Evaluating acute respiratory failure after targeted cancer therapies

Case

A 64-year-old woman with metastatic breast cancer presents with acute respiratory failure requiring high-flow oxygen by nasal canula, prompting intensive care unit admission. Her oncologic therapies include trastuzumab deruxtecan, an antibody-drug conjugate, initiated six months prior. Admission CT chest demonstrates bilateral ground-glass opacities with interlobular septal thickening.

Introduction

Modern cancer therapies have transformed oncologic care but can also be associated with serious pulmonary complications.¹ Commonly used therapies for solid malignancies include tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and antibody-drug conjugates (ADCs). In patients receiving these therapies who present with respiratory symptoms, clinicians should consider infection, disease progression, and therapy-related pulmonary toxicity in the differential diagnosis and apply a practical approach to guide evaluation and early management.

Therapy, timing, and toxicity

Cancer-related therapy toxicities are best recognized by considering therapy class, mechanism of action, timing of symptom onset, typical radiographic patterns, and overall clinical assessment. TKIs can cause inflammatory pneumonitis through off-target kinase inhibition.² In contrast, ICIs can cause immune disinhibition which can result in T-cell mediated pneumonitis, while ADCs may produce off-tumor cytotoxic injury leading to therapy-related interstitial lung disease (ILD).^3,4

Timing of symptom onset further distinguishes these toxicities. Pulmonary toxicity related to TKIs and ICIs typically develop weeks to months after therapy initiation but can occur at any point during treatment. In contrast, respiratory complications emerging several months into the treatment course or after cumulative exposure are more consistent with ADC-pulmonary toxicity.^2-5

CT of the chest can provide important clues to the suspected mechanisms of injury. TKI- and ICI-associated pneumonitis typically manifests as bilateral ground-glass opacities with or without consolidations, often resembling organizing pneumonia or nonspecific interstitial pneumonia (NSIP).^2,3 ADC-induced lung injury typically presents with bilateral ground-glass opacities with or without interlobular septal thickening.^4,5

Management

Management of therapy-related pulmonary toxicity should be initiated promptly. Empiric antibiotics are often warranted while infection remains under evaluation. In parallel, immediate drug cessation and initiation of systemic corticosteroids are recommended for clinically significant disease. Common Terminology Criteria for Adverse Events (CTCAE) grading is often used to inform treatment decisions by stratifying patients according to symptom severity and oxygen requirements. Grade 3-4 toxicity requires initiation of methylprednisolone 1-2 mg/kg/day followed by a gradual taper over 6 weeks (Figure 1). For patients who do not respond to corticosteroids within 72 hours, additional immunosuppressive therapy should be considered.^3-5

Figure 1.

Pulmonary toxicities associated with targeted cancer therapies. Comparative overview of key distinguishing features and general management considerations for pulmonary toxicities associated with tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and antibody–drug conjugates (ADCs). CTCAE, Common Terminology Criteria for Adverse Events.

Case conclusion

The patient was initially treated empirically for severe community-acquired pneumonia; however, a negative infectious evaluation and subacute timing of symptoms in relation to prolonged ADC exposure made ADC pulmonary toxicity the likely diagnosis. Her severe dyspnea and need for supplemental oxygen met criteria for CTCAE Grade 3 pneumonitis. The ADC was discontinued, methylprednisolone was initiated at 1 mg/kg/day, and she demonstrated clinical resolution over several days.

Author contributions

All authors contributed to conceptualization, writing, review, editing and manuscript preparation. J.C. led drafting of figure; K.M. led manuscript supervision.

Supplementary material

Supplementary material is available at ATS Scholar online.

Conflicts of interest

Please see the ICMJE disclosure forms, which have been provided as supplementary material. The authors report no conflicts of interest.

Disclaimers

None of the authors has relevant financial disclosures to this work.

Artificial intelligence disclaimer

No artificial intelligence tools were used in writing this manuscript.