What are the treatment regimens for esophageal adenocarcinoma?

Treatment Regimens for Esophageal Adenocarcinoma

For locally advanced esophageal adenocarcinoma, perioperative chemotherapy with FLOT (docetaxel, oxaliplatin, leucovorin, and fluorouracil) is the preferred first-line regimen, while preoperative chemoradiotherapy with carboplatin/paclitaxel plus 41.4-50.4 Gy radiation is the alternative first-line option, both followed by surgery. 1

First-Line Treatment for Localized Disease (M0)

Perioperative Chemotherapy Approach

• FLOT regimen is the standard of care for perioperative chemotherapy in esophageal adenocarcinoma, consisting of 4 preoperative and 4 postoperative 2-week cycles: docetaxel 50 mg/m², oxaliplatin 85 mg/m², leucovorin 200 mg/m², and fluorouracil 2,600 mg/m² as 24-hour infusion on day 1 1
• Where FLOT is unavailable, use cisplatin 80 mg/m² IV on day 1 plus fluorouracil 1 g/m² per day IV on days 1-4, given for 2-3 preoperative cycles 1
• Alternative regimen: cisplatin/5-FU with or without epirubicin for locally advanced disease 1

Preoperative Chemoradiotherapy Approach

• Carboplatin/paclitaxel weekly with concurrent radiation 41.4-45 Gy in 1.8 Gy fractions is the preferred chemoradiotherapy regimen 1
• Alternative: cisplatin/5-FU combined with 40-50.4 Gy radiation 1
• European and Japanese centers use 60 Gy or more for definitive chemoradiotherapy based on dose-response correlation 1

Surgical Component

• Transthoracic esophagectomy with en bloc two-field lymphadenectomy is mandatory after neoadjuvant therapy 2
• Adequate lymphadenectomy requires harvesting at least 16-18 and preferably 20 lymph nodes 1
• Minimally invasive esophagectomy (MIE) is preferred over open approaches in experienced centers 2

Decision Algorithm: Chemotherapy vs. Chemoradiotherapy

Choose perioperative chemotherapy (FLOT) when:

• Tumor is smaller and located at the gastroesophageal junction 2
• High likelihood of achieving complete surgical resection 2
• Patient cannot tolerate radiation therapy 2
• Surgery will be performed at a high-volume center with adequate lymphadenectomy 1

Choose preoperative chemoradiotherapy when:

• Tumor is bulkier with proximal extension 2
• Concern exists about achieving complete surgical resection 2
• Surgery will be performed at centers with less extensive lymphadenectomy 1
• Patient has locally advanced T3-T4 disease 1

Adjuvant Therapy Post-Surgery

• Adjuvant nivolumab should be administered if preoperative chemoradiotherapy was given and residual disease exists in the resection specimen 2
• Complete the remaining postoperative cycles of chemotherapy if perioperative chemotherapy was initiated 2
• No adjuvant chemotherapy is recommended after surgery alone in adenocarcinoma, though data from gastric cancer may be extrapolated 1

First-Line Treatment for Metastatic Disease

HER2-Positive Tumors

• Screen all esophagogastric junction tumors for HER2 overexpression or gene amplification 1
• For HER2-positive metastatic tumors, use trastuzumab plus cisplatin/fluoropyrimidine combination as first-line therapy 1

HER2-Negative Tumors

• Platinum/fluoropyrimidine combinations (cisplatin/5-FU, carboplatin/paclitaxel, or oxaliplatin/5-FU) are standard first-line options 1, 3
• These newer regimens offer higher efficacy and improved quality of life compared with classical cisplatin/5-FU 1
• Chemotherapy is indicated for patients with good performance status 1

Definitive Chemoradiotherapy (Non-Surgical Candidates)

• For patients unable or unwilling to undergo surgery, definitive chemoradiotherapy with cisplatin/5-FU plus 50.4-60 Gy radiation is the standard treatment 1
• Four courses of cisplatin/5-FU combined with 50.4 Gy radiation is the U.S. standard 1
• European and Japanese protocols use 60 Gy or more based on dose-response data 1
• Combined chemoradiation is superior to radiotherapy alone 1, 4

Critical Pitfalls to Avoid

• Do not use surgery alone for locally advanced disease (T3-T4), as complete resection is achieved in only 50-70% and long-term survival rarely exceeds 20% 1
• Do not skip HER2 testing in metastatic esophagogastric junction tumors, as trastuzumab significantly improves outcomes in HER2-positive disease 1
• Postoperative complications are more severe with chemoradiotherapy compared to chemotherapy alone, requiring careful patient selection 1
• Postoperative mortality increases with higher radiation doses and shorter intervals between radiotherapy and surgery 1
• Do not proceed without multidisciplinary tumor board discussion including medical oncology, radiation oncology, and thoracic surgery 3, 2

Nuances in Evidence

The 2020 ASCO guideline 1 represents the most recent high-quality evidence and establishes FLOT as standard perioperative chemotherapy, while earlier ESMO guidelines 1 emphasized cisplatin/5-FU. Both approaches have strong evidence, with FLOT showing superiority in gastric cancer trials that included esophagogastric junction tumors. The choice between perioperative chemotherapy and preoperative chemoradiotherapy remains controversial, as no direct phase III comparison exists 1, 5, though both strategies demonstrate survival benefits over surgery alone 1.