Neoadjuvant and adjuvant therapy for locally advanced resectable esophagogastric junction and gastric cardia adenocarcinoma

INTRODUCTION — 

Esophageal and gastric cancers are aggressive tumors with a generally poor prognosis. The gastroesophageal junction (GEJ; also called the esophagogastric junction [EGJ]) and the gastric cardia (figure 1) represents an anatomical site with a rapidly increasing incidence of adenocarcinoma. (See "Epidemiology of gastric cancer", section on 'Changes in histologic pattern' and "Epidemiology and risk factors for esophageal cancer", section on 'Epidemiology'.)

These tumors are treated using various combinations of surgery, systemic therapy, and radiation therapy (RT).

This topic will provide an overview of neoadjuvant (ie, preoperative), perioperative, and adjuvant (ie, postoperative) therapy for locally advanced, resectable GEJ and gastric cardia adenocarcinomas. Related topics on the management of esophageal and gastric cancer are discussed separately.

●(See "Surgical management of invasive gastric cancer".)

●(See "Surgical management of resectable esophageal and esophagogastric junction cancers".)

●(See "Management of locally advanced unresectable or inoperable esophageal cancer".)

●(See "Adjuvant and neoadjuvant treatment of gastric cancer".)

●(See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer".)

●(See "Barrett's esophagus: Surveillance and management".)

●(See "Management of superficial esophageal cancer".)

DEFINITION AND CLASSIFICATION — 

The definition of the gastroesophageal junction (GEJ) is not standardized. It is defined differently by anatomists, physiologists, endoscopists, surgeons, and pathologists:

●Anatomists and surgeons localize the GEJ at the level of the angle of His, the point at which the tubular esophagus joins the cardia of the saccular stomach [1].

●Physiologists define the GEJ as the distal border of the lower esophageal sphincter, as determined by manometry.

●Endoscopically, the GEJ corresponds to the most proximal extent of the longitudinal gastric folds (figure 2) [2,3]. It is not the same as the squamocolumnar junction (SCJ), which forms a visible Z-line that marks the juxtaposition between the reddish columnar epithelium lining the gastric cardia and the pale glossy squamous epithelium lining the esophagus (picture 1). The SCJ is located approximately 3 to 10 mm proximal to the anatomically defined GEJ [4]. (See "Barrett's esophagus: Epidemiology, clinical manifestations, and diagnosis", section on 'Identify possible Barrett's'.)

●Pathologically, the GEJ is defined in an opened esophagogastrectomy specimen as the most proximal aspect of the gastric folds. The GEJ is located in the opened specimen by following the mucosa of the tubular esophagus to the top of the gastric folds. The GEJ location as defined by the pathologist is likely more precise than the location that is defined endoscopically, which can be limited both by respiratory and diaphragmatic motion during an endoscopic examination, as well as by the presence of a hiatal hernia.

The use of anatomic or endoscopic definitions such as "end of the tubular esophagus" or "proximal limit of the gastric folds" to define the GEJ should be avoided as these definitions place the GEJ at a point that can be over 2 cm proximal to the true physiologic GEJ, or over 2 cm distal to it, within the cardia of the stomach.

The gastric cardia is also imprecisely defined (figure 1). Anatomists describe the cardia as that zone of the stomach that is adjacent to the orifice of the tubular esophagus, but there is no anatomical landmark for the distal margin of the cardia. A definition of the cardia commonly used in Japan is the area within 2 cm above and below the GEJ [4].

The lack of a clear definition of the GEJ and gastric cardia has contributed to difficulties in the classification of these tumors and has hampered the definition of the optimal multimodality strategy.

AJCC classification — The tumor, node, metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) for esophageal and gastric cancer is used universally (table 1). In the eighth edition (2017) of the AJCC staging classification [5], tumors involving the GEJ with the tumor epicenter no more than 2 cm into the proximal stomach are staged as esophageal cancers. By contrast, GEJ tumors with their epicenter located more than 2 cm into the proximal stomach are staged as stomach cancers, as are all cardia cancers not involving the GEJ, even if they are within 2 cm of the GEJ (table 2).

Other changes from the 2010 classification include the provision of unique prognostic stage groupings based on clinically determined TNM categories, and unique pathologic (p) and post-treatment pathologic (yp) TNM prognostic stage groupings, which are specific for adenocarcinomas and squamous cell carcinomas. Stage-stratified prognostic estimates for esophageal adenocarcinomas are based on data from the Worldwide Esophageal Cancer Collaboration (figure 3) [6-11]. (See "Clinical presentation, diagnosis, and staging of gastric cancer", section on 'TNM staging criteria' and "Clinical manifestations, diagnosis, and staging of esophageal cancer".)

Siewert classification — Siewert and Holsher published a topographic-anatomic subclassification scheme for GEJ adenocarcinomas in 1987 [12] that has been adopted by many clinicians; it was approved by the Seventh International Society for Diseases of the Esophagus in 1995 and by the Second International Gastric Cancer Congress in 1997 [13]. Within this classification, GEJ adenocarcinomas encompass all tumors with an epicenter within 5 cm proximal or distal to the GEJ [13].

Siewert described three distinct categories of GEJ adenocarcinoma based on anatomic location, for which the surgical approach differs (figure 4):

●Type I tumor (located between 5 and 1 cm proximal to the GEJ [14]) – Adenocarcinoma of the distal esophagus that usually arises from an area with specialized intestinal metaplasia of the esophagus (ie, Barrett's esophagus) and that may infiltrate the GEJ from above.

●Type II tumor (located between 1 cm proximal and 2 cm distal to the GEJ) – True carcinoma of the cardia arising from the cardiac epithelium or short segments with intestinal metaplasia at the GEJ; this entity is also often referred to as "junctional carcinoma."

●Type III tumor (located between 2 and 5 cm distal to the GEJ) – Subcardial gastric carcinoma that infiltrates the GEJ and distal esophagus from below.

In most cases, classification is relatively straightforward based on the results of contrast radiography, endoscopy with retroflexed view of the GEJ, computed tomography (CT), and sometimes, intraoperative appearance. However, in some cases, it may be difficult to distinguish the type for very locally advanced tumors that obliterate the GEJ and cross boundaries. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'Pretreatment staging evaluation' and "Endoscopic ultrasound for evaluating patients with esophageal cancer", section on 'Preoperative staging'.)

There are some data suggesting that type II/III tumors might be better staged (and treated) as gastric cancers [15,16]. However, as noted above, in the newest eighth edition TNM classification system, cancers involving the GEJ that have their epicenter within the proximal 2 cm of the cardia and involve the GEJ are still staged as esophageal cancers (table 1) [5]. Cancers whose epicenter is more than 2 cm distal from the GEJ, even if the GEJ is involved, and all proximal cardia tumors that do not involve the GEJ (even if they are within 2 cm of the GEJ) are staged as stomach cancers (table 3). (See "Clinical presentation, diagnosis, and staging of gastric cancer", section on 'TNM staging criteria'.)

Siewert I, II, and III type tumors share a number of common morphologic features and a similar prognosis, but there are differences with regard to epidemiology, etiology, distribution, and pattern of nodal metastases [17-20]:

●Siewert type I tumors have epidemiologic and histologic characteristics that are similar to distal thoracic esophageal adenocarcinomas, including a strong male predominance, association with a history of reflux symptoms, and a predominance of intestinal-type histology, having arisen from Barrett's intestinal metaplasia secondary to gastroesophageal reflux [21]. (See "Barrett's esophagus: Pathogenesis and malignant transformation" and "Epidemiology and risk factors for esophageal cancer", section on 'Epidemiology' and "Epidemiology and risk factors for esophageal cancer", section on 'Risk factors' and "Barrett's esophagus: Epidemiology, clinical manifestations, and diagnosis", section on 'Intestinal metaplasia at GEJ'.)

By contrast, type III tumors resemble distal (non-cardia) gastric cancers, with a similar proportion of diffuse and intestinal histologic types and no association with reflux. They arise from the gastric mucosa, and their origin might be associated with Helicobacter pylori and atrophic gastritis [22]. Type III (and II) tumors have a less strong male predominance than do type I cancers. (See "Epidemiology of gastric cancer" and "Risk factors for gastric cancer".)

There is increasing evidence to suggest that Siewert type II tumors have two distinct etiologies, some being esophageal adenocarcinomas probably arising from short or ultrashort Barrett's esophagus, and others gastric adenocarcinomas caused by H. pylori infection and atrophic gastritis (as with type III tumors) [23-25].

●For the purpose of multimodality treatment, GEJ tumors are all treated similarly, although the operative approach differs, partly because of the differing pattern of nodal spread (figure 4) [26].

•In general, type I cancers more frequently involve lymph nodes in the upper mediastinum (tracheal bifurcation and above) [27]. Patients with type I tumors are not appropriate candidates for a purely transabdominal approach to resection. The standard surgical approach is a transthoracic en bloc esophagectomy combined with resection of the upper part of the stomach and two-field lymphadenectomy.

•On the other hand, for type II and III carcinomas, nodal metastases are more frequently found in the lower mediastinum and around the celiac trunk (table 4) [28]. The optimal treatment for type II cancer is controversial. Some surgeons recommend an esophagectomy with a proximal gastrectomy, which allows the dissection of both the abdominal and mediastinal nodes. Others advocate for a total gastrectomy and extended lymph node dissection with a transhiatal approach into the posterior mediastinum [29].

•For type III carcinomas, the standard surgical approach is a transhiatally extended total gastrectomy with distal esophageal resection and systemic lymphadenectomy of nodes that drain the stomach. (See "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Esophagogastric junction cancer resection'.)

PRETREATMENT STAGING EVALUATION — 

The diagnosis of adenocarcinoma of the gastroesophageal junction (GEJ) and gastric cardia is usually established by an endoscopic biopsy. In addition to achieving a biopsy, to assist with treatment planning, the endoscopist should document tumor location relative to both the teeth and the GEJ, tumor length, extent of circumferential involvement, degree of obstruction, and any evidence of Barrett's esophagus. The Siewert type (I, II, or III) can often be defined endoscopically, although endoscopic localization of the GEJ can be hindered by the presence of a hiatal hernia and by respiratory and diaphragmatic motion. (See 'Siewert classification' above and 'Definition and classification' above and "Surgical management of resectable esophageal and esophagogastric junction cancers" and "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'Endoscopic biopsy'.)

Once a diagnosis is established, staging is undertaken to ascertain disease extent and location. At the completion of staging, information on tumor location, extent, and potential resectability enables the choice of the most appropriate multimodality treatment.

Staging involves an assessment of both locoregional and potentially distant (metastatic) disease. Integrated positron emission tomography (PET)/computed tomography (CT) imaging is the preferred approach to evaluate for metastatic disease. (See 'Role of PET and integrated PET/CT' below.)

However, contrast-enhanced CT of the chest/abdomen/pelvis is often obtained as the initial imaging study.

Role of PET and integrated PET/CT — Positron emission tomography (PET) and integrated PET/CT scans are more accurate than CT alone for detecting metastatic disease and may be performed initially in lieu of CT. However, we still recommend integrated PET/CT even if contrast-enhanced CT was performed initially, in the absence of demonstrable metastatic disease. Suspicious PET findings should be confirmed with biopsy before excluding a patient from treatment with curative intent. PET has a high rate of false positive findings [30,31].

Integrated PET/CT imaging is favored over PET alone due to better spatial resolution. PET and CT are performed sequentially during a single visit on a hybrid PET/CT scanner. The CT component of integrated PET/CT imaging is performed in most institutions without intravenous (IV) contrast, which limits the detection of small metastases both within and outside of the liver. Without IV contrast, an integrated PET/CT cannot substitute for a dedicated IV contrast-enhanced CT. At some institutions, PET/CT is carried out with IV contrast, but this practice is not widespread.

Integrated PET/CT may also be of clinical utility in restaging after induction therapy. (See 'PET-directed therapy' below.)

Endoscopic ultrasound and endoscopic mucosal resection — Patients without distant disease undergo locoregional staging with endoscopic ultrasonography (EUS). This uses high frequency ultrasound to create detailed images of esophageal masses, the depth of involvement into the five-layered esophageal wall and the extent of locoregional lymph node metastasis. EUS is the most accurate technique for locoregional staging of invasive esophageal cancer (including tumors arising at the GEJ), with an overall accuracy for tumor (T) and node (N) staging of 80 to 90 percent. EUS allows assessment of both perigastric and mediastinal lymph nodes, which may be sampled with a fine needle aspiration biopsy. (See "Endoscopic ultrasound for evaluating patients with esophageal cancer", section on 'Preoperative staging'.)

Diagnostic laparoscopy — Intraperitoneal metastases are common with GEJ adenocarcinomas and are notoriously difficult to diagnose noninvasively. The role of staging laparoscopy is controversial, and there is no consensus on this issue from expert groups. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'Laparoscopy and thoracoscopy'.)

We routinely perform diagnostic laparoscopy, usually prior to starting neoadjuvant therapy, for patients who have potentially cT3 or cT4 (table 1) disease, Siewert II to III adenocarcinomas of the GEJ, or bulky nodal metastases, or if there is suspicion for intraperitoneal metastatic disease that cannot otherwise be confirmed [32]. The procedure involves full inspection of the peritoneal cavity to evaluate for peritoneal and liver metastases. The GEJ area is visualized, and biopsies of gastrohepatic ligament and the celiac axis lymph nodes can be undertaken. Lavage may also be sent for peritoneal cytology.

Opinion differs as to the optimal way to manage patients with positive peritoneal cytology but no overt peritoneal metastases. At some institutions, patients without overt intraperitoneal metastases but with positive peritoneal washings are referred for neoadjuvant therapy. They are then restaged and, if converted to negative cytology, proceed to potentially curative surgery. (See "Surgical management of invasive gastric cancer", section on 'Positive peritoneal cytology'.)

The optimal timing and procedures undertaken during diagnostic laparoscopy are discussed separately. (See "Surgical management of invasive gastric cancer", section on 'Preoperative and staging evaluation' and "Diagnostic staging laparoscopy for digestive system cancers", section on 'Esophagogastric junction and gastric cancer'.)

Indicators of unresectability — For most patients, the presence of peritoneal, lung, bone, adrenal, brain, or liver metastases, or extraregional lymph node spread (eg, para-aortic or retroperitoneal nodes, or mesenteric lymphadenopathy) makes resection unlikely to be curative. However, there are a few patients with isolated nonregional nodes such as these that may be potentially curable with resection [33].

Celiac nodal metastases and mediastinal/supraclavicular nodes are scored as "regional" nodal disease in the American Joint Committee on Cancer (AJCC) eighth edition tumor, node, metastasis (TNM) staging criteria (figure 5 and table 1) [34]. Regardless of the primary tumor location; it is the number of involved nodes rather than location that determines the N stage. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer".)

T1 to T3 lesions are potentially resectable as are T4 lesions that involve the pericardium, pleura, or diaphragm (ie, T4a lesions (table 1)). Involvement of other structures/organs (ie, T4b disease) precludes resection.

EVOLUTION OF TREATMENT PHILOSOPHY — 

The geographic variation and changes in the epidemiology of esophageal cancer are striking, especially in Western (non-Asian) countries. Worldwide, squamous cell cancer (SCC) is the most common subtype but adenocarcinoma is the most prevalent subtype in Western countries. In Western countries, the primary tumor location changed in tandem with histology. Distal esophagus, gastroesophageal junction (GEJ), and proximal gastric cancers are the dominant sites of disease in Western countries [35]. These epidemiologic shifts have focused attention on adenocarcinomas of the distal esophagus, GEJ, and proximal stomach as distinct entities. (See "Epidemiology of gastric cancer", section on 'Changes in histologic pattern' and "Epidemiology and risk factors for esophageal cancer", section on 'Epidemiology'.)

Combined modality therapy is a standard approach for patients with stages IIA, IIB, and III esophageal, GEJ, and gastric cardia cancers (table 1). However, the best form of multimodality therapy is not established. Patients with GEJ adenocarcinoma may receive neoadjuvant or perioperative chemotherapy alone, preoperative chemoradiation (CRT), or postoperative chemotherapy depending mostly on the biases of the treating team and, in some cases, whether the patient is initially seen by a surgeon or a medical/radiation oncologist.

Evolution of multimodality therapy — GEJ adenocarcinomas anatomically straddle the distal esophagus and proximal stomach, and their management reflects approaches for both esophageal and gastric adenocarcinomas. (See 'Siewert classification' above and "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Esophagogastric junction cancer resection'.)

Although complete surgical resection alone can be curative [36-38], the poor results with surgery alone prompted an evaluation of multimodality (ie, neoadjuvant [preoperative] and adjuvant [postoperative]) strategies aimed at improving survival in patients with resectable disease.

Defining optimal multimodality treatment for GEJ adenocarcinomas is difficult for a number of reasons [39], one of which is the lack of trials that focus on the GEJ. For example, only one trial, the German POET trial of neoadjuvant CRT versus induction chemotherapy alone, treated GEJ tumors as a separate entity.

Most of the data that inform the multimodality treatment of GEJ adenocarcinoma are derived from trials that involved predominantly gastric or esophageal cancers. Within the trials designed primarily for gastric cancer (which will be classified as "lower tract trials" for the purpose of this review), patients with GEJ tumors account for only approximately 20 percent of all enrollees [40,41]. There are epidemiologic and pathologic differences between GEJ and non-cardia gastric adenocarcinomas that raise concern as to whether results from predominantly gastric cancer trials can be extrapolated to GEJ tumors. Gastric tumors are associated with H. pylori infection, chronic gastritis, and low acid production, while GEJ tumors tend to be associated with obesity, high acid production, gastroesophageal reflux disease (GERD), and are inversely associated with H. pylori [42]. (See "Risk factors for gastric cancer".)

On the other hand, the clinical characteristics, biologic behavior, and survival after esophagectomy for GEJ adenocarcinomas seem to be similar to those of adenocarcinomas arising in the distal esophagus [43] and gastric cardia [44]. Trials of multimodality therapy for esophageal cancer (which will be designated "upper tract trials" for this review) included a larger percentage of patients with distal esophageal and GEJ adenocarcinomas, although in some cases, the majority were still SCCs. While most clinical studies did not stratify outcomes by histology, increasing evidence supports a difference between SCCs and adenocarcinomas in terms of pathogenesis, epidemiology, tumor biology, and prognosis. Esophageal SCCs are strongly associated with alcohol and tobacco use while adenocarcinomas are associated with gastroesophageal reflux and high body mass index. (See "Epidemiology and risk factors for esophageal cancer", section on 'Pathobiologic differences'.)

In acknowledgment of these differences, the American Joint Committee on Cancer (AJCC) eighth edition tumor, node, metastasis (TNM) staging system (table 1) [34,45] provides separate stage groupings (but similar definitions for T, N, M, and grade [G] categories) for SCCs and adenocarcinomas of the esophagus and GEJ. In addition, there are separate groupings for clinical, pathologic, and post-neoadjuvant therapy stage that are also histology specific [34]. (See 'AJCC classification' above.)

Nevertheless, histology increasingly dictates the therapeutic approach. As an example, in the 2020 American Society of Clinical Oncology (ASCO) guideline for treatment of locally advanced esophageal carcinoma analyzed the available data according to histologic subtype [46]. Although multimodality treatment was suggested for all locally advanced esophageal carcinomas, the guidelines recommended preoperative CRT or perioperative chemotherapy for those with adenocarcinoma, and preoperative CRT or definitive CRT was recommended for locally advanced SCC. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer", section on 'Squamous cell versus adenocarcinoma'.)

Significant progress has been made in the multimodality management of locally advanced, non-metastatic gastric and esophageal cancers. In particular, several major trials that included patients with GEJ tumors influenced multimodality management:

●The Intergroup trial 0116 demonstrated the advantage of postoperative CRT in patients with resected gastric and GEJ adenocarcinomas [41]. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Adjuvant chemoradiation'.)

●The MAGIC trial demonstrated the survival benefit of perioperative chemotherapy with ECF (epirubicin, cisplatin, and fluorouracil [FU]) in patients with distal esophageal, GEJ, and gastric adenocarcinoma [40]. The success of this trial raised questions as to whether radiation therapy (RT) was a necessary component of treatment for gastric and GEJ cancers. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Neoadjuvant/perioperative chemotherapy'.)

●The POET trial demonstrated modest, clinically relevant but not statistically significant benefits of neoadjuvant chemotherapy plus CRT versus induction chemotherapy alone in patients with GEJ adenocarcinoma [47].

●The CROSS trial demonstrated a significant survival benefit for neoadjuvant concurrent CRT versus surgery alone in patients with potentially resectable esophageal or GEJ cancers. (See 'Neoadjuvant CRT' below.)

●The ESOPEC trial demonstrated an overall survival (OS) benefit for perioperative FLOT chemotherapy compared with neoadjuvant CRT for resectable esophageal and GEJ adenocarcinoma [48]. (See 'Perioperative chemotherapy versus neoadjuvant CRT' below.)

Necessity for surgery — Patients with clinically resectable GEJ or gastric cardia adenocarcinoma who complete initial neoadjuvant therapy should subsequently proceed to surgery. Resection is generally integral to achieving the best outcomes with multimodality therapy. The surgical approach is based on tumor location. Minimally invasive techniques are preferred, where local expertise is available. Principles of surgical management for these tumors are discussed in detail separately. (See "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Esophagogastric junction cancer resection' and "Surgical management of invasive gastric cancer".)

Definitive CRT — Definitive chemoradiation (CRT) is a reasonable option for patients with unresectable disease, those who are not surgical candidates, or those who decline surgery. Most of the data on definitive CRT for esophageal cancer are in patients with SCC. There are less data for adenocarcinoma, and pathologic complete response (pCR) rates after CRT are lower for adenocarcinoma as compared with SCC. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer", section on 'Chemoradiation responders'.)

Whether there is a survival benefit for trimodality therapy (which included post-RT or post-CRT esophagectomy) over definitive RT or CRT alone has been addressed in two meta-analyses, which came to opposite conclusions:

●One meta-analysis included data from eight studies (16,647 patients), only one of which was a randomized controlled trial [49]. OS was improved with neoadjuvant CRT as compared with definitive CRT in combined populations (hazard ratio [HR] for death 0.55, 95% CI 0.49-0.62), and the benefit was seen in both the adenocarcinoma and SCC subgroups. The authors did not address the impact of treatment response on outcomes.

●On the other hand, a 2016 Cochrane review of eight randomized trials concluded that there was no difference in long-term mortality between definitive and neoadjuvant CRT (HR 0.88, 95% CI 0.76-1.03; 602 participants; four studies; low-quality evidence), and no difference in long-term recurrence between non-surgical treatment and surgery (HR 0.96, 95% CI 0.80-1.16; 349 participants; two studies; low-quality evidence) [50]. The difference between non-surgical and surgical treatments was imprecise for short-term mortality (risk ratio [RR] 0.39, 95% CI 0.11-1.35; 689 participants; five studies; very low-quality evidence), the proportion of participants with serious adverse in three months (RR 0.61, 95% CI 0.25-1.47; 80 participants; one study; very low-quality evidence), and the risk for local recurrence at maximal follow-up (RR 0.89, 95% CI 0.70-1.12; 449 participants; three studies; very low-quality evidence).

However, an important point is that the potential for cure without surgery for adenocarcinomas is also supported by Radiation Therapy Oncology Group (RTOG) 0436, a phase III randomized trial that compared survival for patients receiving cetuximab plus platinum/taxane and RT with the same CRT regimen alone [51]. Overall, 62 percent of patients had adenocarcinoma, and these patients had a median OS of 19.7 months, which was similar to those with SCC. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer", section on 'Necessity for surgery'.)

CLINICAL T1N0 DISEASE — 

Patients with clinical Tis or T1N0 gastroesophageal junction (GEJ) adenocarcinoma are treated with either endoscopic resection or surgery (esophagectomy). Further details are discussed separately. (See "Management of superficial esophageal cancer".)

Patients with GEJ adenocarcinoma who are treated with surgery should be evaluated for adjuvant therapy, if necessary, based on the postoperative pathology. (See 'Indications and choice for adjuvant therapy' below.)

Patients with clinical Tis or T1N0 gastric cardia adenocarcinoma are treated with either endoscopic resection or gastrectomy. Further details are discussed separately. (See "Early gastric cancer: Management and prognosis".)

Patients with gastric cardia adenocarcinoma who are treated with surgery should be evaluated for adjuvant therapy, if necessary, based on the postoperative pathology. Further details are discussed separately. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Initial potentially curative resection'.)

CLINICAL T2N0 DISEASE — 

For most patients with clinical T2N0 gastroesophageal junction (GEJ) adenocarcinomas, we suggest initial systemic therapy, with or without radiation therapy (RT), rather than initial surgery. Although data for this specific population are limited, patients with T2N0 GEJ adenocarcinoma are often included in clinical trials evaluating neoadjuvant chemoradiation (CRT) [52] or neoadjuvant chemotherapy [48] in patients with locoregionally advanced esophageal and GEJ adenocarcinoma. Neoadjuvant therapy is also preferred for those who also have adverse features on biopsy (eg, poorly differentiated tumors, lymphovascular invasion) since these patients are often found to have a higher pathologic stage if they proceed directly to esophagectomy. (See 'Clinical T3-4 or node-positive disease' below.)

Definitive CRT is an alternative for patients who are not surgical candidates. (See "Management of locally advanced unresectable or inoperable esophageal cancer".)

CLINICAL T3-4 OR NODE-POSITIVE DISEASE

Our recommended approach — The following represents our approach to therapy in patients with clinical T3 or 4, or node-positive adenocarcinoma of the gastroesophageal junction (GEJ) and gastric cardia (see 'Pretreatment staging evaluation' above):

●For most patients, we suggest initial systemic therapy, with or without radiation therapy (RT), rather than initial surgery. However, initial surgery is an alternative for the rare patient who is anticipated to not tolerate neoadjuvant therapy and has cT3N0 disease that is clearly resectable. (See 'Patients not yet resected' below.)

Patients with clinically resectable adenocarcinoma who are treated with initial systemic therapy with or without RT should proceed to surgery.

Definitive chemoradiation (CRT) is a reasonable alternative for those patients who refuse surgery or are not surgical candidates. (See 'Definitive CRT' above.)

●In patients getting initial systemic therapy with or without RT, prior to surgery, our approach is as follows:

•For patients with clinical T3-T4 or node-positive esophageal or GEJ adenocarcinoma who are younger with good performance status and minimal comorbidities, we suggest perioperative chemotherapy with fluorouracil (FU), leucovorin, oxaliplatin, and docetaxel (FLOT) (table 5) rather than neoadjuvant CRT. For older patients, those with multiple comorbidities, and/or those who are unlikely to tolerate the toxicities of FLOT (eg, neuropathy), neoadjuvant CRT is an appropriate alternative. Patients treated with neoadjuvant CRT followed by surgery should be evaluated for adjuvant therapy (eg, immunotherapy for those without a pathologic complete response [pCR]). (See 'Perioperative chemotherapy versus neoadjuvant CRT' below.)

•The optimal type, dose, combination, and schedule of drugs for use during concurrent CRT is not established. For most patients, we suggest a low-dose weekly carboplatin and paclitaxel regimen as was used in the Dutch CROSS trial (table 6) rather than other regimens. This is based largely on better tolerance and ease of administration. FOLFOX concurrent with RT is a reasonable alternative.

•The optimal RT dose fractionation schedule for CRT is not known. Many landmark trials were conducted before the era of contemporary RT techniques, such as three-dimensional conformal RT (3D-CRT) and intensity-modulated RT (IMRT). These techniques use CT scan for RT planning and offer a dose-volume histogram that includes normal organs at risk, such as the lungs, heart, and spinal cord. This improves the feasibility of delivering RT that maximizes tumor response with tolerable radiation doses. Although the CROSS trial used 41.4 Gy, most clinicians administer 50.4 Gy as the standard radiation dose with concurrent chemotherapy, regardless of the chemotherapy regimen. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer", section on 'Technique for preoperative RT'.)

●Perioperative chemotherapy is also a reasonable treatment approach for those with true gastric cardia cancer or those with a high clinical suspicion for occult metastatic disease. (See 'Perioperative chemotherapy versus surgery alone' below and 'Is there an optimal regimen?' below.)

•Our preferred options include a docetaxel-containing triplet such as FLOT for fit patients with good performance status, as was used in the FLOT-4 AIO trial; oxaliplatin plus leucovorin and short-term infusional FU (FOLFOX; as was used in CALGB 80803), oxaliplatin plus capecitabine (CAPOX; if the patient is able to swallow), or oxaliplatin plus S-1 (where available). Another option is infusional FU plus cisplatin, as was used in the French FNLCC/FFCD and Medical Research Council (MRC) trials.

For most patients, we suggest using one of these regimens rather than an epirubicin-containing regimen such as epirubicin, cisplatin, and FU (ECF), as was used in the MAGIC trial (table 7); or epirubicin, cisplatin and capecitabine (ECX) (table 8) as in the MRC OEO5 trial. The benefits of an anthracycline have been called into question in this setting. However, if ECX or ECF are chosen, it is reasonable to limit the number of preoperative cycles to four rather than six. (See 'Is there an optimal regimen?' below.)

●Following induction chemotherapy or CRT, we restage with integrated positron emission tomography (PET)/CT no earlier than four weeks after the completion of induction therapy. Biopsy must be performed for a new lesion before excluding the patient from surgery. PET-directed changes in therapy are not part of the standard treatment approach. (See 'PET-directed therapy' below.)

●Resection following CRT is integral to achieving the highest rate of cure. Surgical approach is based on tumor location. Minimally invasive techniques are increasingly used, and laparoscopy and/or thoracoscopy by experienced surgeons may avoid laparotomy and/or thoracotomy. (See "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'How should esophagectomy be performed?'.)

●Pathologic response guides postoperative therapy:

•For patients who received preoperative chemotherapy, we suggest postoperative chemotherapy rather than CRT. There are no data for changing the postoperative regimen in patients who do not achieve a pCR, and we suggest not pursuing this approach.

We reserve postoperative RT for cases with a histologically positive resection margin. (See 'After chemotherapy alone' below.)

•Patients with a pCR on the surgical specimen after initial CRT do not require further therapy and may proceed to post-treatment surveillance. (See 'Post-treatment surveillance' below.)

For patients without a pCR in the surgical specimen after initial CRT, we suggest adjuvant nivolumab. For those who are ineligible for nivolumab, options include post-treatment surveillance (for ypN0-1 tumors only) or adjuvant chemotherapy with different agents than those given preoperatively (eg, FOLFOX if the initial CRT regimen included concurrent carboplatin and paclitaxel). (See 'After CRT' below.)

●For patients who undergo initial surgery rather than neoadjuvant therapy, we recommend postoperative adjuvant therapy for those with margin-positive disease, node-positive disease, or a pT3 or higher primary tumor stage. Either chemotherapy alone or CRT is a reasonable option. We favor chemotherapy alone for most patients, unless they have a margin-positive resection or extensive nodal disease. (See 'Adjuvant CRT' below and 'Adjuvant chemotherapy' below.)

The optimal management of pT2N0 tumors is controversial. We do not favor routine use of adjuvant therapy following resection with pT2N0 disease when induction treatment was not used, although we would discuss the relative benefits and risks of adjuvant chemotherapy, with or without RT, for patients with clinicopathologic high-risk features. (See 'Indications and choice for adjuvant therapy' below.)

Patients not yet resected — We suggest initial systemic therapy, with or without RT, rather than initial resection for most patients. However, surgery is an option for a clearly resectable clinical T3N0 tumor when there is concern that the patient might not tolerate preoperative therapy. (See 'Our recommended approach' above.)

Perioperative chemotherapy versus surgery alone — Pre- and postoperative systemic chemotherapy has been extensively studied as a strategy to improve the chances of pCRs and R0 (microscopically complete) resection. treat early micro-metastatic disease, and improve OS [53].

In general, trials focused on two groups: distal esophagus/GEJ (upper tract) and GEJ/true gastric (lower tract). In each case, the GEJ subtype usually made up the minority of tumors (approximately 15 percent), and most upper tract studies included squamous cell cancer (SCC). Many of these trials suffer from misclassification of the anatomic site of involvement.

●Upper tract trials – Two trials of preoperative chemotherapy for resectable esophageal cancer included those with GEJ primary sites. The MRC OEO2 trial of surgery with or without preoperative cisplatin plus FU demonstrated a survival benefit for this approach [54,55]. The United States Intergroup trial 0113 (which used the same basic design) did not [56]. These trials are discussed in more detail separately. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer", section on 'Neoadjuvant chemotherapy'.)

●Lower tract trials – There are three trials of perioperative chemotherapy versus surgery alone in patients with gastric cancer that included individuals with GEJ tumors; two showed a survival benefit (MAGIC and French FNLCC/FFCD trials [40,57]), while a third (EORTC trial 40954 [58]) did not. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Neoadjuvant/perioperative chemotherapy'.)

Data from these trials that are pertinent to GEJ and gastric cardia adenocarcinomas are as follows:

●MAGIC trial – In the MRC MAGIC trial, 503 patients with potentially resectable gastric (74 percent), lower esophageal (15 percent), or GEJ adenocarcinomas (11 percent) were randomly assigned to surgery alone or surgery plus perioperative chemotherapy (three preoperative and three postoperative cycles of ECF (table 7)) [40].

A higher proportion of chemotherapy-treated patients with gastric cancer who underwent radical surgery had a potentially curative procedure (79 versus 70 percent), and significantly more had T1/2 tumors (52 versus 37 percent) and N0/N1 disease (84 versus 71 percent) [40]. Chemotherapy was well tolerated. Excluding patients with neutropenia (23 percent), fewer than 12 percent of patients had grade 3 or 4 adverse events. Despite this limited toxicity, only 104 patients (42 percent) completed protocol treatment of surgery and all three cycles of postoperative chemotherapy. These data further emphasize the difficulty in tolerating all postoperative chemotherapy cycles.

Nevertheless, at a median four-year follow-up, progression-free survival and overall survival (OS) were significantly worse in the surgery alone group (hazard ratio [HR] for OS 0.75; HR 0.60 to 0.93). The 25 percent reduction in the risk of death favoring chemotherapy translated into an improvement in five-year OS from 23 to 36 percent. Local failure occurred in 14 percent of the chemotherapy-treated patients compared with 21 percent of those undergoing surgery alone, while distant metastases developed in 24 and 37 percent of patients, respectively.

●French FNLCC/FFCD – A similar benefit for neoadjuvant chemotherapy was noted in a French multicenter trial in which 224 patients with resectable stage II or greater adenocarcinoma of the stomach (25 percent), GEJ (64 percent), or distal esophagus (11 percent) were randomly assigned to two to three cycles of preoperative chemotherapy (infusional FU 800 mg/m² per day for five consecutive days, once every 28 days plus cisplatin 100 mg/m² on day 1) or surgery alone [57]. Three to four cycles of the same postoperative chemotherapy were administered to patients who tolerated the preoperative regimen and who had no evidence of progressive disease (only approximately 50 percent of all patients received more than one cycle).

Patients undergoing perioperative chemotherapy were significantly more likely to undergo R0 resection (84 versus 73 percent), and there was a statistically insignificant trend toward fewer pT3/4 lesions (58 versus 68 percent) and fewer node-positive tumors (67 versus 80 percent). At a median 5.7-year follow-up, perioperative chemotherapy resulted in a 35 percent reduction in risk of disease recurrence. OS was significantly better in the chemotherapy group (HR for death 0.69, 95% CI 0.50-0.95), which translated into a five-year OS of 38 versus 24 percent.

●EORTC 40954 – In another randomized trial (EORTC 40954), 144 patients with locally advanced adenocarcinoma of the stomach or GEJ were randomly assigned to surgery with or without preoperative chemotherapy (two 48-day cycles of cisplatin 50 mg/m² on days 1, 15, and 29, plus weekly administration of leucovorin 500 mg/m² followed by FU 2000 mg/m² by continuous infusion over 24 hours, on days 1, 8, 15, 22, 29, and 36) [58]. The study closed prematurely due to poor accrual. Although the patients treated with upfront chemotherapy had a significantly higher R0 resection rate (82 versus 67 percent), there was no OS benefit.

●Meta-analysis – A survival benefit for neoadjuvant chemotherapy over surgery alone has been shown in several meta-analyses [59-61]. As an example, in one individual patient data meta-analysis included 12 randomized trials comparing neoadjuvant chemotherapy versus surgery alone for thoracic esophageal or GEJ cancers [61]. In this study, neoadjuvant chemotherapy increased OS compared to surgery alone (HR 0.86, 95% CI 0.75-0.99).

Selection of perioperative chemotherapy regimen

Is there an optimal regimen? — For patients with excellent performance status and minimal comorbidities who are able to tolerate intensive therapy, we prefer perioperative chemotherapy with FU, leucovorin, oxaliplatin, and docetaxel (FLOT), as was used in the FLOT-4 AIO trial for patients with gastric and GEJ adenocarcinoma [62,63] and the ESOPEC trial for patients with esophageal and GEJ adenocarcinoma [48]. (See 'FLOT' below and 'Perioperative FLOT' below.)

Appropriate alternatives, particularly for patients with worse performance status or more comorbidities, include FOLFOX, CAPOX, FU plus cisplatin, or oxaliplatin plus S-1 (where available).

The following data are available to address the issue of choosing one regimen over another.

●Is an anthracycline necessary with platinum/fluoropyrimidine? – Indirect comparison of several studies that did or did not include anthracyclines in the perioperative regimen enables an assessment of the contribution of these agents to the use of a platinum agent plus a fluoropyrimidine:

•The FFCD trial and the MRC OEO2 trial [54], conducted in a wider range of patients with thoracic esophageal cancer, used two to three cycles of preoperative cisplatin/FU (CF), while the MAGIC trial administered three preoperative and three postoperative courses of ECF. Only approximately 50 percent of patients enrolled in the MAGIC trial were able to receive three postoperative chemotherapy courses. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer", section on 'Neoadjuvant chemotherapy'.)

•Additional data are available from the ALLIANCE 80403 trial, in which 245 patients with previously untreated metastatic esophageal or GEJ cancer were randomly assigned to ECF, irinotecan plus cisplatin (IC), or FOLFOX (oxaliplatin, leucovorin, and bolus and infusional FU) [64,65]. All treatment programs included cetuximab once per week. Response rates were similar with ECF and FOLFOX (61 versus 54 percent), as was median progression-free survival (PFS; 7.1 versus 6.8 months), and FOLFOX was better tolerated.

Taken together, these trials demonstrate the failure of epirubicin to contribute to improving the outcomes with a platinum/FU regimen doublet and the failure of more cycles of chemotherapy to improve outcomes. If perioperative chemotherapy is chosen, we prefer either FLOT (docetaxel, oxaliplatin, and leucovorin with short-term infusional FU) or FOLFOX/CAPOX, or where available, oxaliplatin plus S-1 [66]. (See 'FOLFOX' below and 'FLOT' below.)

●Docetaxel-based triplet therapy versus a platinum/fluoropyrimidine combination – The FLOT-4 trial demonstrated better outcomes with the FLOT regimen but more treatment-related toxicity compared with epirubicin plus cisplatin/fluoropyrimidine. In general, we prefer FLOT for young and fit patients. (See 'FLOT' below.)

Further details on these perioperative chemotherapy regimens in advanced gastric cancer are discussed separately. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Choice of regimen and patient selection'.)

FLOT — The phase II/III FLOT-4 AIO trial compared four preoperative and four postoperative courses of the docetaxel-based triplet FLOT regimen (docetaxel 50 mg/m² plus oxaliplatin 85 mg/m² and leucovorin 200 mg/m² with short-term infusional FU 2600 mg/m² as a 24-hour infusion, all on day 1, administered every two weeks) to epirubicin-based triplet therapy in patients with resectable adenocarcinoma of the stomach or GEJ. The epirubicin-based group used the approach used in the MAGIC trial. (See 'Perioperative chemotherapy versus surgery alone' above.)

Two reports are available from this trial:

●In the open-label phase II part, the 300 patients with resectable gastric or GEJ adenocarcinoma treated with FLOT achieved a higher pCR rate (16 versus 8 percent) with lower toxicity [62]. There was less grade 3 or 4 nausea (9 versus 17 percent), fatigue (9 versus 14 percent), and vomiting (3 versus 10 percent) with FLOT, but higher rates of grade 3 or 4 neutropenia (52 versus 38 percent).

●The phase III component randomized 716 patients with resectable gastric (44 percent) or GEJ (56 percent) adenocarcinoma. Overall, 91 and 37 percent of patients receiving ECF/ECX and 90 and 50 percent of patients with FLOT completed the planned preoperative and postoperative cycles [63]. At a median follow-up of 43 months, median OS (50 versus 35 months, HR 0.77, 95% CI 0.63-0.94) and three-year OS (57 versus 48 percent) were greater with FLOT. Perioperative complications were similar (51 percent with ECF/ECX and 50 percent for FLOT). Significantly more grade 3 or 4 nausea (16 versus 7 percent), vomiting (8 versus 2 percent), and thromboembolic events (6 versus 3 percent) were seen with ECF/EC. More grade 3 or 4 diarrhea (10 versus 4 percent), neutropenia (51 versus 39 percent), infections (18 versus 9 percent), and sensory neuropathy (7 versus 2 percent) were seen with FLOT.

Based on these data, we suggest FLOT rather than other chemotherapy regimens for young and fit patients.

FOLFOX — For patients not receiving FLOT, support for neoadjuvant FOLFOX (table 9) is provided by results from the phase II United States cooperative group trial, in which 257 patients with resectable esophageal or GEJ adenocarcinoma were randomly assigned to one of two induction chemotherapy regimens (oxaliplatin plus FU and leucovorin [FOLFOX] or carboplatin plus paclitaxel [CP]) for five to six weeks [67]. PET responders continued the same chemotherapy regimen during subsequent CRT, while poor responders crossed over to the other chemotherapy regimen with CRT. Surgery was undertaken six weeks after CRT. (See 'PET-directed therapy' below.)

Notably, the pCR rate in the PET responders who received initial FOLFOX was 40 percent while it was only 14 percent in the CP responders (table 10). When assessed by induction chemotherapy group, survival rates were similar for individuals initially assigned to CP whether they were PET responders or nonresponders (two-year survival 56.9 versus 53.1 percent; at 60 months, 43.9 versus 40 percent), despite the fact that the pCR rates were low in nonresponders. On the other hand, there were greater differences in the group initially assigned to FOLFOX when responders and nonresponders were compared (two-year OS 76.1 versus 61.5 percent; at 60 months, 53 versus 37.5 percent).

The use of PET-directed changes in induction therapy is discussed below. (See 'PET-directed therapy' below.)

Neoadjuvant CRT

Rationale — Neoadjuvant (preoperative) chemoradiation (CRT) followed by surgery is an option for the treatment of locally advanced resectable GEJ and gastric cardia adenocarcinoma. In most high-quality randomized trials, the addition of neoadjuvant CRT to surgery improved OS and was well-tolerated [52,68]. Several meta-analyses also support a survival benefit for neoadjuvant concurrent CRT compared with surgery alone for esophageal and GEJ cancer [59,61,69,70]. As an example, one meta-analysis included 12 randomized trials of neoadjuvant CRT (either concurrent or sequential) versus surgery [61]. In this study, neoadjuvant CRT conferred an OS benefit over surgery alone (HR 0.77, 95% CI 0.68-0.87).

Relevant randomized trials supporting this approach are as follows:

●Concurrent CRT with carboplatin plus paclitaxel – In a phase III trial (CROSS) conducted in the Netherlands, 363 patients with potentially resectable distal esophageal (89 percent) or GEJ tumors (11 percent) were randomly assigned to either neoadjuvant CRT followed by surgery or surgery alone [52,71,72]. Most patients had adenocarcinoma (75 percent), while the remainder had SCC (23 percent) or large-cell undifferentiated carcinoma (2 percent). Patients receiving neoadjuvant CRT were treated with low-dose weekly paclitaxel (50 mg/m²) plus carboplatin (area under the curve [AUC] of 2) plus concurrent RT (41.4 Gy given in 23 daily fractions of 1.8 Gy each, five fractions per week), which is also known as the "CROSS regimen."

At a median follow-up of 45 months, the addition of neoadjuvant CRT to surgery improved OS in the entire study population (median OS 49 versus 24 months, HR 0.66, 95% CI 0.50-0.87), including those with adenocarcinoma (HR 0.73, 95% CI 0.52-1) [52]. With extended follow-up, the OS benefit with neoadjuvant CRT persisted in the entire study population (five-year OS 47 versus 33 percent, HR 0.67, 95% CI 0.51-0.87 [71]; 10-year OS 38 versus 25 percent, HR 0.70, 95% CI 0.55-0.89 [72]). Neoadjuvant CRT also improved the R0 resection rate (92 versus 69 percent) [52]. Among patients receiving neoadjuvant CRT, the pCR rate was 29 percent (23 percent for those with adenocarcinoma, 49 percent for those with SCC). Although the addition of neoadjuvant CRT to surgery reduced isolated locoregional and synchronous locoregional plus distant relapses, the isolated distant relapse rate was similar between the two treatment arms [72]. Neoadjuvant CRT was well-tolerated, with a patient compliance rate of 91 percent [52]. The most common grade ≥3 toxicities due to neoadjuvant CRT included leukopenia (6 percent), anorexia (5 percent), fatigue (3 percent), and neutropenia (2 percent) [71,72].

●Concurrent CRT with cisplatin plus FU – In a phase III trial (CALGB 9781), 56 patients with esophageal cancer (77 percent adenocarcinoma) were randomly assigned to either neoadjuvant CRT followed by surgery or surgery alone. Patients receiving neoadjuvant CRT were treated with cisplatin (100 mg/m² on days 1 and 29) and infusional FU (1000 mg/m² per day by continuous infusion for 96 hours, days 1 through 4 and 29 through 32, after cisplatin) plus concurrent RT (50.4 Gy in 28 daily fractions of 1.8 Gy each, five fractions per week) [68]. The study was closed early due to poor accrual. The addition of neoadjuvant CRT to surgery improved OS (median OS 4.48 versus 1.79 years; five-year OS 39 versus 16 percent). For those receiving neoadjuvant CRT, the pCR rate was 40 percent. Perioperative morbidity and mortality rates were similar between the two treatment arms. An OS benefit with neoadjuvant CRT using cisplatin plus FU was also seen in another randomized trial conducted in Ireland [73].

Although a few randomized trials failed to show an OS benefit for the addition of neoadjuvant CRT with cisplatin plus FU to surgery, these trials had several limitations. Some studies were underpowered [74,75] while others were limited to patients with stage I and II disease and only included a small proportion of patients with adenocarcinoma (30 percent) [74-76].

Selection of radiosensitizing regimen

Carboplatin plus paclitaxel — For patients receiving neoadjuvant CRT, we suggest concurrent radiosensitization with low-dose weekly carboplatin plus paclitaxel (table 6) rather than other regimens due to better tolerance and ease of administration. FOLFOX is an appropriate alternative radiosensitizing regimen that is effective and well-tolerated but requires the use of a continuous infusional FU pump. (See 'FOLFOX' below.)

There are no randomized trials comparing the efficacy and toxicity of various radiosensitizing regimens for neoadjuvant CRT, although there are some data in the setting of definitive CRT [77]. Selection of the appropriate regimen is mainly based on treatment-related toxicity and patient convenience. Neoadjuvant CRT with carboplatin plus paclitaxel is generally well-tolerated (particularly with respect to mucositis, cytopenias, and fatigue) compared with other regimens (eg, cisplatin plus FU, FOLFOX). It can also be conveniently administered on a weekly basis, with all chemotherapy given in the infusion center. The addition of neoadjuvant carboplatin plus paclitaxel to surgery also improved OS in a phase III trial (CROSS) [52], which is discussed separately. (See 'Rationale' above.)

FOLFOX — For patients receiving neoadjuvant CRT, FOLFOX is an appropriate alternative radiosensitizing regimen. Studies suggest it is effective and generally well-tolerated (particularly with respect to less mucositis, kidney toxicity, and alopecia compared with cisplatin plus FU) [77-79]. Patients who receive this regimen are required to carry a continuous infusional FU pump for 46 hours, which may be less convenient for some patients compared to other regimens (eg, low-dose weekly carboplatin plus paclitaxel, which is completely administered in the infusion clinic and does not require the patient to take home any chemotherapy). Data are as follows:

●In a prospective clinical trial, 38 patients with locally advanced (16 patients with stage I or II disease) or metastatic (22 patients with stage IV disease) esophageal carcinoma were treated with concurrent CRT using oxaliplatin (85 mg/m² on days 1, 15, and 29) and protracted-infusion FU (180 mg/m² for 24 hours from days 8 through 42) [79]. RT was administered at 50.4 Gy in 28 daily fractions of 1.8 Gy each starting on day 8. At the completion of cycle one of chemotherapy, patients either underwent surgery or began cycle two of chemotherapy without RT. Patients who underwent surgery could receive cycle two of chemotherapy in the adjuvant setting. Patients with stage IV disease were allowed three cycles in the absence of disease progression. Among the entire study population, 36 patients (95 percent) completed cycle 1, and 24 patients (67 percent) completed cycle 2 of chemotherapy. After cycle 1, 29 patients (81 percent) had no cancer in the esophageal mucosa. Among the 16 patients with locally advanced disease, 13 patients (81 percent) underwent surgical resection with curative intent, and five patients (38 percent) had a complete pathologic response. Treatment was well-tolerated with no grade 4 toxicities reported.

Similar results with this CRT regimen were seen in another single-arm phase II trial (S0356) [78]. In this study, 93 patients with stage II or III esophageal adenocarcinoma were treated with concurrent CRT using oxaliplatin (85 mg/m² on days 1, 15, and 29) and protracted-infusion FU (180 mg/m² per day on days 8 through 43). RT was administered at 45 Gy in 25 daily fractions of 1.8 Gy each (five fractions per week). Most patients (85 percent) underwent surgery following preoperative CRT. Among those treated with surgery, the R0 resection rate was 68 percent, with a pCR rate of 28 percent. At a median follow-up of 39 months, three-year OS was 45 percent. The grade 3 or 4 toxicity rate with neoadjuvant CRT was 47 percent.

●The use of FOLFOX for neoadjuvant CRT is also extrapolated from a phase II/III trial (PRODIGE5/ACCORD17) in patients with localized esophageal cancer treated with definitive CRT which compared radiosensitization with either FOLFOX or FU plus cisplatin [77]. Further details of this trial are discussed separately. (See "Management of locally advanced unresectable or inoperable esophageal cancer", section on 'FOLFOX'.)

Regimens not used — We do not offer cisplatin plus FU as a concurrent radiosensitizing regimen for neoadjuvant CRT. Although the addition of neoadjuvant CRT with cisplatin plus FU to surgery improves OS [68,73], this regimen causes more toxicity (ie, mucositis, cytopenias, alopecia, kidney toxicity) compared with other regimens [77]. This regimen is also more complex to administer and less convenient since it requires the patient to carry a continuous infusional FU pump for 96 hours. (See 'Rationale' above.)

Perioperative chemotherapy versus neoadjuvant CRT

Perioperative FLOT — For patients with cT3 to T4 or node-positive resectable esophageal and GEJ adenocarcinoma who are younger with good performance status and minimal comorbidities, we suggest perioperative chemotherapy with FLOT (table 5) rather than neoadjuvant chemoradiation (CRT). For older patients, those with multiple comorbidities, and/or those who are unlikely to tolerate the toxicities of FLOT (eg, neuropathy), neoadjuvant CRT is an appropriate alternative. Patients treated with neoadjuvant CRT followed by surgery should be evaluated for adjuvant therapy. (See 'After CRT' below.)

Both neoadjuvant CRT and perioperative chemotherapy conferred an OS benefit over surgery alone in separate phase III trials (CROSS and MAGIC, respectively) [40,52,63,80]. Subsequent randomized trials have directly compared these two management strategies to determine the optimal treatment approach. In one phase III trial (neo-AEGIS), OS was similar for neoadjuvant CRT relative to perioperative chemotherapy with either ECF or FLOT, although the study was underpowered and closed early [81]. In another phase III trial (ESOPEC), perioperative FLOT improved OS relative to neoadjuvant CRT with good compliance rates and similar postoperative morbidity and mortality [48].

●Perioperative FLOT versus neoadjuvant CRT – In an open-label phase III trial (ESOPEC), 438 patients with locally advanced (cT1, N1-3, M0 or cT2-4a, N0-3, M0) adenocarcinoma of the esophagus, including Siewert type I GEJ tumors (ie, tumor epicenter within 5 cm of the GEJ and extension into the esophagus) (figure 4), were randomly assigned to either eight cycles of perioperative chemotherapy with FLOT (four preoperative [neoadjuvant] cycles, followed by surgery and four postoperative [adjuvant] cycles) or neoadjuvant CRT (41.4 Gy of RT with concurrent carboplatin plus paclitaxel) followed by surgery [48]. Patients who received neoadjuvant CRT and surgery did not receive adjuvant therapy. This study also excluded patients with gastric cancer.

•At median follow-up of 55 months, relative to neoadjuvant CRT, perioperative FLOT improved OS (median 66 versus 37 months; five-year OS 51 versus 39 percent, HR 0.70, 95% CI 0.53-0.92) and PFS (median 38 versus 16 months, five-year PFS 44 versus 31 percent, HR 0.66, 95% CI 0.51-0.85) [48]. Clinical OS benefit for perioperative FLOT was seen in all clinically relevant subgroups, including sex, age, ECOG performance status, clinical tumor (T) stage, and clinical node (N) stage.

•Among the 371 patients who underwent surgery, relative to neoadjuvant CRT, perioperative FLOT demonstrated similar rates of R0 resection (94 versus 95 percent) and R1 resection (5 versus 4 percent); similar postoperative nodal stage (ypN0 51 versus 54 percent) and a higher pathologic complete remission rate (ypT0 ypN0; 17 versus 10 percent).

•Among the patients treated with FLOT, most completed neoadjuvant treatment (87 percent) and received both neoadjuvant treatment and surgery (86 percent), but a lesser proportion received or completed adjuvant therapy (63 and 53 percent, respectively). Among those treated with neoadjuvant CRT, 68 percent completed all neoadjuvant treatment (with 98 percent completing all 41.4 Gy of RT) and 83 percent received neoadjuvant treatment plus surgery. Postoperative morbidity and mortality were similar between the two treatment arms.

However, the OS benefit seen with perioperative chemotherapy in the ESOPEC trial must be interpreted in the context of several points, which suggest the comparator treatment (neoadjuvant CRT) might have been at a disadvantage.

•The ESOPEC trial did not include the use of adjuvant immunotherapy in those treated with neoadjuvant CRT who had residual disease (ie, lacked a pCR) at surgery; this approach improved disease-free survival in a phase III trial (CheckMate 577) and became standard of care while the ESOPEC trial was being conducted. (See 'After CRT' below.)

•Patients treated with neoadjuvant CRT received RT at a dose of 41.4 Gy; while this dosing was used in the CROSS trial, it is lower than the dose typically used in standard clinical practice (50.4 Gy).

•The pCR rate for neoadjuvant CRT in the ESOPEC trial was lower than that seen in the CROSS trial (10 versus 23 percent) [40,81].

•Relative to those treated with neoadjuvant CRT in the CROSS trial, less patients treated with neoadjuvant CRT in the ESOPEC trial completed neoadjuvant therapy (68 versus 91 percent) or had surgery (83 versus 94 percent) [40,81].

•Studies are conflicting as to whether patient compliance is better with perioperative chemotherapy or neoadjuvant CRT. Based on data from the CROSS and MAGIC trials and other studies, patient compliance rates were higher with neoadjuvant CRT (over 90 percent) than with perioperative chemotherapy (between 42 and 46 percent) [40,52,63]. By contrast, in the ESOPEC trial, patient compliance rates were lower with neoadjuvant CRT (68 percent) than with neoadjuvant chemotherapy (87 percent). (See 'Perioperative chemotherapy versus surgery alone' above and 'Neoadjuvant CRT' above.)

●Perioperative ECF or FLOT versus neoadjuvant CRT – In an open-label phase III trial (Neo-AEGIS) of 362 patients with cT2-3, N0-N3, M0 adenocarcinoma of the esophagus or GEJ, neoadjuvant CRT with concurrent carboplatin plus paclitaxel was compared with perioperative chemotherapy (three preoperative and three postoperative cycles of modified ECF, or four preoperative and four postoperative cycles of FLOT) [81]. At a median follow-up of 39 months, relative to perioperative chemotherapy, neoadjuvant CRT increased the rate of R0 resection (96 versus 82 percent) as well as the pCR rates for the primary tumor (14 versus 4 percent) and the lymph nodes (60 versus 44 percent) but failed to improve OS (median OS 49 versus 48 months; three-year OS 57 versus 55 percent, HR 1.03, 95% CI 0.77-1.38). There was no significant difference between the treatment arms for therapy-related complications or postoperative mortality. The trial was closed at the second interim analysis for futility and due to the impact of the COVID-19 pandemic.

No role for adding neoadjuvant CRT to perioperative chemotherapy — We do not offer the addition of neoadjuvant chemoradiation (CRT) to perioperative chemotherapy in locally advanced GEJ and gastric cardia adenocarcinoma. In multiple randomized trials, this approach failed to improve OS despite increasing pCRs, improving margin-negative resection rates, and reducing locoregional recurrence rates [47,82-86]. Most meta-analyses, but not all [87,88], also failed to show an OS benefit for this approach [46,61,70,89]. Data are as follows:

●In a phase III trial (TOPGEAR), 574 patients with resectable adenocarcinoma of the stomach or GEJ were randomly assigned to receive either neoadjuvant CRT (45 Gy in 25 fractions plus FU infusion) plus perioperative chemotherapy (either ECF or FLOT) or perioperative chemotherapy alone [82,90]. At a median follow-up of 67 months, the addition of neoadjuvant CRT to perioperative chemotherapy improved the pCR rate (17 versus 8 percent) but failed to improve OS (median 46 versus 49 months, HR 1.05, 95% CI 0.83-1.31) [82]. The rates of grade ≥3 toxicity (66 versus 61 percent) and surgical complications (18 versus 16 percent) were similar between the two treatment arms.

●In an open-label phase III trial (POET), 354 patients with locally advanced (endoscopic ultrasonography [EUS]-staged T3-4NXM0) adenocarcinoma of the lower esophagus, GEJ, or gastric cardia were randomly assigned to either neoadjuvant chemotherapy (15 weeks of cisplatin, FU, and leucovorin) or induction (ie, preoperative) chemotherapy plus CRT (12 weeks of cisplatin, FU, and leucovorin followed by three weeks of neoadjuvant CRT with concurrent cisplatin and etoposide), both followed by surgery [47]. The study closed early due to poor accrual.

•At a median follow-up of 46 months, three-year OS was higher for preoperative chemotherapy followed by neoadjuvant CRT compared with preoperative chemotherapy alone, but the difference was not statistically significant (three-year OS 47 versus 28 percent) [47]. This same finding was confirmed with longer follow-up (five-year OS 40 versus 24 percent, HR 0.65, 95% CI 0.42-1.01) [84].

•Compared with preoperative chemotherapy alone, preoperative chemotherapy followed by neoadjuvant CRT had similar R0 resection rates (72 versus 70 percent) but higher rates of pCR (16 versus 2 percent) and pathologically negative lymph nodes (64 versus 38 percent).

•There was a nonstatistically significant trend toward higher postoperative mortality rates for the addition of neoadjuvant CRT to preoperative chemotherapy (10 versus 4 percent) [47].

•The local failure rate for preoperative chemotherapy alone was high (41 percent), which is a finding reported by many others (although not all) when RT was not a component of trimodality therapy [56]. As an example, in the MAGIC trial in which neither group received RT, local failure rates with surgery alone and with perioperative chemotherapy were 21 and 14 percent, respectively [40]. (See 'Perioperative chemotherapy versus surgery alone' above.)

●Similar results were seen in several other randomized phase II and phase III trials of patients with locally advanced esophageal and GEJ tumors [85,86]. These studies also failed to show an OS benefit for the addition of neoadjuvant CRT to preoperative chemotherapy, despite higher rates of pCR and margin negative resection.

PET-directed therapy — We order a postinduction integrated fluorodeoxyglucose positron emission tomography (FDG-PET)/CT no earlier than four weeks after the completion of induction therapy as a method to assess for development of metastatic disease prior to surgical referral [91]. If a new lesion is identified, a biopsy is performed. PET-directed changes during the neoadjuvant therapy regimen are not part of the standard treatment approach.

Integrated FDG-PET/CT detects distant metastases in approximately 8 percent of patients following induction CRT [92]. In many cases, the metastases are located in sites (eg, skeletal muscle, subcutaneous soft tissue, brain, thyroid) that are not imaged well by conventional staging radiographic evaluation [93]. These postinduction therapy findings may not apply to patients who have undergone initial staging with integrated FDG-PET/CT scans, which are widely used for detecting occult metastases if metastases are not seen on the initial staging CT scans. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'CT, PET, and integrated PET/CT'.)

In addition to detecting occult metastatic disease after neoadjuvant CRT, early metabolic findings observed on PET scans during induction chemotherapy may be both predictive and prognostic [94-97]. As an example, the phase II MUNICON study showed in patients with adenocarcinomas of the esophagus or GEJ that PET scanning two weeks into neoadjuvant chemotherapy showed that metabolic responders had a significantly better prognosis than nonresponders [94]. Other series report accurate assessment of response to therapy and significant differences in prognosis according to the findings on post-CRT or postinduction chemotherapy PET [98-104], although this is not a universal finding.

Whether there is benefit to tailoring the chemotherapy component of CRT based upon the postinduction chemotherapy PET was studied in a phase II United States cooperative group trial (CALGB 80803, NCT01333033). Two hundred fifty-seven patients with resectable esophageal or GEJ adenocarcinoma were randomly assigned to one of two induction chemotherapy regimens (oxaliplatin plus FU and leucovorin [FOLFOX] or carboplatin plus paclitaxel [CP]) for five to six weeks [67]. PET responders continued the same chemotherapy regimen during subsequent CRT, while nonresponders crossed over to the other chemotherapy regimen with CRT [67]. The pCR rate in the PET nonresponders who crossed over to the other chemotherapy regimen was 18 and 20 percent for those initially treated with FOLFOX and CP, respectively (table 10). This compared favorably with expected rates of <5 percent for nonresponders regardless of regimen. Notably, the pCR rates in the PET responders who received initial FOLFOX was 40 percent and only 14 percent in the CP responders. Furthermore, the median OS for PET nonresponders who crossed over to the alternative regimen was still worse than that of the PET responders (27.4 versus 48.8 months). When assessed by induction chemotherapy group, survival rates were similar for individuals initially assigned to CP whether they were PET responders versus nonresponders (table 10) despite the fact that the pCR rates were low in nonresponders. On the other hand, there were greater differences in the group initially assigned to FOLFOX when responders versus nonresponders were compared (two-year OS 76.1 versus 61.5 percent; at 60 months, 53 versus 37.5 percent).

It is difficult to know how to interpret these complex results. It seems reasonable to conclude that early response assessment using PET to direct a change to alternative chemotherapy after induction therapy can increase the pCR rate, and the fact that median OS in PET nonresponders was not significantly worse than that of PET responders (27.4 versus 48.8 months) suggests that changing treatment in this poor prognosis group may bring outcomes closer to those of the PET responder group. However, in our view, PET-directed changes during neoadjuvant therapy should not be part of the standard treatment approach for the following reasons:

●The lack of a random assignment between using PET findings to change treatment versus not changing treatment on the basis of the PET scan limits any interpretation as to whether the better results obtained in those who crossed over to the alternative regimen could be definitively attributed to the change in chemotherapy.

●The small number of patients and events in each group limits the validity of comparing pCR and survival rates among the groups.

●Follow-up of this trial is relatively short, and more mature data are needed to assess survival impact of this strategy.

●The best way to measure response to induction chemotherapy or CRT is not well established. Whether PET/CT outperforms CT or EUS for assessment of locoregional tumor response to preoperative therapy is unclear; and there are no randomized trials that yet prove that a change in therapy will improve prognosis in nonresponders.

Management of postoperative residual disease — Patients who have substantial residual disease at resection after neoadjuvant therapy (particularly nodal metastases [105-107]) have a relatively poor prognosis, and the best way to manage this situation depends on whether initial treatment was chemotherapy alone or CRT.

After CRT — For patients with GEJ adenocarcinoma and any residual disease in the surgical specimen after initial chemoradiation (CRT), we suggest adjuvant nivolumab. For patients who are ineligible for nivolumab, options include post-treatment surveillance (for ypN0-1 tumors only) or adjuvant chemotherapy with different agents than those given preoperatively (eg, FOLFOX if the initial CRT regimen included concurrent paclitaxel and carboplatin).

●Nivolumab – Benefit for nivolumab was shown in the CheckMate 577 trial, in which 794 patients who had received neoadjuvant CRT for esophageal or GEJ cancer (70 percent adenocarcinoma) and had residual pathologic disease at the time of surgery were randomly assigned to nivolumab (240 mg) or placebo every 2 weeks for 16 weeks followed by nivolumab 480 mg or placebo every 4 weeks; the maximum treatment duration was one year [108]. Enrollment was irrespective of programmed death receptor-1 ligand 1 (PD-L1) overexpression. Tumor site was esophagus in 60 percent and GEJ in 40 percent; histology was adenocarcinoma in 71 percent and SCC in 29 percent. At a median follow-up of 24.4 months, median disease-free survival, the primary endpoint, was twice as long with nivolumab (22.4 versus 11 months, HR for disease progression or death was 0.69, 95% CI 0.56-0.86), and the benefits were seen across all patient subgroups (histology, location, initial and post-treatment disease stage, PD-L1 overexpression or not). OS data were not mature. Although treatment-related adverse effects were frequent, most were grade 1 or 2 and only 9 percent of patients discontinued adjuvant nivolumab because of adverse effects. The benefits were gained without any significant decline in patient-reported health-related quality of life over the year of nivolumab treatment.

Based on these results, the US Food and Drug Administration has approved nivolumab as adjuvant therapy for patients who previously received neoadjuvant CRT following complete resection of esophageal or gastroesophageal junction cancer with residual pathologic disease.

●Chemotherapy – Administering postoperative chemotherapy is difficult due to intolerance of therapy. Data from at least three trials (Radiation Therapy Oncology Group [RTOG] 85-01, Intergroup 0116, the MAGIC trial, and the CRITICs trial) indicate only a 50 to 60 percent rate of delivery of postoperative therapy [40,41,109,110]. In addition to concerns of tolerability, the potential benefit from more of the same preoperative chemotherapy is open to question.

A potential survival benefit for adjuvant chemotherapy in patients with residual nodal disease after CRT was reported in two retrospective analyses, derived from the National Cancer Database (NCDB), of patients with esophageal cancer who were treated after neoadjuvant CRT [111,112]. Additional support is provided by a meta-analysis of ten studies involving 6462 patients (one randomized trial, the rest cohort studies); most utilized neoadjuvant CRT rather than induction chemotherapy [113]. When compared with neoadjuvant therapy and esophagectomy alone, adjuvant therapy groups had a significantly lower mortality at both one-year (risk ratio [RR] 0.52, 95% CI 0.41-0.65) and five-year follow-up (RR 0.91, 95% CI 0.86-0.96).

After chemotherapy alone — We suggest either postoperative CRT or the same chemotherapy as was used preoperatively for patients with GEJ adenocarcinoma who have residual node-positive or pT3 disease after preoperative chemotherapy. There are no data for changing the postoperative regimen in patients who do not achieve a pCR, and we suggest not pursuing this approach. We reserve postoperative RT for cases with a histologically positive resection margin.

Patients with gastric cardia adenocarcinoma who receive preoperative chemotherapy and have residual disease on the surgical specimen should complete the postoperative component of the selected chemotherapy regimen. The use of adjuvant CRT is individualized. Further details are discussed separately. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Postoperative management of poor responders'.)

Among patients who undergo preoperative chemotherapy without RT, it is not known whether postoperative CRT will be beneficial, particularly in the setting of multiple pathologic positive nodes. Perioperative chemotherapy decreases the risk of metastatic disease but has less effect on locoregional control as CRT. This was addressed in a phase III trial (CRITICS) [110]. In this study, all patients with potentially resectable gastric cancer received induction chemotherapy followed by surgery were then randomly assigned to postoperative chemotherapy versus CRT. Patients with GEJ tumors (17 percent) were eligible if their main tumor bulk was in the stomach. At a median follow-up of 61.4 months, there was no difference in median OS between chemotherapy and CRT (HR 1.01, 95% CI 0.84-1.22) [110]. Ninety-four percent of patients proceeded to resection after induction chemotherapy. However, only 59 percent proceeded to adjuvant chemotherapy and 62 percent started adjuvant CRT. This study further highlights the challenges associated with postoperative therapy [110].

Is there a role for adding immunotherapy to perioperative chemotherapy? — There is no established clinical role for the addition of an immune checkpoint inhibitor to perioperative chemotherapy or postoperative (adjuvant) chemotherapy in locally advanced resectable GEJ or gastric cardia adenocarcinoma, and this approach remains investigational.

●Pembrolizumab – Although early phase clinical trials suggested a clinical benefit for the addition of pembrolizumab to perioperative platinum-based chemotherapy [114], this combination failed to improved OS in a randomized phase III trial (KEYNOTE-585) of untreated, locally advanced, resectable gastric or GEJ adenocarcinoma [115].

●Nivolumab – Similarly, a phase III trial (ATTRACTION-5) of stage III gastric or GEJ cancer, the addition of nivolumab to postoperative chemotherapy (S-1 or CAPOX) failed to improved recurrence-free survival [116].

●Other agents – Other immune checkpoint inhibitors that are being investigated in combination with perioperative FLOT include atezolizumab [117] and durvalumab [118,119].

Patients who undergo surgery first

Indications and choice for adjuvant therapy — For patients with completely resected pT2N1-2, pT3, or T4 GEJ adenocarcinoma who have not received neoadjuvant therapy, we recommend adjuvant therapy. It is not known whether there are advantages for adjuvant CRT over chemotherapy alone. Data comparing these two approaches for GEJ tumors are limited. (See 'Adjuvant chemotherapy' below.)

In our view, either approach is reasonable, but randomized trials are necessary. For most patients, we favor chemotherapy alone, but we prefer CRT for patients with extensive nodal involvement and those with a margin-positive resection, unless the patient is deemed unlikely to tolerate CRT. If chemotherapy alone is chosen, we suggest FOLFOX or FLOT (for a fit patient) rather than an epirubicin-containing regimen. If CRT is chosen, either the regimen used in the Intergroup 0116 trial or the ARTIST trial [41,120] is reasonable. (See 'Adjuvant CRT' below.)

The optimal management of pT2N0 esophageal adenocarcinoma is controversial. For most patients, we suggest not routinely using adjuvant therapy following resection of pT2N0 disease when induction treatment was not used. The exception is patients with clinicopathologic high-risk features (eg, poorly differentiated or higher-grade cancer, lymphovascular invasion, perineural invasion, or age <50) in whom we would discuss the relative benefits and risks of adjuvant chemotherapy, with or without RT.

For patients with gastric cardia adenocarcinoma who undergo potentially curative gastric resection and did not receive neoadjuvant therapy, the approach to adjuvant therapy is discussed separately. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Initial potentially curative resection'.)

Adjuvant CRT — All of the trials evaluating adjuvant chemoradiation (CRT) are "lower tract" trials. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Adjuvant chemoradiation'.)

●In the United States Intergroup study 0116, 556 patients with potentially curatively resected T1 to T4, N0 or N1 gastric or GEJ adenocarcinoma (20 percent) were randomly assigned to either observation or adjuvant-combined CRT [41]. Treatment consisted of one cycle of FU (425 mg/m² per day) plus leucovorin calcium (20 mg/m² per day) daily for five days, followed one month later by 45 Gy (1.8 Gy/day) RT given with FU and leucovorin calcium (400 mg/m² and 20 mg/m², respectively) on days 1 through 4 and on the last three days of RT. Two additional five-day cycles of chemotherapy (FU 425 mg/m² per day and leucovorin calcium 20 mg/m² per day) were given at monthly intervals beginning one month after completion of RT.

Three-year disease-free survival and OS rates (50 versus 41 percent, HR for death 1.35, 95% CI 1.09-1.66) were significantly better with combined modality therapy, as was median survival (36 versus 27 months), despite the fact that only 64 percent of patients completed all of the planned treatment. Patients with GEJ tumors appeared to derive the same benefit as did those with non-cardia gastric cancer. Results from this trial, including treatment-related toxicity, are described in more detail separately. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Adjuvant chemoradiation'.)

These results changed the standard of care in the United States for patients undergoing potentially curative resection of stage IIA or higher gastric cancer from observation alone to adjuvant CRT. While this approach is still used, in the United States, GEJ tumors are more often approached with neoadjuvant chemotherapy with or without RT than with upfront surgery followed by adjuvant therapy. Completing the intensive four-month postoperative regimen is difficult due to toxicity of CRT (approximately 30 percent did not complete). (See 'Neoadjuvant CRT' above and 'Perioperative chemotherapy versus surgery alone' above.)

●CALGB 80101, a United States Intergroup study, directly compared the Intergroup 0116 protocol regimen with postoperative ECF before and after FU plus concurrent RT in 546 patients with completely resected gastric or GEJ tumors that extended beyond the muscularis propria or were node positive [121]. The percentage with GEJ tumors was not reported. The ECF-containing arm had lower rates of diarrhea, mucositis, and grade 4 or worse neutropenia. However, OS, the primary endpoint, was not significantly better with ECF (at five years, 44 percent in both groups). This trial is discussed in more detail separately. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Adjuvant chemoradiation'.)

The Intergroup 0116 regimen remains a standard option when adjuvant CRT is indicated.

●The ARTIST trial regimen is also an option (two courses of postoperative capecitabine plus cisplatin [XP] followed by CRT [45 Gy RT with concurrent daily capecitabine (825 mg/m² twice daily)] and two additional courses of XP). This trial is discussed in more detail separately [120]. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Adjuvant chemoradiation'.)

Adjuvant chemotherapy — There are no randomized trials exploring the benefit of adjuvant chemotherapy in patients with esophageal or GEJ adenocarcinoma. The CLASSIC trial and several meta-analyses support adjuvant chemotherapy in gastric cancer, with some trials including patients with GEJ and gastric cardia cancers. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Adjuvant chemotherapy'.)

●An uncontrolled trial conducted by the Eastern Cooperative Oncology Group (ECOG) included patients with distal esophageal (n = 9), GEJ (n = 34), or gastric cardia (n = 12) tumors [122]. Eligible patients had either T2N1-2 or T3 or 4 disease that was completely resected with negative margins; 49 (89 percent) were node-positive. Treatment consisted of four three-week cycles of paclitaxel (175 mg/m²) followed by cisplatin (75 mg/m²). With a median follow-up of four years, the three-year survival rate was 44 percent. However, there was not a surgery alone group.

●A survival benefit for adjuvant chemotherapy was also suggested by a retrospective review of 1694 patients from the NCDB who underwent esophagectomy for node-positive adenocarcinoma with negative margins without any induction therapy [123].

Adjuvant chemotherapy was given to 874 patients (52 percent), and the five-year survival was significantly better than that of patients who did not receive adjuvant chemotherapy (24 versus 15 percent).

●A benefit for postoperative chemotherapy (capecitabine plus oxaliplatin) for gastric cancer was also shown in the CLASSIC trial, which included a small proportion of patients with GEJ tumors (2.3 percent of the total enrolled) [124]. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Choice of regimen'.)

Chemotherapy versus chemoradiation — All of the trials directly comparing adjuvant chemotherapy with CRT are lower gastrointestinal tract (gastric) trials; some, like the Dutch CRITICS trial, enrolled a minority of patients with proximal gastric/GEJ tumors. (See 'After chemotherapy alone' above.)

Despite the large number of trials (and a meta-analysis of six of them), the available data do not resolve a difference in benefit between CRT over chemotherapy. This subject is discussed in detail separately. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Adjuvant chemoradiation'.)

INVESTIGATIONAL APPROACHES

HER2-targeted therapy for HER2+ adenocarcinomas — Among patients with advanced gastric adenocarcinoma, the addition of trastuzumab to a cytotoxic chemotherapy backbone improves survival for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing tumors. (See "Initial systemic therapy for metastatic esophageal and gastric cancer", section on 'HER2-positive adenocarcinomas'.)

There are emerging data on the safety and potential benefit of combining trastuzumab with cytotoxic chemotherapy in the perioperative setting for potentially resectable gastroesophageal junction (GEJ) and gastric adenocarcinomas, but there are no high-quality trials proving benefit over standard therapy, and this remains an investigational approach. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'HER2-targeted therapy'.)

A lack of benefit for HER2-targeted therapy was noted in the phase III randomized NRG Oncology/Radiation Therapy Oncology Group (RTOG) 1010 trial, 203 HER2+ patients with newly diagnosed T1N1-2, T2-3N0-2 adenocarcinomas of the mid or distal esophagus, GEJ or stomach (within 5 cm of the GEJ) were all treated with radiation therapy (RT) (50.4 Gy) plus weekly paclitaxel plus carboplatin, followed five to eight weeks later by resection; those randomly assigned to trastuzumab also received trastuzumab weekly during chemoradiation (CRT), a loading dose just prior to surgery, and then postoperative maintenance trastuzumab every three weeks for 13 treatments [125]. At a median follow-up of 2.8 years, the addition of trastuzumab to CRT did not worsen treatment-related toxicity but it also did not improve disease-free or overall survival.

Neoadjuvant immunotherapy for dMMR tumors — Mismatch repair deficiency (dMMR)/high levels of microsatellite instability (MSI-H) are seen in approximately 3 to 22 percent of patients with gastric cancer. Among patients with advanced esophagogastric cancer, dMMR/MSI-H status predicts potential benefit from immune checkpoint inhibitor immunotherapy. (See "Initial systemic therapy for metastatic esophageal and gastric cancer", section on 'Mismatch repair deficient/MSI-H tumors' and "Second- and later-line systemic therapy for metastatic gastric and esophageal cancer", section on 'Defective mismatch repair'.)

Studies are evaluating the use of neoadjuvant immunotherapy in patients with dMMR/MSI-H GEJ and gastric adenocarcinoma [126,127]. While exciting, additional follow-up and randomized trials comparing this approach to perioperative chemotherapy are needed before it can be concluded that neoadjuvant immunotherapy is a preferred approach for patients with dMMR gastric or GEJ tumors. Further details are discussed separately. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Immunotherapy for dMMR tumors'.)

POST-TREATMENT SURVEILLANCE — 

We perform history, physical examination, and targeted blood work (for a symptomatic patient, or if there was a serum tumor marker that was elevated preoperatively) every four months for the first three years and also perform restaging CT scans of the chest and abdomen at three-month intervals for two years then six-month intervals for three more years.

We do not carry out surveillance endoscopy unless there was a preoperative history of Barrett's esophagus, a questionable margin at the time of surgery, or if the patient has a recalcitrant stricture that is worrisome for an occult local recurrence.

When planning the post-treatment surveillance strategy, care should be taken to limit the number of CT scans, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. (See "Radiation-related risks of imaging".)

There are no randomized trials to guide the postoperative surveillance strategy and no data that demonstrate improvement in quality of life or longevity from earlier detection of asymptomatic recurrences. Nevertheless, our approach is consistent with consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [91], which suggest the following:

●History and physical examination every three to six months for one to two years, then every 6 to 12 months for years 3 to 5, then annually

●Complete blood count and chemistry profile, as clinically indicated

●Radiologic imaging and upper gastrointestinal endoscopy, as clinically indicated

●Dilation for anastomotic stenosis

●Nutritional counseling

●Confirm that human epidermal growth factor receptor 2 (HER2) testing has been performed if metastatic disease was present at diagnosis

(See "Initial systemic therapy for metastatic esophageal and gastric cancer", section on 'HER2-positive adenocarcinomas'.)

Some clinicians check tumor markers (particularly carcinoembryonic antigen [CEA]) with each follow-up visit, if initially elevated, and perform restaging CT scans every three to six months, at least for the first two years. However, the utility of tumor marker and radiographic surveillance is controversial. Although early detection of recurrence can facilitate treatment before the development of symptomatic bulky disease that may be difficult to manage (eg, bowel entrapment from peritoneal metastases), there are no data that support the view that early detection of an asymptomatic recurrence by tumor marker elevation or radiologic imaging improves quality of life or prolongs survival [128,129]. In keeping with this point of view, consensus-based guidelines from European Society for Medical Oncology (ESMO) emphasize the lack of evidence that regular follow-up after initial therapy has an impact on survival outcomes, with the possible exception of patients who might be potential candidates for endoscopic reintervention or early "salvage surgery" after failing definitive CRT [130]. They advise that follow-up visits concentrate on symptoms, nutrition, and psychosocial support. In the case of a complete response to chemoradiation (CRT) in a patient who did not undergo resection, a three-month follow-up based on endoscopy, biopsy, and CT scan may be recommended to detect early recurrence, leading to a discussion about salvage surgery.

We disagree with this approach. In our view, patients tend to better candidates for chemotherapy protocols when their metastatic disease is diagnosed earlier rather than later.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastric cancer" and "Society guideline links: Esophageal cancer" and "Society guideline links: Gastric surgery for cancer".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Esophageal cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●General principles – Tumors involving the gastroesophageal junction (GEJ; also called the esophagogastric junction [EGJ]) or gastric cardia with the tumor epicenter no more than 2 cm into the proximal stomach are staged and treated as esophageal cancers (table 2). These tumors are treated using various combinations of surgery, systemic therapy, and radiation therapy (RT). (See 'AJCC classification' above and 'Introduction' above.)

●Initial therapy for clinical Tis or T1N0 disease

•GEJ adenocarcinoma – Patients with clinical Tis or T1N0 GEJ adenocarcinoma are treated with either endoscopic resection or surgery (esophagectomy). Further details are discussed separately. (See "Management of superficial esophageal cancer".)

•Gastric cardia adenocarcinoma – Patients with clinical Tis or T1N0 gastric cardia adenocarcinoma are treated with either endoscopic resection or gastrectomy. Further details are discussed separately. (See "Early gastric cancer: Management and prognosis".)

•Evaluate for adjuvant therapy – Patients with GEJ adenocarcinoma and gastric cardia adenocarcinoma who are treated with initial surgery should be evaluated for adjuvant therapy, if necessary, based on the postoperative pathology. (See 'Indications and choice for adjuvant therapy' above and "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Initial potentially curative resection'.)

●Initial therapy for clinical T2 or greater disease

•Clinical T2N0 GEJ adenocarcinoma – For most patients with clinical T2N0 GEJ adenocarcinomas, we suggest initial systemic therapy, with or without radiation therapy RT, rather than initial surgery (Grade 2C). Although data are limited, these patients are often included in clinical trials evaluating neoadjuvant chemoradiation (CRT) or neoadjuvant chemotherapy for locoregionally advanced tumors. (See 'Clinical T2N0 disease' above.)

•Clinical T3-4 or node-positive GEJ adenocarcinoma – For most patients with clinical T3-4 or node-positive GEJ adenocarcinoma, we suggest initial systemic therapy, with or without radiation therapy RT, rather than initial surgery (Grade 2B). However, initial surgery is an alternative for the rare patient who is anticipated to not tolerate neoadjuvant therapy and has cT3N0 disease that is clearly resectable. (See 'Patients not yet resected' above.)

•Unresectable GEJ adenocarcinoma – For patients with GEJ adenocarcinoma that is unresectable, those who are not surgical candidates, or those who decline surgery, definitive CRT is an alternative. (See 'Definitive CRT' above.)

•Clinical T2 or greater gastric cardia adenocarcinoma – For patients with clinical T2N0 or higher resectable gastric cardia cancer, or those with a high clinical suspicion of occult metastatic disease, perioperative chemotherapy is the preferred treatment approach. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Potentially resectable clinical T2N0 disease or higher that is not yet resected'.)

●Patients receiving initial systemic therapy

•Chemotherapy versus CRT – In patients receiving initial systemic therapy with or without RT, prior to surgery, our approach is as follows:

-Resectable GEJ adenocarcinoma – For most patients with clinical T3-4 or node-positive resectable esophageal or GEJ adenocarcinoma who are younger with good performance status and minimal comorbidities, we suggest perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) (table 5) rather than neoadjuvant CRT (Grade 2B). For older patients, those with multiple comorbidities, and/or those who are unlikely to tolerate the toxicities of FLOT (eg, neuropathy), neoadjuvant CRT is an appropriate alternative. Patients treated with neoadjuvant CRT followed by surgery should also be evaluated for adjuvant therapy (eg, adjuvant immunotherapy for those without a pathologic complete response [pCR]). (See 'Perioperative chemotherapy versus neoadjuvant CRT' above and 'Our recommended approach' above.)

For most patients receiving neoadjuvant CRT, we suggest concurrent radiosensitization with weekly carboplatin and paclitaxel (table 6) rather than other regimens (Grade 2C). FOLFOX is a reasonable alternative radiosensitizing regimen. (See 'Neoadjuvant CRT' above and 'Selection of radiosensitizing regimen' above.)

A standard dose of RT with concurrent chemotherapy is 50.4 Gy, regardless of the specific chemotherapy regimen used. Three-dimensional (3D) conformal techniques should be used for radiation treatment planning. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer", section on 'Technique for preoperative RT'.)

-Resectable gastric cardia cancer – For patients with clinical T2 or higher resectable gastric cardia adenocarcinoma, good performance status, and no significant comorbidities who are able to tolerate intensive therapy, we prefer perioperative chemotherapy regimen with FLOT (table 5). Appropriate alternatives, especially for patients with worse performance status or more comorbidities, include FU, leucovorin, and oxaliplatin (FOLFOX) (table 9); capecitabine plus oxaliplatin (CAPOX) (table 11); FU plus cisplatin; or oxaliplatin plus S-1 (where available). (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Choice of regimen and patient selection' and 'Is there an optimal regimen?' above.)

-Assessment after neoadjuvant therapy – We perform a PET/CT no earlier than four weeks after the completion of neoadjuvant therapy to assess for distant metastatic disease. PET-directed changes during neoadjuvant therapy are not part of the standard treatment approach. (See 'PET-directed therapy' above.)

•Surgical resection after neoadjuvant therapy – Patients with clinically resectable GEJ or gastric cardia adenocarcinoma who complete neoadjuvant therapy should subsequently proceed to surgery. Resection is generally integral to achieving the best outcomes with multimodality therapy. The surgical approach is based on tumor location. Minimally invasive techniques are preferred, where local expertise is available. Principles of surgical management for these tumors are discussed in detail separately. (See "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Esophagogastric junction cancer resection' and "Surgical management of invasive gastric cancer" and 'Necessity for surgery' above.)

•Management of residual disease

-GEJ adenocarcinoma, after CRT – Patients with GEJ adenocarcinoma and a pCR on the surgical specimen after initial CRT do not require further therapy and may proceed to post-treatment surveillance. (See 'Post-treatment surveillance' above.)

For patients without a pCR after initial CRT, we suggest adjuvant nivolumab (Grade 2B). For those who are ineligible for nivolumab, options include post-treatment surveillance (for ypN0-1 tumors only) or adjuvant chemotherapy with different agents than those given preoperatively (eg, FOLFOX if the initial CRT regimen included concurrent carboplatin and paclitaxel). (See 'After CRT' above.)

-GEJ adenocarcinoma, after chemotherapy – For patients with GEJ adenocarcinoma who have residual node-positive or pT3 disease after preoperative chemotherapy, we suggest postoperative CRT or completing perioperative chemotherapy using the same regimen as was used preoperatively (Grade 2C). There are no data for changing the postoperative regimen in patients who do not achieve a pCR to initial neoadjuvant chemotherapy. In this setting, we reserve postoperative RT for cases with a histologically positive resection margin. (See 'After chemotherapy alone' above.)

-Gastric cardia adenocarcinoma, after chemotherapy – Patients with gastric cardia adenocarcinoma who receive preoperative chemotherapy and have residual disease on the surgical specimen should complete the postoperative component of the selected chemotherapy regimen. The use of adjuvant CRT is individualized. Further details are discussed separately. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Postoperative management of poor responders'.)

●Patients who undergo initial surgery: Indications for adjuvant therapy

•GEJ adenocarcinoma – For patients with GEJ adenocarcinoma who undergo initial surgery rather than neoadjuvant therapy and who have margin-positive disease, node-positive disease, or a pT3 or higher primary tumor stage, we recommend postoperative adjuvant therapy (Grade 1B). Either chemotherapy alone or CRT is a reasonable option; we tend to favor chemotherapy alone for most patients, unless they have a margin-positive resection or extensive nodal disease. (See 'Adjuvant CRT' above and 'Adjuvant chemotherapy' above.)

The optimal management of pT2N0 tumors is controversial. For most patients, we suggest not routinely using adjuvant therapy (Grade 2C). For patients with clinicopathologic high-risk features (eg, poorly differentiated or higher grade cancer, lymphovascular invasion, perineural invasion, or age <50) we discuss the relative benefits and risks of adjuvant chemotherapy, with or without RT. (See 'Indications and choice for adjuvant therapy' above.)

•Gastric cardia adenocarcinoma – For patients with gastric cardia adenocarcinoma who undergo potentially curative gastric resection and did not receive neoadjuvant therapy, the approach to adjuvant therapy is discussed separately. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Initial potentially curative resection'.)

●Post-treatment surveillance – We generally follow consensus-based guidelines for post-treatment surveillance from the National Comprehensive Cancer Network (NCCN). (See 'Post-treatment surveillance' above.)

ACKNOWLEDGMENTS — 

The UpToDate editorial staff acknowledges Ajlan Atasoy, MD, and Noah C Choi, MD, who contributed to earlier versions of this topic review.