Can pembrolizumab (pembrolizumab) cause changes in voice?

Can Pembrolizumab Cause Voice Changes?

Yes, pembrolizumab can cause voice changes, though this is not among the most commonly reported adverse events. Voice alterations can occur through several mechanisms related to immune-mediated toxicity affecting the larynx and surrounding structures.

Mechanisms of Voice Change with Pembrolizumab

Laryngeal mucous membrane pemphigoid has been documented as an immune-related adverse event (irAE) of pembrolizumab, which directly affects the laryngeal mucosa and can alter voice quality 1. This represents an autoimmune attack on the laryngeal tissues triggered by immune checkpoint inhibition.

Autoimmune inner ear disease has been reported with pembrolizumab, manifesting as bilateral sensorineural hearing loss 2. While this primarily affects hearing rather than voice production, it demonstrates the potential for immune-mediated damage to structures in the head and neck region.

Common Adverse Events That May Indirectly Affect Voice

The FDA-approved drug label and NCCN guidelines identify several common adverse events that could secondarily impact voice 3, 4:

• Fatigue, cough, and dyspnea are among the most frequent side effects, occurring in a substantial proportion of patients 3, 4
• Endocrinopathies including thyroid dysfunction (hypothyroidism/hyperthyroidism) can cause voice changes through thyroid-related mechanisms 5
• Pneumonitis as an immune-mediated adverse event may cause respiratory symptoms that affect voice projection 5

Specific Laryngeal Manifestations

Laryngeal mucous membrane pemphigoid requires early recognition based on clinical history, serologic testing, and symptomatic presentation 1. Management involves:

• Discontinuation of pembrolizumab
• Initiation of immunosuppression (typically corticosteroids)
• Close monitoring for symptomatic improvement 1

Clinical Monitoring Recommendations

Voice changes warrant immediate evaluation for potential immune-mediated adverse events affecting the larynx, thyroid, or respiratory system 3, 4. The ESMO guidelines emphasize that immune-related adverse events can affect any organ system and may present at any time during or after treatment 6.

Endocrine evaluation is essential if voice deepening occurs, as this may indicate thyroid dysfunction or other hormone gland problems 4. The FDA label specifically lists "your voice gets deeper" as a potential sign of hormone gland problems requiring medical attention 4.

Management Algorithm

For patients developing voice changes on pembrolizumab:

1. Immediate assessment for grade and severity of symptoms 3
2. Evaluate for thyroid dysfunction with TSH, free T4, and thyroid antibodies if voice deepening is present 4
3. Laryngoscopy if hoarseness, dysphonia, or laryngeal symptoms are prominent 1
4. Consider autoimmune laryngeal involvement with serologic testing if mucosal lesions are suspected 1
5. Initiate corticosteroids for confirmed immune-mediated laryngeal disease 1
6. Temporarily or permanently discontinue pembrolizumab depending on severity 1

Critical Pitfalls to Avoid

Do not dismiss voice changes as minor symptoms, as they may represent serious immune-mediated toxicity requiring prompt intervention 1. Laryngeal mucous membrane pemphigoid is a newly described irAE that requires early suspicion for proper diagnosis and management 1.

Do not delay endocrine evaluation if voice deepening occurs, as this may indicate significant thyroid or other endocrine dysfunction 4. Multiple autoimmune toxicities can occur simultaneously in the same patient, particularly in elderly individuals 5.