ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment

Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment
Literature review current through: Jan 2024.
This topic last updated: Sep 12, 2023.

INTRODUCTION — Adverse drug reactions (ADRs) due to antineoplastic agents are a common form of iatrogenic injury, and the lungs are a frequent target [1-4]. While some antineoplastic agent-induced ADRs are potentially preventable (particularly those that are related to cumulative dosing), many are idiosyncratic and unpredictable.

This topic review will provide an overview of the clinical presentation, pathogenesis, diagnosis, and treatment of pulmonary toxicity associated with antineoplastic agents. Specific patterns of lung injury seen with individual agents (table 1) are reviewed separately. (See "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents" and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents" and "Bleomycin-induced lung injury" and "Busulfan-induced pulmonary injury" and "Chlorambucil-induced pulmonary injury" and "Cyclophosphamide pulmonary toxicity" and "Methotrexate-induced lung injury" and "Mitomycin pulmonary toxicity" and "Nitrosourea-induced pulmonary injury" and "Taxane-induced pulmonary toxicity".)

EPIDEMIOLOGY — Some estimate that 10 to 20 percent of all patients treated with an antineoplastic agent have some form of lung toxicity, although the incidence varies depending on the specific agent, dose, and other factors [5-9]. A population-based study found an incidence of respiratory failure attributable to drug-induced lung injury of 6.6 per 100,000 patient-years [9]; 53 percent were associated with chemotherapeutic agents. The high prevalence of lung toxicity may be a result of the lungs receiving the entire blood supply, leading to greater exposure to potentially harmful antineoplastic agents compared to other organs [10]. While some evidence suggests that drug-induced acute respiratory distress syndrome may have a more favorable course than when not drug-induced [11], the prognosis of patients with antineoplastic therapy-induced lung toxicity (at least in the setting of advanced non-small cell lung cancer) is poor with a median survival of 3.5 months (95% CI, 2.3-7.2 months) [8].

PATHOGENESIS — The pathogenesis of antineoplastic agent-induced lung injury is poorly understood. Most toxic effects are thought to result from direct cytotoxicity. The following pathophysiologic mechanisms have been proposed [12-14]:

Direct injury to pneumocytes or the alveolar capillary endothelium with the subsequent release of cytokines and recruitment of inflammatory cells.

The systemic release of cytokines (eg, by gemcitabine) may result in endothelial dysfunction, capillary leak syndrome, and noncardiogenic pulmonary edema. (See "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents", section on 'Gemcitabine'.)

Cell-mediated lung injury due to activation of lymphocytes and alveolar macrophages. (See "Drug hypersensitivity: Classification and clinical features", section on 'Drug-induced hypersensitivity syndrome'.)

Oxidative injury from free oxygen radicals (eg, bleomycin-related lung injury). (See "Bleomycin-induced lung injury".)

Unintended dysregulation of the immune system and T-cell activation caused by immune-checkpoint blockade. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Pneumonitis'.)

Epidermal growth factor receptors (EGFR) are expressed on type II pneumocytes, and are involved in alveolar wall repair; agents targeting the EGFR may impair alveolar repair mechanisms. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents".)

Radiation recall pneumonitis is mediated by the presence of subclinical cumulative parenchymal radiation-induced injury that becomes apparent when another pulmonary insult (ie, cytotoxic chemotherapy) is encountered at a later date. (See "Radiation-induced lung injury".)

It is also conceivable that exposure to high fractions of inspired oxygen, common in cancer patients, could explain some of the predilection for lung toxicity; this has been best documented for patients exposed to bleomycin [15].

CLINICAL MANIFESTATIONS — The clinical presentation of antineoplastic agent-induced lung disease is variable, and several clinical syndromes have been described (table 1) [12]. The exact definition of these clinical syndromes is unclear as different criteria and terminologies are frequently used. Most clinical trials do not report the details of pulmonary toxicity, and literature reports may describe pulmonary toxicity based upon clinical or radiographic criteria (eg, acute lung injury, pneumonitis, noncardiogenic pulmonary edema, acute respiratory distress syndrome (ARDS)) or on pathologic findings (eg, diffuse alveolar damage, organizing pneumonia, neutrophilic alveolitis) (table 1).

Symptoms and signs — The clinical manifestations of most of these syndromes are nonspecific and include cough, dyspnea, low-grade fever, and hypoxemia. Chills and sputum production are rarely reported, while constitutional symptoms, such as weight loss, may be present [13]. Lung auscultation may reveal bibasilar crackles, but is often normal. Wheezing is rare, but when present, suggests a hypersensitivity mechanism with a component of bronchoconstriction. A concomitant morbilliform rash would provide evidence of hypersensitivity to a drug, such as drug-induced hypersensitivity (DIHS), also known as drug rash with eosinophilia and systemic symptoms (DRESS). (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

The timing of the clinical manifestations is variable; they may present early during the first cycle of therapy or with subsequent treatment courses. Except for rare cases of delayed fibrosis seen with nitrosoureas and bleomycin [16] or delayed pneumonitis seen with immunotherapy [14], lung toxicity typically occurs within weeks to a few months after initiation of therapy [12]. (See "Nitrosourea-induced pulmonary injury" and "Toxicities associated with immune checkpoint inhibitors", section on 'Pneumonitis'.)

As most modern antineoplastic therapy protocols consist of multiple drugs, it may be difficult to pinpoint the specific agent that is responsible for the lung toxicity. Respiratory manifestations are almost never specific enough to incriminate one agent over another.

EVALUATION

Pulmonary function tests — In patients with pneumonitis due to antineoplastic therapy, pulmonary function testing (PFT) often reveals a decrease in diffusing capacity for carbon monoxide (DLCO), which may be the first and the only PFT abnormality [17-22]. A restrictive PFT pattern (ie, reduced total lung capacity (TLC) and reduced forced vital capacity (FVC)) may be present in advanced cases, or on long-term follow-up following acute lung injury [21]. (See "Overview of pulmonary function testing in adults" and "Diffusing capacity for carbon monoxide".)

Abnormal gas transfer may also be manifest in reduced oxygen saturation at rest or on exertion.

Chemotherapy regimens that include bleomycin, gemcitabine, paclitaxel, one of the platinum drugs, cyclophosphamide, or doxorubicin are associated with significant reductions in DLCO; however, small changes do not correlate with symptoms [17,23,24]. (See "Bleomycin-induced lung injury".)

Pulmonary veno-occlusive disease (eg, due to cyclophosphamide, gemcitabine, mitomycin) is associated with gas transfer abnormalities, such as reduction in DLCO, with minimal or no abnormalities in spirometry or lung volumes. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Low diffusing capacity and poor oxygenation'.)

Imaging — Various radiographic patterns of drug-induced injury are described, including patchy, unilateral or bilateral reticular markings, ground glass opacities or consolidations [12,25,26]. These patterns may be mixed in an individual patient. Pleural effusions and focal nodular consolidations that mimic tumor involvement may also be seen (image 1).

The most common abnormalities on high resolution computed tomography (HRCT) are ground glass opacities, consolidation, interlobular septal thickening, and centrilobular nodules [26]. The pattern, distribution, and extent of HRCT abnormalities are of limited diagnostic and prognostic value [25]. (See "High resolution computed tomography of the lungs", section on 'HRCT patterns'.)

The radiographic manifestations of bleomycin-induced lung injury are variable (table 2). The classic pattern of early pulmonary fibrosis includes bibasilar subpleural reticular and ground glass opacification with volume loss and blunting of the costophrenic angles; fine nodular densities may also be present. These early findings give way to progressive consolidation and honeycombing. (See "Bleomycin-induced lung injury".)

Radiation recall pneumonitis has been described with carmustine, doxorubicin, etoposide, gefitinib, gemcitabine, paclitaxel and trastuzumab [12]. Chest imaging shows a unique pattern of pulmonary opacities in exactly the same distribution as the previous radiation therapy portal. (See "Radiation-induced lung injury".)

CT features of pulmonary veno-occlusive disease include enlarged central arteries, centrilobular ground glass opacities, septal thickening, and pleural effusion. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Computed tomography'.)

Drug-induced hilar lymphadenopathy is uncommon, except in the case of methotrexate-induced lung disease. (See "Methotrexate-induced lung injury", section on 'Imaging'.)

Cardiac evaluation — It is prudent to assess cardiac function during the initial evaluation of interstitial lung disease (ILD), as heart failure, pulmonary hypertension, and pulmonary veno-occlusive disease are in the differential diagnosis of ILD. The evaluation typically includes an electrocardiogram, serum brain natriuretic peptide or N-terminal-proBNP level, and an echocardiogram. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Cardiac evaluation'.)

Bronchoscopy and bronchoalveolar lavage — There are no specific findings for drug-induced lung toxicity on bronchoscopy or bronchoalveolar lavage (BAL). BAL fluid cell counts are usually elevated; lymphocytosis, neutrophilia, or rarely, eosinophilia may be seen [12]. Neither the pattern of cellularity, nor any other finding can specifically establish the diagnosis of drug-induced lung toxicity; the main role of bronchoscopy is to exclude infection, especially opportunistic organisms, or recurrent malignancy. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and "Epidemiology of pulmonary infections in immunocompromised patients".)

Histopathology — Virtually all histopathologic patterns of lung injury have been described in patients with pulmonary toxicity associated with antineoplastic agents, including usual interstitial pneumonia, nonspecific interstitial pneumonia, desquamative interstitial pneumonia, eosinophilic pneumonia, hypersensitivity pneumonitis, organizing pneumonia, diffuse alveolar damage, alveolar hemorrhage, and rarely, non-necrotizing granulomatosis, pulmonary veno-occlusive disease, and alveolar proteinosis [27]. (See "Idiopathic interstitial pneumonias: Classification and pathology" and "The diffuse alveolar hemorrhage syndromes" and "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

DIAGNOSIS — No specific tests establish the diagnosis of antineoplastic agent-induced pulmonary toxicity, other than rechallenge with the implicated agent after a period of discontinuation. Instead, the diagnosis is usually suspected when patients present with a compatible clinical pattern (table 1) in the setting of treatment with a drug known to be associated with lung toxicity, and alternatives diagnoses, such as infection or pulmonary involvement from the underlying malignancy, are felt to be less likely.

Routine testing — Laboratory testing (eg, complete cell counts, coagulation tests, B-type natriuretic peptide (BNP), blood cultures, sputum cultures, viral serology) is used to determine whether other disease processes are contributing to the patient's respiratory compromise.

Pulmonary function tests are more important in assessing the degree of pulmonary impairment than in making a specific diagnosis. Radiographic studies are rarely specific enough to establish the diagnosis, but are helpful as a measure of disease severity and to exclude other processes (eg, pulmonary embolism). (See 'Differential diagnosis' below.)

Bronchoscopy — The main role of bronchoscopy and bronchoalveolar lavage (BAL) is to exclude other processes such as infection, diffuse alveolar hemorrhage, and lymphangitic spread of tumor.

Lavage samples should be obtained and processed for bacterial, fungal, and mycobacterial smear, special stains, and culture. Samples can also be sent for viral culture and cytologic examination for viral inclusion bodies. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

The BAL technique for identifying pulmonary hemorrhage consists of three sequential lavages in a single site. The effluent is increasingly hemorrhagic with each successive sample. This is confirmed by cytologic studies showing hemosiderin-laden macrophages. (See "The diffuse alveolar hemorrhage syndromes", section on 'Bronchoalveolar lavage'.)

Cytologic analysis for malignant cells should also be performed. Bronchoalveolar cell dysplasia in acute lung injury and acute respiratory distress syndrome (ARDS) may mimic malignancy, so morphologic studies should be interpreted with caution and when possible combined with immunohistochemical or molecular testing to confirm the cell lineage [28].

In patients without specific contraindications, transbronchial lung biopsy may improve the likelihood of identifying lymphangitic spread of tumor or an invasive fungal infection over BAL alone. In addition, biopsy allows distinction between colonization and invasion in fungal (or viral) infection. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and "Flexible bronchoscopy in adults: Indications and contraindications", section on 'Contraindications'.)

Surgical lung biopsy — Surgical lung biopsy has a very limited role in the evaluation of patients with suspected lung injury from antineoplastic agents. Lung biopsy rarely establishes an antineoplastic agent as the definitive cause of the lung injury, as there are no pathognomonic findings, and definitive histologic criteria for drug-induced lung disease have not been established. Given the potential risks associated with the procedure, surgical lung biopsy should be considered only based on other diagnostic possibilities. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

DIFFERENTIAL DIAGNOSIS — The diagnosis of antineoplastic agent-induced lung toxicity is challenging and largely one of exclusion. For most patients with respiratory symptoms and/or pulmonary infiltrates who might have antineoplastic agent-induced pulmonary toxicity, the differential diagnosis is extensive:

Infection is a common cause of pulmonary infiltrates and respiratory compromise in patients with cancer. Patients undergoing chemotherapy are often immunosuppressed, both from the treatment and their underlying disease, and are prone to a variety of opportunistic pulmonary infections and atypical presentations of more common pneumonias. (See "Epidemiology of pulmonary infections in immunocompromised patients" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

Radiation-induced lung injury may have a synergic effect on antineoplastic agent-induced lung toxicity in patients receiving concurrent or sequential chemotherapy plus radiation. (See "Radiation-induced lung injury" and "Taxane-induced pulmonary toxicity", section on 'Concomitant radiotherapy'.)

Cardiogenic and non-cardiogenic pulmonary edema are occasionally encountered in patients treated with antineoplastic agents. As examples, doxorubicin is associated with a dose-dependent cardiomyopathy that may present as heart failure; cumulative exposure to docetaxel is associated with a capillary leak syndrome resulting in a clinical picture of noncardiogenic pulmonary edema with or without pleural effusions. (See "Taxane-induced pulmonary toxicity", section on 'Capillary leakage and docetaxel' and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

Pulmonary edema may also be unrelated to the antineoplastic therapy. In assessing the etiology of pulmonary edema, a cardiogenic cause is suggested if the echocardiogram suggests left ventricular dysfunction, and serum B-type natriuretic peptide (BNP) is elevated. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults".)

Direct involvement of the lungs by the neoplastic process may occur (eg, pulmonary metastases, lymphangitic carcinomatosis, or pulmonary tumor embolism). This may be diagnosed by a typical radiographic pattern (eg, lymphangitic carcinomatosis), cytologic evidence of malignant cells, or lung biopsy (image 2A-B). (See "Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Diagnostic evaluation and management" and "High resolution computed tomography of the lungs", section on 'Lymphangitic carcinomatosis'.)

Pulmonary hemorrhage, which may be unrelated or indirectly related to drug therapy. For example, alveolar hemorrhage, a complication of advanced squamous cell lung cancer, is more likely in patients treated with the anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibody bevacizumab and sunitinib and sorafenib, small molecule inhibitors of the VEGF tyrosine kinase receptor [29], so that these agents should not be used in these patients. Alveolar hemorrhage has also been reported in patients treated with gemcitabine. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents" and "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents", section on 'Gemcitabine'.)

If the diagnosis of drug toxicity is considered likely, discontinuation of the suspected culprit agent should be considered. However, discontinuation of an agent on suspicion alone may deprive the patient of a potentially life-prolonging treatment (eg, a patient who develops pulmonary infiltrates while receiving adjuvant trastuzumab for HER2-positive early breast cancer). A multidisciplinary discussion regarding patient management is always recommended. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Trastuzumab'.)

TREATMENT — In general, treatment of antineoplastic agent-induced pulmonary injury is empiric rather than evidence-based. The key components include drug discontinuation, glucocorticoid therapy, and supportive care.

Drug discontinuation — For the majority of antineoplastic agents, no specific treatment has proven effective besides discontinuation of the suspected offending agent. In general, suspicion of significant lung toxicity justifies discontinuation of the drug. However, the clinician involved in the decision-making process must carefully weigh risks and benefits, as well as the availability of alternative treatments, as drug discontinuation may result in elimination of a highly effective agent.

An exception to this rule is the differentiation syndrome seen in patients with acute promyelocytic leukemia who are treated with a differentiating agent (ie, all-trans retinoic acid or arsenic trioxide). In the differentiation syndrome, the differentiating agent can usually be continued, as long as glucocorticoid therapy is initiated promptly [30]. However, the development of severe respiratory compromise may force discontinuation of the differentiating agent. (See "Differentiation syndrome associated with treatment of acute leukemia".)

Glucocorticoids — The decision to initiate glucocorticoid therapy usually depends on the severity and rapidity of worsening of pulmonary impairment. The evidence to support benefit of glucocorticoids in the setting of drug-induced lung toxicity is largely observational [27]. Additional support comes from the observation that a histopathologic pattern consistent with glucocorticoid responsiveness (eg, nonspecific interstitial pneumonia, organizing pneumonia, eosinophilic pneumonia) is often observed in patients with acute or subacute onset of pulmonary toxicity who undergo lung biopsy. However, clinicians are often faced with choosing whether to initiate systemic glucocorticoids before a histopathologic diagnosis is available.

For patients who have stable or improving pneumonitis, with the exception of the differentiation syndrome described above, glucocorticoids are generally withheld while observing for spontaneous improvement, as resolution of pulmonary toxicity often accompanies drug discontinuation.

In contrast, empiric glucocorticoid therapy is usually initiated in a patient who has rapidly progressive or more severe pulmonary toxicity, although evidence from randomized trials to support this practice is lacking. Severe lung toxicity is characterized by dyspnea at rest, a decrease in oxygen saturation below 90 percent or more than a 4 percent decrease from baseline, worsening clinical status, or the need for ventilatory support. According to the National Cancer Institute common toxicity criteria (NCI-CTC) used to grade the severity of pneumonitis/pulmonary infiltrates, this severity constitutes grade 3 or 4 toxicity (table 3).

Possible exceptions to the empiric use of glucocorticoids would include patients with a strong contraindication to glucocorticoids and those with evidence of a disease process that is unlikely to be glucocorticoid-responsive, such as veno-occlusive disease or advanced usual interstitial pneumonia. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Evaluation and approach to clinical diagnosis' and "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Usual interstitial pneumonia' and "Treatment of idiopathic pulmonary fibrosis".)

When considering the option of systemic glucocorticoid therapy, it is important to exclude an infectious etiology, which may require a bronchoscopy with BAL, if the patient can tolerate it. Empiric antimicrobial therapy directed at likely pathogens is often indicated while diagnostic procedures and cultures are performed. (See 'Bronchoscopy' above and 'Surgical lung biopsy' above.)

There is no established glucocorticoid treatment schedule, but severe respiratory compromise is often treated with prednisone 40 to 60 mg daily; intravenous glucocorticoids (eg, methylprednisolone with doses up to 1 gm daily for three days) have been used in patients with impending respiratory failure or in those who require mechanical ventilation. If the patient's response permits, tapering of the oral dose can be carried out over one to two months. Systemic glucocorticoid therapy is associated with a number of adverse effects, including opportunistic infection. Depending on the degree of immunosuppression due to concomitant agents, hematopoietic cell transplantation, underlying malignancy, or AIDS, prophylaxis may be indicated. The indications for Pneumocystis jirovecii prophylaxis are discussed separately. (See "Major adverse effects of systemic glucocorticoids" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

Supportive care — Supportive care may include supplemental oxygen, inhaled bronchodilating medication (eg, beta agonists) when there is evidence of bronchoconstriction (eg, wheezing, airflow obstruction on pulmonary function tests), and mechanical ventilation, if clinically indicated [12,31].

Particularly in patients who have received bleomycin, supplemental oxygen using high inspired O2 concentrations should be avoided; supplemental oxygen should only be added when the oxygen saturation is below 89 percent and then titrated to an oxygen saturation of 89 to 93 percent. (See "Bleomycin-induced lung injury".)

Rechallenge — The decision to reintroduce the same drug in a patient who has recovered from drug-induced pulmonary toxicity must be made on a case by case basis, and should be based upon the individual agent, the severity of the reaction, and the availability of alternative therapies. When the diagnosis of symptomatic pulmonary toxicity from an antineoplastic agent is reasonably secure, we generally do not reintroduce the agent. However, there are some exceptions. For example, successful rechallenge has been reported with the differentiating agents (ie, all-trans retinoic acid or arsenic trioxide), dasatinib, and possibly temsirolimus or everolimus. (See "Differentiation syndrome associated with treatment of acute leukemia" and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Bcr-Abl tyrosine kinase inhibitors' and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Rapamycin and analogs'.)

SCREENING — Screening methods to detect early evidence of respiratory impairment include asking about dyspnea, auscultation for crackles, serial chest radiographs, and serial pulmonary function tests. However, the role of screening for early evidence of lung toxicity remains unclear, largely because of the lack of specificity of available tests.

Many centers perform serial monitoring of diffusing capacity for carbon monoxide (DLCO) in patients receiving bleomycin, particularly when the cumulative dose approaches 400 units. Several authors recommend that bleomycin be discontinued if the DLCO falls to less than 60 percent of an individual's baseline value. The US Food and Drug Administration-approved package insert recommends frequent chest radiographs in patients receiving bleomycin, and optional monthly determinations of DLCO with discontinuation of drug when the DLCO falls to below 30 to 35 percent of the pretreatment value. However, many other institutions do not routinely monitor DLCO during bleomycin therapy.

Monitoring of uptake on 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning is being evaluated as another potential screening method. Increased uptake on PET scanning has been reported in patients with pneumonitis caused by several different antineoplastic agents [32-36]. However, a PET scan would not differentiate between lymphangitic tumor and drug-induced pneumonitis.

SUMMARY AND RECOMMENDATIONS

Approach to evaluation – Antineoplastic agent-induced pulmonary toxicity is relatively frequent and the diagnosis should be entertained once careful investigation has excluded alternative explanations, including opportunistic infections, radiation-induced lung injury, or metastatic involvement of the lungs. (See 'Introduction' above.)

Imaging characteristics – Various radiographic patterns of drug-induced injury are described, including alveolar, interstitial, or mixed opacities, pleural effusions, and focal nodular consolidations that mimic tumor involvement (table 1). (See 'Imaging' above.)

Diagnostic work-up – The main purpose of bronchoalveolar lavage (BAL) is to exclude other processes such as infection, alveolar hemorrhage, and metastatic spread of the underlying cancer. A lung biopsy is indicated when the patient has progressive or severe disease and the cause of the pneumonitis is uncertain. Drug-induced lung disease can cause a broad spectrum of histologic patterns. (See 'Diagnosis' above and 'Histopathology' above.)

Establishing a diagnosis – The diagnosis of chemotherapy-induced pneumonitis can be made with some confidence when pneumonitis develops shortly after the initiation of treatment, an alternative explanation for the respiratory compromise is lacking, and resolution of the pneumonitis follows withdrawal of the presumed agent. Establishing the diagnosis may have dramatic consequences for the patient, potentially leading to discontinuation of a highly effective agent. (See 'Diagnosis' above and 'Differential diagnosis' above.)

Treatment

Drug discontinuation, except in differentiation syndrome – For the majority of patients with pulmonary toxicity caused by an antineoplastic agent, the treatment of choice is drug discontinuation, although the risks, benefits, and availability of alternative treatments must be carefully weighed. An exception is the differentiation syndrome, in which the differentiating agent (ie, all-trans retinoic acid or arsenic trioxide) can usually be continued unless respiratory failure is imminent. (See 'Drug discontinuation' above and "Differentiation syndrome associated with treatment of acute leukemia".)

Supportive care – Supportive care may include cautiously titrated supplemental oxygen, inhaled bronchodilating medication (eg, beta agonists) when there is evidence of bronchoconstriction (eg, wheezing, airflow obstruction on pulmonary function tests), pulmonary rehabilitation, and in selected patients ventilatory support. No specific treatment has proven effective besides discontinuation of the suspected offending agent. (See 'Treatment' above.)

Glucocorticoids, for severe pulmonary toxicity – For patients with acute or subacute onset of severe pulmonary toxicity (eg, dyspnea at rest, a decrease in oxygen saturation below 90 percent or more than 4 percent decrease from baseline, or worsening clinical status), we suggest initiating systemic glucocorticoid therapy, rather than observation and supportive care alone (Grade 2C). We generally use oral prednisone 40 to 60 mg daily; intravenous glucocorticoids may be used initially in patients who have impending respiratory failure. (See 'Glucocorticoids' above.)

-For patients with less severe and less rapidly progressive respiratory impairment and also those with a clinical presentation or pathology indicative of a pulmonary disease process that is unlikely to be glucocorticoid-responsive (eg, pulmonary veno-occlusive disease or usual interstitial pneumonitis), we avoid glucocorticoid use. (See 'Glucocorticoids' above.)

-We generally taper oral glucocorticoids over one to two months based on clinical response. (See 'Glucocorticoids' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James Jett, MD, who contributed to earlier versions of this topic review.

  1. Ozkan M, Dweik RA, Ahmad M. Drug-induced lung disease. Cleve Clin J Med 2001; 68:782.
  2. Rosenow EC 3rd, Limper AH. Drug-induced pulmonary disease. Semin Respir Infect 1995; 10:86.
  3. Snyder LS, Hertz MI. Cytotoxic drug-induced lung injury. Semin Respir Infect 1988; 3:217.
  4. Nebeker JR, Barach P, Samore MH. Clarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting. Ann Intern Med 2004; 140:795.
  5. Camus P, Fanton A, Bonniaud P, et al. Interstitial lung disease induced by drugs and radiation. Respiration 2004; 71:301.
  6. Bonniaud P, Georges M, Favrolt N, Camus P. [Drug-induced interstitial lung diseases]. Rev Prat 2014; 64:951.
  7. Camus P. Interstitial lung disease from drugs, biologics, and radiation. In: Interstitial Lung Disease, 5th, Schwarz M, King TE Jr (Eds), People's Medical Publishing House-USA, Shelton CT 2011. p.637.
  8. Fujimoto D, Kato R, Morimoto T, et al. Characteristics and Prognostic Impact of Pneumonitis during Systemic Anti-Cancer Therapy in Patients with Advanced Non-Small-Cell Lung Cancer. PLoS One 2016; 11:e0168465.
  9. Dhokarh R, Li G, Schmickl CN, et al. Drug-associated acute lung injury: a population-based cohort study. Chest 2012; 142:845.
  10. Leger P, Limper AH, Maldonado F. Pulmonary Toxicities from Conventional Chemotherapy. Clin Chest Med 2017; 38:209.
  11. Anan K, Ichikado K, Kawamura K, et al. Clinical characteristics and prognosis of drug-associated acute respiratory distress syndrome compared with non-drug-associated acute respiratory distress syndrome: a single-centre retrospective study in Japan. BMJ Open 2017; 7:e015330.
  12. Vahid B, Marik PE. Pulmonary complications of novel antineoplastic agents for solid tumors. Chest 2008; 133:528.
  13. Limper AH. Chemotherapy-induced lung disease. Clin Chest Med 2004; 25:53.
  14. Possick JD. Pulmonary Toxicities from Checkpoint Immunotherapy for Malignancy. Clin Chest Med 2017; 38:223.
  15. Sleijfer S. Bleomycin-induced pneumonitis. Chest 2001; 120:617.
  16. O'Driscoll BR, Hasleton PS, Taylor PM, et al. Active lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood. N Engl J Med 1990; 323:378.
  17. Yerushalmi R, Kramer MR, Rizel S, et al. Decline in pulmonary function in patients with breast cancer receiving dose-dense chemotherapy: a prospective study. Ann Oncol 2009; 20:437.
  18. Wardley AM, Hiller L, Howard HC, et al. tAnGo: a randomised phase III trial of gemcitabine in paclitaxel-containing, epirubicin/cyclophosphamide-based, adjuvant chemotherapy for early breast cancer: a prospective pulmonary, cardiac and hepatic function evaluation. Br J Cancer 2008; 99:597.
  19. Dimopoulou I, Galani H, Dafni U, et al. A prospective study of pulmonary function in patients treated with paclitaxel and carboplatin. Cancer 2002; 94:452.
  20. Leo F, Solli P, Spaggiari L, et al. Respiratory function changes after chemotherapy: an additional risk for postoperative respiratory complications? Ann Thorac Surg 2004; 77:260.
  21. Bossi G, Cerveri I, Volpini E, et al. Long-term pulmonary sequelae after treatment of childhood Hodgkin's disease. Ann Oncol 1997; 8 Suppl 1:19.
  22. Castro M, Veeder MH, Mailliard JA, et al. A prospective study of pulmonary function in patients receiving mitomycin. Chest 1996; 109:939.
  23. Dimopoulou I, Efstathiou E, Samakovli A, et al. A prospective study on lung toxicity in patients treated with gemcitabine and carboplatin: clinical, radiological and functional assessment. Ann Oncol 2004; 15:1250.
  24. Rivera MP, Detterbeck FC, Socinski MA, et al. Impact of preoperative chemotherapy on pulmonary function tests in resectable early-stage non-small cell lung cancer. Chest 2009; 135:1588.
  25. Cleverley JR, Screaton NJ, Hiorns MP, et al. Drug-induced lung disease: high-resolution CT and histological findings. Clin Radiol 2002; 57:292.
  26. Torrisi JM, Schwartz LH, Gollub MJ, et al. CT findings of chemotherapy-induced toxicity: what radiologists need to know about the clinical and radiologic manifestations of chemotherapy toxicity. Radiology 2011; 258:41.
  27. Camus P, Bonniaud P, Fanton A, et al. Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med 2004; 25:479.
  28. Poletti V, Poletti G, Murer B, et al. Bronchoalveolar lavage in malignancy. Semin Respir Crit Care Med 2007; 28:534.
  29. Blumenschein GR Jr, Gatzemeier U, Fossella F, et al. Phase II, multicenter, uncontrolled trial of single-agent sorafenib in patients with relapsed or refractory, advanced non-small-cell lung cancer. J Clin Oncol 2009; 27:4274.
  30. Nicolls MR, Terada LS, Tuder RM, et al. Diffuse alveolar hemorrhage with underlying pulmonary capillaritis in the retinoic acid syndrome. Am J Respir Crit Care Med 1998; 158:1302.
  31. Lee C, Gianos M, Klaustermeyer WB. Diagnosis and management of hypersensitivity reactions related to common cancer chemotherapy agents. Ann Allergy Asthma Immunol 2009; 102:179.
  32. Buchler T, Bomanji J, Lee SM. FDG-PET in bleomycin-induced pneumonitis following ABVD chemotherapy for Hodgkin's disease--a useful tool for monitoring pulmonary toxicity and disease activity. Haematologica 2007; 92:e120.
  33. von Rohr L, Klaeser B, Joerger M, et al. Increased pulmonary FDG uptake in bleomycin-associated pneumonitis. Onkologie 2007; 30:320.
  34. Post MC, Grutters JC, Verzijlbergen JF, Biesma DH. PET scintigraphy of etoposide-induced pulmonary toxicity. Clin Nucl Med 2007; 32:683.
  35. Kalkanis D, Stefanovic A, Paes F, et al. [18F]-fluorodeoxyglucose positron emission tomography combined with computed tomography detection of asymptomatic late pulmonary toxicity in patients with non-Hodgkin lymphoma treated with rituximab-containing chemotherapy. Leuk Lymphoma 2009; 50:904.
  36. Yamane T, Daimaru O, Ito S, et al. Drug-induced pneumonitis detected earlier by 18F-FDG-PET than by high-resolution CT: a case report with non-Hodgkin's lymphoma. Ann Nucl Med 2008; 22:719.
Topic 4315 Version 26.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟