Pulmonary Complications of Anticancer Treatment
Summary of Key Points
Radiation-Induced Lung Injury (Radiation Pneumonitis and/or Fibrosis)
Risk Factors
• Risk factors include radiation dose and volume of lung irradiated, which may be expressed as mean lung dose or as the Vx, that is, the percentage of normal lung tissue irradiated to a dose above a certain threshold dose.
• Older age, co-morbidities (including chronic obstructive pulmonary disease), and/or low performance status are risk factors.
• The location of the tumor is a risk factor; irradiation of lower lobe primary lung tumors may carry a higher risk than irradiation of other tumors, although this may reflect the higher volume irradiated with lower lobe tumors.
• Biological factors can carry risk, including levels of circulating cytokines such as transforming growth factor–β and interleukin-6.
Diagnosis
• The predominant symptoms are dyspnea and hypoxia, especially upon exertion.
• Fever (usually low grade if present at all), cough, pleuritic chest pain, and other pulmonary symptoms also frequently occur.
• Diffusing capacity of the lung for carbon dioxide is the most sensitive pulmonary function.
• Interstitial or ground-glass infiltrate usually corresponds to the irradiated volume.
• Findings at bronchoscopy are unremarkable (bronchial lavage may reveal lymphocytosis).
• Pulmonary embolism, infection, and progressive tumor must be ruled out. These conditions can co-exist with radiation pneumonitis.
Treatment
• Prevention is far more important than treatment. Patients must be selected carefully for thoracic radiation, and irradiated volumes must be limited.
• Corticosteroids are very useful in the management of acute and subacute pneumonitis (although they have no prophylactic or therapeutic value in the management of long-term radiation fibrosis).
• A pulmonologist should be consulted for all grade 3 cases and most grade 2 cases.
• Oxygen should be administered as indicated to prevent hypoxia.
• High doses of corticosteroids (60 mg/day of prednisone) should be administered with slow tapering (over several weeks to months) for severe grade 2 or any grade 3 radiation pneumonitis.
• If prolonged corticosteroid treatment is anticipated, prophylaxis against corticosteroid complications is needed, including gastrointestinal, infectious, and osteoporosis prophylaxis and dietary and pharmacologic management of hyperglycemia.
• Antibiotics, bronchodilators, diuretics, and anticoagulation should be used as indicated for co-existing cardiopulmonary illnesses.
Drug-Induced Lung Injury
Risk Factors
• Usually, bleomycin, nitrosoureas, and mitomycin or combinations of several potentially pneumotoxic agents that on their own may only have modest pneumotoxicity (e.g., gemcitabine and weekly docetaxel) are risk factors.
• Bone marrow transplantation/high-dose chemotherapy with or without total body irradiation is a risk factor.
• Concurrent or recent thoracic radiation therapy is a risk factor.
Diagnosis
• Dyspnea and hypoxia are predominant, but a wide range of possible symptoms exists.
• Interstitial or ground-glass infiltrate usually is diffuse throughout both lungs and may be worse in the lower lobes.
• Findings at bronchoscopy are unremarkable (bronchial lavage may reveal lymphocytosis).
• Pulmonary embolism, infection, and progressive tumor must be ruled out and may co-exist with drug-induced lung injury.
• Injury is usually (but not universally) responsive to corticosteroids; it is less likely to respond well to steroids than radiation pneumonitis but more likely to respond well than late radiation fibrosis.
Treatment
• When the diagnosis is suspected, the suspected causative agent should be discontinued.
• Consultation with a pulmonologist is necessary.
• Oxygen should be administered as indicated to prevent hypoxia (high fraction of inspired oxygen levels may be dangerous in bleomycin-related pneumonopathy).
• High doses of corticosteroids (≥60 mg/day of prednisone) with slow taper may be needed for severe grade 2 or any grade 3 pneumonitis.
• If prolonged corticosteroid treatment is anticipated, prophylaxis against corticosteroid complications entails gastrointestinal, infectious and osteoporosis prophylaxis and dietary or pharmacologic management of hyperglycemia.
• Antibiotics, bronchodilators, diuretics, and anticoagulation should be administered to manage co-existing cardiopulmonary illnesses.
1. Radiation pneumonitis differs from radiation pulmonary fibrosis (RF) in that radiation pneumonitis:
A Has an earlier presentation and does not respond to steroids
B Has an earlier presentation and responds to steroids
2. Which of the following is probably not a risk factor for clinically significant radiation pneumonopathy?
3. Compared with radiation pneumonopathy (RP), chemotherapy (e.g., bleomycin)-induced lung injury is ___ common, and affects a more ___ region of lung.
4. Which of the following chemotherapy agents is considered highest risk for combining with radiation therapy?
5. Which of the following statements is true regarding signal transduction systemic therapy and lung toxicity?
A Lung toxicity is the most frequent cause of the requirement to discontinue erlotinib/gefitinib for lung cancer.
B Erlotinib/gefitinib-induced lung toxicity appears to be more common in Japanese patients than in American patients.
C Imatinib is far more likely to cause pleural effusions than is dasatinib.
D Mammalian target of rapamycin inhibitors such as temsirolimus rarely cause radiographic findings consistent with pneumonitis.
1. Answer: B. Radiation pneumonitis usually develops over several weeks to months after irradiation and resolves within 6 to 12 months, whereas RF may not begin for several months after radiation therapy but progresses relentlessly over years. Whereas radiation pneumonitis responds very well to steroids, RF usually does not respond well; RF management is supportive, focusing on reducing symptoms and treating acute infections.
2. Answer: E. Neoadjuvant chemotherapy before radiation therapy does not greatly affect the risk of radiation pneumonopathy; however, concurrent chemoradiotherapy can increase the risk for lung injury. The other answer choices are all risk factors for pneumonopathy.
3. Answer: D. Unlike RP, which usually affects regions of lung close to the radiation field, systemic chemotherapy agents can cause more diffuse pneumonopathy. Chemotherapy-induced lung injury is relatively rare compared with RP but can have a higher fatality rate than RP.
4. Answer: C. Severe radiation pneumonitis with concurrent radiotherapy plus gemcitabine is relatively common, particularly with full-dose gemcitabine and/or large-field radiotherapy.
5. Answer: B. The rate of serious pneumonitis during treatment with gefitinib/erlotinib has been reported to be about 3%, compared with a rate slightly below 1% in the large U.S. TRIBUTE trial for erlotinib.
