Cyclophosphamide pulmonary toxicity

INTRODUCTION — Cyclophosphamide is an alkylating agent that is used in combination with other chemotherapeutic agents for the treatment of a variety of malignant processes. It also has immunosuppressive properties and is used for the treatment of certain autoimmune diseases, either as a sole agent or in combination with glucocorticoids. Long-term use of cyclophosphamide is associated with a multitude of significant side effects, such as hair loss, leukopenia, hemorrhagic cystitis, infertility, the development of secondary malignancies, and pulmonary toxicity.

The pathogenesis, clinical manifestations, diagnosis, and treatment of cyclophosphamide pulmonary toxicity will be presented here. Other toxicities of cyclophosphamide are discussed separately. (See "General toxicity of cyclophosphamide in rheumatic diseases" and "General principles of the use of cyclophosphamide in rheumatic diseases" and "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients" and "Effects of cytotoxic agents on gonadal function in adult men".)

PATHOLOGY — Histopathologic findings observed in patients with cyclophosphamide pulmonary toxicity are nonspecific. The characteristic picture is the presence of atypical cells in the alveolar and bronchiolar epithelium, hyperplasia of type II pneumocytes, and interstitial and alveolar edema and fibrosis [1]. Diffuse alveolar damage, organizing pneumonia (also known as bronchiolitis obliterans organizing pneumonia or BOOP), and alveolar hemorrhage have been reported [2], and a pattern indistinguishable from usual interstitial pneumonitis (UIP) also can be seen [3]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

Among patients with late onset pulmonary toxicity, a pattern of pleuroparenchymal fibroelastosis can be seen, affecting the upper and lateral aspects of the pleura [4-7].

PATHOGENESIS — The parent drug cyclophosphamide is nontoxic to the lung but it is metabolized in the liver, and to a lesser extent in the lung, to the toxic metabolites 4-hydroxycyclophosphamide, acrolein, and phosphoramide mustard [8]. Lung tissue from different species varies in its ability to locally metabolize cyclophosphamide, and susceptibility to cyclophosphamide-induced lung fibrosis in humans may depend upon genetic differences in local pulmonary drug metabolism [9]. Genetic susceptibility is further supported by the absence of a clear dose-response relationship for the development of lung toxicity in humans [3,10].

In vitro models also suggest the involvement of transforming growth factor-beta in cyclophosphamide-induced pulmonary fibrosis [11]. However, the exact mechanisms by which cyclophosphamide-induced lung injury causes the observed increase in transforming growth factor-beta (TGF-beta) expression and the associated upregulation of collagen synthesis and irreversible fibrosis remain unclear.

RISK FACTORS — Animal models and clinical observations suggest that oxidative stress may contribute to cyclophosphamide pulmonary toxicity [9]. Concomitant radiation therapy, use of other cytotoxic agents with known lung toxicity (eg, bleomycin, busulfan), concomitant use of other drugs such as amiodarone [12-14], and exposure to high inspired oxygen concentrations have all been implicated as additional risk factors for the development of the syndrome [15]. (See "Radiation-induced lung injury" and "Bleomycin-induced lung injury".)

It is unclear whether a higher total dose of cyclophosphamide is a risk factor for lung toxicity, as affected patients have received doses ranging from 150 mg to 81 g [3,14]. On the other hand, when cyclophosphamide is given as a conditioning agent prior to bone marrow transplantation, a dose response has been reported [14].

CLINICAL FEATURES — Cyclophosphamide-induced pulmonary injury appears to be rare; the frequency is <1 percent [16]. However, the risk may be increased by the concomitant use of radiation therapy, oxygen therapy, or other drugs with potential pulmonary toxicity; these factors also may confound attempts to estimate the true incidence of cyclophosphamide-induced lung injury, and to recognize cyclophosphamide-induced pulmonary toxicity when it develops.

There are two distinct clinical patterns of pulmonary toxicity associated with cyclophosphamide: an acute pneumonitis that occurs early in the course of treatment and a chronic, progressive, fibrotic process that may occur after prolonged therapy [3]. A single case of acute pulmonary edema after intravenous cyclophosphamide also has been reported [17].

Early-onset pneumonitis — Affected patients present with cough and dyspnea within one to six months of starting therapy; fever and fatigue also may be present [1,3]. Chest radiographs and computed tomography (CT) scans can show reticular markings and/or a ground glass appearance. Discontinuation of the drug and institution of glucocorticoids usually result in complete resolution of this syndrome.

Late-onset pneumonitis and fibrosis — Late-onset pulmonary toxicity develops in patients who have received prolonged treatment over several months to years with relatively low doses of cyclophosphamide (typically in the setting of immunosuppressive therapy) [3,18]. As an example, five patients with late onset pneumonitis received one to four years of cyclophosphamide therapy and developed lung disease six months to six years after stopping cyclophosphamide [3].

The clinical picture is one of relentlessly progressive lung fibrosis. The onset of symptoms is insidious, with slowly progressive dyspnea and a nonproductive cough. This disorder differs from usual interstitial pneumonitis (UIP) in that clubbing of the fingers and "velcro-type" inspiratory crackles are lacking, and the diffuse reticular or nodular opacities that are observed on chest radiographs do not have the typical bibasilar predominance seen in UIP. (See "Approach to the adult with interstitial lung disease: Clinical evaluation".)

Some patients develop combined pleural and pulmonary fibrosis; these patients are at risk for pneumothorax [4,5,18]. (See 'Pathology' above.)

Late-onset pneumonitis and fibrosis associated with long-term cyclophosphamide use is minimally responsive to glucocorticoids and to discontinuation of the drug. It almost inevitably leads to terminal respiratory failure.

DIAGNOSIS — Cyclophosphamide pulmonary toxicity is primarily a clinical diagnosis, based upon symptoms, history of cyclophosphamide use, compatible findings on chest imaging studies, and the absence of an alternative diagnosis (eg, infection, recurrence of underlying disease, hypersensitivity pneumonitis).

Symptoms and signs — Patients with early-onset pneumonitis usually seek medical attention after a short duration of cough, dyspnea, fever, and fatigue [3]. Some patients are asymptomatic, and the disease is suspected because of unexplained radiographic or lung function abnormalities. Late-onset pulmonary toxicity should be suspected when patients with prior or ongoing cyclophosphamide exposure for six months or longer complain of progressively worsening nonproductive cough and dyspnea. There are no specific symptoms associated with this fibrotic process. (See "Approach to the adult with interstitial lung disease: Clinical evaluation".)

Laboratory studies — No specific laboratory tests help to establish the diagnosis. Laboratory testing is aimed at the exclusion of other causes for the pulmonary opacities and dyspnea, such as infection or hypersensitivity pneumonitis. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis".)

Pulmonary function testing — Patients with cyclophosphamide pulmonary toxicity typically display a restrictive pattern with a reduced diffusing capacity on pulmonary function testing. Although these findings are diagnostically nonspecific, serial pulmonary function testing may be useful in following the clinical course of these patients.

Chest imaging studies — Bilateral reticular or nodular diffuse opacities are the hallmark of both early-onset and late-onset pulmonary toxicity [3]. In the case of early-onset pneumonitis, computed tomography (CT) of the chest reveals "ground-glass" opacities predominantly in the periphery of the upper lungs. (See "High resolution computed tomography of the lungs", section on 'HRCT patterns'.)

The radiographic opacities of late-onset pneumonitis have a more fibrotic appearance on CT; however, nodular opacities with volume loss have been described [3]. The honeycombing pattern characteristic of usual interstitial pneumonitis (UIP) is lacking, and the lower lungs are not predominantly affected. Bilateral pleural thickening of the mid- and upper lung regions is a common feature which also helps in differentiating this process from UIP [3,19-21]. The observed radiographic features of late-onset pneumonitis are similar to those described for pleuroparenchymal fibroelastosis [3,6].

Bronchoscopy — The main role of bronchoscopy and bronchoalveolar lavage (BAL) is to exclude other processes such as infection, diffuse alveolar hemorrhage, or, in patients with a malignant disease, lymphangitic tumor spread. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and "Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Diagnostic evaluation and management".)  

Lung biopsy — Thoracoscopic and open lung biopsy do not play a significant role in the evaluation of patients with possible cyclophosphamide pulmonary toxicity unless other conditions such as infection, hypersensitivity pneumonitis, or diffuse malignancy cannot be excluded by other means [2]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

Biopsy findings in late onset pneumonitis are often nonspecific, showing interstitial thickening and an inflammatory infiltrate of lymphocytes with a few neutrophils and eosinophils [1,3]. Well-formed granulomas have been described, distributed along lymphatic pathways associated with nonspecific interstitial pneumonia and hemosiderin deposition [3].

TREATMENT AND PROGNOSIS — Early-onset pneumonitis is generally a reversible process with a good prognosis, although fatalities have been reported [1]. Most patients respond to discontinuation of cyclophosphamide, but the improvement may be gradual; disappearance of symptoms and clearing of chest radiographs may take weeks to months [3].

The role of glucocorticoids in the treatment of early-onset pneumonitis remains unclear. Most, but not all, successfully treated patients described in the literature have received glucocorticoids, but the magnitude of benefit due to glucocorticoid use (versus treatment discontinuation alone) is unknown [22]. We typically prescribe systemic glucocorticoid therapy in patients with more severe initial symptoms and impairment on pulmonary function testing. The optimal dose is unknown; based on clinical experience we initiate therapy with the equivalent of prednisone 60 mg per day, and taper slowly as tolerated.

Late-onset pneumonitis with fibrosis is essentially irreversible and follows a chronically progressive course over months to years [3]. Treatment is largely supportive, as systemic glucocorticoids have not been beneficial in reversing fibrosis. Lung transplantation may be considered in selected cases. (See "Lung transplantation: An overview".)

Mortality due to progressive respiratory failure in late onset pneumonitis is estimated to be over 60 percent [1,3,23].

SUMMARY AND RECOMMENDATIONS

●Incidence – Cyclophosphamide-induced pulmonary injury appears to be rare; the frequency is <1 percent. However, the risk may be increased by the concomitant use of radiation, oxygen therapy, or other drugs with potential pulmonary toxicity. (See 'Introduction' above.)

●Early-onset acute pneumonitis – Patients with early-onset cyclophosphamide pneumonitis develop cough and dyspnea within one to six months after the onset of cyclophosphamide therapy; fever and fatigue also may be present. Key findings on computed tomography include diffuse parenchymal lung disease (eg, areas of consolidation, ground glass opacities, nodular opacities, intralobular septal thickening). (See 'Early-onset pneumonitis' above and 'Chest imaging studies' above.)

●Late-onset pneumonitis – Late-onset cyclophosphamide pneumonitis occurs after prolonged (more than six months) treatment with relatively low doses of cyclophosphamide. Presenting manifestations include progressive nonproductive cough and dyspnea. Key findings on computed tomography include interlobular and intralobular septal thickening and often bilateral pleural thickening of the mid- and upper lung regions, but absence of honeycombing. (See 'Late-onset pneumonitis and fibrosis' above and 'Chest imaging studies' above.)

●Diagnosis – Cyclophosphamide pulmonary toxicity is primarily a clinical diagnosis based on the history of cyclophosphamide use, compatible symptoms and findings on chest imaging studies, and the absence of an alternative diagnosis (eg, infection, recurrence of underlying disease, hypersensitivity pneumonitis). (See 'Diagnosis' above.)

●Treatment

•Acute pneumonitis – Early-onset pneumonitis due to cyclophosphamide should be treated with drug discontinuation; the condition is generally reversible with good prognosis. For patients with severe symptoms or impaired pulmonary function, we suggest use of systemic glucocorticoids (Grade 2C) to assist in relieving pulmonary inflammation. We typically use 60 mg of oral prednisone daily or the equivalent, followed by a taper over several weeks based on changes in symptoms. (See 'Treatment and prognosis' above.)

•Late-onset pneumonitis – Late-onset pneumonitis with fibrosis is essentially irreversible and follows a progressive course that is unresponsive to glucocorticoid therapy. Treatment with cyclophosphamide has generally already ceased, but it should be discontinued if still in active use. Lung transplantation may be considered in selected patients. (See 'Treatment and prognosis' above and "Lung transplantation: An overview".)