement in gemcitabine-related pulmonary toxicity. The first pattern is a nonspecific, self-limiting dyspnea reported within hours to days of treatment. A second, relatively uncommon, pattern is that of an acute hypersensitivity reaction with bronchospasm. A third pattern of severe respiratory involvement is occasionally seen. This is a severe idiosyncratic reaction with profound dyspnea and pulmonary opacities that may progress to life-threatening respiratory insufficiency within hours of infusion ( Fig. 71-4 ). Most cases of gemcitabine-related pulmonary toxicity resolve with discontinuation of this drug. In cases of severe symptoms, discontinuation of the agent along with institution of corticosteroids, careful fluid management, and diuretic therapy may be warranted. Cases of diffuse alveolar hemorrhage, pulmonary veno-occlusive diseases, and thrombotic microangiopathy have also been described.
Fludarabine
Fludarabine, another nucleoside analogue, is widely employed in the management of chronic lymphoproliferative disorders. The incidence of pulmonary toxicity related to fludarabine has been estimated to be approximately 8.6% in a series of 105 patients. Affected individuals experience dyspnea as early as 3 days after the first round of chemotherapy, though later onset of pulmonary symptoms has also been reported. The chest radiograph reveals either interstitial or mixed alveolar-interstitial opacities. Nodular opacities have also been described. As is often the case with chemotherapeutic agents, particular attention should be given to the possibility of opportunistic infections. Most patients respond to discontinuation of the drug and receive symptomatic and objective benefits from additional corticosteroid therapy.
Piritrexim
Piritrexim is an oral inhibitor of the dihydrofolate reductase used in the treatment of parasitic infections, psoriasis, and transitional cell carcinoma. It is closely related to methotrexate, and pulmonary toxicity has been observed in up to 14% of patients.
Nitrosoureas
Nitrosourea compounds have a role in the treatment of gliomas and other central nervous system tumors, as well as in conditioning protocols preceding autologous bone marrow stem cell transplantation. Pulmonary toxicity related to nitrosoureas is well recognized and represents one of the most common side effects of these agents. In particular, bischlorethyl nitrosourea (BCNU, carmustine) has been described to induce both acute-onset pulmonary injury (see eFig. 91-13 ) and delayed-onset pulmonary fibrosis, with a predilection for the upper lobes. The incidence of pulmonary toxicity associated with the administration of BCNU varies from 1.5% to 20% and is dose related, with up to a 50% incidence of lung disease in those receiving a total dose of greater than 1500 mg/m 2 . However, there have also been reports of pulmonary effects with much lower doses. The duration of therapy before the onset of pulmonary toxicity for the acute variant of nitrosourea lung injury has generally ranged from 6 months to 3 years. There appears to be a synergistic effect with cyclophosphamide, radiation therapy, and possibly other chemotherapeutic agents. The outcome may be unpredictable and sometimes fatal. There have been fewer case reports of pulmonary toxicity with methyl-chloroethyl cyclohexyl nitrosourea (methyl-CCNU) and chloroethyl cyclohexyl nitrosourea (CCNU). Apparently, fever is less commonly associated with this form of pulmonary toxicity than with many other chemotherapeutic drugs. Therapy usually consists of withholding the offending agent and institution of corticosteroids, which has variable and often only transient beneficial effects.
A long-term complication of BCNU toxicity is upper lobe fibrosis that may appear many years after the completion of chemotherapy. O’Driscoll and colleagues followed 17 patients for up to 17 years, and 12 of the 17 (71%) developed delayed upper lobe fibrosis. The fibrosis is insidious in onset and, once discovered, appears to be intractably progressive. Corticosteroid therapy has not proven to be effective in delayed BCNU upper lobe fibrosis. Another unusual reported complication that is almost exclusively associated with nitrosourea compounds is pneumothorax. This may be related to the upper lobe fibrobullous changes present in patients with BCNU lung toxicity.
Cases of pulmonary fibrosis have also been reported with other nitrosourea agents, including lomustine (CCNU), semustine (methyl-CCNU), fotemustine (CENU), and chlorozotocin (DCNU). Pneumothoraces have rarely been described with these agents.
Podophyllotoxins
Etoposide and Teniposide
Etoposide (VP-16), a topoisomerase II inhibitor, has been widely used in combination chemotherapy for non–small cell and small cell lung carcinoma. Despite its extensive use, only a few cases of etoposide-associated pulmonary toxicity have been reported. Toxicity may become apparent shortly after the first round of chemotherapy, although most of the associated cases present after prolonged treatment. Tissue examination reveals features of alveolar edema, diffuse alveolar damage, and atypical type II pneumocytes. Therapy consists of withdrawal of the agent and administration of corticosteroids, which provide variable improvement. In addition, etoposide may increase the intracellular levels of methotrexate and thus, the combination of methotrexate and etoposide may synergistically increase the likelihood of adverse reactions.
Teniposide, another podophyllotoxin agent, is also associated with hypersensitivity reactions in 3.6% to 6.5% of the cases. This toxicity may present with dyspnea, bronchospasm, and hypertension.
Paclitaxel
Paclitaxel is a highly potent chemotherapeutic agent used in the treatment of lung, breast, and ovarian carcinomas. Well-documented cases of pulmonary toxicity induced by paclitaxel can be found in the literature, but the frequency is unclear. Patients may complain of respiratory symptoms including cough, dyspnea, wheezing, and chest tightness within minutes of administration of the drug, suggesting a type I hypersensitivity reaction. Immunoglobulin E antibodies against paclitaxel itself or perhaps its vehicle, Cremophor EL, are thought to be responsible. This reaction may be seen in up to 30% of patients, and premedication with corticosteroids is sometimes considered. Reticular and nodular opacities have been reported on chest radiographic studies. Cases of transient pulmonary opacities and suspected interstitial pneumonitis have also been described ( eFig. 71-6 ). The true incidence of lung toxicity directly related to paclitaxel is not well understood. A prospective study of lung function in 33 patients receiving paclitaxel with carboplatin (an agent with little lung toxicity) in the setting of nonthoracic malignancy revealed an isolated decrease in D l CO without other clinical or radiographic evidence of pulmonary toxicity. In other studies, conducted on patients with lung carcinoma, significant early and late pulmonary toxicity has been noted in 10% and 68% of patients, respectively. Attributing the toxicity directly to paclitaxel is confounded by the underlying thoracic neoplasm, as well as other cytotoxic agents used in these patients. Nonetheless, clinicians should be aware of the potential of paclitaxel impairing pulmonary function.
Docetaxel
Docetaxel (Taxotere) is another taxane compound that has activity in the treatment of breast and non–small cell lung cancer. Occasional pulmonary toxicity based on a hypersensitivity reaction has been observed. These patients have responded rapidly to corticosteroid therapy. A small case series has suggested that the combination of docetaxel and gemcitabine has a particular propensity to induce severe pulmonary toxicity. Some patients may develop capillary leak syndrome with peripheral edema, noncardiogenic pulmonary edema, and/or pleural effusions. The severity of fluid retention can be reduced by prophylactic treatment with corticosteroids.
Vinblastine
Vinblastine, a vinca plant alkaloid, is one of the oldest chemotherapeutic agents still in use. Vinblastine continues to be included in a wide variety of chemotherapeutic regimens for hematologic and solid malignancies. Traditionally, vinblastine was thought to have little if any pulmonary toxicity. However, reports have associated vinblastine with pulmonary complications when it is combined with other agents, particularly mitomycin C. This combination has been complicated by bronchospasm, interstitial pneumonitis, and a noncardiac pulmonary edema.
All- Trans Retinoic Acid
All-trans retinoic acid (ATRA) has been employed in acute promyelocytic leukemia, in which it promotes differentiation of myeloid precursors and stimulates the maturation of leukemic cells, thereby promoting remission. It has also been reported to reduce disseminated intravascular coagulation and hemorrhagic complications during promyelocytic leukemia. The main complication limiting its use is the development of the differentiation syndrome (previously called retinoic acid syndrome) in up to 25% of patients treated. This syndrome consists of diffuse edema, pleuropericardial effusions, and noncardiogenic pulmonary edema that may evolve into a generalized capillary leak syndrome ( eFigs. 71-7 and 71-8 ). Hypotension and acute renal failure are commonly present. Toxicity may manifest suddenly between days 2 and 21 of treatment. Its pathogenesis remains elusive, but it is thought to result from a massive release of cytokines from newly mature myeloid cells and adhesion of granulocytes to the pulmonary endothelium. Indeed, high leukocyte counts have been associated with an increased incidence of the syndrome in some, but not all, studies. In addition, multiple hemorrhagic complications have also been described. In one study, 9 of 35 patients with promyelocytic leukemia receiving ATRA developed respiratory distress. Intravenous corticosteroid therapy seemed to be of benefit to these patients. On the basis of these observations, an additional study has suggested that the incidence of ATRA-associated pulmonary complications may be reduced to roughly 10% through the use of preventative treatment with oral corticosteroids.
The mortality associated with ATRA-induced pulmonary toxicity is estimated at around 9%. Tissue examinations of lungs affected by ATRA have revealed interstitial infiltration with maturing myeloid cells. However, the overall spectrum of the ATRA-associated pulmonary syndrome is continuing to evolve and includes the presence of myeloid cells and blasts in BAL fluid, nodular pulmonary opacities, pulmonary leukostasis, noncardiogenic pulmonary edema, ARDS, Sweet syndrome, and diffuse alveolar hemorrhage.
Irinotecan and Topotecan
Irinotecan, a semisynthetic camptothecin, has been employed for advanced colorectal cancer either alone or in combination with 5-fluorouracil, as well as in some lung cancer trials. Early studies of irinotecan in Japan documented a 1.8% incidence of pneumonitis. In those studies, clinical features included dyspnea, fever, and reticulonodular pulmonary opacities. Empirical corticosteroids were recommended, but some patients progressed to fatal respiratory failure. In subsequent U.S. trials, cough and dyspnea were described in roughly 20% of treated patients. However, many of these patients had intrathoracic malignancies. The reported incidence of serious pulmonary toxicity related to irinotecan was much lower in these subsequent trials (≈0.4%). Radiotherapy and preexisting lung disease may increase the risk. Nonetheless, cases of serious irinotecan-associated interstitial pneumonitis have been reported in the United States. Patients with preexisting pulmonary disease may be at enhanced risk.
Topotecan is a similar agent and has rarely been reported to induce pulmonary toxicity, including cases of diffuse alveolar damage and constrictive bronchiolitis.
Targeted Therapy
Monoclonal Antibodies
As our understanding of the pathogenesis of malignant processes continues to increase, the identification of specific target tumoral antigens has led to the development of specific immunotherapeutic tools, including monoclonal antibodies. Several new molecules have emerged as potentially beneficial adjunct agents in a variety of neoplastic processes.
Bevacizumab.
Bevacizumab (Avastin) is a monoclonal antibody targeting the vascular endothelial growth factor, and designed to inhibit tumoral neoangiogenesis. It has been used in conjunction with conventional chemotherapeutic agents in the treatment of metastatic colon, renal cell cancer, breast cancer, sarcoma, ovarian cancer, glioblastoma, and nonsquamous non–small cell lung cancers. It is associated with hemorrhagic complications including fatal pulmonary hemorrhage thought to result from extensive tumor necrosis. These complications have been predominantly seen in patients with squamous cell lung cancer. Although it may seem counterintuitive, bevacizumab is thought to increase the incidence of thromboembolic disease by twofold. This may be secondary to vascular injury with secondary exposure of the underlying endothelium with secondary activation of the coagulation cascade. Cases of thrombotic microangiopathy with hypertension and acute renal failure have also been described. Cases of congestive heart failure have also been described, mostly in association with anthracycline agents, raising questions about this reported association. Tracheoesophageal and bronchoesophageal fistulas have been described in patients treated with bevacizumab for lung cancer.
Cetuximab and Panitumumab.
Cetuximab and panitumumab are two monoclonal antibodies directed against the epidermal growth factor receptor (EGFR) that are increasingly used in treatment of a number of neoplasms. Both have been associated with rare pulmonary toxicity. Interstitial lung disease has been reported in 0.4% of patients with cetuximab, and there may be infusion reactions with bronchospasm and hoarseness in 23% of the cases. With panitumumab, there may be similar infusion reactions, which may be severe in 1% of the cases. Panitumumab has now been associated with an increasing number of interstitial lung disease and pulmonary fibrosis cases. The interstitial lung disease has been found to be fatal in some cases, so if toxicity becomes apparent, panitumumab should be stopped and steroids should be considered.
Trastuzumab and Ado-Trastuzumab Emtansine.
Trastuzumab selectively binds the human epidermal growth factor receptor-2 (HER-2) protein and is an adjuvant treatment of metastatic HER-2–positive breast cancer. As seen with other monoclonal antibodies, infusion reactions may present in 15% of the cases and are potentially associated with angioedema, fever, and bronchospasm. Trastuzumab reactions may also present as an acute or subacute interstitial pneumonia in approximately 0.5% of the cases, with a mortality rate estimated at 0.1%. An increasing number of case reports suggest that interstitial pneumonia is likely a rare but real toxicity of trastuzumab. Ado-trastuzumab is an antibody-drug conjugate that contains trastuzumab and a cytotoxic microtubule inhibitor. It is also used in breast cancer and has been associated with acute pneumonitis. The incidence is low at 0.8% to 1.2% but may be life-threatening, so if pneumonitis develops, ado-trastuzumab should be discontinued.
Rituximab.
Rituximab is an anti-CD20 chimeric monoclonal antibody approved in 1997 for the treatment of non-Hodgkin lymphoma. Its ever-increasing indications have led to an exponential increase in its use in a variety of diverse conditions from autoimmune inflammatory diseases to posttransplantation lymphoproliferative disorders. The most common side effect of rituximab is an infusion reaction in more than 50% of patients. Symptoms include fever, chills, dyspnea, hypotension, rhinitis, urticaria, pruritus, and a sensation of throat and tongue swelling. Slowing or stopping the rituximab infusion may help resolve the symptoms. Corticosteroids are occasionally required. Other pulmonary complications of rituximab appear fairly rare overall. A review of the literature in 2007 only identified 16 cases of interstitial lung disease assumed to be secondary to rituximab use. Specific patterns of lung injury have also been described in pathologic specimens, including diffuse alveolar hemorrhage and desquamative interstitial pneumonia, but the experience is often limited to isolated case reports.
Tyrosine Kinase Inhibitors
Gefitinib.
Gefitinib (Iressa) is a selective EGFR tyrosine kinase inhibitor used in patients with advanced non–small cell lung cancer and EGFR-activating mutations. Acute interstitial pneumonia has been associated with this drug, and the overall incidence of gefitinib-associated interstitial lung disease may be in the range of 1%, with a mortality rate approaching 30%. The most common presentation is acute dyspnea with or without cough or fever. The median onset of symptoms was 24 to 31 days in Japanese and 42 days in American patients. Diffuse ground-glass opacities and multifocal airspace consolidation have been reported on CT scan. Tissue examination demonstrates diffuse alveolar damage, interstitial inflammation with or without fibrosis, and organizing pneumonia. Although some patients respond to withdrawal of the agent and institution of corticosteroid therapy, others progress to fulminant respiratory insufficiency. Hence the clinician needs to remain mindful of this pulmonary complication of gefitinib therapy and discontinue the agent if symptoms and radiographic abnormalities develop. The benefit of corticosteroids is unclear.
Erlotinib.
Erlotinib (Tarceva), another EGFR antagonist, is used widely in the United States for the treatment of advanced lung adenocarcinomas with EGFR mutations. Erlotinib has also been rarely associated with pulmonary toxicity including fatalities. Patients who have undergone lung biopsy have shown organizing pneumonia or diffuse alveolar damage. The presentation is similar to most drug-induced lung injury with dyspnea, cough, and low-grade fever. The median time to toxicity is 47 days. Treatment is supportive with removal of the drug. The benefit of corticosteroids is unclear.
Imatinib.
Imatinib (Gleevec) is an inhibitor of the Bcr-Abl, KIT, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases. It is used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. Fluid retention causing peripheral, periorbital, and pulmonary edema is a common complication. There have been cases reported of pulmonary infiltration with eosinophilia or acute interstitial pneumonia. Symptoms of dyspnea, cough, and low-grade fever develop at a median time of 49 days. Radiographic studies have shown ground-glass opacities, consolidation, or nodular opacities. BAL findings demonstrate lymphocytes, foamy macrophages, and, in some cases, eosinophilia. Peripheral eosinophilia has also been demonstrated. Lung biopsies have demonstrated interstitial inflammation and fibrosis, alveolitis, and pulmonary alveolar proteinosis. Treatment is removal of the drug and, in many cases, corticosteroids. Rechallenge of the drug does not always cause recurrence of the lung injury, so physicians must carefully consider alternative agents and the risk and benefit of rechallenge.
Dasatinib.
Dasatinib is a Bcr-Abl tyrosine kinase inhibitor that is used to treat Philadelphia chromosome–positive chronic myeloid leukemia. Dasatinib is associated with pleural effusions, pulmonary hypertension, and pulmonary parenchymal abnormalities. Pleural effusions have been reported in 10% to 35% of patients treated. Effusions are mostly lymphocytic and exudative. Concomitant lung disease and higher initial daily dose were risk factors for development of pleural effusions. Treatment of the pleural effusions is unclear but has included glucocorticoids, diuretics, thoracentesis, and discontinuation of dasatinib. Pulmonary arterial hypertension is a rare complication of dasatinib use with symptom onset after 8 to 48 months of therapy. Presenting symptoms included tachypnea, exertional dyspnea, fatigue, and peripheral edema. Dasatinib therapy should be discontinued if pulmonary hypertension develops, and there should not be a rechallenge of the drug. Pneumonitis is another rare complication of dasatinib. In one study of patients treated with dasatinib, 40 (23%) patients developed a lung abnormalitiy. The lung changes resolved or partially resolved in all 9 patients with parenchymal abnormalities. Discontinuation of dasatinib resulted in resolution in 5 patients, and glucocorticoids were used in 1 patient with complete resolution. Rechallenge with dasatinib can be considered in patients with parenchymal abnormalities.
Bosutinib.
Bosutinib is another tyrosine kinase inhibitor that targets Bcr-Abl and is used to treat Philadelphia chromosome–positive CML. Like dasatinib, pleural effusion is the most common pulmonary toxicity.
Sunitinib and Sorafenib.
Sunitinib and sorafenib are small molecule tyrosine kinase inhibitors that block the intracellular domain of the vascular endothelial growth factor (VEGF) receptor. Sunitinib is used to inhibit angiogenesis in the treatment of gastrointestinal stromal tumors and renal cell cancer. Sunitinib has been reported to cause dyspnea and cough. Pulmonary embolism has also rarely been reported. Sorafenib is used to inhibit angiogenesis in renal cell carcinoma and unresectable hepatocellular carcinoma. Pulmonary toxicity has been reported during sorafenib use with diffuse pulmonary opacities, dyspnea, cough, and fever. Although a rare toxicity, it was fatal in some patients, so the drug should be stopped immediately if pulmonary toxicity is suspected.
Immunomodulatory Agents
Interferons.
Interferons have been used in a wide variety of malignant, infectious, and inflammatory disorders. Interferon-alfa and interferon-beta have been employed in the treatment of hairy cell leukemia, myeloma, T-cell lymphoma, chronic myelogenous leukemia, malignant pleural effusions, melanoma, renal cell carcinoma, and Kaposi sarcoma. Interferon-gamma has been included in investigative trials for mesothelioma, non–small cell lung carcinoma, and idiopathic pulmonary fibrosis.
Administration of interferons has been associated with a variety of pulmonary reactions. For instance, interferon-alfa has been linked to severe exacerbation of bronchospasm in patients with preexisting asthma. In addition, a granulomatous reaction indistinguishable from sarcoidosis ( eFig. 71-9 ) has been described in relation to interferon therapy. These toxicities usually respond to either reduction or withdrawal of the interferon treatment with or without the addition of corticosteroids. Noncaseating granulomas have been documented in the lung, lymph nodes, liver, and skin of affected patients.
Interferon-associated interstitial lung disease has also been reported. Dyspnea and cough are observed and bilateral opacities are present on chest radiography. A CD8-predominant lymphocytic response is found in the BAL fluid, and a cellular interstitial pattern is present on histology. In some cases, interferon therapy has also been associated with an organizing pneumonia pattern. Most affected patients respond to discontinuation of the interferon and administration of corticosteroids. Recently, interferon-gamma has been used in idiopathic pulmonary fibrosis. A series has been reported in which four patients with advanced idiopathic pulmonary fibrosis developed acute hypoxemic respiratory failure during interferon-gamma treatment. This was not responsive to corticosteroids and was fatal in three cases. Interferon-gamma is also associated with a high incidence of severe radiation pneumonitis when it is used in multimodality therapy for non–small cell lung carcinoma.
Rapamycin Analogs.
Sirolimus was initially developed as an antifungal agent isolated from Streptomyces hygroscopicus. It is a macrolide antibiotic inhibitor of the mammalian target of rapamycin (mTOR) with antiproliferative and immunosuppressive properties essentially used to prevent rejection in solid-organ transplantation and as a coating agent in drug-eluting stents. It is currently under investigation for the treatment of lymphangioleiomyomatosis. Several patterns of drug toxicity have been described with sirolimus, including the subacute onset of interstitial pneumonitis ( eFig. 71-10 ) (which usually resolves after discontinuation of therapy), an organizing pneumonia injury pattern, and diffuse alveolar hemorrhage. Rare cases of alveolar proteinosis and granulomatosis have also been reported. Typically, these pulmonary complications are reversible after discontinuation of therapy, but occasionally they represent a difficult diagnostic challenge in an immunosuppressed population prone to a variety of opportunistic infections.
Everolimus is a similar inhibitor of the mTOR pathway that has been used as an immunosuppressive agent in solid-organ transplantation and in treatment of renal cell cancer and neuroendocrine tumors. Several types of pulmonary toxicity have been described, including organizing pneumonia and the subacute onset of interstitial pneumonitis. The interstitial pneumonitis has been reported in varying severity. In one report of interstitial lung disease while receiving everolimus, four patients underwent BAL, which demonstrated lymphocytosis; two patients also had increased eosinophil counts. Transbronchial biopsies from three of the patients demonstrated interstitial lymphocytic inflammation and septal thickening. Treatment may involve observation in mild cases but can require discontinuation of the drug and initiation of glucocorticoids in severe cases. The use of glucocorticoids is of unclear benefit.
Temsirolimus is active against a variety of solid tumors, including endometrial cell carcinoma, breast cancer, and neuroendocrine tumors. It is FDA-approved for the treatment of advanced renal cell carcinoma. In a retrospective review of 22 patients treated with temsirolimus, eight patients (36%) developed pulmonary complications. Half of these patients were symptomatic. On radiographic studies, two different patterns of involvement were identified consisting of ground-glass opacities or alveolar consolidation. Pneumonitis has recurred in some cases with rechallenge. Discontinuation of the drug is advised.
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