Download Pulmonary toxicity from novel antineoplastic agents

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
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•
•
•
•
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
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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
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Japanese
Prior RT or chemo in thorax
Smoking Hx
IPF , pnemonia
• Pathophysiology
– EGFR: regeneration of epithelium
• Up-regulated in acute lung injury
• Impair repairexacerbate 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