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Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents

Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents
Authors:
Fabien Maldonado, MD, MSc
Andrew H Limper, MD
Amanda S Cass, PharmD, BCPS, BCOP
Section Editor:
Kevin R Flaherty, MD, MS
Deputy Editors:
Sonali M Shah, MD
Paul Dieffenbach, MD
Literature review current through: Jan 2024.
This topic last updated: May 09, 2022.

INTRODUCTION — Adverse drug reactions (ADRs) due to antineoplastic agents are a common form of iatrogenic injury, and the lungs are a frequent target, as they process the entire cardiac output [1-3]. 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 incidence and specific patterns of lung toxicity seen with cytotoxic chemotherapy agents. Separate monographs are available for many of the drugs that are most commonly associated with pulmonary toxicity. (See "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".)

A general discussion of the clinical presentation, pathogenesis, diagnosis, differential diagnosis, and management of antineoplastic agent-induced pulmonary toxicity is covered elsewhere, as is lung toxicity associated with molecularly targeted agents. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment" and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents".)

BLEOMYCIN — (See "Bleomycin-induced lung injury".)

BORTEZOMIB AND CARFILZOMIB

Bortezomib — Bortezomib is a reversible proteasome inhibitor that is used for the treatment of multiple myeloma (MM) and mantle cell lymphoma. In clinical trials, approximately 5 percent of patients report severe (grade 3 or worse) dyspnea, although the specific causality of bortezomib and the role of contributing factors such as anemia, respiratory infection, and cardiac dysfunction are unclear [4]. Cases of severe interstitial lung disease (some fatal) have been reported, mainly from Japan [5-7]. In addition, a few cases of pulmonary hypertension have been reported in the absence of left heart failure or significant pulmonary parenchymal disease [4,8]. The specific incidences of lung toxicity and pulmonary hypertension are unknown.

An increased incidence of opportunistic infections is reported in patients receiving bortezomib for myeloma [9,10], underscoring the importance of a diagnostic workup to exclude pulmonary infection before concluding that drug toxicity is responsible for respiratory symptoms or radiographic opacities. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Bronchoscopy and bronchoalveolar lavage'.)

There is limited information on management. A rapid response to glucocorticoid therapy was noted in one case of pneumonitis [5]. General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

There are no data that address retreatment in patients who develop pulmonary toxicity. In general, we would not rechallenge a patient who developed severe (grade 3 or 4) pulmonary toxicity or any grade of pulmonary hypertension unless there are no other therapeutic alternatives.

Carfilzomib — Carfilzomib is an irreversible, second-generation selective proteasome inhibitor that is used to treat relapsed or refractory MM. Carfilzomib has been associated with dyspnea, pulmonary hypertension, and cardiac dysfunction.

●In an open-label study, 266 patients with MM received intravenous carfilzomib for up to 12 weeks [11]. Dyspnea was noted in 34 percent, although carfilzomib was considered to be responsible in only one-half of cases. Dyspnea was transient and not associated with progressive lung injury; pulmonary hypertension was not reported.

●In a separate open-label study, in which carfilzomib was administered weekly for three of every four weeks up to 12 months to 129 patients with MM, treatment-related dyspnea was reported in 29 percent [12]. Pulmonary hypertension was not reported.

●According to the US Food and Drug Administration (FDA)-approved manufacturer's prescribing information, treatment with carfilzomib was associated with development of pulmonary hypertension in 2 percent of patients [13]. Pulmonary hypertension was severe (grade 3 or greater) in less than 1 percent.

●When carfilzomib has been administered in combination with dexamethasone and the anti-CD38 monoclonal antibody daratumumab, grade ≥3 respiratory tract infections occurred in 29 percent of patients compared with 16 percent of those receiving carfilzomib and dexamethasone alone [14]. However, rates of dyspnea were similar.

It is unclear from these reports whether anemia or cardiac dysfunction contributed to dyspnea that was not related to pulmonary hypertension. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Proteasome inhibitors'.)

For patients who develop severe (grade 3 or 4) dyspnea or pulmonary hypertension while receiving carfilzomib, treatment should be withheld at least until respiratory symptoms and signs have resolved. There are no data regarding the safety of carfilzomib rechallenge in these patients. The FDA-approved manufacturer's labeling suggests a dose reduction if carfilzomib is reinstituted [13]. However, we generally suggest not rechallenging such patients unless there are no other reasonable therapeutic alternatives.

BUSULFAN — (See "Busulfan-induced pulmonary injury".)

CARMUSTINE (BCNU) — (See "Nitrosourea-induced pulmonary injury".)

CHLORAMBUCIL — (See "Chlorambucil-induced pulmonary injury".)

CYCLOPHOSPHAMIDE — (See "Cyclophosphamide pulmonary toxicity".)

CYTARABINE — Cytarabine is used to induce remission in acute myeloblastic leukemia and in preparation for hematopoietic cell transplantation. Lung toxicity described as noncardiogenic pulmonary edema has been reported in leukemic patients receiving cytarabine at intermediate to high doses (1 to 3 g every 12 hours for four to six days); it develops a median of one to two weeks (range 1 to 21 days) after initiation of therapy [15-17]. The overall incidence is unclear. In older reports, up to 14 percent of patients were affected [16], but more recent clinical trials suggest much lower rates [18,19].

Affected patients present with a subacute development of low-grade fever, mild dyspnea, tachypnea, cough, moderate to severe hypoxemia, and crackles on lung auscultation [15]. Chest radiographs show confluent alveolar consolidation with or without pleural effusions. Histopathology may reveal the presence of proteinaceous material in the alveoli without cellular atypia, a nonspecific finding.

Discontinuation of the drug is warranted. Otherwise, treatment is essentially supportive and consists of supplemental oxygen, diuresis, and ventilatory support, if needed. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults".)

The role of glucocorticoid therapy is anecdotal and of unproven value, except in cases of organizing pneumonia, which has been rarely reported in association with cytarabine [15]; too few patients in the literature have received glucocorticoid therapy to judge its value. General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

The clinical course is most often characterized by eventual resolution, although fatalities are reported. In a review of 72 published cases of cytarabine-related pulmonary toxicity not derived from autopsy series, there were 20 deaths [15].

DOXORUBICIN AND RELATED COMPOUNDS — The antitumor antibiotics doxorubicin, amrubicin, and mitoxantrone are inhibitors of topoisomerase II and have been associated with pulmonary toxicity when used alone and in combination with other antineoplastic agents. General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

Doxorubicin — Doxorubicin has a broad range of antitumor activity. Although doxorubicin is far more commonly associated with cumulative cardiac toxicity, several cases of interstitial pneumonia and, rarely, organizing pneumonia have been described [20]. Whether lung toxicity was directly attributable to doxorubicin in these case reports is unclear, as all patients were concurrently receiving other agents that are also implicated in causing lung injury. Reactivation of prior radiation pneumonitis (radiation-recall pneumonitis) has also been observed with doxorubicin. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Pathogenesis'.)

There is limited information on management of pneumonitis due to doxorubicin.

Dyspnea may also be caused by an infusion reaction, which is more commonly seen with pegylated liposomal doxorubicin (Doxil) than with free drug. (See "Infusion reactions to systemic chemotherapy", section on 'Anthracyclines and related agents'.)

Amrubicin — Amrubicin is a novel anthracycline that is approved in Japan for the treatment of small cell lung cancer. The major toxicity is myelosuppression, and cardiac toxicity is minimal. Pulmonary toxicity has been reported, including severe interstitial pneumonitis [21-23]. Among 100 patients treated with amrubicin, pulmonary toxicity developed in seven, four of whom had preexisting fibrotic lung disease [21]. The typical presentation was acute onset of dyspnea, cough, and fever. Computed tomography (CT) scans showed ground-glass opacities and/or consolidation. Three of six patients treated with high-dose methylprednisolone improved, but three died of progressive respiratory failure. Thus, the role of glucocorticoid therapy in the treatment of amrubicin-induced pneumonitis is unclear.

Amrubicin should be used with caution, if at all, in patients with underlying interstitial lung disease, due to the higher rate of lung toxicity observed among those with preexisting pulmonary fibrosis compared with those without (33 versus 7 percent) [21,24].

Mitoxantrone — There are case reports of interstitial pneumonia with mitoxantrone [25,26], but most patients were receiving other antineoplastic agents that could have been responsible for the pulmonary toxicity. Severe cases appear to respond rapidly to oral glucocorticoid therapy. General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

FLUDARABINE — Fludarabine is a purine analog that is mainly used in the treatment of indolent lymphoproliferative disorders, such as chronic lymphocytic leukemia. Case reports describe interstitial pneumonitis during therapy [27-31]; the incidence was approximately 10 percent in the largest series [27]. Most cases develop within weeks of starting drug treatment, although delayed presentations are also reported.

Radiographic studies typically show mixed alveolar and interstitial opacities. Nodular opacities that may be concerning for malignancy or fungal infection have also been reported. Histology is nonspecific, typically showing interstitial inflammation with mild fibrosis.

The onset of dyspnea and cough during treatment with fludarabine should always suggest the possibility of drug-induced lung disease. However, opportunistic pulmonary infections are actually more common. Fludarabine induces severe immunosuppression, which increases the recipient's risk of potentially life-threatening infections with unusual pathogens. Patients who develop respiratory symptoms or pulmonary infiltrates with or without fever while receiving fludarabine should undergo a diagnostic bronchoscopy and bronchoalveolar lavage analysis, if possible. (See "Prevention of infections in patients with chronic lymphocytic leukemia" and "Overview of the complications of chronic lymphocytic leukemia" and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Bronchoscopy and bronchoalveolar lavage'.)

After infection is ruled out as a cause of the symptoms, discontinuation of the drug and administration of glucocorticoids usually leads to prompt resolution [30-32]. However, fatal complications have been reported. Rechallenge is contraindicated because of the high likelihood of recurrence [27]. General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

GEMCITABINE — Gemcitabine is a pyrimidine analog that is used mainly for the treatment of pancreatic and advanced non-small cell lung cancer. Up to 23 percent of patients treated with gemcitabine develop dyspnea during treatment, but only a small fraction develop severe dyspnea that is accompanied by radiographic findings.

Early reports suggested that significant pulmonary toxicity developed in as many as 13 percent of cases [33]. More recent series suggest that severe lung toxicity may have been largely overestimated and is probably more in the range of 1 to 2 percent [34-41]. The highest frequency of gemcitabine-induced lung toxicity (over 20 percent) has been observed in trials combining gemcitabine with bleomycin or a taxane (paclitaxel, docetaxel) [42,43]. The risk of gemcitabine-induced interstitial lung disease is also increased among patients with preexisting pulmonary fibrosis [44]. (See "Taxane-induced pulmonary toxicity", section on 'Concomitant drugs'.)

Gemcitabine is a potent radiosensitizer, and concurrent use of radiotherapy may also synergistically worsen gemcitabine-induced lung toxicity [44-48]. Gemcitabine may also cause radiation recall, a process characterized by reactivation of previous subclinical radiation-induced lung injury [44,49]. (See "Radiation-induced lung injury".)

A range of pulmonary toxicities has been described, including interstitial pneumonitis, diffuse alveolar damage, capillary leak syndrome with noncardiogenic pulmonary edema, alveolar hemorrhage, pleural effusions, and acute eosinophilic pneumonia [40,50,51]. In a review of gemcitabine-associated lung injury, dyspnea, fever, and cough associated with new radiographic opacities was the most common presentation and occurred a median of 48 days after institution of chemotherapy [42]. The typical radiographic findings are bilateral ground-glass opacities, reticular opacities, and thickened septal lines [40,52]. Centrilobular nodules can also be seen [52].

Bronchoconstriction is rare, as are thrombotic microangiopathy and pulmonary veno-occlusive disease [50,53-55]. Acute eosinophilic pneumonia has been reported [51].

Given that myelosuppression is the most common adverse reaction with gemcitabine, opportunistic bacterial and/or viral lung infections need to be considered in the differential diagnosis of gemcitabine-induced lung toxicity [56].

Treatment is generally supportive and includes discontinuation of the drug. For severe cases, a short oral course of glucocorticoids frequently leads to a rapid improvement in clinical and radiographic parameters (within days) [35,36,38,39,53,57]. However, fatalities are reported. In one review, the mortality rate with severe gemcitabine lung toxicity was 20 percent [39].

Subsequent reintroduction of gemcitabine is contraindicated, as this may result in fatal pulmonary toxicity. General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

HYDROXYUREA — Hydroxyurea (hydroxycarbamide) is an antimetabolite that is used to treat myeloproliferative neoplasms and sickle cell disease. (See "Hydroxyurea use in sickle cell disease" and "Essential thrombocythemia: Treatment and prognosis", section on 'Age ≥40 years and no potential for pregnancy'.)

Case reports describe interstitial lung disease including pulmonary fibrosis, diffuse pulmonary opacities, pneumonitis, and alveolitis/allergic alveolitis (including fatal cases) in patients receiving hydroxyurea for myeloproliferative neoplasms [58-61]. The true incidence is unknown. Patients should be frequently monitored for pyrexia, cough, and dyspnea during treatment. Should pulmonary toxicity develop, the drug should be discontinued, and glucocorticoid treatment should be initiated.

IFOSFAMIDE — Ifosfamide is similar in structure to cyclophosphamide, which is associated with both early-onset and late-onset pulmonary toxicity. (See "Cyclophosphamide pulmonary toxicity".)

There are scattered case reports of interstitial pneumonia during treatment with single-agent ifosfamide [62,63]. However, there are other reports of pneumonitis (at times fatal) occurring in patients treated with ifosfamide in combination with other agents [7]; the contribution of ifosfamide to the development of pneumonitis in these cases is unclear.

For patients who develop shortness of breath while receiving ifosfamide, the differential diagnosis should include methemoglobinemia [64]. (See "Methemoglobinemia".)

The role of glucocorticoids in the management of severe interstitial pneumonitis in patients treated with ifosfamide is unclear as there are no published reports. General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

IRINOTECAN AND TOPOTECAN — Pneumonitis is a dose-limiting side effect of irinotecan, a semisynthetic camptothecin that is used most commonly for treatment of advanced colorectal cancer [65].

Dyspnea and/or pulmonary toxicity of any grade have been reported in 0 to 20 percent of patients treated on clinical trials using standard doses of irinotecan [65-69]. However, the incidence of severe lung toxicity with irinotecan alone is probably in the range of 1 to 2 percent [69], with the higher rates initially observed in the United States related to the concurrent use of other antineoplastic agents (particularly gemcitabine [70]) and radiotherapy in patients with thoracic malignancies [71,72].

Pulmonary toxicity is characterized by the nonspecific onset of cough, shortness of breath, and fever. Radiographic studies demonstrate reticulonodular infiltrates and occasional pleural effusions.

Discontinuation of the treatment is warranted. Glucocorticoids have been used in a couple of case reports with good response [67,73]. However, deaths have been reported in spite of the institution of empiric glucocorticoid therapy, even after a single dose of irinotecan [67]. General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

Topotecan, a related agent, has only rarely been associated with pulmonary toxicity [74,75]. The reported patterns include organizing pneumonia, diffuse alveolar damage, and in rare cases, constrictive bronchiolitis [76].

LURBINECTEDIN — Lurbinectedin is an alkylating agent used in the treatment of small cell lung cancer. (See "Treatment of refractory and relapsed small cell lung cancer", section on 'Lurbinectedin'.)

In the phase II study leading to approval by the US Food and Drug Administration, grade ≥3 dyspnea, pneumonia, and respiratory tract infections occurred in 6, 7, and 5 percent of patients, respectively [77,78]. However, none of these events led to treatment discontinuation or treatment-related death. General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

MELPHALAN — Melphalan is an alkylating agent used in the treatment of multiple myeloma. Rarely, acute pneumonitis and acute bronchoconstriction have been attributed to this agent [79-81]. Management typically includes discontinuation of the drug and initiation of glucocorticoids [79]. Inhaled beta-adrenergic agents are used to treat bronchoconstriction. General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

METHOTREXATE — (See "Methotrexate-induced lung injury".)

MITOMYCIN — (See "Mitomycin pulmonary toxicity".)

OXALIPLATIN — Oxaliplatin, which is used in combination with fluorouracil and leucovorin mainly for the treatment of advanced colorectal cancer, has rarely been associated with lung toxicity [82-86]. The described patterns include interstitial pneumonia, cryptogenic organizing pneumonia, eosinophilic pneumonia, and diffuse alveolar damage.

There are case reports of complete resolution with supportive treatment and glucocorticoid therapy [82,85], although fatalities are described even with empiric glucocorticoid therapy [83,84,87]. General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

PEMETREXED — Pemetrexed is a multisite folic acid inhibitor approved for the treatment of malignant pleural mesothelioma and nonsquamous histology non-small cell lung cancer. Pemetrexed has been rarely associated with various types of pulmonary toxicity, including subacute and acute pulmonary fibrosis as well as acute respiratory distress syndrome [88-91]. A possible case of diffuse alveolar hemorrhage has also been reported [92]. Prompt discontinuation of the drug and initiation of glucocorticoids, after exclusion of an infectious cause, is warranted, although descriptions of glucocorticoid benefit are limited to single case reports [91,93].

ETOPOSIDE — Etoposide (VP-16) is a topoisomerase II inhibitor widely used for the treatment of bronchogenic carcinoma. Approximately 1 to 3 percent of patients treated with intravenous (IV) etoposide have a hypersensitivity reaction with features of anaphylaxis (angioedema, chest discomfort, bronchoconstriction, and hypotension); the reaction is thought to be due to the vehicle rather than the drug. (See "Infusion reactions to systemic chemotherapy", section on 'Etoposide'.)

Otherwise, pulmonary toxicity appears to be infrequent, with most of the cases occurring after prolonged oral, rather than IV, therapy [94-97]. Earlier presentations may sometimes be observed. The reaction is characterized histopathologically by diffuse alveolar damage with atypical type II pneumocytes. Treatment relies on discontinuation of the agent. Some cases have been treated with corticosteroids, though data supporting their use are not available.

Etoposide can also increase the risk of radiation pneumonitis. (See "Radiation-induced lung injury".)

PROCARBAZINE — Rarely, procarbazine causes a pneumonitis that is thought to be a hypersensitivity phenomenon, as it is characterized by acute onset and is associated with eosinophilia [98]. Resolution usually follows discontinuation of the agent.

RALTITREXED — Raltitrexed is a multisite folic acid inhibitor approved for the treatment of malignant pleural mesothelioma and colorectal cancer; it is only available outside of the United States. Rare reports describe alveolar hemorrhage and acute interstitial pneumonitis [99,100]. In all cases, drug discontinuation is advised. Initiation of glucocorticoids, after exclusion of infection, is warranted, although there is no published experience as to efficacy.

TAXANES: PACLITAXEL AND DOCETAXEL — (See "Taxane-induced pulmonary toxicity".)

TEMOZOLOMIDE — Temozolomide, an oral alkylating agent used mainly in the treatment of brain tumors, may have caused pneumonitis in 2 to 5 percent of patients in phase II trials [101,102]. One case of organizing pneumonia has been described that resolved after drug discontinuation and treatment with oral glucocorticoids [103]. General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

THALIDOMIDE AND RELATED AGENTS — Thalidomide is mainly used for treatment of multiple myeloma. The most common pulmonary side effect is dyspnea, which is reported in up to one-half patients, but severe pulmonary symptoms (grade 3 or 4) occur in fewer than 5 percent [104-106].

Thalidomide is also associated with an increased risk of thromboembolic disease, particularly when used in association with other agents. (See "Multiple myeloma: Prevention of venous thromboembolism".)

Thalidomide has also been associated with rare cases of nonthromboembolic pulmonary hypertension [107-109].

Thalidomide-induced pneumonitis is extremely rare, but interstitial fibrosis, lymphocytic alveolitis, eosinophilic pneumonia, and organizing pneumonia have all been described [110-116]. An increased incidence of opportunistic infections is reported in patients receiving thalidomide for myeloma [117-119], underscoring the importance of a diagnostic workup to exclude pulmonary infection patients who develop respiratory symptoms or pulmonary infiltrates while receiving thalidomide. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Bronchoscopy and bronchoalveolar lavage'.)

General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

Lenalidomide — Lenalidomide is an analog of thalidomide with fewer nonhematologic side effects. Dyspnea and cough of any grade are reported in approximately 15 percent of patients, 4 percent severe [120]. In addition, pneumonitis is reported in approximately 10 percent of cases, approximately one-half are severe (grade 3 to 4 (table 1)) [120-122]. General aspects of management of suspected lung toxicity with antineoplastic agents are discussed elsewhere. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

Similar to thalidomide, lenalidomide is also associated with an increased risk of thromboembolic disease, particularly when used in association with other agents. (See "Multiple myeloma: Prevention of venous thromboembolism".)

VINCA ALKALOIDS — Rare cases of lung toxicity have been reported with vinblastine and vinorelbine. Bronchoconstriction, interstitial pneumonitis, lung nodules, and noncardiogenic pulmonary edema have been observed with vinblastine [123,124]. Vinorelbine has also been associated with interstitial pneumonitis as a single agent [125-127], but in most of the case reports, the drug was given in combination with gemcitabine, complicating the assessment of causality.

SUMMARY

●Adverse drug reactions due to antineoplastic agents are a common form of iatrogenic injury, and the lungs are a frequent target. While some reactions are related to the cumulative dose (eg, bleomycin), many are idiosyncratic and unpredictable.

●The most common patterns of lung toxicity include interstitial pneumonitis (bortezomib, anthracyclines and anthracycline-like agents, fludarabine, gemcitabine, ifosfamide, irinotecan, oxaliplatin, thalidomide and lenalidomide, vinca alkaloids), organizing pneumonia (doxorubicin, oxaliplatin), diffuse alveolar damage (gemcitabine, oxaliplatin, etoposide), opportunistic infections (bortezomib, fludarabine), noncardiogenic pulmonary edema (cytarabine, gemcitabine, vinblastine), radiation recall pneumonitis (doxorubicin, paclitaxel, gemcitabine), eosinophilic pneumonia (gemcitabine, oxaliplatin, procarbazine), alveolar hemorrhage (gemcitabine), nonthromboembolic pulmonary hypertension (thalidomide), and thromboembolic disease, which may affect the lungs (thalidomide and lenalidomide).

●In most cases, the risk of lung toxicity associated with each drug is small (<10 percent), and the respiratory adverse reaction is generally reversible with drug discontinuation. However, fatalities have been reported.

●A general discussion of the clinical presentation, pathogenesis, diagnosis, differential diagnosis, and management of antineoplastic agent-induced pulmonary toxicity is covered elsewhere, as is lung toxicity associated with molecularly targeted agents. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment" and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents".)

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

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Topic 4327 Version 30.0

References

1 : Drug-induced lung disease.

2 : Drug-induced pulmonary disease.

3 : Cytotoxic drug-induced lung injury.

4 : Cytotoxic drug-induced lung injury.

5 : Rapid response to high-dose steroids of severe bortezomib-related pulmonary complication in multiple myeloma.

6 : Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma.

7 : Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide.

8 : Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study.

9 : Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents.

10 : Interstitial pneumonitis caused by Pneumocystis jirovecii pneumonia (PCP) during bortezomib treatment.

11 : A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma.

12 : An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma.

13 : An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma.

14 : Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study.

15 : Cytarabine-related lung infiltrates on high resolution computerized tomography: a possible complication with benign outcome in leukemic patients.

16 : Fatal pulmonary failure complicating high-dose cytosine arabinoside therapy in acute leukemia.

17 : Non-cardiogenic pulmonary edema complicating intermediate and high-dose Ara C treatment for relapsed acute leukemia.

18 : Sequential multiagent chemotherapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age: Cancer and Leukemia Group B Study 9222.

19 : Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B.

20 : Doxorubicin and BOOP. A possible near fatal association.

21 : Severe interstitial lung disease associated with amrubicin treatment.

22 : Randomized phase II trial comparing amrubicin with topotecan in patients with previously treated small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0402.

23 : Phase II study of amrubicin in previously untreated patients with extensive-disease small cell lung cancer: West Japan Thoracic Oncology Group (WJTOG) study.

24 : Chemotherapy-induced pulmonary toxicity in lung cancer patients.

25 : Interstitial pneumonitis following mitozantrone, chlorambucil and prednisolone (MCP) chemotherapy.

26 : Interstitial pneumonitis possibly due to mitoxantrone.

27 : Fludarabine-related pulmonary toxicity: a distinct clinical entity in chronic lymphoproliferative syndromes.

28 : Pulmonary toxicity associated with fludarabine monophosphate.

29 : Fludarabine for prolymphocytic leukaemia and risk of interstitial pneumonitis.

30 : Pulmonary toxicity and acute respiratory failure associated with fludarabine monophosphate.

31 : Corticosteroid responsive fludarabine pulmonary toxicity.

32 : Steroid-responsive interstitial pneumonitis after fludarabine therapy.

33 : Gemcitabine-related pulmonary toxicity.

34 : Gemcitabine--a safety review.

35 : A report on serious pulmonary toxicity associated with gemcitabine-based therapy.

36 : Fatal pulmonary toxicity resulting from treatment with gemcitabine.

37 : Severe acute lung injury induced by gemcitabine.

38 : Diffuse alveolar damage in a patient treated with gemcitabine.

39 : Gemcitabine-induced severe pulmonary toxicity.

40 : Gemcitabine pulmonary toxicity: CT features.

41 : Severe non-haematological toxicity after treatment with gemcitabine.

42 : Clinical features and correlates of gemcitabine-associated lung injury: findings from the RADAR project.

43 : Gemcitabine added to doxorubicin, bleomycin, and vinblastine for the treatment of de novo Hodgkin disease: unacceptable acute pulmonary toxicity.

44 : Interstitial lung disease associated with gemcitabine treatment in patients with non-small-cell lung cancer and pancreatic cancer.

45 : Phase I study of twice-weekly gemcitabine and concurrent thoracic radiation for patients with locally advanced non-small-cell lung cancer.

46 : A Phase I study of gemcitabine with concurrent radiotherapy in stage III, locally advanced non-small cell lung cancer.

47 : Gemcitabine and radiosensitization in human tumor cells.

48 : Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: cancer and leukemia group B study 9431.

49 : Gemcitabine-induced radiation recall.

50 : Pulmonary complications of novel antineoplastic agents for solid tumors.

51 : Gemcitabine-induced acute eosinophilic pneumonia.

52 : High-resolution computed tomography findings for patients with drug-induced pulmonary toxicity, with special reference to hypersensitivity pneumonitis-like patterns in gemcitabine-induced cases.

53 : Gemcitabine-induced pulmonary toxicity: case report and review of the literature.

54 : Dyspnea with gemcitabine is commonly seen, often disease related, transient, and rarely severe

55 : Severe pulmonary toxicity in a patient treated with gemcitabine.

56 : Advanced breast cancer: a phase II trial with gemcitabine.

57 : Successful treatment of gemcitabine toxicity with a brief course of oral corticosteroid therapy.

58 : Hydroxyurea-induced interstitial pneumonitis: case report and review of the literature.

59 : Hydroxyurea-induced Pneumonitis in a Patient with Chronic Myelomonocytic Leukemia: An Autopsy Case.

60 : Fibrotic Lung Toxicity Induced by Hydroxycarbamide.

61 : Hydroxyurea-Induced Pneumopathy in a Patient With Myeloproliferative Syndrome.

62 : Interstitial pneumonitis associated with ifosfamide therapy.

63 : Phase II study of ifosfamide with mesna in adult patients with recurrent diffuse astrocytoma.

64 : Methemoglobinemia after infusion of ifosfamide chemotherapy: first report of a potentially serious adverse reaction related to ifosfamide.

65 : Dose-escalation study of weekly irinotecan and daily carboplatin with concurrent thoracic radiotherapy for unresectable stage III non-small cell lung cancer.

66 : A phase II study of CPT-11, a new derivative of camptothecin, for previously untreated non-small-cell lung cancer.

67 : Irinotecan-associated pulmonary toxicity.

68 : Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer.

69 : Phase II trial of irinotecan in patients with metastatic colorectal carcinoma.

70 : Phase II trial of irinotecan/gemcitabine as second-line therapy for relapsed and refractory small-cell lung cancer: Cancer and Leukemia Group B Study 39902.

71 : Dose escalation study of paclitaxel in combination with fixed-dose irinotecan in patients with advanced non-small cell lung cancer (JCOG 9807).

72 : Risk factors of pneumonitis following chemoradiotherapy for lung cancer.

73 : Irinotecan-induced interstitial pneumonia.

74 : Diffuse alveolar damage after a single dose of topotecan in a patient with pulmonary fibrosis and small cell lung cancer.

75 : Pulmonary drug toxicity: radiologic and pathologic manifestations.

76 : Topotecan-induced bronchiolitis.

77 : Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial.

78 : Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial.

79 : Melphalan-associated pulmonary toxicity following high-dose therapy with autologous hematopoietic stem cell transplantation.

80 : Melphalan-induced pulmonary interstitial fibrosis.

81 : Reversible melphalan-induced lung damage.

82 : Exacerbation of pre-existing interstitial lung disease after oxaliplatin therapy: a report of three cases.

83 : Eosinophilic lung disease under chemotherapy with oxaliplatin for colorectal cancer.

84 : Is acute dyspnea related to oxaliplatin administration?

85 : Cryptogenic organizing pneumonitis during oxaliplatin chemotherapy for colorectal cancer: case report.

86 : Fatal diffuse alveolar damage associated with oxaliplatin administration.

87 : Fatal pneumonitis induced by oxaliplatin.

88 : Interstitial pneumonitis after treatment with pemetrexed: a rare event?

89 : Interstitial Pneumonitis after Treatment with Pemetrexed for Non-small Cell Lung Cancer.

90 : Pemetrexed-induced pneumonitis: a case report.

91 : Fatal pemetrexed-induced lung injury in patients with advanced mesothelioma: a report of two cases.

92 : Alveolar hemorrhage associated with pemetrexed administration.

93 : Pemetrexed induced pneumonitis.

94 : Etoposide-induced pulmonary toxicity.

95 : [Etoposide-induced pneumonitis].

96 : [Administration of oral etoposide for one year as adjuvant chemotherapy for non-small cell lung cancer-side effect].

97 : Phase II study of daily oral etoposide in refractory germ cell tumors.

98 : Pulmonary toxicity secondary to procarbazine.

99 : Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors.

100 : Raltitrexed-related pulmonary toxicity.

101 : A phase II trial of temozolomide for patients with recurrent or progressive brain metastases.

102 : A phase II study of temozolomide therapy for poor-risk patients aged>or=60 years with acute myeloid leukemia: low levels of MGMT predict for response.

103 : Temozolomide-associated organizing pneumonitis.

104 : Dyspnea during thalidomide treatment for advanced ovarian cancer.

105 : Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma.

106 : Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes.

107 : Non-thromboembolic pulmonary hypertension in multiple myeloma, after thalidomide treatment: a pilot study.

108 : Pulmonary hypertension related to thalidomide therapy in refractory multiple myeloma.

109 : Reversible pulmonary hypertension and thalidomide therapy for multiple myeloma.

110 : Thalidomide-induced organizing pneumonia.

111 : Thalidomide may induce interstitial pneumonia preferentially in Japanese patients.

112 : Side effects and good effects from new chemotherapeutic agents. Case 2. Thalidomide-induced interstitial pneumonitis.

113 : Single-institute phase 2 study of thalidomide treatment for refractory or relapsed multiple myeloma: prognostic factors and unique toxicity profile.

114 : Thalidomide-induced reversible interstitial pneumonitis in a patient with recurrent ovarian cancer.

115 : Pulmonary toxicity from novel antineoplastic agents.

116 : Thalidomide-Related Eosinophilic Pneumonia: A case report and brief literature review.

117 : Disseminated herpes simplex virus and varicella zoster virus coinfection in a patient taking thalidomide for relapsed multiple myeloma.

118 : Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors.

119 : Immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infections.

120 : Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma.

121 : Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma.

122 : Pulmonary toxicity after long-term treatment with lenalidomide in two myeloma patients.

123 : Vinblastine-associated pulmonary toxicity in patients receiving combination therapy with mitomycin and cisplatin.

124 : Fatal acute respiratory failure after vinblastine-mitomycin therapy in lung carcinoma.

125 : UFT plus vinorelbine in advanced non-small cell lung cancer: a phase I and an elderly patient-directed phase II study.

126 : A phase II study of vinorelbine, a new derivative of vinca alkaloid, for previously untreated advanced non-small cell lung cancer. Japan Vinorelbine Lung Cancer Study Group.

127 : Pulmonary toxicity associated with vinorelbine-based chemotherapy in breast cancer.

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