Chemotherapy Induced LungDiseaseDr. Varun GoelRajiv gandhi cancer institutedelhi
Drug Induced Lung Disease Drug induced lung disease is increasing being
recognized with over 150 drugs described as causing adverse pulmonary reactions.
In the 1960s, the first drug reported to induce chemotherapy-related lung disease was busulfan.
All parts of the respiratory system can be affected.
Overall, less than 10% of patients who receive chemotherapeutic agents develop pulmonary toxicities
Chemotherapeutic Agents
Sign and symptomssymptoms may occur acutely or
insidiously cough, fever, dyspneaCrackles.PFT- ↓ DLCO
Problems in Recognition Drugs are given as part of multidrug regimens
and offending agent may not be clear Other conditions, such as pulmonary infection,
pulmonary thromboembolic disease or progression of cancer, occur considerably more frequently
No pathognomonic clinical, radiographic or pathologic findings
New agents or new combinations are frequently being used and unrecognized or new types of toxicity occur.
Recognition
High index of suspicion Knowledge of patterns of toxicity
associated with drugs Exclusion of other likely entities
Laboratory Findings↑ TLC, ESR and CRP↑Serum Krebs von den Lunge-6 (KL-6)
expressed by type II alveolar pneumocytes may be useful for ruling out other causes of
pneumonitis.
Radiologic FindingsHRCT –findings are not specific.
Interstitial, alveolar, or mixed infiltrative patterns
Pleural effusion with or without parenchymal lung disease
Lymphadenopathy is typically not present
Bronchoalveolar lavage several studies reported the presence of a characteristic
or predominant cells associated with particular drugs but results are variable.
Useful to exclude atypical or typical infections.
Histologic Findings not mandatory, cannot confirm the diagnosis it helps support it and can exclude other diseases may show diffuse alveolar damage, organizing
pneumonia, nonspecific pneumonitis, or neutrophilic alveolitis
Patterns of Toxicity
Interstitial pneumonitis/fibrosis Hypersensitivity pneumonitis Non cardiac pulmonary edema Acute pneumonia
Patterns of Toxicity
Interstitial Pneumonitis/ Fibrosis Acute pneumoniaBleomycin Mitomycin/VincaMitomycin C GefinitibBusulfanCyclophosphamideCarmustine
Hypersensitivity Pneumonitis Capillary leak/edemaMethotrexate Retinoic AcidPaclitaxel GemcitabineCytosine Arabinoside
Interstitial Pneumonitis/Fibrosis Presentation is subacute
to chronic Dyspnea and dry cough Bibasilar crackles Radiographs show
increased marking, peripherally/ bases can progress to honeycombing
Intersitial Pneumonitis/Fibrosis Histopathology shows
areas of fibrosis and varying degrees of mononuclear cell infiltration
Atypical type II pneumocytes are present
Chemotherapeutic DrugsInterstitial Fibrosis PatternBleomycinCyclophosphamideMitomycinBCNUBusulfan
gemcitabine, fludarabine, paclitaxel, docetaxel, irinotecan, gefitinib, imatinib, bortezomib, methotrexate, 6-mercaptopurine, oxaliplatin, thalidomide, azathioprine
Interstitial Pneumonitis/FibrosisMechanism of Toxicity
BAL in animals and humans in bleomycin induced show increased number of neutrophils and in some cases eosinophils (similar to IPF)
Direct toxicity with imbalance in oxidant - antioxidant systems
Vascular damage with influx of inflammatory cells and fibroblasts; induction of cytokines
Increased TGF- Beta Imbalance between the protease and
antiprotease system
• Iron chelators ameliorate the pulmonary toxicity of bleomycin in animal models
• Bleomycin induces reactive oxygen radicals by forming a complex with Fe3+
Incidence of toxicity is 4% but subclinical toxicity based on PFTS is 25%
Bleomycin hydrolase - major enzyme responsible for metabolism
lung and skin have the lowest levels of the enzyme most common targets for bleomycin toxicity
Bleomycin ToxicityRisk Factors
Dose > 450 units, although toxicity can occur at any dose
Radiation to thorax Supplemental oxygen – no safe threshold Age >70 years Elevated Creatinine ? Use of GCSF
animal studies suggest GCSF t/t is associated with bleomycin-induced pulmonary toxicity
data in humans are conflicting
Some data suggest that continuous infusion of bleomycin may be associated with less pulmonary toxicity than bolus therapy; however, these data are inconclusive
Bleomycin Pulmonary Toxicity
Interstitial fibrosis most common, rare hypersensitivity pneumonitis
Treatment involves no further drug, possible corticosteroids, avoidance of oxygen/radiation if possible
Late exacerbations can occur
Cyclophosphamide
MOA- reactive oxygen species. Endothelial swelling; pneumocyte
dysplasia; lymphocytic and histiocytic infiltration; fibrosis.
bibasilar reticular pattern; <1% incidence; no direct dose
dependence Drug withdrawal; corticosteroids may be
Hypersensitivity Pneumonitis Acute to subacute
presentation with systemic symptoms fever, fatigue, arthralgia – dyspnea and cough may be late
Eosinophilia may be present
Radiographs show air space disease
Hypersensitivity PneumonitisHistopathology shows1) eosinophils inalveoli and interstitium(Loffler’s syndrome) or2) mixed mononuclearcell infiltrates witheosinophils, looselyformed granulomas
Chemotherapy DrugsHypersensitivity Pneumonitis
MethotrexatePaclitaxelDocetaxel
imatinib, cyclophosphamide, nitrogen mustards, busulfan, bleomycin, fludarabine, rituximab, temozolomide
Methotrexate Toxicity
Usually presents with malaise, myalgias, fever, cough and dyspnea, skin rash in some cases
Radiographs vary from normal to mild atelectasis to bilateral alveolar infiltrates: Gallium scans are positive
Dramatic response to corticosteroids Seldom leads to fibrosis
Methotrexate PneumonitisMechanism of Toxicity
Immunological mechanism, supported by BAL findings and dramatic response to steroids
lymphocytic alveolitis is a consistent finding in methotrexate pneumonitis
imbalance of the CD4-to-CD8 ratio
Taxanes Paclitaxel
Associated with hypersensitivity reaction during infusion with dyspnea, bronchospasm, urticaria, rash and hypotension ( up to 1/3 patients)
suspension vehicle (Cremophor El) causes, not the drug.
Premed with steroids, antihistamines and H2 blockers ameliorates( 1% incidence)
Docetaxel - Little data
Paclitaxel Pulmonary ToxicitySyndromes
Dyspnea during infusion – common Hypersensitivity pneumonitis –
Subacute development of dyspnea CT scans show transient ground glass infiltrate
or interstitial infiltratesUsually resolves spontaneously or with
corticosteroids Rare presentations of acute
pneumonia/intersitial fibrosis
Non Cardiac Pulmonary Edema Respiratory distress occurs
over several hours Subacute capillary leak syndrome
Can be associated with effusions and edema
Radiographs show diffuse bilateral alveolar filling densities
Usually responds to withdrawal of offending drug
Found with gemcitabine/ATRA
Non Cardiac Pulmonary Edema
All trans retinoic acidGemcitabineCytarabine ( ARA C)
Imatinib, azathioprine, G-CSF, IL-2, MMC, nitrogen mustards, paclitaxel, interferon α, pentostatin, decitabine, vinorelbine
ATRAAll trans retinoic acid Fluid overload develops with weight gain,
peripheral edema, pleural effusion Patients present with dyspnea and edema
and usually weight gain. Increased risk with elevated WBC Can be treated with corticosteroids.
Gemcitabine Dyspnea reported in up to 10% with severe
dyspnea in 5% -Self limited– Acute hypersensitivity with bronchospasm– Capillary leak
Infiltrates – subtle capillary leak to interstitial infiltrate to pulmonary edema picture– Usually responds to holding drug or giving steroids
Acute Pneumonia Syndrome similar to non cardiac pulmonary
edema– Respiratory distress develops over several hours– Bilateral interstitial-alveolar infiltrates
Improvement but persistent pulmonary abnormalities persist
Pathology studies show inflammatory cells with endothelial inflammation as well as vascular leak
Acute Pneumonia Syndrome
Mitomycin -Vinca alkaloid reactionGefitinib
Erlotinib, imatinib, gemcitabine, temsirolimus, everolimus, thalidomide, taxanes, bortezomib, irinotecan, procarbazine, piritrexim, temozolomide, trastuzumab, cetuximab, pemetrexed
Mitomycin-Vinca AlkaloidReactions Syndrome of acute dyspnea without other
respiratory symptoms within hours of receiving vinca alkaloid in patients on mitomycin
Respiratory failure can occur Treated with supportive care and combinations
of diuretics, bronchodilators and corticosteroids Improvement occurs but chronic toxicity occurs
Gefitinib Main toxicity is mild acne like rash and
limited diarrhea Interstitial lung disease has been reported
which can be serious – up to 2% Unclear mechanism augmentation of pulmonary fibrosis by decreasing
EGFR phosphorylation resulting in a decrease in regenerative epithelial proliferation
Diffuse ground glass opacities have been observed on CT imaging
Bevacizumab Recombinant humanized monoclonal
antibody targets vascular endothelial growth factor (VEGF)– Approved for colorectal cancer; under study for
breast cancer, renal cancer and lung cancer Side effects
– Thromboembolic events– Hypertension– Hemorrhage– Gastrointestinal perforation
Serious tumor related bleeding with hemoptysis /hematemesis in 6 cases, all with centrally located pulmonary tumors close to major blood vessels.
(Clin Res Cancer 2004; 10: 4258S)
Imatinib/Dasatinib Mechanism of Injury- Unknown
one case of imatinib Hypersensitivity suggested by high number of lymphocytes with low CD4/CD8 ratio
Exudative pleural effusion/pulmonary edema; eosinophilic infiltration; interstitial inflammation/fibrosis
M-TOR INHIBITORS Sirolimus
Possibly evoking Th1 response and recruitment of an inflammatory response in lung.
BOOP, lymphocytic alveolitis 5%-15% incidence Risks factors include late switch to
drug and/or renal impairment. Temsirolimus/Everolimus
.5%–5% incidence
-Thank u…..