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…..