Long-Term Postsurgical Outcomes of Neoadjuvant Chemoradiation (CROSS) Versus Chemotherapy (FLOT) for Multimodal Treatment of Adenocarcinoma of the Esophagus and the Esophagogastric Junction

Abstract

Background: The question of the ideal neoadjuvant therapy for locally advanced esophagogastric adenocarcinoma has not been answered to date. Multimodal treatment has become a standard treatment for these adenocarcinomas. Currently, perioperative chemotherapy (FLOT) or neoadjuvant chemoradiation (CROSS) is recommended.

Methods: A monocentric retrospective analysis compared long-term survival after CROSS versus FLOT. The study enrolled patients with adenocarcinoma of the esophagus (EAC) or the esophagogastric junction type I or II undergoing oncologic Ivor-Lewis esophagectomy between January 2012 and December 2019. The primary objective was to determine the long-term outcome in terms of overall survival. The secondary objectives were to determine differences regarding the histopathologic categories after neoadjuvant treatment and the histomorphologic regression.

Results: The findings showed no survival advantage for one or the other treatment in this highly standardized cohort. All the patients underwent open (CROSS: 9.4% vs. FLOT: 22%), hybrid (CROSS: 82% vs. FLOT: 72%), or minimally invasive (CROSS: 8.9% vs. FLOT: 5.6%) thoracoabdominal esophagectomy. The median post-surgical follow-up period was 57.6 months (95% confidence interval [CI] 23.2-109.7 months), and the median survival was longer for the CROSS patients (54 months) than for the FLOT patients (37.2 months) (p = 0.053). The overall 5-years survival was 47% for the entire cohort (48% for the CROSS and 43% for the FLOT patients). The CROSS patients showed a better pathologic response and fewer advanced tumor stages.

Conclusion: The improved pathologic response after CROSS cannot be translated into longer overall survival. To date, the choice of which neoadjuvant treatment to use can be made only on the basis of clinical parameters and the patient's performance status.

Keywords: CROSS; Esophageal adenocarcinoma; FLOT; Long-term prognosis; Multimodal treatment; Neoadjuvant radiochemotherapy; Perioperative chemotherapy.

Fig. 1

Kaplan–Meier survival analysis (log-rank test) of the long-term survival (in months) of patients who received neoadjuvant CROSS versus FLOT followed by esophagectomy due to esophageal adenocarcinoma (n = 578). Patients receiving neoadjuvant chemoradiation analogous to the CROSS regimen showed a (non-significantly) better (p = 0.053) postsurgical outcome than those who received neoadjuvant chemotherapy analogous to the FLOT regimen.

Fig. 2

Kaplan–Meier survival analysis (log-rank test) of the patients (in months) depending on the resulting ypT and ypN status after neoadjuvant CROSS versus FLOT followed by esophagectomy due to esophageal adenocarcinoma. Subgroup survival analyses of the cohort according to the respective ypT (a–e) and ypN (f–i) status of the patients. No prognostically significant difference could be found for all the different groups. The majority of the patients showed an only limited therapeutic response (ypT3). In this context, (d) neoadjuvant chemoradiation analogous to the CROSS regimen had a survival benefit compared with neoadjuvant chemotherapy analogous to the FLOT protocol (although statistical significance was not reached; p = 0.076). Similarly, the prognosis was (non-significantly) better for the ypT1 patients (b) in the CROSS versus the FLOT cohort.

Fig. 2

Kaplan–Meier survival analysis (log-rank test) of the patients (in months) depending on the resulting ypT and ypN status after neoadjuvant CROSS versus FLOT followed by esophagectomy due to esophageal adenocarcinoma. Subgroup survival analyses of the cohort according to the respective ypT (a–e) and ypN (f–i) status of the patients. No prognostically significant difference could be found for all the different groups. The majority of the patients showed an only limited therapeutic response (ypT3). In this context, (d) neoadjuvant chemoradiation analogous to the CROSS regimen had a survival benefit compared with neoadjuvant chemotherapy analogous to the FLOT protocol (although statistical significance was not reached; p = 0.076). Similarly, the prognosis was (non-significantly) better for the ypT1 patients (b) in the CROSS versus the FLOT cohort.

Fig. 3

Kaplan–Meier survival analysis (log-rank test) of the patients depending on the post-neoadjuvant therapy (ypTNM) stage groups according to UICC after neoadjuvant CROSS versus FLOT followed by esophagectomy due to esophageal adenocarcinoma. UICC, Union for International Cancer Control. Subgroup survival analyses of the cohort according to post-neoadjuvant therapy (ypTNM) stage groups as shown by UICC. (a–f) No significant prognostic differences in dependence are shown in CROSS versus FLOT. UICC, Union for International Cancer Control