When is neoadjuvant chemoradiotherapy indicated in esophageal cancer?

Neoadjuvant Chemoradiotherapy in Esophageal Cancer

Neoadjuvant chemoradiotherapy is strongly indicated for patients with locally advanced esophageal cancer (T3-T4 N0-3 M0), as surgery alone is not a standard treatment due to poor long-term survival rates rarely exceeding 20% even after complete tumor resection. 1

Indications by Disease Stage and Histology

Locally Advanced Disease (T3-T4 N0-3 M0)

For Squamous Cell Carcinoma (SCC):

• Preoperative chemoradiotherapy is the standard of care 1
• Provides significant survival benefit compared to surgery alone (HR 0.453) 1
• CROSS regimen (carboplatin/paclitaxel with 41.4 Gy radiotherapy) is preferred due to:
  • Improved overall survival (median 81.6 months vs 21.1 months with surgery alone) 2
  • Lower toxicity profile compared to older regimens 1
  • Reduction in both local and systemic disease recurrence 1

For Adenocarcinoma (AC):

• Two standard approaches:
  1. Preoperative chemoradiotherapy (preferred for selected patients) 1
     • Particularly beneficial for high-risk patients with locally more advanced stages 1
     • CROSS regimen shows survival benefit (median 43.2 months vs 27.1 months with surgery alone) 2
  2. Perioperative chemotherapy with platinum/fluoropyrimidine 1
     • FLOT regimen (docetaxel, oxaliplatin, fluorouracil) shows superior survival compared to ECX 1

Early Stage Disease (T1-2 N0-1 M0)

• For T1-2 N0: Surgery alone is standard treatment 1
• For T1-2 N1-3: Preoperative therapy is recommended, especially for adenocarcinoma 1
• For very early stage cancers: Neoadjuvant CRT showed no benefit in a randomized trial 1

Special Situations

• Cervically localized tumors: Definitive chemoradiotherapy is recommended 1
• Patients unfit for surgery: Definitive chemoradiotherapy (at least 50.4 Gy) 1

Treatment Regimens

Recommended Chemoradiotherapy Protocols:

• CROSS regimen: Weekly carboplatin (AUC 2) and paclitaxel (50 mg/m²) with concurrent radiotherapy (41.4 Gy in 23 fractions) 2
• Alternative regimens: Cisplatin/5-FU or oxaliplatin/5-FU with 41.4-50.4 Gy radiotherapy 1

Radiation Doses:

• Preoperative setting: 41.4-45 Gy in 1.8 Gy fractions 1
• Definitive chemoradiotherapy: At least 50.4 Gy in 1.8 Gy fractions 1
• Higher doses (up to 60 Gy) may be used in definitive treatment in parts of Europe and Japan 1

Post-Treatment Considerations

• For adenocarcinoma: Even after complete clinical response to preoperative therapy, patients should proceed to surgery 1
• For SCC: Two options with equivalent overall survival:
  1. Chemoradiotherapy followed by planned surgery 1
  2. Definitive chemoradiotherapy with close surveillance and salvage surgery for local tumor persistence/progression 1

Clinical Pitfalls and Caveats

1. Surgical complications: Preoperative chemoradiotherapy may increase post-operative mortality rates 1

   • Requires experienced multidisciplinary teamwork
   • Post-operative mortality increases with higher radiation doses

2. Patient selection: Consider fitness for surgery

   • Exclude patients with poor performance status, respiratory insufficiency, portal hypertension, renal insufficiency, recent myocardial infarction, and advanced peripheral arterial disease 1

3. Histology-specific considerations:

   • SCC shows greater benefit from chemoradiotherapy than adenocarcinoma 1, 2
   • Recent data suggests comparable outcomes between neoadjuvant chemoradiotherapy and chemotherapy for cT3-4aN0-1M0 ESCC 3, though pathological complete response rates are significantly higher with chemoradiotherapy

4. Emerging approaches:

   • Addition of immunotherapy (PD-1 inhibitors) to neoadjuvant chemotherapy shows promising results in early studies 4
   • Induction chemotherapy before neoadjuvant CRT remains unconfirmed with inconsistent results 1

By following these evidence-based recommendations, clinicians can optimize treatment outcomes for patients with esophageal cancer requiring neoadjuvant therapy.