The Superiority of the FLOT Regimen in Resectable Esophageal Cancer

Esophageal cancer is relatively rare, affecting approximately 1500 people each year in Turkey. Nevertheless, it deserves attention because it is usually diagnosed at an advanced stage and its incidence has increased in recent years.

Esophageal cancer is primarily divided into two main subtypes: squamous cell carcinoma and adenocarcinoma.

• Squamous Cell Carcinoma: More common in the upper and middle parts of the esophagus, this type is widespread globally, particularly in Asia and Africa. Tobacco and alcohol use are important risk factors.
• Adenocarcinoma: This type is more common in the lower esophagus, near the stomach. It is more prevalent in Western countries, particularly the United States and Europe. Chronic gastroesophageal reflux disease (GERD), obesity, and Barrett's esophagus are important risk factors.

Worldwide, squamous cell carcinoma is the more common type of esophageal cancer. However, adenocarcinoma has increased markedly in Western countries and has become more common in these regions.

Esophageal cancer is usually diagnosed at an advanced stage . A large proportion of patients have locally advanced or metastatic disease at diagnosis. Staging is based on tumor size, lymph node involvement, and the presence of distant metastases. Esophageal cancer stages are classified as follows:

• Stage I: Cancer is confined to the inner lining of the esophagus.
• Stage II: Cancer has spread into deeper layers of the esophagus and/or to nearby lymph nodes.
• Stage III: Cancer has spread to the outer layer of the esophagus and/or to more lymph nodes.
• Stage IV: Cancer has metastasized to distant organs.

In treating esophageal adenocarcinoma, standard approaches vary according to disease stage:

• Stage I: Surgery is generally preferred. Endoscopic resection or surgical removal of part of the esophagus may be performed.
• Stages II and III: Neoadjuvant treatment, given before surgery, is generally used at these stages. Neoadjuvant chemotherapy or chemoradiotherapy aims to shrink the tumor, followed by surgery. CROSS and FLOT are commonly used regimens.
• Stage IV: Treatment is generally palliative, aiming to improve quality of life and relieve symptoms. Chemotherapy, radiotherapy, and targeted therapies may be used. Immunotherapy is also among the newer treatment options.

The Search for the Best Treatment

Long-running debate over the best approach to treating esophageal adenocarcinoma has begun to be clarified by the ESOPEC results presented at the ASCO 2024 annual meeting. This study showed that the perioperative chemotherapy regimen, given before and after surgery, known as FLOT, produced better outcomes when administered before and after surgery than the neoadjuvant, or preoperative, chemoradiotherapy approach known as CROSS.

Study Details

The phase-3 ESOPEC trial demonstrated that perioperative FLOT chemotherapy offered an overall survival advantage over neoadjuvant CROSS chemoradiotherapy in patients with resectable, locally advanced esophageal adenocarcinoma.

The ESOPEC clinical trial compared two treatment strategies for locally advanced esophageal adenocarcinoma that could be treated surgically.

The CROSS protocol consists of chemoradiotherapy before surgery.

The FLOT protocol consists of chemotherapy before and after surgery.

A total of 221 participants were randomized to the FLOT arm and 217 to the CROSS arm. Their median age was 63, and 89% were male. Approximately 70% of esophageal cancer diagnoses occur in men.

Key Findings

• Among all participants, 403 began some form of treatment and 371 underwent surgery: 191 in the FLOT arm and 180 in the CROSS arm.
• Within 90 days of surgery, 4.3% of participants died (3.2% in the FLOT arm and 5.6% in the CROSS arm). After a median follow-up of 55 months, 218 participants had died: 97 in the FLOT arm and 121 in the CROSS arm.
• Median overall survival in the FLOT arm was 66 months (5 years and 6 months), compared with 37 months (3 years and 1 month) in the CROSS arm.
• At 3 years, participants receiving FLOT had a 30% lower risk of death than those receiving CROSS. The 3-year overall survival rates were 57% in the FLOT arm and 51% in the CROSS arm.
• Among the 359 participants with known tumor regression status, 35 patients in the FLOT arm and 24 patients in the CROSS arm achieved a pathologic complete response .

Many patients in the United States and Europe are still treated with the CROSS chemoradiotherapy protocol. This study indicates that patients with resectable esophageal cancer should receive FLOT chemotherapy before and after surgery to maximize the chance of long-term treatment of their tumors.

Next Steps

The researchers will investigate whether surgery can be avoided in cancers treated with FLOT or CROSS that show no growth during active surveillance. Active surveillance involves regular tests, such as blood tests and imaging, to monitor whether cancer has returned. Avoiding surgery preserves the esophagus, improving patients' quality of life.