Immunotherapy-Related Toxicity in Lung Cancer: Clinical Characteristics and Managing Strategy

Immunotherapy-Related Toxicity in Lung Cancer: Clinical Characteristics and Managing Strategy

Lung cancer remains the most prevalent malignancy globally and the leading cause of cancer-related mortality. The advent of immune checkpoint inhibitors (ICIs), including programmed cell death protein-1/programmed cell death protein ligand-1 (PD-1/PD-L1) inhibitors and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors, has revolutionized the treatment landscape for advanced lung cancer. Despite their efficacy, ICIs are associated with systemic toxicities that can affect nearly every organ system. These toxicities, termed immune-related adverse events (irAEs), range from mild to life-threatening. Understanding their clinical characteristics and implementing effective management strategies are critical to optimizing patient outcomes.

Clinical Characteristics of Immunotherapy-Related Toxicities

Digestive Toxicity

Digestive toxicities primarily manifest as hepatitis (hepatic toxicity) and colitis (gastrointestinal toxicity). In clinical trials involving PD-1/PD-L1 inhibitors, the incidence of any-grade hepatic toxicity ranges from 2% to 9%, with severe (grade ≥3) cases occurring in less than 1% to 4% of patients. Gastrointestinal toxicity, characterized by diarrhea or colitis, occurs in 1% to 15% of patients, with grade ≥3 events in less than 1% to 3%. Notably, gastrointestinal toxicity is more frequent with CTLA-4 inhibitors than PD-1/PD-L1 inhibitors. Combination therapy (e.g., ipilimumab plus nivolumab) amplifies the risk, with a 13.6% incidence of all-grade colitis.

Endocrine Toxicity

Endocrine toxicities commonly involve thyroid dysfunction (hypothyroidism: 4%–11%; hyperthyroidism: 1%–8%). Severe endocrine events are rare (<1%). Thyroid dysfunction is more prevalent with PD-1/PD-L1 inhibitors, whereas hypophysitis is linked to CTLA-4 inhibitors. Other rare endocrine complications include thyroiditis, type 1 diabetes, and primary adrenal insufficiency.

Pulmonary Toxicity

Pneumonitis is a critical concern in lung cancer patients, representing the leading cause of ICI-related mortality. The incidence of any-grade pneumonitis with PD-1/PD-L1 inhibitors ranges from 3% to 9%, with grade ≥3 events in 1%–3%. Risk factors include advanced age (≥70 years), Asian ethnicity, smoking history, squamous histology, preexisting chronic lung diseases (e.g., interstitial lung disease, COPD), and combination therapies (ICI-ICI or ICI-EGFR-TKI). Radiologic patterns include cryptogenic organizing pneumonia (COP), hypersensitivity pneumonitis (HP), acute interstitial pneumonia/acute respiratory distress syndrome (AIP/ARDS), and nonspecific interstitial pneumonia (NSIP).

Cardiovascular Toxicity

Cardiovascular toxicities, though rare, carry high mortality. Myocarditis, pericardial disease, arrhythmias, and acute coronary syndromes have been reported. Myocarditis has a mortality rate of up to 40%. Risk factors include female sex, age ≥75 years, and ICI combination therapy.

Management of Immunotherapy-Related Toxicity

Pretreatment Evaluation

Baseline assessments are essential to identify risk factors and establish reference data. These include:

• Medical history: Autoimmune diseases, infections (hepatitis B/C, HIV), pregnancy, organ transplantation.
• Laboratory tests: Complete blood count, metabolic panel, infectious disease screening.
• Imaging: CT scans (chest, abdomen, pelvis), echocardiography.

Toxicity Assessment and Grading

Adverse events must be differentiated from disease progression or unrelated conditions. Clinical, laboratory, endoscopic, and imaging findings are compared with baseline data. Toxicity severity is graded using the Common Terminology Criteria for Adverse Events (CTCAE):

• Grade 1: Mild; continue immunotherapy without corticosteroids.
• Grade 2: Moderate; temporarily withhold immunotherapy, consider corticosteroids.
• Grade 3: Severe; hospitalize, discontinue immunotherapy, initiate systemic corticosteroids.
• Grade 4: Life-threatening; admit to intensive care, permanently discontinue immunotherapy, administer corticosteroids and intravenous immunoglobulin.

For refractory grade 3/4 toxicities, additional immunosuppressants (e.g., anti-TNF-α antibodies, mycophenolate) may be used under specialist guidance.

Organ-Specific Management

• Digestive Toxicity:
  • Hepatitis: Monitor liver function; grade ≥2 requires corticosteroid therapy.
  • Colitis: Endoscopic evaluation for confirmation; corticosteroids for grade ≥2, with infliximab or vedolizumab for refractory cases.
• Endocrine Toxicity:
  • Thyroid dysfunction: Hormone replacement for hypothyroidism; beta-blockers for symptomatic hyperthyroidism.
  • Hypophysitis: High-dose corticosteroids and hormone replacement.
• Pulmonary Toxicity:
  • Pneumonitis: Immediate corticosteroids (prednisone 1–2 mg/kg/day); consider immunosuppressants for non-responders.
• Cardiovascular Toxicity:
  • Myocarditis: High-dose corticosteroids (methylprednisolone 1 g/day for 3–5 days), followed by gradual tapering.

Future Directions

Key unresolved issues include:

1. Risk Stratification: Identifying biomarkers or clinical factors predictive of specific toxicities.
2. Combination Therapy Risks: Characterizing toxicity profiles of novel regimens (e.g., ICI-TKI combinations).
3. Ethnic Considerations: Investigating toxicity patterns in underrepresented populations, such as Chinese patients.
4. Long-Term Monitoring: Developing protocols for surveillance of delayed or chronic toxicities.

Conclusion

Immunotherapy has transformed lung cancer treatment, but its benefits are tempered by the risk of irAEs. A proactive, multidisciplinary approach—encompassing early recognition, prompt intervention, and tailored management—is vital to mitigate morbidity and mortality. Ongoing research into risk prediction, ethnic variability, and optimal immunosuppressive strategies will further refine the therapeutic paradigm.

doi.org/10.1097/CM9.0000000000001287

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