Stage 2 and 3 Esophageal Cancer – Comparing Surgery, Chemotherapy and Radiotherapy

Esophageal cancer ranks 9th among cancers causing the most deaths worldwide. Although many treatment methods are available, their effectiveness and impact on patient survival have not been clearly defined in clinical practice. In particular, neoadjuvant chemoradiotherapy (nCRT) followed by surgery, known as trimodality treatment, and perioperative chemotherapy (before and after surgery) have demonstrated substantial benefits. However, information on their real-world use and effectiveness remains limited compared with clinical trial data.

On October 21, 2024, JAMA Network Open published a large retrospective study that examined data from 57116 patients to assess in detail how different esophageal cancer treatments affect survival.

Study Details

Researchers examined patients diagnosed with clinical stage II-III esophageal cancer between 2006-2020 in the American College of Surgeons' National Cancer Database. Patients included in the study had received one of four treatments:

• Perioperative chemotherapy (PC)
• Trimodality treatment (neoadjuvant chemoradiotherapy and surgery)
• Definitive chemoradiotherapy (dCRT)
• Single-modality radiotherapy (RT)

The study included 57116 patients in total, of whom 66% had esophageal adenocarcinoma (EAC) and 29% had esophageal squamous cell carcinoma (ESCC).

Definitive chemoradiotherapy (dCRT) combines chemotherapy and radiotherapy concurrently in esophageal cancer patients who are unsuitable for surgery or decline it. To achieve local tumor control and control systemic disease, it generally involves platinum-based chemotherapy (such as cisplatin or carboplatin) and radiotherapy at a dose of 50-60 Gray. 

What Is Perioperative Chemotherapy and How Is It Given?

In the study, patients receiving perioperative chemotherapy were generally treated using the FLOT protocol . This regimen is frequently preferred for esophageal adenocarcinoma (EAC) and provides a survival benefit.

• Neoadjuvant (Before Surgery) Phase:
  The FLOT protocol is given for 4 cycles before surgery. Each cycle is scheduled at approximately 2-week intervals . During this period, patients are prepared for surgery and the tumor is reduced in size to make it suitable for surgery.

• Surgery:
  After neoadjuvant chemotherapy is completed, an esophagectomy is performed to remove the tumor.

• Adjuvant (After Surgery) Phase:
  After surgery, patients receive a further 4 cycles of FLOT chemotherapy. This targets remaining micrometastases to reduce the risk of recurrence.

Study Findings

Survival and Treatment Patterns

• Perioperative Chemotherapy (PC):

  • Median survival: 66.2 months
  • Associated with the best survival compared with all other treatments. However, only 0.5% of patients in the study received this treatment.

• Trimodality Treatment (nCRT + Surgery):

  • Median survival: 43.9 months
  • Particularly recommended for patients able to tolerate surgery.

• Definitive Chemoradiotherapy (dCRT):

  • Median survival: 18.1 months
  • The most widely used approach for patients who are unsuitable for surgery.

• Single-Modality Radiotherapy:

  • Median survival: 13.5 months
  • Generally selected only as a palliative option.

The Effects of Age and Histologic Subtype

• The Effect of Age:
  In patients over 65, perioperative chemotherapy and trimodality treatment provided significantly longer survival than other approaches.

  • Perioperative chemotherapy: 56.7 months
  • Trimodality treatment: 40.1 months

• The Effect of Histologic Subtype:
  Patients with EAC had higher survival rates than those with ESCC.

  • Perioperative chemotherapy for EAC: 56.7 months
  • Definitive chemoradiotherapy for ESCC: 20.1 months

Socioeconomic Factors

• Patients with private insurance were more likely to receive perioperative chemotherapy or trimodality treatment. Greater distance from the treatment center also increased the likelihood of surgery.

The image below presents Kaplan–Meier curves comparing the effects of esophageal cancer treatment modalities on survival. It consists of two panels:

Panel A: All Patients

This panel compares survival with four treatments (CRT alone, CRT + surgery, PC and RT alone) in all patients included in the study:

1. CRT Alone (Definitive Chemoradiotherapy):
   Survival is lower than with the other active treatment approaches.
   Median survival is approximately 18 months.

2. CRT + Surgery (Trimodality Treatment):
   Survival is substantially higher than with CRT alone and RT alone.
   Median survival is approximately 44 months.

3. PC (Perioperative Chemotherapy):
   The treatment approach with the best survival.
   Median survival is 66 months, but this treatment group was the smallest in the study (the sample size was very small).

4. RT Alone (Single-Modality Radiotherapy):
   The approach with the lowest survival.
   Median survival is approximately 13 months, and it is generally used as a palliative option.

Panel B: Patients Over 65

This panel compares survival by treatment type in patients over 65:

1. CRT Alone (Definitive Chemoradiotherapy):
   Survival is also lower than with the other approaches in this age group.

2. CRT + Surgery (Trimodality Treatment):
   It substantially improves survival in older patients as well, although its effect is somewhat smaller than in younger patients. Median survival is approximately 40 months.

3. PC (Perioperative Chemotherapy):
   It also provides the best survival in this age group. Median survival is approximately 57 months.

4. RT Alone (Single-Modality Radiotherapy):
   It also has the lowest survival in patients over 65.

Treatment Choices and Clinical Decision-Making

• Underuse of Perioperative Chemotherapy:
  The study showed that perioperative chemotherapy was the least-used treatment in clinical practice despite its superiority in the literature. This may be related to barriers to treatment access.

• Surgery and Performance Status:
  Patients' general health and functional capacity were decisive in the choice of surgery. Particularly for older patients, multidisciplinary approaches are important for assessing treatment options without ruling out surgery.

Study Limitations

• Retrospective Design:
  The retrospective nature of the study led to data-related biases and a small sample size in the perioperative chemotherapy group.

• Clinical Diversity:
  The database includes data from different centers, so regional and institutional differences between treatment protocols should be kept in mind.

Conclusion

This large study shows that perioperative chemotherapy and trimodality treatment produce the greatest improvements in survival in esophageal cancer. The superiority of perioperative chemotherapy is particularly notable in patients with adenocarcinoma. Even older patients can benefit from these options. However, broader adoption of these treatments in clinical practice requires improvements in patient selection, socioeconomic barriers and health policies.