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Pulmonary toxicity by cystostatics


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Chemoterapy-induced lung toxicity

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Pulmonary toxicity by cystostatics

  1. 1. Pulmonary toxicity caused by cytotoxic drugs DR. J. ROIG CUTILLAS HOSPITAL NOSTRA SRA. MERITXELL ANDORRA
  2. 2. Alkylating agents Cyclophosphamide, nitrosureas, ifosfamide, procarbazine, busulfan, melphalan, chlorambucil Antimetabolites Methrotrexate, gemcitabine, azathioprine, 6-mercaptopurine, cytosine arabinoside, fludarabine Antibiotics Mitomycin, doxorubicin, bleomycin, neocarzinostatin Antimicrotubule agents Vinca alkaloids Taxanes: paclitaxel, docetaxel Miscellaneous Topotecan, irinotecan Etoposide, teniposide Gefitinib, ATRA, arsenic trioxide Chemotherapeutic agents and pulmonary toxicity Roig J et al. Clin Pulm Med 2006
  3. 3. Chemoterapy-induced lung toxicity: differential diagnosis • Pulmonary infection • Malignancy-related thromboembolism • Local tumor progression • Iatrogenic diffuse alveolar hemorrhage • Radiation-induced pneumonitis • O2, transfusion, other drug-induced toxicity • Postoperative complications
  4. 4. Chemoterapy-induced lung toxicity: clinical clues • Time course & high index of suspicion • Not distinctive features; sometimes fever • Subacute or even abrupt onset are possible • X-ray lags behind clinical symptoms: CT • Decreased DLCO: early marker & monitor • Increased DLCO: diffuse alveolar bleeding • Nonspecific imbalance of CD4/CD8 (BAL)
  5. 5. Chemotherapy-induced lung toxicity: role of other factors • Biological response modifiers • Hormonal agents • Other agents: • Interactions with radiotherapy • Interactions in combination chemotherapy • Thoracic surgery following chemotherapy
  6. 6. Chemotherapeutic agents used in lung cancer that may cause acute pneumonitis Cyclophosphamide Docetaxel Etoposide Gemcitabine Ifosfamide Ipomeanol Irinotecan Methotrexate Mitomycin Paclitaxel Procarbazine Vinca alkaloids
  7. 7. Tissue Reactions in Chemotherapy-induced Pulmonary Toxicity Chronic interstitial pneumonia Diffuse alveolar damage – Acute interstitial pneumonia Bronchiolitis obliterans organizing pneumonia (BOOP) Obliterative bronchiolitis Hypersensitivity pneumoniaa Lung fibrosis Pulmonary edema Pulmonary hemorrhage Pulmonary hypertension Pulmonary veno-occlusive disease a Poorly formed granulomas in methotrexate lung toxicity
  8. 8. Chemotherapeutic agents used in lung cancer that may cause ADRS Gemcitabine Gefitinib Methotrexate Mitomycin Paclitaxel Vinca alkaloids + mitomycin Roig J et al. Clin Pulm Med 2006; Inoue A. Lancet 2003
  9. 9. Chemotherapeutic agents used in lung cancer that may cause pulmonary fibrosis Cyclophosphamide Etoposide Methotrexate Mitomycin Nitrosureas Roig J et al. Clin Pulm Med 2006
  10. 10. Chemotherapeutic agents used in lung cancer that may cause pleural disease Cyclophosphamide Docetaxela Doxorubicinb Methotrexate Mitomycin Procarbazine Vinblastine + mitomycin Roig J et al. Clin Pulm Med 2006 a Trasudative pleural effussion caused by fluid retention syndrome b Trasudative pleural effussion caused by congestive heart failure
  11. 11. Chemotherapeutic agents used in lung cancer that may cause an hypersensitivity reaction with respiratory symptoms Roig J et al. Clin Pulm Med 2006 Docetaxel Etoposide Gemcitabine Ifosfamide + mesna Irinotecan Methotrexate Mitomycin Paclitaxel Procarbazine Topotecan Vinca alkaloids
  12. 12. Bronchial artery infusion in central lung cancer and metastasis Risk of massive hemoptysis 1 to 3 months after BAI Herald: hemoptoic sputum Need urgent arteriography Bronchial vascular fistula Rare esophageal ulceration Bronchial esophageal fistula Spinal cord damage Osaki T. Chest 1999; Suzuki T. J Bronchol 2001
  13. 13. Neglected respiratory toxicity(1) • Vincristine, procarbazine, cytarabine, chlorambucil may cause neuropathy that might affect respiratory muscle function • Does it imply an increased anesthesia risk ? • Risk of acute encephalopaty and respiratory depression with ifosfamide, metothrexate in SAS and advanced COPD with hypercapnic failure Aldrich T, Clin Chest Med 1990; Klein D, Can A Sc J 1983; Roig J, Clin Pulm Med 2006
  14. 14. Neglected respiratory toxicity(2) • Some cases of intrathoracic extravasation • Venous thromboembolism associated with central venous lines and subcutaneous ports • Increased hypercoagulability of concomitant therapies (erythropoietin, megestrol acetate) and malignancy itself Bozkurt AK.. Am J Clin Oncol 2003; Verso M. J Clin Oncol 2003; Biffi R. Cancer 2001; Bauer K. J Clin Oncol 2000; Wun T. Cancer 2003, Bolen J. A Am Med Dir Assoc 2000
  15. 15. Chemoterapy-induced lung toxicity: prevention in COPD • High-risk (30%) if nitrosureas are used • Sleepness with ifosfamide, methotrexate • More risk in “overlap”: COPD + SAS • Water retention: taxotere, ciclophosphamide • Increased risk of O2 toxicity • Sensorimotor neuropathy and interactions
  16. 16. Ifosfamide-induced lung toxicity Clinical presentation Respiratory features Incidence Outcome Acute Hypersensitivity reaction (mesna) Encephalopathy and respiratory depressiona Rare acute pneum CNS depression <12% Usually recovery a Concern in advanced COPD and SAS Cameron JC. Cancer Nurs 1993; Baker WJ. Cancer 1990
  17. 17. Campothecin-induced lung toxicity Agent Type Incidence Outcome Topotecan Irinotecan (CPT-11) Mild dyspnea Dyspnea Acute pneumonitis <3% < 22% 1-13% Reversible Maksymiuk A, Am J Clin Oncol 1998; Masuda N, J Clin Oncol 1992;Takeda K, Br J Cancer 1999
  18. 18. Gemcitabine-induced lung toxicity Clinical presentation Respiratory features Incidence Outcome Acute Hypersensitivity reaction Acute pneumonitis Rarely ARDS, PVODa <1 % Usually complete recovery except in ARDS a Pulmonary venoocclusive disease Proc ASCO 2000; Tempero MA. Cancer 1998; Marruchella A. Eur Resp J 1998; Nackaerts KL. Ann Oncol 1998; Vansteenkiste J. Lung Cancer 2001.
  19. 19. Mitomycine - induced lung toxicity Clinical presentation Respiratory features Incidence Outcome Acute Chronic, dose-related (total dose >30 mg/m2 ) Acute pneumonitis Very rarely thrombotic microangiopathy with ARDS 3 % -12 % Fatality rate 40% Increased risk if combined therapy with vinca alk. Increased risk of microangiopathy if associated with fluoruracil (highest mortality) Rivera MP. Am J Clin Oncol 1995, Linette DC. Ann Pharm 1992, Verweij J. Cancer 1987 Thompson C. South Med J 1992 A
  20. 20. Paclitaxel - induced lung toxicity Clinical presentation Respiratory features Incidence Outcome Acute Hypersensitivity reaction Acute pneum. HR <1% if pretreated Rare if dosage <350mg/m2 Usually recovery with mandatory pretreatment Risk of ARDS if high dose therapy or concomitant radiotherapy Essayan DM. J Clin Oncol 1996; Bookman MA. Ann Oncol 1997 Ramanthan R. Chest 1996; Robert F. Semin Radiat Oncol 1999
  21. 21. Docetaxel - induced lung toxicity Clinical presentation Respiratory features Incidence Outcome Acute Chronic Acute pneumonitis Fluid retention syndrome Very rare Increased risk of retention if >400 mg/m2 Usually complete recovery Etienne B. Rev Mal Respir 1998; Briasoulis E. Respiration 2000
  22. 22. DIFF. DIAGNOSIS: ALGORITHMIC APPROACH Chest symptoms + abnormal X-ray Clinical evaluation Non-infectious cause Infection not excluded Appropriate treatment Non-invasive work-up Early antibiotic No impr. Improved Continue AbInvasive proc.Keep Ab + -
  23. 23. Invasive diagnostic work-up •FOB: bronchial aspirates, PSB, BAL, TBB •Transthoracic needle aspiration (TNA) •Lung biopsy – VATS •Open lung biopsy: minithoracotomy Dorca J. 1995: ultrathin (25G)TNA in 97 cases of non-mechanically ventilated pneumonia Transient hemoptysis: 5 cases (5.2%) Self-limited partial pneumothorax: 3 cases (3%) Sensitivity 60.9%; PPV 100%; modified treatment in 30%
  24. 24. HRCT in patients with dyspnea, fever of unknown origin and normal X-ray • Immunocompromise, severe emphysema • May detect an unsuspected alveolar infiltrate or a subtle interstitial pattern • Guide for FOB techniques ► better yield Brown MJ. Acute lung disease in the immunocpmpromised host: CT and pathologic findings. Radiology 1994; Ramila E. Bronchoscopy guided by HRCT for the diagnosis of pulmonary infections in patients with hemathologic malignancies and normal plain chest X-rays. Haematologica 2000
  25. 25. Reliability of transbronchial biopsy • High utility only in case of: –Sarcoidosis –Lung cancer and some mestastases –Opportunistic infections in immunocompromised host –Lung transplantation Gal A. Adv Anat Pathol 2005
  26. 26. Lymphatic carcinomatosis may mimic severe bronchial asthma • Mendeloff A. Severe asthmatic dyspnea as the sole presenting symptom of generalized endolymphatic carcinomatosis: report of two cases with autopsy findings and review of the literature. N Eng J Med 1945 • Masson RG. Pulmonary microvascular cytology in the diagnosis of lymphangitic carcinomatosis. N Eng J Med 1989
  27. 27. Microscopic pulmonary tumor embolism may cause respiratory failure • Sometimes is the initial, subacute presentation of occult malignancy • Clue: precapillary pulmonary hypertension without thromboembolic disease and negative usual complementary tests • Value of wedge aspiration cytology Masson RG. Pulmonary microvascular cytology. A new diagnostic application of the pulmonary artery catheter. Chest 1985; Stucky A. A rare cause of fatal right heart failure. Eur J Intern Med 2006
  28. 28. Chemoterapy-induced lung toxicity: therapeutic approach • Early detected, non-severe cases: cessation • Severe cases: steroids on a timely fashion • Dosage & tapering: individualized basis • Transplant? (Santamauro JT, Chest 1994) • Desensitization possible, not recommended • Premedication mandatory with some agents • Future: Gene therapy? (West J, Chest 2001)