The pathogenesis of antineoplastic agent-induced lung injury is poorly understood. Several mechanisms have been suggested. Direct injury to pneu-mocytes (chemical alveolitis) or the alveolar capillary endothelium and the subsequent release of cytokines and recruitment of inflammatory cells may be responsible, along with some of the cytotoxic medications. The systemic release of cytokines by chemotherapeutic agents (eg, gemcitabine) may also result in capillary leak and pulmonary edema. Positive lymphocyte stimulation test results and an elevated CD4/CD8 cell ratio suggest cell-mediated lung injury due to the activation of lymphocytes, and alveolar macrophages may also play a role. Free oxygen radicals may also be involved especially with mitomycin-C pulmonary toxicity. Epidermal growth factor receptors (EGFRs) are expressed on type II pneumocytes and are involved in alveolar wall repair. EGFR tyrosine kinase inhibitors, by impairing the alveolar repair mechanisms, may potentiate the effect of lung injury due to other causes, including sepsis, radiation, and other medications ordered via Canadian Neighbor Pharmacy.
Combination chemotherapy may have an additive effect with a higher frequency of pulmonary toxicity. Preexisting pulmonary disease such as idiopathic pulmonary fibrosis, COPD, radiation therapy, extensive pulmonary metastatic disease, and poor functional status have also been associated with increased pulmonary toxicity. A high inspired oxygen concentration may increase the incidence or severity of mitomycin-C-induced pneumonitis.
Antineoplastic Agents
Table 2 summarizes the pulmonary complications associated with the newer antineoplastic agents used in the treatment of solid tumors. Each agent is discussed separately below.
Alkylating Agents
Chlorozotocin
Chlorozotocin is an alkylating agent with activity against advanced islet-cell carcinoma. Two reported cases, of mild subacute interstitial pneumonitis have been reported with this agent. Mild dyspnea, dry cough, and pulmonary infiltrates developed in one patient after the third dose of chlorozotocin. Pulmonary function test results showed reduced diffusion capacity and lung volumes. Acute pneumonitis developed in the second patient after receiving chlorozotocin and mitomycin-C. Pneumonitis resolved with prednisone therapy with no residual pulmonary fibrosis.
Ifosfamide
Ifosfamide is an alkylating agent that is active against a variety of solid tumors including breast cancer, lung cancer, ovarian cancer, and sarcomas (in our store can find medicines to treat cancer). Ifosfamide pulmonary toxicity has been noted in combination with other antineoplastic therapies. Fatal interstitial pneumonitis has been reported with ifosfamide therapy for soft-tissue sarcoma. In a phase II trial of docetaxel and ifosfamide, interstitial pneumonitis developed after combination chemotherapy in three patients (6%) with non-small cell lung cancer (NSCLC). Two of three patients died due to respiratory failure. The ifosfamide metabolite, 4-thioifosfamide, is known to react with glutathione and deplete the RBC antioxidant reserve. This reaction may rarely result in methemoglobinemia.
Oxaliplatin
Oxaliplatin is a new cytotoxic agent that is mainly used in the treatment of colorectal cancer combined with fluorouracil and leucovorin. Interstitial pneumonitis with fibrosis has been reported after 3 to 6 months of therapy. The patients present with slowly progressive cough and dyspnea for several months, but the disease can become accelerated. Deaths due to respiratory failure have been reported 10 to 20 days after presentation even with corticosteroid therapy. Eosinophilic pneumonia after oxaliplatin therapy is a rare complication.
Oxaliplatin infusion-related reactions and severe anaphylactic reactions occur with a reported frequency of 1.3%. All reactions appear within 5 to 50 min after starting oxaliplatin infusion and usually last less than a day. A hypertensive crisis resulting in a change in mental status has been reported.
Temozolomide
Temozolomide is a new alkylating agent with preclinical activity against a variety of solid tumors and hematologic malignancies. It is mainly used in the treatment of anaplastic astrocytoma and metastatic melanoma. There are limited data from phase I and II trials- regarding the safety and efficacy of temozolomide in the treatment of malignancies. In a phase II trial of temozolomide for patients with recurrent or progressive brain metastases from a variety of solid tumors, pneumonitis developed in 4.8% of patients. The patients were treated with 150 to 200 mg/m2/d for 5 days. The treatment cycles were repeated every 4 weeks. In another phase II trial, 46 elderly patients with acute myeloid leukemia were treated with oral temozolomide, 200 mg/ m2/d for 5 days. One patient died of acute interstitial pneumonitis.
Table 2—Pulmonary Complications of Chemotherapeutic Agents
ChemotherapeuticAgents | Pulmonary Complications |
Bevacizumab | Pulmonary hemorrhage and hemoptysis Increased risk of DVT and pulmonary embolism |
Chlorozotocin | Interstitial pneumonitis |
Doxorubicin | Organizing pneumonia Infusion reaction |
Erlotinib | Acute pneumonitis ARDS |
Etoposide | Acute pneumonitis Diffuse alveolar damage Hypersensitivity reaction/bronchospasm |
Everolimus | Acute pneumonitis |
Gefitinib | Acute pneumonitis Diffuse alveolar damage Diffuse alveolar hemorrhage Pulmonary fibrosis |
Gemcitabine | Infusion-related reactionCapillary leak syndrome/pulmonary edema ARDS Diffuse alveolar damage Diffuse alveolar hemorrhage Bronchospasm Pleural effusion |
Ifosfamide | Interstitial pneumonitis Methemoglobinemia |
Imatinib | Acute pneumonitisFluid retention and pulmonary edema Pleural effusion |
Irinotecan | Moderate-to-severe pneumonitis Severe hypoxemia and respiratory failure |
Oxaliplatin | Pulmonary fibrosis Respiratory failure Eosinophilic pneumonia Infusion-related reactions |
Matuzumab | Bronchospasm |
Mitozantrone | Acute pneumonitis |
Piritrexim | Acute pneumonitis |
Taxanes | Acute pneumonitis Infusion-related reactions Pleural effusion |
Temozolomide | Acute pneumonitis |
Temsirolimus | Acute pneumonitis |
Thalidomide | Pulmonary embolism Organizing pneumonia Acute pneumonitis Pleural effusion |
Teniposide | Hypersensitivity reaction/bronchospasm |
Topotecan | Bronchiolitis and organizing pneumonia |
Trastuzumab | Acute lung injury Acute pneumonitis Organizing pneumonia Infusion-related reaction Bronchospasm |