What is the recommended treatment for unresectable metastatic esophageal cancer?

Treatment of Unresectable Metastatic Esophageal Cancer

For unresectable metastatic esophageal cancer, first-line treatment should be immunotherapy plus chemotherapy based on PD-L1 expression and HER2 status, with the specific regimen determined by tumor histology (adenocarcinoma versus squamous cell carcinoma) and biomarker testing. 1

Mandatory Biomarker Testing Before Treatment

• Test all adenocarcinomas for HER2 status (IHC 2+ with FISH-positive or IHC 3+) as this determines eligibility for trastuzumab-based therapy 1
• Test all tumors for PD-L1 expression using Combined Positive Score (CPS), which includes PD-L1 positive tumor cells, lymphocytes, and macrophages 1
• Consider MSI/dMMR testing, particularly in adenocarcinomas, as MSI-high tumors predict exceptional response to immunotherapy 1

First-Line Treatment Algorithm

For Adenocarcinoma (Including GEJ Tumors)

If HER2-positive:

• Trastuzumab plus pembrolizumab in combination with fluoropyrimidine and oxaliplatin-based chemotherapy 1
• This represents the highest priority regimen for HER2-positive disease based on improved survival outcomes 1

If HER2-negative with PD-L1 CPS ≥5:

• Nivolumab in combination with fluoropyrimidine- and platinum-based chemotherapy 1
• Alternative: Pembrolizumab in combination with fluoropyrimidine- and platinum-based chemotherapy 1

If HER2-negative with PD-L1 CPS 1-4:

• Consider nivolumab or pembrolizumab in combination with fluoropyrimidine- and platinum-based chemotherapy on a case-by-case basis 1
• Factors favoring immunotherapy addition: good performance status (ECOG 0-1), younger age, absence of autoimmune disease 1

If HER2-negative with PD-L1 CPS 0:

• Fluoropyrimidine- and platinum-based chemotherapy alone, without immunotherapy 1
• Standard regimens: oxaliplatin or cisplatin combined with 5-FU or capecitabine 1

For Squamous Cell Carcinoma

If PD-L1 CPS ≥10:

• Nivolumab plus ipilimumab (dual checkpoint inhibition) 1
• Alternative: Nivolumab plus fluoropyrimidine- and platinum-based chemotherapy 1

If PD-L1 CPS ≥5:

• Nivolumab in combination with fluoropyrimidine- and platinum-based chemotherapy 1
• Pembrolizumab plus chemotherapy is also an option 1

If PD-L1 CPS 1-4:

• Consider immunotherapy plus chemotherapy on a case-by-case basis 1

If PD-L1 CPS 0:

• Fluoropyrimidine- and platinum-based chemotherapy without immunotherapy 1
• Note: The value of palliative chemotherapy is less proven in squamous cell carcinoma compared to adenocarcinoma 1, 2
• Best supportive care or palliative monotherapy should be strongly considered as alternatives to combination chemotherapy in poor performance status patients 1, 2

Specific Chemotherapy Regimens

Platinum/fluoropyrimidine doublets (standard backbone):

• Oxaliplatin 130 mg/m² day 1 plus capecitabine 1000 mg/m² twice daily days 1-14, every 3 weeks 1
• Cisplatin 80 mg/m² day 1 plus 5-FU 800-1000 mg/m² continuous infusion days 1-5, every 3-4 weeks 1, 3
• Oxaliplatin plus infusional 5-FU (FOLFOX) 1

Key considerations:

• Oxaliplatin and cisplatin are equivalent in efficacy but differ in toxicity: oxaliplatin causes more neuropathy and diarrhea; cisplatin causes more thromboembolic events and requires aggressive hydration 1
• Capecitabine can replace infusional 5-FU if swallowing tablets is not compromised 1, 2
• Irinotecan may be an alternative in patients unsuitable for platinum 1

Second-Line Treatment Options

For adenocarcinoma with disease progression after first-line therapy:

• Ramucirumab plus paclitaxel (VEGFR2 inhibitor plus taxane) 1
• This is the standard second-line regimen for gastroesophageal adenocarcinoma 1

For squamous cell carcinoma:

• Taxane monotherapy (docetaxel or paclitaxel) 1, 2
• Consider single-agent immunotherapy if not previously used and PD-L1 positive 1

For all histologies:

• If MSI-high/dMMR: pembrolizumab monotherapy is FDA-approved as second-line and later therapy 1

Palliative Interventions for Dysphagia

For symptom control of dysphagia (critical for quality of life):

• Single-dose brachytherapy is the preferred option, even after prior external beam radiotherapy, as it provides better long-term relief with fewer complications than metal stent placement 1, 2, 4
• Metal esophageal stenting is cost-effective for restoring oral nutrition when brachytherapy is unavailable 1, 2
• External beam radiotherapy with small-dose fractions can be used for patients with reasonable performance status 2

Performance Status Requirements

Chemotherapy eligibility:

• Chemotherapy is indicated for patients with ECOG performance status 0-2 or Karnofsky ≥60 2, 5
• Best supportive care only for patients with ECOG ≥3 or Karnofsky <60 5

Critical Pitfalls to Avoid

Do not proceed with treatment without HER2 testing in adenocarcinoma - this represents a missed opportunity for highly effective targeted therapy that significantly improves survival 1, 2

Do not use combination chemotherapy indiscriminately in squamous cell carcinoma - the benefit is less proven than in adenocarcinoma, and monotherapy or best supportive care may be more appropriate for patients with borderline performance status 1, 2

Do not overlook nutritional support - enteral nutrition via gastrostomy/jejunostomy should be considered before or concurrent with chemotherapy, as malnutrition significantly impacts treatment tolerance and outcomes 1, 2

Do not ignore PD-L1 testing - treatment decisions and expected outcomes differ substantially based on CPS scores, particularly at thresholds of 1,5, and 10 1, 3

Recognize histology-specific differences - adenocarcinoma responds better to systemic chemotherapy while squamous cell carcinoma demonstrates superior response to chemoradiotherapy in the locally advanced setting 5

Response Evaluation

• Assess response through tumor-related symptoms, endoscopy, and CT scan 1, 4
• In adenocarcinomas, FDG-PET can predict tumor response early, though this does not currently change therapeutic strategy 2, 4
• Regular follow-up after initial therapy has no proven impact on outcome and should focus on symptoms, nutrition, and psychosocial support rather than routine imaging 2, 4