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Download Pulmonary toxicity from novel antineoplastic agents
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Annals of Oncology 17: 372–379, 2006 • 10% of antineoplastic agents – pulmonary toxicity. • Diagnosis – history of drug exposure – the exclusion of other causes • infections,fluid overload, pulmonary edema, pulmonary embolism • lung involvement from the underlying neoplasm Pulmonary toxicity from antineoplastic agents • Interstitial lung disease (ILD) – the most common – interstitial lung damage, alveolar filling processes • • • • • non-specific interstitial pneumonitis hypersensitivity pneumonitis interstitial lung fibrosis BOOP ARDS, diffuse alveolar damage(hemorrhage) Interstitial Lung Disease • Many conditions that involve lung parenchyme – Alveoli, alveolar epithelium, capillary endothelium, interstitial space • Classification – Predominant inflammation and fibrosis – Predominant granulomatous reaction • Known and unknown cause • Nonmalignant disorder and are not caused by identified infectious agents – Precise pathway to fibrosis is not known Allergy 2000;55;1103-1120 • Basic aspects of the development of alveolitis – triggering of CD4 T cells by local antigen presenting cell – release of cytokines with multiple and overlapping functions – intra-alveolar and interstitial accumulation of alveolar macrophages , CD4+ T cells, CD8+ T cells, neutrophils Table 243–1. Major Categories of Alveolar and Interstitial Inflammatory Lung Disease Known Cause Asbestos Fumes, gases Drugs (antibiotics, amiodarone, gold) and chemotherapy drugs Radiation Aspiration pneumonia Residual of adult respiratory distress syndrome Unknown Cause Idiopathic interstitial pneumonias Idiopathic pulmonary fibrosis (usual interstitial pneumonia) Desquamative interstitial pneumonia Respiratory bronchiolitis-associated interstitial lung disease Acute interstitial pneumonia (diffuse alveolar damage) Cryptogenic organizing pneumonia (bronchiolitis obliterans with organizing pneumonia) Nonspecific interstitial pneumonia Connective tissue diseases Systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, systemic sclerosis, Sjögren's syndrome, polymyositisdermatomyositis Pulmonary hemorrhage syndromes Goodpasture's syndrome, idiopathic pulmonary hemosiderosis, isolated pulmonary capillaritis Pulmonary alveolar proteinosis Lymphocytic infiltrative disorders (lymphocytic interstitial pneumonitis associated with connective tissue disease) Eosinophilic pneumonias Lymphangioleiomyomatosis Amyloidosis Inherited diseases Tuberous sclerosis, neurofibromatosis, Niemann-Pick disease, Gaucher's disease, Hermansky-Pudlak syndrome Gastrointestinal or liver diseases (Crohn's disease, primary biliary cirrhosis, chronic active hepatitis, ulcerative colitis) Graft-vs.-host disease (bone marrow transplantation; solid organ transplantation) Bird fancier's, breeder's, or handler's lungb Parakeet, pigeon, chicken, turkey proteins Avian droppings or feathers Cephalosporium HP Contaminated basement (sewage) Cephalosporium Cheese washer's lung Penicillium casei Moldy cheese Chemical worker's lunga Isocyanates Polyurethane foam, varnishes, lacquer Coffee worker's lung Coffee bean dust Coffee beans Compost lung Aspergillus Compost Detergent worker's disease Bacillus subtilis enzymes (subtilisins) Detergent Familial HP Bacillus subtilis Contaminated wood dust in walls Farmer's lunga Thermophilic actinomycetesb "Moldy" hay, grain, silage Laboratory worker's HP Male rat urine Laboratory rat Lycoperdonosis Lycoperdon puffballs Puffball spores Malt worker's lung Aspergillus fumigatus or A. clavatus Moldy barley Maple bark disease Cryptostroma corticale Maple bark Miller's lung Sitophilus granarius (wheat weevil) Infested wheat flour Miscellaneous medication Amiodarone, bleomycin, Medication efavirenz, hydralazine, hydroxyurea, iosoniazid, methotrexate, paclitaxel, penicillin, procarbazine, propanolol, sulfasalazine Table 237–1. Selected Examples of Hypersensitivity Pneumonitis (HP) Table 237–1. Selected Examples of Hypersensitivity • 6 days after the third dose of irinotecan • a new dry cough with progressive shortness of breath • BAL: – 64% lymphocytes, 15% macrophages, 2% segmented neutrophils, • Bx: – lymphocytic pneumonia with fibrosis of the alveolar septa – a patchy infiltrate was seen preferentially around blood vessels without endothelitis Biopsy Biopsy To prevent pulmonary toxicity • Identification of patients at risk – History of asthma, allergic rhinitis – underlying lung disease • (emphysema, chronic bronchitis or metastases) – Monitoring of DLCO should help to detect subclinical toxic effects. – Steroids are an effective immediate therapy, • recurs after reducing the dose Classification of antineoplastic drugs • Antimetabolites – Gemcitabine, Fludarabine, Cladribine, Pentostatin • Taxanes – Paclitaxel,Docetaxel • Topoisomerase I inhibitors – Irinotecan, Topotecan • Platinum analogs – Oxaliplatin,Cisplatin • Tyrosine kinase inhibitors – Gefitinib, Imatinib mesylate,Erlotinib • Monoclonal antibodies • Thalidomide • Bortezomib Antimetabolites-Gemcitabine • Pyrimidine analog • Uncommon – lung toxicity of 1.4% and <1%, • self-limiting dyspnea of uncertain etiology – bronchoconstriction – non-specific interstitial pneumonitis • Steroid responsive Antimetabolites-Gemcitabine • Impair PFTs – Advanced NSCLC – Gemcitabine and cisplatin – DLCO decreased significantly • Non-thoracic malignancy – 24%, clinical silent,reversible decrease in DLCO – Other lung function: no change • Close structural feature to Ara-C – Toxic damage on the respiratory endothelium of pul capillary vessel – Capilary leak synd. – Hypersensitivity (sterod responsive,patho inflm) Fludarabine • Nucleoside analog – Low grade lymphoma , CLL – Intersitial and eosinophilic pneumonitis – Increased risk of oppotunistic infec. – Lung toxicity • • • • 9/105(8.6%) Interstitial , alveolar infiltrate Small pleural effusion Treated with steroid Taxane-Paclitaxel • Type I hypersensityvity reaction – 30% – Dyspnea, chest tightness, bronchospasm, urticaria, hypotension – After 2-3 min – IgE, Cremophor EL vehicle, histamine, vasoactive substances – Premedication Taxane-Paclitaxel • ILD • 1% • Concurrently with RT (47%) • With other agent(Gemcitabine)-33% • Impair PFT – NSCLC – With Cisplatin , RT – DLCO decreased for several months Docetaxel • Taxane derivative • Frequent hypersensitivity – Polysorbate-80, histamine release • premedication • Acute Intersitial pneumonitis – Responsive to steroid – With Gemcitabine(23%) • Capillary leak syndrome – Cumulative dosage>500mg/M(50%) – MPD 40mg daily Topoisomerase I inhibitor-Irinotecan • Metastatic colorectal ca • >20% in US studies – Hx of 5-FU exposure – Steroid responsive interstitial pneumonitis • A few cases – Incidence of pnemonitis • 1.8% in the elderly Japanese trial • Higher with paclitaxel(12.5%) • Higher with RT(56%) • Immunopathological mechanism? – Hx of asthma or seasonal rhinitis Platinum analog-Oxaliplatin • Laryngeal dysthesia – Neurosensory effect • Monotherapy-pul toxicity: rare – Acute diffuse alveolar damage – With 5-FU, leucovorin – Steroid responsive • 5-FU monotherapy: Lung toxicity? • DDx other causes Tyrosine kinase inhibitor-Gefitinib • EGFR tyrosine kinase inhibitor • Advance NSCLC, ovary, breast, H&N, Colon • ILD – During the 1st 3mon – Dyspnea with cough or low grade fever – Diffuse alveolar and or interstitial damage Tyrosine kinase inhibitor-Gefitinib • Risk factor – – – – Japanese Prior RT or chemo in thorax Smoking Hx IPF , pnemonia • Pathophysiology – EGFR: regeneration of epithelium • Up-regulated in acute lung injury • Impair repairexacerbate lung injury • With pul. comorbidities Imatinib mesylate • BCR-ABL tyrosine kinase – CML, Inoperable GIST • Fluid retension syndrome – Pleural effusion, pul edema – 2.3 % in late CML • Interstitial Pneumonits – More rare Monoclonal antibodies-Rituximab • CD20+ B lymphocytes. • lung injury – in <0.03% – interstitial pneumonitis – cytokine release – serious toxicity in • decrease in lymphocyte count after rituximab • resolved after steroid treatment, with no late sequelae • concomitant steroids- not prevent the occurrence of pneumonitis Trastuzumab • Epidermal growth factor type 2(HER2) – Overexpress in 25% of breast ca • Bronchospasm – Only serious adverse event – 15 cases(0.04%): fatal – Within 2.5 h – Poor performance status – Severe underlying pul problem Bevacizumab • VEGF • Advanced colorectal ca • Hemoptysis with NSCLC – Centrallly located tumor – Prox to major vessel – Squamous cell type Cetuximab(Erbitux) • Anti-EGFR monoclonal Ab – Colon and H&N • Dyspnea – Severe in 13% of cases – Related to infusion – Poor performance status – With underlying lung dis. Thalidomide • multiple myeloma primarily – but also of prostate and renal cancer – immunomodulatory and antiangiogenic effects, along with anticytokine activity. • dyspnea without further details – 4% to 54% – Transient – reintroduced at a reduced dose • The most serious side effect – thromboembolic disease – combined with dexamethasone or other agents • Rare adverse effects – interstitial pneumonitis and pleural effusion Bortezomib • inhibitor of 26-S proteasome – a large protein complex that degrades ubiquitinated proteins • for recurrent and/or refractory myeloma. • Lung toxicity - uncommon and – consists mainly of dyspnea • ILD is very rare; – one case of pneumonitis
