Pulmonary Complications of Antineoplastic Agents : Era of Targeted Therapy

Transcription

1 Pulmonary Complications of Antineoplastic Agents : Era of Targeted Therapy Poster No.: C-1230 Congress: ECR 2013 Type: Educational Exhibit Authors: H. Y. Kim, J. H. Hwang, Y.-W. Chang, J. Y. Moon; Seoul/KR Keywords: Toxicity, Education, CT, Thorax DOI: /ecr2013/C-1230 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. Page 1 of 30

2 Learning objectives Learning objectives To review the spectrum of pulmonary complications in patients with various targeted antineoplastic therapy. To learn pulmonary complications according to each specific targeted agent. To illustrate findings on chest radiograph and CT on patients with pulmonary complications caused by targeted agents. Background Background A better understading of cancer cell biology has suggested many new targets for cancer drug discovery and development. Molecular targeted chemotherapy agents have different mechanisms of action than do classic cytotoxic agents. Therefore, the onset and presentation of the molecular targeted chemotherapeutic drugs may differ with cytotoxic agents. Cytotoxic anti-neoplastic therapy (Table. 1) Interfere with RNA and DNA synthesis or cell division Affect cell growth by various action mechanisms May cause cell death or apoptosis with severe cell damage and impair repair Greatly effect on rapidly dividing cells Lead to dose-related GI toxicity, myelosuppression Affect any organ, depending on the drug Peripheral nerve, lungs, kidneys, heart, CNS Targeted anti-neoplastic therapy Commonly used for treatment of various malignancies nowdays. Classic cytotoxic chemotherapy agents inhibit cell division and target rapidly proliferating cells. The newer molecular targeted therapies are directed to specific molecules responsible for regulating cell activities. May different toxicity of targeted and cytotoxic agents in both clinical and radiologic presentation. Page 2 of 30

3 Targeted anti-neoplastic therapy : Mechanism of action (Table. 2) 1. Monoclonal antibodies Bind to antigenic determinants of specific molecules Sometimes upregulated expression in malignancy Not necessarily rely on the activation of immune effector cells 2. Tyrosine kinase inhibitors (TKIs) Prevent phosphorylation of messengers, thereby interrupting the upregulated intracellular signaling pathway(s) 3. Agents that target other molecules Inhibit intracellular molecules rather than membrane receptors 4. Immunotherapy cytokines Regulate innate and adaptive immune systems, functioning in cascades 5. Immunomodulatory therapies Engage all cytotoxic T-cell of a patient for tumor cell lysis Pulmonary toxicity of targeted chemotherapy (Table. 3, 4) Infrequent with most commonly used targeted therapies However, may cause life-threatening respiratory side effects Less frequent and often less predictable Only a minority of treated patients develops lung toxicity 1. Causes for individual susceptibility Treated condition Occupational factors Associated treatments:concomitant drug, radiation, O2 therapy Renal or hepatic failure Rate of drug infusion and total dose Genetic predisposition Concomitant administration of drugs that affect metabolism 2. Difficult diagnosis of drug-induced lung disease Nonspecific clinical manifestations Confusion with infection, RT pneumonitis, recurrence of underlying disease Use of combination drug regimens Page 3 of 30

4 3. DLco # : Important and early clinical finding 4. Early recognition is important! Progressive and fatal injury if undiagnosed Stabilization or even reversal of disease by cessation of drug Diagnosis of drug-induced lung toxicity Diagnosis of drug-induced lung disease Appropriate history of drug exposure Dose Duration Concomitant drug, radiation, oxygen therapy Clinical signs and symptoms Dyspnea Cough Fever Decreased gas transfer Compatible radiographic and imaging findings Exclusion of alternative diagnoses Infection Malignancy Preexisting lung disease Response to therapy Withdrawal of offending agent Corticosteroids Histopathology (rarely obtained) Stereotypical, but nonspecific in most cases Primarily used to exclude other diagnoses Page 4 of 30

5 Uncommonly pursued except in difficult cases Drug-induced lung toxicity 1. Potential pathways of lung injury Direct toxic action on lung tissue : Caused by the drug or by products of its metabolism or bioactivation (toxic oxygen species, free radicals) Hypersensitivity response to either the drug or its metabolites Neural or hormonal mechanisms Induction of an autoimmune state Multiple mechanisms with a given drug 2. Chest radiography Primary imaging technique in suspected disease 3. CT Detect findings at an earlier stage than chest radiography Good for categorization of pulmonary reaction type 4. Imaging features Reflect the underlying histopathologic pattern of lung injury Fairly characteristic and often associated with specific drugs 5. Knowledge of these patterns and of the drugs can facillitate diagnosis!! Important clinicopathologic manifestations of drug-induced lung toxicity Injury due to toxic action on lung tissue # Diffuse alveolar damage # Interstitial pneumonia # Organizing pneumonia Injury due to hypersensitivity reactions # Drug-induced asthma # Eosinophilic pneumonia Injury due to neural or hormonal mechanisms # Drug-induced pulmonary edema # Drug-induced asthma Injury due to autoimmune mechanisms Page 5 of 30

6 # Drug-induced lupus # Drug-induced vasculitis Drug-induced pulmonary granulomatosis # Granulomatous vasculitis # Drug-induced sarcoidosis # Exogenous lipoid pneumonia Miscellaneous # Drug-induced pulmonary hemorrhage # Drug-induced vasospasm # Drug-induced pulmonary calcification # Drug-related pleural effusions and fibrosis # Drug-related lymphadenopathy # Drug-induced infection # Drug-induced pulmonary thromboembolism Treatment Immediately discontinuing the offending drug Appropriate management of the pulmonary symptoms General supportive measures including : - Smoking cessation - Control of underlying lung disease - Prompt treatment of concomitant respiratory infections Consider corticosteroids for severe disease Prognosis Usually disappear in hours or longer Over 1/3 cases : Fatal outcome Increased risk of drug-induced pulmonary toxicity - Pre-existing lung or cardiovascular disease - Patient treated in the accelerated phase of underlying disease Page 6 of 30

7 Images for this section: Table 1: Cytotoxic anti-neoplastic therapy Page 7 of 30

8 Table 2: Targeted anti-neoplastic therapy : Mechanism of action Table 3: Targeted agents: lung toxicities Page 8 of 30

9 Table 4: Lung toxicities : targeted agents Page 9 of 30

10 Imaging findings OR Procedure details Diffuse alveolar hemorrhage (Fig. 1) 1. Imaging findings Chest radiograph HRCT Early Normal Scattered or diffuse GGO Progression Bilateral diffuse Fibrosis such as irregular heterogenous or linear architectural opacities, homogenous opacities distortion, bronchiectasis traction 2. Differential diagnosis Pulmonary edema, lymphangitic carcinomatosis, leukemic/lymphomatous infiltration, Pneumocystis pneumonia, pulmonary hemorrhage of other cause Clinical setting and sequence of event is helpful Interstitial pneumonia (Fig. 2, 3, 4, 5) 1. Most common manifestation of drug-induced lung disease 2. Various patterns of interstitial pneumonia Nonspecific acute interstitial lung disease, cellular interstitial pneumonia, drug-induced fibrosis (Fig. 2, 3) Usual interstitial pneumonia (Fig. 4) Nonspecific interstitial pneumonia (Fig. 5) Lymphoid interstitial pneumonia Desquamative interstitial pneumonia Acute interstitial pneumonia 3. Chest radiograph Heterogenous parenchymal opacities Either diffuse or basal in distribution Page 10 of 30

11 4. HRCT Scattered areas of GGO, focal area of consolidation, irregular linear opacities Frequently associated with reticulation and volume loss Traction bronchiectasis and bronchiolectasis Basal and peribronchovascular distribution Organizing pneumonia (Fig. 6, 7) 1. Inflammatory cell infiltration and fibrosis that predominantly involves the air spaces 2. Histopathology Fibroblastic plug within respiratory bronchiole, alveolar duct, adjacent alveolar space Organizing pneumonia in surrounding lung with accumulation of lipid-laden macrophage in distal air spaces 3. Chest radiograph Peripheral, rounded, scattered areas of air space consolidation Patchy or confluent 4. HRCT Bilateral scattered areas of air space consolidation and GGO Centrilobular nodules and branching linear opacities Peribronchial and peripheral distribution Eosinophilic pneumonia (Fig. 8) 1. Histopathology Accumulation of eosinophil and macrophage in alveolar space Infiltration of eosinophil, lymphocyte, plasma cell within alveolar septa and adjacent interstitium 2. Diagnosis Presence of parenchymal opacification on chest radiograph Peripheral blood eosinophilia Page 11 of 30

12 Eosinophilic infiltration of the lung parenchyma Administration of a known drug without other causes of pulmonary disease 3. Chest radiograph Various extent of air space consolidations Random distribution or in peripheral lungs Tend to fleeting and migrating 4. HRCT GGO and air space consolidation Predominantly upper lobe and peripheral distribution Pulmonary edema (Fig. 9, 10) Common cause of non-cardiogenic pulmonary edema Mechanism Altered pulmonary capillary permeability with fluid leak into pulmonary interstitium and alveoli Water and salt retention with fluid imbalance Indistinguishable from other form of edema in radiographic findings and clinical course Leading to systemic process in late stage : ARDS Differential diagnosis New onset interstitial pulmonary edema of other clinical cause No additional corticosteroid therapy, diuretics 1. Chest radiograph Interstitial and alveolar infiltrates No cardiomegaly and pulmonary vascular redistribution 2. Chest CT Diffuse air space disease with ground glass opacities (m/c) Diffuse interstitial thickening Pleural effusion Usually occurs in the setting of the SLE syndrome Over 50% of patients with drug-induced lupus at some stage of their illness Also occur in the setting of hypersensitivity reactions Elevated level of pleural eosinophils resolution without sequelae Page 12 of 30

13 Pulmonary thromboembolism (Fig. 11) 1. More frequently arterial thromboembolic event Possible association with VEGF receptor therapy Mechanism : VEGF's role of integrity of vascular endothelium Thrombus formation Mostly cardiac and cerebrovascular system Aorta and arteries of the mesentery, pelvis, and extremities 2. Increased risk of venous thromboembolism Thalidomide-based therapy on a patient with multiple myeloma 3. Risk factor of vascular complication Prior arterial thromboembolic events Age older than 65 years Images for this section: Page 13 of 30

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15 Fig. 1: Rituximab-induced lung toxicity. Chest CT scan on 3 days after initiation of treatment shows bilateral diffuse and peribronchial air space consolidations and ground glass attenuations. Lung parenchymal opacification revealed rapid clearing on follow-up chest radiography(not shown). Page 15 of 30

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17 Fig. 2: Erlotinib(Gemcitabine)-induced lung toxicity. Chest CT scan on a month after initiation of treatment shows diffuse bilateral heterogeneous ground glass opacities with no remarkable zonal predominance. There is seen associated mild reticulation. Page 17 of 30

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19 Fig. 3: Bevacizumab-induced lung toxicity. Chest CT scan on 5 months after treatment shows bilateral diffuse and patchy ground glass attenuations and air space consolidations. Mild interlobualr and intralobular septal thickening is associated without zonal predominance. Fig. 4: Imatinib-induced lung toxicity. Chest CT scan on 2 years following treatment shows diffuse subpleural irregularities and reticulation with mild lower lung predominance, which was seen as progressed on retrospective review of previous chest radiographs. Page 19 of 30

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21 Fig. 5: Imatinib-induced lung toxicity. Chest CT scan on 2 years after treatment shows diffuse heterogeneous ground glass attenuations in the lungs. Which is associated with reticulation, bronchiolar dilatation. Subpleural sparing is seen in lower lobes. Fig. 6: Rituximab-induced lung toxicity. Chest CT scan on 11 months after treatment shows focal areas of air space consolidation with mild peripheral GGO in RUL and RLL (a, b), which are improved 3 months later (c, d). Page 21 of 30

22 Fig. 7: Trastuzumab induced lung toxicity. Chest CT scan on 9 months after starting treatment (a-c) shows peripheral and peribronchovasular air space consolidation in both lungs, greater extent in BLLs. Follow-up CT scan 3 months later (d-f) reveals resolution of previously noted bilateral lung parenchymal opacifications, however, there are newly appeared patchy GGOs BLLs (arrows). Fig. 8: Rituximab-induced lung toxicity. Chest CT scan on 3 days after treatment (a-c) shows patchy or nodular GGOs in LUL (arrows). Follow-up CT scan 3 months later (d-f) reveals newly appeared patchy or lobular GGOs anterior aspect of BULs and resolution of previously noted patchy GGOs in LUL (migrating pattern) (arrows). Persistent peripheral blood eosinophilia was identified. Page 22 of 30

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24 Fig. 9: Imatinib-induced lung toxicity. Chest CT scan on 3 months after treatment shows diffuse or lobular grond glas opacities in both lungs. Diffuse interlobular septal thickening is also noted and is associated with small amount of bilateral pleural effusion. Page 24 of 30

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26 Fig. 10: Rituximab-induced lung toxicity. Chest CT scan on a day after initiation of treatment shows diffuse extensive bilateral air space consolidation and ground glass opacity in both lungs. Anteroposterior gradient is seen on axial image. Page 26 of 30

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28 Fig. 11: Bortezomib-induced toxicity. Chest CT scan on 11 months after treatment shows thromboembolism in bilateral pulmonary arteries. No venous thrombosis was identified on both lower extremities and no other clinical predisposing causes were revealed on careful review. Page 28 of 30

29 Conclusion Pulmonary complications caused by targeted anti-neoplastic agents are infrequent and varied. It is important for the radiologist to know and recognize these potential complications. Discerning these pulmonary complications may help in making decision on diagnosis and therapy particularly for those with pulmonary and cardiovascular co-morbidities. References Jean M. Torrisi, Lawrence H. Schwartz, Marc J. Gollub, et al., MDC findings of chemotherapy induced toxicity: What radiologists need to know about the clinical and radiologic manifestations of chemotherapy toxicity. Radiology 2011;258:41-56 Nicholas A. Barber, Apar Kishor Ganti, Pulmonary toxicities from targeted therapies: a review. Targ Oncol 2011;6: Masanori Akira, Hideo Ishikawa, Satoru Yamamoto, Drug-induced pneumonitis: thin-section CT findings in 60 patients. Radiology 2002;224: Santiago E. Rossi, Jeremy J. Erasmus, H. Page McAdams, et al., Pulmonary Drug Toxicity : Radiologic and pathologic manifestations. RadioGraphics 2000; 20: Carolina A. S., Nestor L. M., Takeshi J., et al., Drug-Induced Eosinophilic pneumonia : high-resolution CT Findings in 14 patients. AJR 2006;186: Personal Information Presenter : Ha Youn Kim, M.D. Department of Radiology, Soonchunhyang University Hospital 59 Daesagwan-gil, Yongsan-gu Seoul , Republic of Korea. s102864@schmc.ac.kr Page 29 of 30

30 Corresponding author : Jung Hwa Hwang, M.D., Ph.D., Department of Radiology, Soonchunhyang University Hospital 59 Daesagwan-gil, Yongsan-gu Seoul , Republic of Korea. jhhwang@schmc.ac.kr Page 30 of 30