Pulmonary Toxicity of Chemotherapeutic Agents

Vamsi P. Guntur

Rajiv Dhand

Pulmonary toxicity is recognized with a growing number of chemotherapeutic agents. An estimated 5% to 20% or more of patients receiving chemotherapy develop pulmonary toxicity¹^,² either as a result of direct cytotoxicity, oxidative injury, systemic release of cytokines, impairment of alveolar repair and angiogenesis, abnormal apoptosis, capillary damage, or immune-mediated reactions.¹^,²^,³ The risk of pulmonary toxicity with chemotherapy also increases with older age, history of smoking, presence of preexisting pulmonary disease (especially interstitial lung disease [ILD]), multimod therapy, and high concentrations of supplemental oxygen.²^,⁴ Genetically determined differences in drug metabolism, the chemical nature of the drug, hypersensitivity reactions, the presence of underlying lung disease, or other host and environmental factors could account for individual susceptibility to develop pulmonary toxicity.¹^,²^,³^,⁵

DIAGNOSIS

Chemotherapy-related lung toxicity often presents a diagnostic challenge in the absence of any specific clinical, radiologic, physiologic, laboratory, or histologic features. Moreover, infections, aspiration, embolism, alveolar hemorrhage, cancer spread or recurrence, toxicity because of radiation therapy, pulmonary manifestations of disease elsewhere (especially cardiogenic or noncardiogenic pulmonary edema [NCPE]), or pulmonary drug toxicity because of other non-chemotherapeutic agents produce similar patterns of lung involvement. Because combinations of chemotherapeutic agents are commonly employed, it is difficult to impute causation to a particular drug/agent. The increased risk of opportunistic pulmonary infections in patients receiving chemotherapy⁶ further complicates the problem. Transbronchial or open lung biopsy may be required to differentiate between several causes that present with similar patterns of lung injury.

SYMPTOMS

Most patients present with a subacute illness and nonspecific symptoms such as fever, cough, dyspnea, and hypoxemia.¹^,²^,³ The relationship to drug administration is obvious when pulmonary toxicity follows soon after exposure, but the causal association may be much more difficult to diagnose when lung injury occurs several years later (e.g., with bleomycin, busulfan, or cyclophosphamide).⁷ Supplemental oxygen in high concentrations may provoke lung injury in patients previously treated with chemotherapy.⁸^,⁹ Some drugs¹^,¹⁰ such as trastuzumab, iodinated contrast agents, and cytokines could produce lung injury by a radiation recall phenomenon many years after discontinuation of radiation therapy to the chest.¹ Characteristically, chest imaging shows pulmonary opacities in the distribution of the previous radiation portal, but these can later progress to involve other areas of both lungs.

PULMONARY FUNCTION

Spirometry commonly reveals a restrictive defect. Reductions in diffusion capacity (DLCO) may occur as the sole abnormality,¹¹^,¹²^,¹³ or may precede clinical and radiographic changes. Decisions about surgical operability should not be based on isolated small changes in DLCO.¹⁴

BRONCHOALVEOLAR LAVAGE

Bronchoalveolar lavage (BAL) is helpful for diagnosing infections, alveolar hemorrhage, progression of cancer, or metastases. Most chemotherapy-related reactions are associated with neutrophilia in BAL fluid, whereas eosinophils predominate in eosinophilic pneumonia.

CLINICAL/RADIOLOGIC/PATHOLOGIC ENTITIES

Patients may manifest symptoms with or without functional and radiologic abnormalities (Table 18-1). Other drugs may predominantly involve the pulmonary parenchyma (Table 18-2) or pulmonary vasculature (Table 18-3). The ILD is the most frequently observed pattern of injury with chemotherapy.

TREATMENT

Concurrent or prior use of corticosteroids reduces the frequency and the severity of pulmonary reactions with several chemotherapeutic agents (e.g., all-trans-retinoic acid [ATRA]).¹⁵^,¹⁶ Along with discontinuation of the suspected agent, supportive treatment, and high-dose corticosteroids (approximately 1 mg prednisone per kg body weight) are given for severe reactions accompanied by hypoxemia or acute respiratory failure.¹⁷ Unfortunately, response to corticosteroids is unpredictable and no well-designed clinical trials support their use or provide guidance about the optimal dose and duration of treatment. Corticosteroids are generally tapered off following clinical and radiographic improvement. Rechallenge with the incriminated drug/agent is generally not recommended, but may be considered on an individual basis for essential drugs producing mild reactions. Early cases generally respond to drug discontinuation and corticosteroids, but delays in diagnosis could lead to irreversible pulmonary fibrosis with a poor outcome. Chemotherapy-related toxicity in the lung usually follows a gradually progressive course, but severe reactions with a rapid march to acute respiratory failure and a high mortality have been reported.¹⁸

Table 18-1 Chemotherapy-Related Drug Reactions Characterized by Symptoms, Pulmonary Function, or Radiographic Changes

Pattern of Lung Involvement	Drugs	Functional/Radiologic Abnormalities
Isolated cough	Interferon α, IL-2, methotrexate	Nonspecific
Isolated acute chest pain	Bleomycin, etoposide, methotrexate, doxorubicin	Nonspecific
Isolated decrease in DLCO	Paclitaxel, BCNU, gemcitabine	Isolated decrease in DLCO
Hemoptysis	Bevacizumab	Bilateral GGO; consolidation; tumor necrosis in squamous cell lung cancer
Hypersensitivity reactions (skin rash, urticaria, angioedema, bronchospasm, hypotension alone, or in combination)	Taxanes, gemcitabine, oxaliplatin, etoposide, teniposide, monoclonal Abs, MMC + vinca alkaloids, interferon α, l-asparaginase	Airflow obstruction; airway hyperreactivity; hyperinflation
Pleural effusion	gemcitabine, fludarabine, imatinib, thalidomide, methotrexate, ATRA, bleomycin, procarbazine, IL-2, etoposide, busulfan, taxanes	Pulmonary restriction, pleural effusion on chest X-ray
Pneumothorax	Carmustine (BCNU)	Pulmonary restriction, pneumothorax on chest X-ray
Mediastinal lymphadenopathy	Methotrexate, bleomycin, interferon	Hilar/mediastinal adenopathy

Table 18-2 Chemotherapy-Related Abnormalities in Pulmonary Parenchyma

Pattern of Lung Involvement	Drugs	Functional/Radiologic Findings	Pathologic Findings
Bronchiolitis	Busulfan, topotecan	Hyperinflation, expiratory chest CT shows air trapping and a mosaic pattern	Concentric luminal narrowing with intense lymphocytic infiltration
Acute pneumonitis	Erlotinib, gefitinib, imatinib, gemcitabine, temsirolimus, everolimus, thalidomide, taxanes, bortezomib, irinotecan, procarbazine, piritrexim, temozolomide, trastuzumab, cetuximab, pemetrexed	Diffuse/patchy GGOs, diffuse reticular/reticulonodular pattern	Hypercellular BAL with neutrophilia or lymphocytosis, nonspecific pneumonitis, acute or chronic interstitial inflammation. Abnormal Type II cells with large and hyperchromatic nuclei.
Pulmonary edema	Imatinib, gemcitabine, ARA-C, ATRA, azathioprine, G-CSF, IL-2, MMC, nitrogen mustards, paclitaxel, interferon α, pentostatin, decitabine, vinorelbine	Diffuse alveolar infiltrates with no cardiomegaly or pleural effusions.	Dilated lymphatics, alveolar septal edema, peribronchial edema, pleural effusion
Pulmonary alveolar proteinosis	Busulfan	Bilateral GGOs, interlobular septal thickening	PAS-positive material in alveoli with minimal inflammation
OP	Bleomycin, rituximab, methotrexate, trastuzumab, cyclophosphamide, MMC, thalidomide, doxorubicin, topotecan, oxaliplatin, mitoxantrone, interferon α, busulfan	Bilateral areas of consolidation, usually subpleural and peribronchial distribution. Frequent GGO	Polypoid intraluminal plugs of proliferating fibroblasts and myofibroblasts with interstitial infiltrates
Hypersensitivity pneumonia	Methotrexate, docetaxel, paclitaxel, imatinib, cyclophosphamide, nitrogen mustards, busulfan, bleomycin, fludarabine, rituximab, temozolomide	Bilateral GGOs and/or small poorly defined centrilobular nodules	Acute inflammation with neutrophils and eosinophils, prominent lymphocytic infiltration. Loose non-necrotizing granulomas
DAD	Fludarabine, erlotinib, oxaliplatin, gefitinib, paclitaxel, docetaxel, irinotecan, bleomycin, procarbazine, interferon α, ATRA, Mo Abs, etoposide, bortezomib, gemcitabine, busulfan, cyclophophamide, BCNU	Bilateral GGOs with or without consolidation, mainly in dependent lung regions. Chronic fibrotic phase may result in extensive reticulation, traction bronchiectasis, and honeycombing	Diffuse lesions with alveolar thickening Exudative phase—edema, acute interstitial inflammation, hyaline membranes Fibrotic phase—organizing fibrosis, Type II pneumocyte hyperplasia
Eosinophilic pneumonia	Fludarabine, oxaliplatin, interferon α	Bilateral areas of consolidation involving mainly the peripheral lung regions. Possible GGOs	High levels of eosinophils in BAL and lung biopsy with or without peripheral eosinophilia
Chronic interstitial pneumonia/fibrosis	Bleomycin, busulfan, gemcitabine, fludarabine, paclitaxel, docetaxel, irinotecan, gefitinib, imatinib, BCNU, bortezomib, cyclophosphamide, methotrexate, 6-mercaptopurine, oxaliplatin, thalidomide, azathioprine	Reticular infiltrates, shrinking lung fields, honeycombing. More involvement in lower lung zones.	Fibrosis, mononuclear interstitial infiltrates, interstitial edema, hyperplastic Type II pneumocytes
Alveolar hemorrhage	Gemcitabine, rituximab, gefitinib, alemtuzumab, gemtuzumab ozogamicin, MMC, ATRA, bevacizumab, azathioprine, fludarabine, ARA-C	Bilateral and diffuse alveolar infiltrates	Hemorrhagic BAL with hemosiderin-laden macrophages. Biopsy shows alveolar hemorrhage and capillaritis may be present with edema and fibrinoid necrosis of alveolar walls

Table 18.3 Pulmonary Vascular Involvement Due to Chemotherapeutic Agents

Pattern of Lung Involvement	Drugs	Functional/Radiologic Findings	Pathologic Findings
Thromboembolism	Thalidomide, bevacizumab, ATRA, tamoxifen, cisplatin, l-asparaginase	Reduction in DLCO	Widespread small vessel thrombosis
Pulmonary arterial hypertension	Interferon α, IL-2, MMC	Increased size of pulmonary artery	Arterial intimal and medial thickening, may progress to plexiform lesions
Pulmonary veno-occlusive disease	MMC, BCNU, CCNU, bleomycin, busulfan	Kerley B lines in the absence of cardiomegaly	Occlusion or narrowing of pulmonary venules by loose or paucicellular fibrous material or collagen-rich connective tissue

DIRECT DNA INTERACTING AGENTS

Alkylating Agents

Cyclophosphamide

Cyclophosphamide alone causes pulmonary toxicity with <1% frequency, but more often when used in high doses or in combination with other cytotoxic agents.¹⁹ Two patterns of pulmonary injury are recognized: (1) early pneumonitis and (2) late injury resulting in pulmonary fibrosis.²⁰^,²¹ Imaging reveals diffuse bilateral reticular and nodular opacities, with ground-glass opacities (GGOs) more prominent in acute injury, whereas fibrosis predominates in late-onset pneumonitis.²⁰ Histologic changes of organizing pneumonia (OP), diffuse alveolar damage (DAD), and fibrosis are described. Treatment includes discontinuation of cyclophosphamide and corticosteroids for early-onset lung injury.

Busulfan

Pulmonary toxicity with busulfan is limited but can occur with cumulative doses >500 mg, with concurrent use of other toxic agents, and with radiation therapy. Lung toxicity usually presents about 4 years (range 8 months to 10 years) after treatment. OP, pulmonary fibrosis, and veno-occlusive disease have been reported.²² The efficacy of corticosteroid treatment after stopping busulfan in a patient with lung toxicity is not established.

Chlorambucil

Chlorambucil rarely causes pneumonitis and pulmonary fibrosis, but pulmonary toxicity is associated with a high (52.6%) mortality²³ and may develop from days to years after initiation of drug exposure. Chronic interstitial pneumonitis, and less commonly OP, and eosinophilic pneumonitis are also described.²³^,²⁴ Treatment is prompt drug withdrawal, and the role of corticosteroids is unclear.²³

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