Esophageal / GEJ Cancer Landmark Atlas

What did the researchers want to learn?

In esophageal cancer that can be operated on, does giving chemotherapy and radiotherapy together before surgery prolong survival?

What did this study change?

In many operable esophageal and gastroesophageal junction cancers, chemoradiotherapy before surgery became a paradigm-changing standard option.

Benefit for patients

Higher likelihood of complete tumor removal at surgery and longer survival.

What did the research find?

NEJM 2012 median overall survival (OS) ~49 vs 24 months; 10-year OS (JCO 2021) 38% vs 25%. Adenocarcinoma and squamous cell results should not be considered identical; CROSS is not a direct comparison with FLOT.

Who does this apply to?

Results are for patients who can be operated on. Histology subgroups are read separately; in adenocarcinoma, the choice of FLOT after ESOPEC is also being discussed.

What did the researchers want to learn?

In esophageal adenocarcinoma, is FLOT chemotherapy given before and after surgery better than chemotherapy plus radiotherapy before surgery (CROSS)?

What did this study change?

In resectable esophageal adenocarcinoma, perioperative FLOT became the option showing an overall survival advantage over CROSS; it is not generalized to squamous cell cancer.

Benefit for patients

Likelihood of longer survival in selected adenocarcinoma patients.

What did the research find?

3-year overall survival (OS) 57.4% (FLOT) vs 50.7% (CROSS); hazard ratio (HR) 0.70; median OS ~66 vs ~37 months. It is not generalized to squamous cell esophageal cancer or to all gastric cancers.

Who does this apply to?

Valid only for esophageal adenocarcinoma; it does not address squamous cell carcinoma or the FLOT4 gastric question.

What did the researchers want to learn?

In patients who had chemoradiotherapy before surgery and still have residual tumor after surgery, does nivolumab delay the return of the disease?

What did this study change?

In suitable patients, postoperative nivolumab became the standard option that improves DFS in residual disease.

Benefit for patients

Longer time without disease returning.

What did the research find?

Median disease-free survival (DFS) was 22.4 vs 11.0 months (hazard ratio [HR] 0.69). It applies to the population with neoadjuvant chemoradiotherapy (CRT) + R0 resection + pathological residual disease; it is not automatically generalized to pathological complete response (pCR) or to a different perioperative strategy. The 2025 overall survival (OS) analysis was not statistically significant.

Who does this apply to?

Only for neoadjuvant chemoradiotherapy (CRT) + R0 resection + residual pathological disease. An overall survival advantage was not statistically demonstrated in 2025.

What did the researchers want to learn?

In squamous cell esophageal cancer, does giving chemotherapy and radiotherapy before surgery prolong survival?

What did this study change?

It is one of the pieces of evidence supporting the option of chemoradiotherapy before surgery in operable squamous cell esophageal cancer.

Benefit for patients

Longer survival and higher complete-resection rates in selected patients.

What did the research find?

Median survival was found to be about 100 months in patients who received treatment before surgery and about 66 months in those who had surgery alone. The proportion of patients in whom the tumor disappeared completely with treatment was 43%.

Who does this apply to?

The study was conducted in China and includes only squamous cell carcinoma; it does not apply to adenocarcinoma. The chemotherapy regimen differs from the one commonly used in other countries.

What did the researchers want to learn?

In squamous cell esophageal cancer, does adding a third drug or radiotherapy to two-drug chemotherapy before surgery improve survival?

What did this study change?

Three-drug chemotherapy before surgery began to be adopted as a new standard in Japanese patients in suitable general condition.

Benefit for patients

Higher three-year survival rate in selected patients.

What did the research find?

At three years, about 63% of those receiving two-drug chemotherapy were alive, compared with about 72% of those receiving three drugs. In the group with radiotherapy added, the rate was about 68%, and the difference from the two-drug group was not found to be significant.

Who does this apply to?

Results are for patients with squamous cell carcinoma in Japan. This does not mean it replaces CROSS or other approaches in Western countries; it applies to patients who can tolerate intensive chemotherapy.

What did the researchers want to learn?

In advanced esophageal cancer, does adding pembrolizumab to chemotherapy in first-line treatment prolong survival?

What did this study change?

Adding immunotherapy to first-line treatment in advanced-stage patients became a widely used option, depending on PD-L1 and cell type.

Benefit for patients

Longer life and improved five-year survival in some patients.

What did the research find?

Median survival was about 12 months in the group with pembrolizumab added and about 10 months in the chemotherapy-alone group. The proportions of patients alive after five years were 10.6% and 3.0%. The benefit was clearer especially in squamous cell cancers with high PD-L1 levels.

Who does this apply to?

Only for advanced, inoperable or metastatic disease; it should not be confused with adjuvant or neoadjuvant studies in operable disease. PD-L1 level and cell type are important for the decision.

What did the researchers want to learn?

In advanced squamous cell esophageal cancer, is first-line nivolumab (with chemotherapy or with ipilimumab) better than chemotherapy alone?

What did this study change?

In advanced squamous cell cancer, first-line nivolumab plus chemotherapy and nivolumab plus ipilimumab became established as standard options showing an overall survival (OS) advantage over chemotherapy.

Benefit for patients

Longer life in selected patients; regimen choice depends on patient status.

What did the research find?

In patients with a PD-L1 value of 1% or higher, median survival was 15.4 months with nivolumab plus chemotherapy, 13.7 months with nivolumab plus ipilimumab, and 9.1 months with chemotherapy alone. In all patients too, both nivolumab approaches were associated with longer survival than chemotherapy. A significant benefit in time without disease progression was seen especially in the nivolumab plus chemotherapy arm; the two immunotherapy arms were not compared with each other for superiority.

Who does this apply to?

Only for advanced squamous cell carcinoma. PD-L1, general condition and suitability for chemotherapy determine the choice of regimen; for adenocarcinoma, different evidence such as KEYNOTE-590 is used.

What did the researchers want to learn?

Does adding the immunotherapy pembrolizumab to chemotherapy and radiotherapy given without surgery improve disease control?

What did this study change?

It provided no justification for routinely adding pembrolizumab to chemoradiotherapy without surgery; therefore there is no change in practice toward adding pembrolizumab.

Benefit for patients

Because benefit was not shown, no gain was defined that would support routinely adding this drug therapy for patients.

What did the research find?

In patients with a high PD-L1 value (combined positive score [CPS] 10 or higher), median event-free survival was 15.2 months in the pembrolizumab group and 14.7 months in the placebo group; the difference was not significant. No benefit in survival was seen in favor of pembrolizumab either. The study was stopped.

Who does this apply to?

Physician review (again 2026-10-28): There is still no peer-reviewed final results paper — ESMO 2026 congress, interim analysis 2 (IA2). Routine definitive chemoradiotherapy (dCRT) plus pembrolizumab is not supported.