What is the recommended approach for chemoradiotherapy in gastroesophageal (GE) junction tumors?

Chemoradiotherapy in Gastroesophageal Junction Tumors

For patients with resectable advanced gastroesophageal junction tumors, perioperative chemotherapy or neoadjuvant chemoradiotherapy is recommended, with the FLOT regimen being the preferred perioperative chemotherapy option for smaller tumors and preoperative chemoradiotherapy preferred for larger, bulky tumors with proximal extension. 1, 2

Classification and Approach

Gastroesophageal junction (GEJ) tumors are classified according to the Siewert classification:

• Siewert type I: Distal esophageal adenocarcinoma
• Siewert type II: True cardia carcinoma
• Siewert type III: Subcardial gastric carcinoma

Treatment approach varies based on:

1. Tumor stage
2. Siewert classification
3. Patient's performance status
4. Tumor size and proximal extension

Treatment Options for Resectable GEJ Tumors

Perioperative Chemotherapy

• Preferred regimen: FLOT (docetaxel, oxaliplatin, leucovorin, and fluorouracil) 2, 3
  • 4 preoperative and 4 postoperative 2-week cycles
  • Best for smaller tumors without significant proximal extension
• Alternative regimens:
  • Cisplatin and fluorouracil
  • ECF (epirubicin, cisplatin, fluorouracil) or modifications
  • Fluorouracil and cisplatin 2

Preoperative Chemoradiotherapy

• Recommended for:
  • Large, bulky tumors with proximal extension
  • Cases where complete surgical resection is challenging 2
• Standard regimen:
  • CROSS regimen (weekly carboplatin and paclitaxel with concurrent radiotherapy) 3
  • Standard radiation dose: 50.4 Gy in 28 fractions 1

Definitive Chemoradiotherapy

• Recommended for patients unfit for surgery
• Standard regimen: 5-FU and cisplatin (CF) with 50.4 Gy radiation 1
• Alternative regimens:
  • Carboplatin and paclitaxel
  • FOLFOX4 (5-FU, leucovorin, and oxaliplatin) 1

Evidence Supporting Treatment Decisions

Perioperative Chemotherapy vs. Preoperative Chemoradiotherapy

• A network meta-analysis ranked preoperative chemoradiotherapy higher than perioperative chemotherapy for overall survival in GEJ cancer (HR 1.00 vs 1.32) 4
• However, the recent TOPGEAR trial showed no significant difference in overall survival between adding preoperative chemoradiotherapy to perioperative chemotherapy compared to perioperative chemotherapy alone (median OS 46 vs 49 months) 5

Definitive Chemoradiotherapy Evidence

• RTOG 85-01 trial demonstrated significant improvement in median survival (14 vs 9 months) and 5-year overall survival (27% vs 0%) with chemoradiotherapy compared to radiotherapy alone 1
• INT 0123 trial established 50.4 Gy as the standard radiation dose, showing no benefit of higher doses (64.8 Gy) 1

Surgical Considerations

• Approach: Transthoracic approach with thoracoscopic (robotic) esophagectomy is recommended 2
• Lymph node dissection: Lower mediastinal and suprapancreatic lymph node stations should be included for tumors with 2-4 cm esophageal invasion 2
• Minimally invasive approach is recommended when a transthoracic approach is indicated 2
• At least 15 lymph nodes should be removed for adequate nodal staging 1

Treatment Algorithm

1. Early-stage (T1-T2, N0):

   • Consider surgery alone or endoscopic resection for superficial neoplasia

2. Locally advanced resectable disease:

   • For smaller tumors without significant proximal extension:
     • Perioperative chemotherapy with FLOT regimen
   • For larger tumors with proximal extension:
     • Preoperative chemoradiotherapy (50.4 Gy with concurrent chemotherapy)

3. Locally advanced unresectable or medically inoperable:

   • Definitive chemoradiotherapy with 5-FU/cisplatin and 50.4 Gy radiation

Important Considerations

• Biomarker testing (HER2, PD-L1 CPS, MSI, claudin 18.2) is essential for guiding treatment in advanced disease 2
• Laparoscopy with peritoneal washings should be considered for clinical stage T3 or node-positive tumors to detect occult metastatic disease 1
• Positive peritoneal cytology in the absence of overt peritoneal metastases is associated with poor prognosis 1
• Regular follow-up is necessary to monitor for recurrence, nutritional status, and treatment-related complications 2

Pitfalls to Avoid

• Avoid using higher radiation doses (>50.4 Gy) as they do not improve outcomes but increase toxicity 1
• Do not underestimate the importance of adequate lymph node dissection, as the number of lymph nodes removed is an independent predictor of survival 1
• Avoid preoperative chemoradiotherapy for early-stage (stage I and II) esophageal cancers, as it may increase operative mortality without survival benefit 1
• Do not neglect biomarker testing, which is crucial for identifying targeted therapy opportunities in advanced disease 2