ChemotherapyInduced LungDiseaseDr. Varun GoelRajiv gandhi cancer institutedelhi
Drug Induced Lung Disease   Drug induced lung disease is increasing    being recognized with over 150 drugs    described ...
Chemotherapeutic Agents
   Sign and symptoms     symptoms  may occur acutely or insidiously     cough, fever, dyspnea     Crackles.     PFT- ...
Problems in Recognition   Drugs are given as part of multidrug regimens    and offending agent may not be clear   Other ...
Recognition High index of suspicion Knowledge of patterns of toxicity  associated with drugs Exclusion of other likely ...
   Laboratory Findings    ↑ TLC, ESR and CRP     ↑Serum Krebs von den Lunge-6 (KL-6)          expressed by type II alv...
   Radiologic Findings     HRCT    –findings are not specific.        Interstitial, alveolar, or mixed infiltrative pat...
   Bronchoalveolar lavage     several studies reported the presence of a      characteristic or predominant cells associ...
Patterns of Toxicity  Interstitial pneumonitis/fibrosis  Hypersensitivity pneumonitis  Non cardiac pulmonary edema  Ac...
Patterns of ToxicityInterstitial Pneumonitis/ Fibrosis   Acute pneumonia   Bleomycin                         Mitomycin/Vin...
Interstitial Pneumonitis/Fibrosis Presentation is subacute  to chronic Dyspnea and dry cough Bibasilar crackles Radiog...
Intersitial Pneumonitis/Fibrosis Histopathology shows  areas of fibrosis and  varying degrees of  mononuclear cell  infil...
Chemotherapeutic Drugs    Interstitial Fibrosis Pattern    Bleomycin    Cyclophosphamide    Mitomycin    BCNU    Busu...
Interstitial Pneumonitis/Fibrosis    Mechanism of Toxicity   BAL in animals and humans in bleomycin    induced show incre...
•Bleomycin induces reactive oxygen radicals by forming a complex with Fe3+• Iron chelators ameliorate the pulmonary toxici...
 Incidence of toxicity is 4% but subclinical  toxicity based on PFTS is 25% Bleomycin hydrolase - major enzyme  responsi...
Bleomycin Toxicity                  Risk Factors   Dose > 450 units, although toxicity can occur    at any dose   Radiat...
   Some data suggest that continuous infusion    of bleomycin may be associated with less    pulmonary toxicity than bolu...
Bleomycin Pulmonary Toxicity Interstitial fibrosis most common, rare  hypersensitivity pneumonitis Treatment involves no...
Cyclophosphamide MOA- reactive oxygen species. Endothelial swelling; pneumocyte  dysplasia; lymphocytic and histiocytic ...
Hypersensitivity Pneumonitis Acute to subacute  presentation with  systemic symptoms  fever, fatigue, arthralgia –  dyspn...
Hypersensitivity PneumonitisHistopathology shows1) eosinophils inalveoli and interstitium(Loffler’s syndrome) or2) mixed m...
Chemotherapy DrugsHypersensitivity Pneumonitis       Methotrexate       Paclitaxel       Docetaxel   imatinib, cycloph...
Methotrexate Toxicity   Usually presents with malaise, myalgias,    fever, cough and dyspnea, skin rash in some    cases...
Methotrexate PneumonitisMechanism of Toxicity Immunological mechanism, supported by  BAL findings and dramatic response t...
Taxanes   Paclitaxel     Associated   with hypersensitivity reaction      during infusion with dyspnea, bronchospasm,   ...
Paclitaxel Pulmonary ToxicitySyndromes Dyspnea during infusion – common Hypersensitivity pneumonitis –     Subacute    ...
Non Cardiac Pulmonary Edema   Respiratory distress occurs    over several hours          Subacute capillary leak syndrom...
Non Cardiac Pulmonary Edema        Alltrans retinoic acid        Gemcitabine        Cytarabine ( ARA C)   Imatinib, az...
ATRAAll trans retinoic acid Fluid overload develops with weight gain,  peripheral edema, pleural effusion Patients prese...
Gemcitabine   Dyspnea reported in up to 10% with severe    dyspnea in 5% -Self limited    – Acute hypersensitivity with b...
Acute Pneumonia   Syndrome similar to non cardiac pulmonary    edema    – Respiratory distress develops over several hour...
Acute Pneumonia Syndrome         Mitomycin     -Vinca alkaloid reaction         Gefitinib   Erlotinib, imatinib, gemcit...
Mitomycin-Vinca AlkaloidReactions   Syndrome of acute dyspnea without other    respiratory symptoms within hours of recei...
Gefitinib Main toxicity is mild acne like rash and  limited diarrhea Interstitial lung disease has been reported  which ...
   Diffuse ground glass opacities have been    observed on CT imaging
Bevacizumab   Recombinant humanized monoclonal    antibody targets vascular endothelial growth    factor (VEGF)    – Appr...
   Serious tumor related bleeding with    hemoptysis /hematemesis in 6 cases, all    with centrally located pulmonary tum...
Imatinib/Dasatinib   Mechanism of Injury- Unknown           one case of imatinib Hypersensitivity suggested            b...
M-TOR INHIBITORS   Sirolimus     Possibly evoking Th1 response and      recruitment of an inflammatory      response in ...
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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
  • Chemotherapy induced lung toxicity dr. varun

    1. 1. ChemotherapyInduced LungDiseaseDr. Varun GoelRajiv gandhi cancer institutedelhi
    2. 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. 3. Chemotherapeutic Agents
    4. 4.  Sign and symptoms  symptoms may occur acutely or insidiously  cough, fever, dyspnea  Crackles.  PFT- ↓ DLCO
    5. 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. 6. Recognition High index of suspicion Knowledge of patterns of toxicity associated with drugs Exclusion of other likely entities
    7. 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. 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. 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. 10. Patterns of Toxicity  Interstitial pneumonitis/fibrosis  Hypersensitivity pneumonitis  Non cardiac pulmonary edema  Acute pneumonia
    11. 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. 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. 13. Intersitial Pneumonitis/Fibrosis Histopathology shows areas of fibrosis and varying degrees of mononuclear cell infiltration Atypical type II pneumocytes are present
    14. 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. 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. 16. •Bleomycin induces reactive oxygen radicals by forming a complex with Fe3+• Iron chelators ameliorate the pulmonary toxicity of bleomycin inanimal models
    17. 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. 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. 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. 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. 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. 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. 23. Hypersensitivity PneumonitisHistopathology shows1) eosinophils inalveoli and interstitium(Loffler’s syndrome) or2) mixed mononuclearcell infiltrates witheosinophils, looselyformed granulomas
    24. 24. Chemotherapy DrugsHypersensitivity Pneumonitis Methotrexate Paclitaxel Docetaxel imatinib, cyclophosphamide, nitrogen mustards, busulfan, bleomycin, fludarabine, rituximab, temozolomide
    25. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 37.  Diffuse ground glass opacities have been observed on CT imaging
    38. 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. 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. 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. 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. 42. - Thank u…..
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