What is the recommended regimen for total neoadjuvant therapy (TNT) in esophageal cancer (Ca Esophagus)?

Total Neoadjuvant Therapy in Esophageal Cancer

For patients with locally advanced esophageal cancer, multimodality therapy should be offered, with preoperative chemoradiotherapy (CRT) or perioperative chemotherapy being the preferred total neoadjuvant therapy approaches based on histology and tumor characteristics. 1

Recommended Regimens Based on Histology

For Esophageal Adenocarcinoma:

• Preoperative chemoradiotherapy (CRT): Weekly carboplatin and paclitaxel with concurrent radiation (41.4-45 Gy in 1.8 Gy fractions) followed by surgery is a preferred option, especially for bulkier tumors 1, 2
• Perioperative chemotherapy: FLOT regimen (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, given as 4 preoperative and 4 postoperative 2-week cycles) is considered standard of care, particularly for smaller tumors at the gastroesophageal junction 1, 2
• Where FLOT is not available, cisplatin and fluorouracil (2 3-weekly cycles of cisplatin 80 mg/m² IV on day 1 and fluorouracil 1 g/m² per day IV on days 1–4) or similar platinum-based regimen can be used 1

For Esophageal Squamous Cell Carcinoma:

• Preoperative chemoradiotherapy: Cisplatin/5-FU or carboplatin/paclitaxel with concurrent radiation (50.4 Gy) is the preferred approach 1, 3
• Preoperative chemotherapy: Cisplatin and 5-fluorouracil is the standard regimen 3
• Perioperative chemotherapy has shown improved overall survival (HR 0.79) and relapse-free survival (HR 0.62) compared to preoperative chemotherapy alone 1

Treatment Selection Considerations

• Factors favoring preoperative chemoradiotherapy:

  • Larger tumor size
  • More proximal tumor extension
  • Concern for achieving complete surgical resection 2
  • Higher likelihood of achieving pathological complete response (pCR) compared to chemotherapy alone (27.7% vs 2.9% in ESCC) 4

• Factors favoring perioperative chemotherapy:

  • Smaller tumor size
  • Higher likelihood of complete surgical resection
  • Patient inability to tolerate radiation therapy 2
  • Concerns about postoperative complications, which may be more severe with CRT compared to CT 1

Important Clinical Considerations

• Surgery remains essential even after complete clinical response to preoperative therapy, as data for a watch-and-wait strategy are limited in esophageal adenocarcinoma 2, 5
• The quality and extent of surgery significantly impacts outcomes - adequate lymphadenectomy (obtaining at least 16-18 and preferably 20 lymph nodes) and clear surgical margins are critical 1
• For patients who cannot undergo surgery, definitive chemoradiotherapy with doses of 50.4-60 Gy is recommended 1, 2
• Adjuvant nivolumab should be administered if the patient received preoperative chemoradiotherapy and has residual disease in the resection specimen 2

Comparative Effectiveness

• Recent data comparing neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy in ESCC showed comparable overall survival (HR 0.82,95% CI 0.58-1.18) despite higher pathological complete response rates with chemoradiotherapy 4
• The addition of radiation therapy is expected to be more beneficial in settings of less optimal or less extensive surgery 1
• Preoperative CT has demonstrated improved survival compared to surgery alone in patients with locally advanced adenocarcinoma 1

Cautions and Pitfalls

• Postoperative complications may be more severe with CRT compared to CT alone 1
• If salvage esophagectomy is being considered after definitive chemoradiotherapy, radiation doses higher than 55 Gy should be avoided due to increased postoperative mortality and morbidity 1
• For early-stage esophageal cancer (T1-T2, N0), preoperative CRT may be inferior to surgery alone and should be avoided 1
• Adequate patient selection is crucial, as not all patients will benefit equally from intensive multimodality approaches 6