What is the best treatment regimen for metastatic laryngeal (larynx) cancer?

Treatment of Metastatic Laryngeal Cancer

For metastatic laryngeal cancer, pembrolizumab combined with platinum-based chemotherapy (cisplatin or carboplatin) plus 5-fluorouracil is the recommended first-line treatment, with pembrolizumab monotherapy reserved for patients with PD-L1 CPS ≥1 who cannot tolerate intensive chemotherapy or do not require rapid tumor shrinkage. 1

First-Line Systemic Treatment Options

The treatment landscape for metastatic laryngeal cancer fundamentally changed with the KEYNOTE-048 trial results, which established two evidence-based approaches:

Option 1: Pembrolizumab + Platinum/5-FU (Preferred for Most Patients)

• This combination significantly improved overall survival to 13 months versus 10.7 months with the older EXTREME regimen (platinum/5-FU/cetuximab), independent of PD-L1 status 1
• Particularly indicated when rapid tumor shrinkage is needed or in symptomatic patients 1
• Objective response rate of 36.3% with progression-free survival of 5.1 months 1
• Grade 3-5 adverse events occur in 83.3% of patients 1

Option 2: Pembrolizumab Monotherapy (For Selected Patients)

• Reserved for patients with PD-L1 CPS ≥1, especially when rapid tumor shrinkage is not urgently needed 1
• Improved median overall survival to 12.3 months (CPS ≥1) or 14.9 months (CPS ≥20) versus 10.7 months with EXTREME 1
• Better tolerated with grade 3-5 adverse events in only 54.7% versus 83.3% with chemotherapy combinations 1
• Lower objective response rate (19.1% for CPS ≥1) and shorter progression-free survival (3.2 months) compared to combination therapy 1

Critical caveat: The survival benefit of pembrolizumab in patients with CPS <1 or CPS 1-19 remains unclear, and platinum/5-FU/pembrolizumab may not improve survival over platinum/5-FU/cetuximab in PD-L1-negative patients 1

Alternative Regimens for Specific Scenarios

When Immunotherapy is Contraindicated or Unavailable

• Platinum (cisplatin or carboplatin) plus 5-FU plus cetuximab (EXTREME regimen) remains an option 1, 2
• Cetuximab with platinum/5-FU achieved median overall survival of 10.1 months versus 7.4 months with chemotherapy alone in the EXTREME trial 2
• Cisplatin 100 mg/m² on day 1 or carboplatin AUC 5 on day 1, plus fluorouracil 1000 mg/m²/day on days 1-4, every 3 weeks for maximum 6 cycles 2
• Cetuximab: 400 mg/m² initial dose, then 250 mg/m² weekly, continuing as monotherapy after chemotherapy completion if no progression 2

For Patients Unfit for Platinum-Based Therapy

• Single-agent options include docetaxel, paclitaxel, methotrexate, or cetuximab with best supportive care 1, 3
• These are appropriate for asymptomatic patients with low disease burden to balance efficacy with toxicity 3

Oligometastatic Disease: Curative-Intent Approach

In highly selected patients with oligometastatic disease (≤2 distant sites, non-visceral), consider local/regional treatment with curative intent, particularly after response to upfront systemic therapy 1

Conversely, patients with high metastatic burden (>2 distant sites, mainly visceral involvement) should prioritize systemic treatment, with locoregional therapy reserved only for symptomatic sites 1

Locoregional Recurrence Management

All patients with locoregional recurrence should be referred to a tertiary center for multidisciplinary evaluation to assess salvage surgery or re-irradiation feasibility 1

• Patients with good performance status and early-stage laryngeal recurrence occurring >2 years after primary treatment can be offered salvage surgery with reasonable oncological outcomes 1
• Poor performance status patients with locally advanced recurrence typically receive palliative systemic or local treatment 1

Critical Treatment Pitfalls to Avoid

1. Do not use pembrolizumab monotherapy in patients requiring rapid tumor response - the lower response rate (19.1%) and shorter PFS (3.2 months) make it unsuitable for symptomatic or rapidly progressive disease 1

2. Verify PD-L1 CPS status before selecting pembrolizumab monotherapy - this approach is only validated for CPS ≥1 1

3. Consider performance status carefully - combination chemotherapy regimens increase toxicity substantially and should be reserved for patients who can tolerate intensive treatment 1, 3

4. Incorporate palliative radiation therapy for symptomatic metastatic sites regardless of systemic treatment choice 3

5. Ensure aggressive symptom management with referral to palliative care and pain management experts for all patients 3

Regulatory Considerations

The FDA approved pembrolizumab in combination with chemotherapy as first-line treatment regardless of PD-L1 expression, and pembrolizumab alone for PD-L1-expressing tumors (CPS ≥1), while the EMA approved pembrolizumab with or without chemotherapy only for CPS ≥1 1