Pulmonary toxicity associated with antineoplastic agents

Definition

Many antineoplastic drugs can cause damage to the lungs, airways, pleura, and pulmonary circulation. Pulmonary toxicities induced by antineoplastic drugs can vary in severity ranging from minor to life threatening. For some antineoplastic drugs such as bleomycin, pulmonary toxicity is the most common dose limiting toxicity.^rr

Pathophysiology

Several pathophysiologic mechanisms have been proposed for antineoplastic drug induced pulmonary toxicity:^rr

• direct chemical injury to pneumocytes or alveolar capillary endothelium, with subsequent cytokine release and inflammatory cell recruitment
• capillary leak and pulmonary oedema due to systemic release of cytokines by antineoplastic agents (e.g. gemcitabine)
• oxidative injury secondary to free oxygen radicals (e.g. bleomycin, mitomycin)
• EGFR-mediated disruption to alveolar repair mechanisms potentiating lung injury from other causes such as sepsis and radiotherapy (e.g. EGFR tyrosine kinase inhibitors)
• activation of lymphocytes causing cell-mediated lung injury (e.g. idiosyncratic drug-induced hypersensitivity, mTOR inhibitors, immunotherapy with antiPD-1 and anti-CTLA4 checkpoint inhibitors).^rrr

Clinical syndromes

The most common pattern of antineoplastic drug induced pulmonary toxicity is interstitial lung disease (ILD).^r Clinical syndromes can be categorised based on either clinical criteria or pathologic findings, and may include acute, subacute or chronic presentation with ILD. 

The specific ILD patterns which are seen associated with antineoplastic drugs are varied, and include chronic and progressive interstitial pneumonia, diffuse alveolar damage, organising pneumonia, pulmonary eosinophilia, non-cardiogenic pulmonary oedema, pulmonary haemorrhage, vascular thrombosis and pulmonary veno-occlusive disease. ^rrr

Some of the above presentations, including organising pneumonia, may progress to pulmonary fibrosis.^r Pulmonary fibrosis is a disorder characterised by the replacement of the lung tissue by connective tissue, leading to progressive dyspnoea, respiratory failure or right heart failure.^r

Incidence/prevalence

The incidence of antineoplastic drug induced pulmonary toxicity according to the literature has been reported as high as 20%, dependent on the antineoplastic agent. However, in practice clinical toxicity is uncommon for most antineoplastic drugs.^rrr The cytotoxic drugs with the highest reported incidence of pulmonary toxicities are bleomycin, carmustine, methotrexate, busulfan, and mitomycin.^rr Everolimus is associated with non-infectious pneumonitis in about 10% (range 2-36%) of patients.^r Ipilimumab is rarely associated with symptomatic pneumonitis (1%).^r For anti-PD1 checkpoint inhibitors such as pembrolizumab and nivolumab, symptomatic pneumonitis is more common for patients with non-small-cell lung cancer compared to other non-lung malignancies (7% vs 2%).^r

Onset/duration

Time of onset can vary from immediately after the first treatment, to several months or years after completion of treatment.^r There have been reported cases of pulmonary toxicity developing decades after completion of treatment with carmustine.^rr The most common manifestation that occurs months to years after treatment is pulmonary fibrosis.^r

Risk factors

Risk factors for developing antineoplastic drug induced pulmonary toxicity may include:

• age (bleomycin, methotrexate)*
• female sex (carmustine)^rr
• history of smoking (bleomycin)**
• pre-existing lung disease^rrr
• reduced renal function (bleomycin)^rrrr
• cumulative drug dose (bleomycin, carmustine)***
• concomitant chemotherapy with known lung toxicity^rr
• concomitant or previous radiation therapy^rrr
• high fraction of inspired oxygen (bleomycin, cyclophosphamide, carmustine)****
• colony stimulating factors (bleomycin, cyclophosphamide)*****

* The risk of bleomycin and methotrexate induced pulmonary toxicity appears higher in older patients; for bleomycin the risk appears to be increased in those over 40 years.^rrr

** There is some data to suggest cigarette smoking increases the risk of bleomycin induced pulmonary toxicity.^rr

*** Cumulative dose of bleomycin greater than 300,000 international units has been associated with higher rates of pulmonary toxicity.^rrr Pulmonary toxicity can however occur with bleomycin cumulative doses less than 50,000 international units.^rrr Cumulative dose of carmustine greater than 1400 mg/m² has been associated with higher rates of pulmonary toxicity.^rr

**** High concentrations of inspired oxygen may increase the risk of pulmonary toxicity in patients treated with bleomycin, cyclophosphamide or carmustine.^rrrr Available evidence is inconsistent, and is largely anecdotal.

***** It has been reported that the risk of bleomycin and cyclophosphamide induced pulmonary toxicity is increased when used in combination with colony stimulating factors.^rrr Available data is conflicting, and has not been confirmed in randomised clinical trials. 

Pulmonary toxicity can be unpredictable; development in young patients and those treated with low doses has been observed.

Symptoms and signs

Clinical presentation can be variable, unpredictable and non-specific. Many patients will present with asymptomatic pulmonary infiltrates, or with one or more of the following:^rr

• dyspnoea and decreased exercise tolerance
• non-productive cough
• fever
• haemoptysis
• increased sputum production
• weight loss
• hypoxaemia  
• tachycardia
• pleuritic or substernal chest pain
• fine inspiratory crackles
• acute respiratory failure and ARDS (acute respiratory distress syndrome).

Investigations and diagnosis

Antineoplastic drug-induced pulmonary toxicity is a diagnosis of exclusion, and there is no single diagnostic tool capable of diagnosing antineoplastic drug induced pulmonary toxicity.^r After exclusion of other causes, diagnosis can be made based on the patient’s history and clinical presentation, together with a chest x-ray, high resolution CT scan and pulmonary function test (PFT).^rr  Radiographic abnormalities include diffuse reticulonodular pattern (seen particularly in patients developing progressive pulmonary fibrosis), bilateral acinar or reticular infiltrates which may clear rapidly, and pleural effusions.  Chest radiographs can also remain normal. PFT may reveal a decrease in diffusing capacity for carbon monoxide (DLCO)^rr and a restrictive pattern, including reduced total lung capacity and reduced forced vital capacity.^r A bronchoscopy with bronchoalveolar lavage may be performed to exclude infection, and a lung biopsy may be performed to characterise the histopathologic pattern of the toxicity, and rule out differentials including infection, tumour progression, and other pulmonary diseases.^rr

Differential diagnosis 

The differential diagnosis of antineoplastic drug induced pulmonary toxicity includes infectious pneumonia, radiation induced lung injury, cardiogenic pulmonary oedema, pulmonary embolus, pulmonary haemorrhage, lymphangitis, and metastatic disease.^rrr Pneumocystis jiroveci pneumonia is an important differential which commonly presents with fever, diffuse pulmonary infiltrates on chest radiograph, hypoxaemia, and diffusion defects on PFTs.^rr

Grading

 Common Terminology Criteria for Adverse Events Version 4.03, (CTCAE) June 2010

 Common Terminology Criteria for Adverse Events Version 4.03, (CTCAE) June 2010

Prevention

While antineoplastic drug induced pulmonary toxicity is well recognised in the literature, there is limited information regarding prevention. The most well established methods for primary and secondary prevention are caution in patients at high risk of drug-specific lung toxicity, monitoring for signs and symptoms, and maximum cumulative dosing (e.g. Bleomycin, refer below and to individual treatment protocols for more information).^rrr The role of screening with chest x-rays, chest CT and pulmonary function tests in the early detection of antineoplastic drug induced pulmonary toxicity is unclear and remains inconsistent in practice. There is no established genetic screening. Bleomycin hydrolase is implicated in bleomycin pulmonary toxicity, however genetic variations in the bleomycin hydrolase gene have not been proven to predict occurrence.^r

Bleomycin

Bleomycin is one of the most well recognised antineoplastic drugs to cause pulmonary toxicity; information regarding prevention of bleomycin pulmonary toxicity should be performed according to the individual treatment protocol and may include:^rrrrrr

• avoid or use with caution in patients at increased risk (see "Risk factors" above)
• cumulative dose of bleomycin should be checked prior to each treatment
• maximum, cumulative dose of bleomycin should not exceed 400,000 international units
• baseline clinical assessment, chest x-ray and PFT, and repeat if clinical signs and symptoms of pulmonary toxicity
• weekly focused respiratory history and examination, and 3-weekly chest x-ray, if patient undergoing BEP chemotherapy regimen
• CT chest and PFT may be considered where clinically appropriate (symptoms or signs of ILD)
• if there is clinical evidence of pulmonary toxicity (cough, dyspnoea, basal crepitation) bleomycin should be ceased
• in the absence of symptoms when there is significant or severe fall in DLCO from the pre-treatment value (a significant fall in DLco may be considered a fall of ≥ 15% from baseline), then further investigation with high resolution CT chest is recommended^rr
• monitor creatinine clearance and consider dose modifications as per individual treatment protocol.

Bleomycin pulmonary toxicity monitoring in Hodgkin lymphoma

For Hodgkin Lymphoma, the eviQ Haematology Reference Committee recommends baseline pulmonary function assessment, then monitor as clinically appropriate. If there is significant or severe reduction in pulmonary function at baseline, it may be appropriate to reconsider the use of bleomycin.

Treatment

There are limited established guidelines for the treatment of antineoplastic drug induced pulmonary toxicity. Management is largely empiric rather than evidence based. The main components of management include prompt drug discontinuation, corticosteroids and supportive therapy including supplemental oxygen to maintain acceptable oxygen saturations.^rrr Evidence to support the use of steroids is largely observational, and based on the effective treatment of the idiopathic interstitial pneumonias.  For example, there is good data for the prompt introduction of high dose corticosteroids for the treatment of idiopathic organising pneumonia.  While there is only observational data for the treatment of organising pneumonia associated with antineoplastic drugs, it is reasonable to consider the prompt use of high dose corticosteroids in its early and inflammatory stage, prior to development of pulmonary fibrosis. An infectious aetiology should always be excluded prior to commencing steroids.^r Early referral to a respiratory physician may be considered appropriate.

There are limited guidelines for reintroducing the drug that has caused pulmonary toxicity; in practice the drug is usually not reintroduced.^r Exceptions are temsirolimus, everolimus and anti-PD1 checkpoint inhibitors such as pembrolizumab and nivolumab; reintroduction should be according to the individual treatment protocol, and dependent on the clinical situation and severity of the toxicity.^rrr

The following table of drugs is not exhaustive; please refer to individual product information for more detailed information. 

Educate patient:

• about the risk of developing a pulmonary toxicity (including acute and delayed onset)
• to report symptoms of pulmonary toxicity (e.g. cough, dyspnoea, chest pain, decreased exercise tolerance)
• to go to the nearest hospital emergency department if the patient becomes short of breath or develops chest pain
• to avoid high flow oxygen (bleomycin)
• about smoking cessation strategies.

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