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Chemotherapy induced lung toxicity dr. varun

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  • KL-6) is a mucinlike high-molecular-weight glycoprotein expressed by type II alveolar pneumocytes
  • poorlydefined centrilobular nodules (arrows) and extensiveareas of ground-glass attenuation
  • Transcript

    • 1. ChemotherapyInduced LungDiseaseDr. Varun GoelRajiv gandhi cancer institutedelhi
    • 2. 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
    • 3. Chemotherapeutic Agents
    • 4.  Sign and symptoms  symptoms may occur acutely or insidiously  cough, fever, dyspnea  Crackles.  PFT- ↓ DLCO
    • 5. 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.
    • 6. Recognition High index of suspicion Knowledge of patterns of toxicity associated with drugs Exclusion of other likely entities
    • 7.  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.
    • 8.  Radiologic Findings  HRCT –findings are not specific.  Interstitial, alveolar, or mixed infiltrative patterns  Pleural effusion with or without parenchymal lung disease  Lymphadenopathy is typically not present
    • 9.  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
    • 10. Patterns of Toxicity  Interstitial pneumonitis/fibrosis  Hypersensitivity pneumonitis  Non cardiac pulmonary edema  Acute pneumonia
    • 11. Patterns of ToxicityInterstitial Pneumonitis/ Fibrosis Acute pneumonia Bleomycin Mitomycin/Vinca Mitomycin C Gefinitib Busulfan Cyclophosphamide CarmustineHypersensitivity Pneumonitis Capillary leak/edema Methotrexate Retinoic Acid Paclitaxel Gemcitabine Cytosine Arabinoside
    • 12. Interstitial Pneumonitis/Fibrosis Presentation is subacute to chronic Dyspnea and dry cough Bibasilar crackles Radiographs show increased marking, peripherally/ bases can progress to honeycombing
    • 13. Intersitial Pneumonitis/Fibrosis Histopathology shows areas of fibrosis and varying degrees of mononuclear cell infiltration Atypical type II pneumocytes are present
    • 14. Chemotherapeutic Drugs Interstitial Fibrosis Pattern Bleomycin Cyclophosphamide Mitomycin BCNU Busulfan gemcitabine, fludarabine, paclitaxel, docetaxel, irinotecan, gefitinib, imatinib, bortezomib, methotrexate, 6- mercaptopurine, oxaliplatin, thalidomide, azathioprine
    • 15. Interstitial Pneumonitis/Fibrosis Mechanism 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
    • 16. •Bleomycin induces reactive oxygen radicals by forming a complex with Fe3+• Iron chelators ameliorate the pulmonary toxicity of bleomycin inanimal models
    • 17.  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
    • 18. Bleomycin Toxicity Risk 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
    • 19.  Some data suggest that continuous infusion of bleomycin may be associated with less pulmonary toxicity than bolus therapy; however, these data are inconclusive
    • 20. 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
    • 21. 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
    • 22. 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
    • 23. Hypersensitivity PneumonitisHistopathology shows1) eosinophils inalveoli and interstitium(Loffler’s syndrome) or2) mixed mononuclearcell infiltrates witheosinophils, looselyformed granulomas
    • 24. Chemotherapy DrugsHypersensitivity Pneumonitis Methotrexate Paclitaxel Docetaxel imatinib, cyclophosphamide, nitrogen mustards, busulfan, bleomycin, fludarabine, rituximab, temozolomide
    • 25. 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
    • 26. 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
    • 27. 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
    • 28. Paclitaxel Pulmonary ToxicitySyndromes Dyspnea during infusion – common Hypersensitivity pneumonitis –  Subacute development of dyspnea  CT scans show transient ground glass infiltrate or interstitial infiltrates  Usually resolves spontaneously or with corticosteroids Rare presentations of acute pneumonia/intersitial fibrosis
    • 29. 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
    • 30. Non Cardiac Pulmonary Edema  Alltrans retinoic acid  Gemcitabine  Cytarabine ( ARA C) Imatinib, azathioprine, G-CSF, IL-2, MMC, nitrogen mustards, paclitaxel, interferon α, pentostatin, decitabine, vinorelbine
    • 31. 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.
    • 32. 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
    • 33. 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
    • 34. Acute Pneumonia Syndrome  Mitomycin -Vinca alkaloid reaction  Gefitinib Erlotinib, imatinib, gemcitabine, temsirolimus, everolimus, thalidomide, taxanes, bortezomib, irinotecan, procarbazine, piritrexim, temozolomide, trastuzumab, cetuximab, pemetrexed
    • 35. 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
    • 36. 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
    • 37.  Diffuse ground glass opacities have been observed on CT imaging
    • 38. 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
    • 39.  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)
    • 40. 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
    • 41. 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
    • 42. - Thank u…..