This document discusses chemotherapy-induced lung disease. It notes that over 150 drugs have been described as causing adverse pulmonary reactions, with the first reported drug being busulfan in the 1960s. All parts of the respiratory system can be affected, with less than 10% of patients receiving chemotherapy developing pulmonary toxicities. Common patterns of toxicity include interstitial pneumonitis/fibrosis, hypersensitivity pneumonitis, non-cardiac pulmonary edema, and acute pneumonia. Specific drugs are associated with each pattern. Diagnosis involves considering the possibility, knowledge of associated drug toxicities, and excluding other likely causes through testing including radiography, BAL, and biopsy.

1. Chemotherapy
Induced Lung
Disease
Dr. Varun Goel
Rajiv gandhi cancer institute
delhi

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 Toxicity
Interstitial Pneumonitis/ Fibrosis Acute pneumonia
Bleomycin Mitomycin/Vinca
Mitomycin C Gefinitib
Busulfan
Cyclophosphamide
Carmustine
Hypersensitivity 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 in
animal 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 Pneumonitis
Histopathology shows
1) eosinophils in
alveoli and interstitium
(Loffler’s syndrome) or
2) mixed mononuclear
cell infiltrates with
eosinophils, loosely
formed granulomas

24. Chemotherapy Drugs
Hypersensitivity 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 Pneumonitis
Mechanism 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 Toxicity
Syndromes
 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. ATRA
All 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 Alkaloid
Reactions
 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. -
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