FLOT or CROSS for Gastroesophageal Junction Cancers

Is the Debate Over Yet?

Bushra Shariff; Rutika Mehta


Chin Clin Oncol. 2023;12(3):24 

In This Article

Abstract and Introduction


In the last two decades, the incidence of gastroesophageal junction (GEJ) adenocarcinomas (AC) has increased, in part due to the increasing prevalence of obesity and untreated gastroesophageal reflux disease (GERD). Esophageal and GEJ cancers have become one of the leading causes of cancer deaths worldwide due to its aggressive nature. While the mainstay of treatment for locally advanced gastroesophageal cancers (GECs) remains surgery, several studies have now shown that multimodality approach yields better outcomes. GEJ cancers have historically been included both in esophageal cancer as well as gastric cancer trials. Therefore, both approaches, neoadjuvant chemoradiation (CRT) or perioperative chemotherapy are considered standard treatment options. thereon the same token, there yet remains a debate for the 'gold standard' treatment of locally advanced GEJ cancers. The landmark trials, fluorouracil, leucovorin, oxaliplatin, docetaxel (FLOT) and ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS), have shown similar improvements in overall survival (OS) and disease-free survival (DFS) for patients with resectable locoregional GEJ cancers. In this review, the authors attempt to highlight the historical evolution of current standard treatments and provide a sneak peek into the future of treatment of GEJ cancers. Several factors must be borne in mind when making the optimal choice for a patient. Some of these include surgical candidacy, tolerance to chemotherapy, eligibility for radiation (RT) as well as institutional preferences.


Gastroesophageal cancers (GECs) are expected to comprise less than 50 thousand new cancer cases in the United States in 2023, however ranks 2nd highest in mortality across the globe.[1–3] GECs encompass tumors spanning from the upper one third of the esophagus into the gastric pylorus.[4] These cancers can be further subclassified by location into: (I) esophageal; (II) gastroesophageal junction (GEJ); and (III) gastric. Histologic subtype differs based on location of the tumor along the gastroesophageal tract, which further dictates treatment options.[1,2,5] Most common histologic subtypes are squamous cell carcinoma (SCC) and adenocarcinoma (AC). While smoking remains a risk factor for the development of either histologic subtype of GEC, the risk for SCC is highest with smoking along with heavy alcohol use.[6,7] A history of uncontrolled gastroesophageal reflux disease (GERD) and Barrett's esophagus are more commonly associated with AC.[6–8] There are some other risk factors such as Helicobacter pylori infection, achlorhydria that are implicated as risk factors among others for gastric cancers.[7]

Staging of GECs is critical not only in making treatment decisions, but also for overall prognosis. Locally advanced GECs are tumors that invade beyond the superficial layer in the esophagus/stomach and/or involve regional lymph nodes but without evidence of distant metastases, i.e., ≥T2 or N+, M0.[2,5] In the locally advanced setting, treatment for GECs arising in the tubular esophagus and true stomach are well defined. However, the GEJ cancers have historically been included in studies for both esophageal and gastric cancers. Therefore, the practice of treating GEJ cancers varies vastly. The Siewert classification has been increasingly used to classify GEJ cancers for the purpose of treatment as well as guide surgical techniques. Siewert class I includes cancers with epicenter 1 to 5 cm above the GEJ. Siewert class II include GEJ tumors with epicenter for tumors 1 cm proximal to GEJ to 2 cm distal to GEJ. Siewert class III include cancers with epicenter within 2 to 5 cm distal to the GEJ.[4,5,9–11]

Studies have shown neoadjuvant or perioperative chemotherapy is superior to surgery alone in locally advanced GECs. Neoadjuvant therapy with chemotherapy and radiation (RT) followed by surgery is now considered standard practice for most esophageal cancers. Tri-modality treatment has significantly improved R0 resection rates, but also improved overall survival (OS) especially for ACs. Peri-operative chemotherapy with epirubicin-based triplet chemotherapy as studied in the MAGIC trial first showed improvement in OS for patients with locally advanced gastric cancer.[1,2,12] However, as an improvement over epirubicin-based chemotherapy, the new standard of care has become another triplet chemotherapy regimen with fluorouracil, leucovorin, oxaliplatin, docetaxel (FLOT).

Both treatment regimens with neoadjuvant chemoradiation (CRT) and perioperative FLOT currently remain the standard of therapy for locally advanced GEJ cancer.[2] Head-to-head comparisons between neoadjuvant CRT to current standard of care perioperative chemotherapy are lacking. In this review article we will discuss important features from the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) and FLOT trials and their impact on clinical practice when it comes to treating GEJ cancers.