Drug-induced interstitial lung disease during cancer therapies: expert opinion on diagnosis and treatment

Abstract

Background: Drug-induced interstitial lung disease (DIILD) is a form of interstitial lung disease resulting from exposure to drugs causing inflammation and possibly interstitial fibrosis. Antineoplastic drugs are the primary cause of DIILD, accounting for 23%-51% of cases, with bleomycin, everolimus, erlotinib, trastuzumab-deruxtecan and immune checkpoint inhibitors being the most common causative agents. DIILD can be difficult to identify and manage, and there are currently no specific guidelines on the diagnosis and treatment of DIILD caused by anticancer drugs.

Objective: To develop recommendations for the diagnosis and management of DIILD in cancer patients.

Methods: Based on the published literature and their clinical expertise, a multidisciplinary group of experts in Italy developed recommendations stratified by DIILD severity, based on the Common Terminology Criteria for Adverse Events.

Results: The recommendations highlight the importance of multidisciplinary interaction in the diagnosis and management of DIILD. Important components of the diagnostic process are physical examination and careful patient history-taking, measurement of vital signs (particularly respiratory rate and arterial oxygen saturation), relevant laboratory tests, respiratory function testing with spirometry and diffusing capacity of the lung for carbon monoxide and computed tomography/imaging. Because the clinical and radiological signs of DIILD are often similar to those of pneumonias or interstitial lung diseases, differential diagnosis is important, including microbial and serological testing to exclude or confirm infectious causes. In most cases, management of DIILD requires the discontinuation of the antineoplastic agent and the administration of short-term steroids. Steroid tapering must be undertaken slowly to prevent reactivation of DIILD. Patients with severe and very severe (grade 3 and 4) DIILD will require hospitalisation and often need oxygen and non-invasive ventilation. Decisions about invasive ventilation should take into account the patient's cancer prognosis.

Conclusions: These recommendations provide a structured step-by-step diagnostic and therapeutic approach for each grade of suspected cancer-related DIILD.

Keywords: antineoplastic agents; diagnostic–therapeutic algorithm; differential diagnosis; interstitial lung disease; pneumonia.

Figure 1

Key elements for the baseline assessment of suspected DIILD in cancer patients. BAL, bronchoalveolar lavage; CRP, C-reactive protein; DIILD, drug-induced interstitial lung disease; DLCO, diffusing capacity of lung for carbon monoxide; ESR, erythrocyte sedimentation rate; HRCT, high-resolution computed tomography; KL-6, Krebs von den Lungen-6; LDH, lactate dehydrogenase; PaO₂, arterial partial pressure of oxygen; SP, surfactant protein; SpO₂, oxygen saturation by pulse oximetry.

Figure 2

(A) Diagnostic algorithm and (B) algorithm for treatment and follow-up of grade 1 DIILD in cancer patients. Grade 1 DIILD definition is adapted from the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (27 November 2017). BAL, bronchoalveolar lavage; CRP, C-reactive protein; CT, computed tomography; DIILD, drug-induced interstitial lung disease; DLCO, diffusing capacity of lung for carbon monoxide; ESR, erythrocyte sedimentation rate; HRCT, high-resolution computed tomography; LDH, lactate dehydrogenase; mTOR, mammalian target of rapamycin; SpO₂, oxygen saturation by pulse oximetry; TKIs, tyrosine kinase inhibitors.

Figure 3

(A) Diagnostic algorithm and (B) algorithm for treatment and follow-up of grade 2 DIILD in cancer patients. Grade 2 DIILD definition is adapted from the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (27 November 2017). BAL, bronchoalveolar lavage; CRP, C-reactive protein; DIILD, drug-induced interstitial lung disease; DLCO, diffusing capacity of lung for carbon monoxide; ESR, erythrocyte sedimentation rate; HRCT, high-resolution computed tomography; KL-6, Krebs von den Lungen-6; LDH, lactate dehydrogenase; PaO₂, arterial partial pressure of oxygen; SP, surfactant protein; SpO₂, oxygen saturation by pulse oximetry; TMP-SMX, trimethoprim/sulfamethoxazole.

Figure 4

(A) Diagnostic algorithm and (B) algorithm for treatment and follow-up of grade 3 DIILD in cancer patients. Grade 3 DIILD definition is adapted from the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (27 November 2017). BAL, bronchoalveolar lavage; CRP, C-reactive protein; DIILD, drug-induced interstitial lung disease; DLCO, diffusing capacity of lung for carbon monoxide; ESR, erythrocyte sedimentation rate; HRCT, high-resolution computed tomography; KL-6, Krebs von den Lungen-6; LDH, lactate dehydrogenase; PaO₂, arterial partial pressure of oxygen; SP, surfactant protein; SpO₂, oxygen saturation by pulse oximetry; TMP-SMX, trimethoprim/sulfamethoxazole.

Figure 5

(A) Diagnostic algorithm and (B) algorithm for treatment and follow-up of grade 4 DIILD in cancer patients. Grade 4 DIILD definition is adapted from the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (27 November 2017). BAL, bronchoalveolar lavage; CRP, C-reactive protein; DIILD, drug-induced interstitial lung disease; DLCO, diffusing capacity of lung for carbon monoxide; ESR, erythrocyte sedimentation rate; FIO₂, fraction of inspired oxygen; HRCT, high-resolution computed tomography; KL-6, Krebs von den Lungen-6; LDH, lactate dehydrogenase; PaO₂, arterial partial pressure of oxygen; SpO₂, oxygen saturation by pulse oximetry; TMP-SMX, trimethoprim/sulfamethoxazole.