Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas

INTRODUCTION — Esophageal and gastric cancers are significant worldwide health problems. They are often lethal diseases, with a case-fatality ratio of 84 (esophageal) and 75 percent (gastric), respectively [1].

The esophagogastric junction (EGJ; also called the gastroesophageal junction or GEJ) and gastric cardia (figure 1) represent anatomical sites with a remarkably high and rapidly rising incidence of adenocarcinoma. (See "Epidemiology of gastric cancer", section on 'Changes in histologic pattern' and "Epidemiology and pathobiology of esophageal cancer", section on 'Epidemiology'.)

Although surgery is the primary curative modality for EGJ cancers, long-term outcomes are not satisfactory with resection alone, even if microscopically complete (R0). This poor long-term outcome has prompted an evaluation of neoadjuvant (preoperative) and adjuvant (postoperative) combined modality therapy. There is no consensus on the best combination of multimodality therapy.

This topic will cover the definition and classification of EGJ tumors. It will provide an overview of the clinical trials that support the multimodality management of locally advanced, potentially resectable EGJ adenocarcinomas. It will also focus on considerations that influence the choice of the multimodality approach. Principles of surgical management for gastric and thoracic esophageal tumors, treatment of locally advanced, unresectable esophageal cancers, adjuvant and neoadjuvant approaches to gastric cancers, and neoadjuvant and adjuvant approaches to tumors of the thoracic esophagus are covered elsewhere, as is management of dysplasia and early superficial cancer (including adenocarcinoma) arising in Barrett's esophagus.

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

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

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

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

●(See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus".)

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

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

DEFINITION AND CLASSIFICATION — The definition of the EGJ is not standardized. It is defined differently by anatomists, physiologists, endoscopists, surgeons, and pathologists:

●Anatomists and surgeons localize the EGJ at the level of the angle of His, the point at which the tubular esophagus joins the cardia of the saccular stomach [2].

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

●Endoscopically, the EGJ corresponds to the most proximal extent of the longitudinal gastric folds (figure 2) [3,4]. 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 EGJ [5]. (See "Barrett's esophagus: Epidemiology, clinical manifestations, and diagnosis", section on 'Identify possible Barrett's'.)

●Pathologically, the EGJ is defined in an opened esophagogastrectomy specimen as the most proximal aspect of the gastric folds. The EGJ is located in the opened specimen by following the mucosa of the tubular esophagus to the top of the gastric folds. The EGJ 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 EGJ should be avoided as these definitions place the EGJ at a point that can be over 2 cm proximal to the true physiologic EGJ, 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 EGJ [5].

The lack of a clear definition of the EGJ and gastric cardia has contributed to difficulties in classification of these tumors and has hampered 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 most recent (2017, eighth edition) revision of the AJCC staging classification [6], tumors involving the EGJ with the tumor epicenter no more than 2 cm into the proximal stomach are staged as esophageal cancers. By contrast, EGJ 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 EGJ, even if they are within 2 cm of the EGJ (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, which are based on data from the Worldwide Esophageal Cancer Collaboration, are outlined in the figure (figure 3) [7-12]. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'TNM staging criteria' and "Clinical features, diagnosis, and staging of gastric cancer", section on 'TNM staging criteria'.)

Siewert classification — Siewert and Holsher published a topographic-anatomic subclassification scheme for EGJ adenocarcinomas in 1987 [13] 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 [14]. Within this classification, EGJ adenocarcinomas encompass all tumors with an epicenter within 5 cm proximal or distal to the EGJ [14].

Siewert described three distinct categories of EGJ 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 EGJ [15]) – 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 EGJ from above.

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

●Type III tumor (located between 2 and 5 cm distal to the EGJ) – Subcardial gastric carcinoma that infiltrates the EGJ 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 EGJ, 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 EGJ 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 [16,17]. However, as noted above, in the newest eighth edition TNM classification system, cancers involving the EGJ that have their epicenter within the proximal 2 cm of the cardia and involve the EGJ are still staged as esophageal cancers (table 1) [6]. Cancers whose epicenter is more than 2 cm distal from the EGJ, even if the EGJ is involved, and all proximal cardia tumors that do not involve the EGJ (even if they are within 2 cm of the EGJ) are staged as stomach cancers (table 3). (See "Clinical features, 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 [18-21]:

●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 [22]. (See "Barrett's esophagus: Pathogenesis and malignant transformation" and "Epidemiology and pathobiology of esophageal cancer", section on 'Epidemiology' and "Epidemiology and pathobiology of esophageal cancer", section on 'Etiologic 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 [23]. 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) [24-26].

●For the purpose of multimodality treatment, EGJ tumors are all treated similarly, although the operative approach differs, partly because of the differing pattern of nodal spread (figure 4) [27].

•In general, type I cancers more frequently involve lymph nodes in the upper mediastinum (tracheal bifurcation and above) [28]. 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) [29]. 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 [30].

•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 EGJ 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 EGJ, 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 EGJ 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 — PET and integrated PET/computed tomography (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 [31,32].

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 EGJ), 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'.)

EUS has limited accuracy for early stage superficial tumors. In such cases, endoscopic mucosal resection can aid in identifying superficially invasive tumors with a low enough risk for nodal metastases that surgical resection might not be needed. (See "Management of superficial esophageal cancer", section on 'Initial assessment' and "Management of superficial esophageal cancer".)

Diagnostic laparoscopy — Intraperitoneal metastases are common with EGJ 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 EGJ, or bulky nodal metastases, or if there is suspicion for intraperitoneal metastatic disease that cannot otherwise be confirmed [33]. The procedure involves full inspection of the peritoneal cavity to evaluate for peritoneal and liver metastases. The EGJ 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 'Significance of positive peritoneal cytology'.)

The optimal timing and procedures undertaken during diagnostic laparoscopy are discussed elsewhere. (See "Surgical management of invasive gastric cancer", section on 'Staging laparoscopy' 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 [34].

Celiac nodal metastases and mediastinal/supraclavicular nodes are scored as "regional" nodal disease in the current 2017 edition tumor, node, metastasis (TNM) staging criteria (figure 5 and table 1) [35]. 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", section on 'Regional lymph nodes'.)

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 — Geographic variation and changes in the epidemiology of esophageal cancer, especially in Western (non-Asian) countries, are striking over the last 20 to 30 years. Worldwide, squamous cell cancer (SCC) is the most common subtype but adenocarcinoma is now the most prevalent in the West. In Western countries, the primary tumor location changed in tandem with histology. Distal esophagus, EGJ, and proximal gastric cancers are now the dominant sites of disease in the West [36]. These epidemiologic shifts have focused attention on adenocarcinomas of the distal esophagus, EGJ, and proximal stomach as distinct entities. (See "Epidemiology of gastric cancer", section on 'Changes in histologic pattern' and "Epidemiology and pathobiology of esophageal cancer", section on 'Epidemiology'.)

Combined modality therapy is a standard approach for patients with stages IIA, IIB, and III esophageal, EGJ, and gastric cardia cancers (table 1). However, the best form of multimodality therapy is not established. Patients with EGJ adenocarcinoma may receive neoadjuvant or perioperative chemotherapy alone, preoperative chemoradiotherapy (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 — EGJ 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 [37-39], 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 EGJ adenocarcinomas is difficult for a number of reasons [40], one of which is the lack of trials that focus on the EGJ. For example, only one trial, the German POET trial of neoadjuvant CRT versus induction chemotherapy alone, treated EGJ tumors as a separate entity.

Most of the data that inform the multimodality treatment of EGJ adenocarcinoma are derived from trials that involved predominantly gastric or esophageal cancers. Within the trials designed primarily for gastric cancer (which will be considered "lower tract trials" for the purpose of this review), patients with EGJ tumors account for only approximately 20 percent of all enrollees [41,42]. There are epidemiologic and pathologic differences between EGJ and non-cardia gastric adenocarcinomas that raise concern as to whether results from predominantly gastric cancer trials can be extrapolated to EGJ tumors. Gastric tumors are associated with H. pylori infection, chronic gastritis, and low acid production, while EGJ tumors tend to be associated with obesity, high acid production, gastroesophageal reflux disease (GERD), and are inversely associated with H. pylori [43]. (See "Risk factors for gastric cancer".)

On the other hand, the clinical characteristics, biologic behavior, and survival after esophagectomy for EGJ adenocarcinomas seem to be similar to those of adenocarcinomas arising in the distal esophagus [44] and gastric cardia [45]. 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 EGJ 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 pathobiology of esophageal cancer", section on 'Pathobiologic differences'.)

In acknowledgment of these differences, the current eighth edition tumor, node, metastasis (TNM) staging systems [35,46] (table 1) provide separate stage groupings (but similar definitions for T, N, M, and grade [G] categories) for SCCs and adenocarcinomas of the esophagus and EGJ. In addition, there are separate groupings for clinical, pathologic, and post-neoadjuvant therapy stage that are also histology specific [35]. (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 [47]. 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 "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Squamous cell versus adenocarcinoma'.)

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

●The United States Intergroup trial 0116 demonstrated the advantage of postoperative CRT in patients with resected gastric and EGJ adenocarcinomas [42]. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Adjuvant chemoradiotherapy'.)

●The European MAGIC trial demonstrated the survival benefit of perioperative chemotherapy with ECF (epirubicin, cisplatin, and fluorouracil [FU]) in patients with distal esophageal, EGJ, and gastric adenocarcinoma [41]. The success of this trial raised questions as to whether radiation therapy (RT) was a necessary component of treatment for gastric and EGJ cancers. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Neoadjuvant/perioperative chemotherapy'.)

●The German POET trial demonstrated modest, clinically relevant but not statistically significant benefits of neoadjuvant chemotherapy plus CRT versus induction chemotherapy alone in patients with EGJ adenocarcinoma [48].

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

Definitive CRT and necessity for surgery — For patients with clinically resectable adenocarcinoma, we suggest inclusion of surgery rather than definitive chemoradiotherapy (CRT) alone, especially in adenocarcinomas.

Definitive CRT is a reasonable option for patients who are not surgical candidates. Most of the data on definitive CRT for esophageal cancer are in patients with SCC. There are fewer data for adenocarcinoma, and pathologic complete response rates after CRT are lower for adenocarcinoma as compared with SCC. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Chemoradiotherapy 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]. Overall survival 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 year 2016 Cochrane review of eight randomized trials concluded that there was no difference in long-term mortality between definitive and neoadjuvant chemoradiotherapy (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 (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 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 overall survival of 19.7 months, which was similar to those with SCC. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Necessity for surgery'.)

Nevertheless, resection is generally considered integral to achieving the best outcomes from multimodality therapy. For patients with adenocarcinoma of the EGJ, we generally reserve definitive CRT for those who refuse surgery or are not surgical candidates. This approach is consistent with year 2020 ASCO guidelines on treatment of locally advanced esophageal cancer [47].

Principles of surgical management for EGJ tumors are discussed in detail elsewhere. (See "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Esophagogastric junction cancer resection'.)

PATIENTS WITH 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 EGJ and gastric cardia (see 'Pretreatment staging evaluation' above):

●For most patients, we suggest neoadjuvant therapy rather than initial surgery. However, surgery might be considered first when there is a clearly resectable lesion and concern for tolerance of preoperative therapy. (See 'Patients not yet resected' below.)

For patients with clinically resectable adenocarcinoma, we suggest inclusion of surgery rather than definitive chemoradiotherapy (CRT) alone. Definitive CRT is a reasonable alternative for those patients who refuse surgery or are not surgical candidates. (See 'Definitive CRT and necessity for surgery' above.)

●If neoadjuvant therapy is chosen, for most patients, we suggest preoperative CRT rather than perioperative chemotherapy. (See 'Neoadjuvant CRT versus chemotherapy alone' 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 5) rather than other regimens. This is based largely on better tolerance and ease of administration. A reasonable alternative is two courses of cisplatin and fluorouracil (FU) as per the CALGB 9781 trial (table 6).

•The optimal radiation therapy (RT) dose fractionation schedule for CRT is not known. Many landmark trials were conducted before the era of modern RT techniques, such as three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT). These techniques use computed tomography (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 consider that standard dose radiation for use with concurrent chemotherapy is 50.4 Gy, regardless of the chemotherapy regimen. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Technique for preoperative RT'.)

●Perioperative chemotherapy is a reasonable alternative for patients who cannot tolerate radiation and for those with true gastric cardia cancer. If there is a high clinical suspicion for occult metastatic disease, this may be preferred as well. An optimal regimen is not established. (See 'Perioperative chemotherapy' below and 'Is there an optimal regimen?' below.)

Our preferred options include 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), oxaliplatin plus S-1 (where available), or, for fit patients with an excellent performance status, a docetaxel-containing triplet such as FLOT as was used in the FLOT4-AIO trial. Another option is infusional FU plus cisplatin, as was used in the French FNLCC/FFCD and MRC trials. Year 2020 guidelines from the American Society of Clinical Oncology (ASCO) recognize FLOT as the standard of care, but if not available or feasible, cisplatin plus FU or a similar platinum-based regimen is acceptable [47].

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 Medical Research Council (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 cannot yet be considered a standard 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 'Principles of surgical resection'.)

●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 pathologic complete response, and we suggest not pursuing this approach.

We reserve postoperative RT for cases with a histologically positive resection margin. This is in keeping with consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [52], which suggest postoperative fluoropyrimidine-based CRT for patients with a margin-positive resection, and chemotherapy alone (if used preoperatively) for patients who have residual node-positive but margin-negative disease. (See 'After chemotherapy alone' below.)

Our approach for patients with residual nodal disease after neoadjuvant CRT is to administer adjuvant chemotherapy with different agents than those given preoperatively (eg, ECF if the initial CRT regimen included only cisplatin and FU). There are no consensus-based recommendations from the NCCN in this situation, and observation after surgery is a reasonable approach [52]. (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. Guidelines from the NCCN [52] recommend consideration of preoperative CRT for selected patients with high-risk features, including poorly differentiated or higher-grade cancer, lymphovascular invasion, perineural invasion or age <50. Year 2020 ASCO guidelines state that surgery alone may be considered for patients with T2N0 esophageal carcinoma after discussion with a multidisciplinary team, and that this approach may be more appropriate for patients with low-risk lesions (ie, well differentiated, <2 cm) [47].

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 — As noted above, we prefer neoadjuvant therapy rather than initial resection for most patients. However, surgery might be considered first for a clearly resectable tumor when there is concern that the patient might not tolerate preoperative therapy, or if the preoperative staging evaluation suggests a T1/2N0 tumor. (See 'Our recommended approach' above.)

Perioperative chemotherapy — Pre- and postoperative systemic chemotherapy was extensively studied as a strategy to both improve chances of R0 (microscopically complete) resection and treat early micro-metastatic disease. In general, trials focused on two groups: distal esophagus/EGJ (upper tract) and EGJ/true gastric (lower tract). In each case, the EGJ 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 anatomic site of involvement.

●Upper tract trials – Two trials of preoperative chemotherapy for resectable esophageal cancer included those with EGJ primary sites. The Medical Research Council (MRC) OEO2 trial of surgery with or without preoperative cisplatin plus FU demonstrated a survival benefit for this approach [53,54]. The United States Intergroup trial 0113 (which used the same basic design) did not [55]. These trials are discussed in more detail elsewhere. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", 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 EGJ tumors; two showed a survival benefit (MAGIC and French FNLCC/FFCD trials [41,56]), while a third (EORTC trial 40954 [57]) did not. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Neoadjuvant/perioperative chemotherapy'.)

The following sections will review the data from these trials that are pertinent to EGJ and gastric cardia adenocarcinomas.

MAGIC trial — In the largest and most influential of these trials, the MRC MAGIC trial, 503 patients with potentially resectable gastric (74 percent), lower esophageal (15 percent), or EGJ adenocarcinomas (11 percent) were randomly assigned to surgery alone or surgery plus perioperative chemotherapy (three preoperative and three postoperative cycles of ECF (table 7)) [41].

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) [58]. 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 trial — 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), EGJ (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 [56]. 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 — EORTC trial 40954 randomly assigned 144 patients with locally advanced adenocarcinoma of the stomach or EGJ 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) [57]. 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.

FLOT4 — The phase II/III FLOT4-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 EGJ. The epirubicin-based group used the MAGIC approach. (See 'MAGIC trial' above.)

Two reports are available from this trial:

●In the open-label phase II part, the 300 patients with resectable gastric or EGJ adenocarcinoma treated with FLOT achieved a higher pathologic complete response rate (16 versus 8 percent) with lower toxicity [59]. 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 EGJ (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 [60]. 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.

ALLIANCE 80803 — For patients not receiving FLOT, support for neoadjuvant FOLFOX is provided by results from the phase II United States cooperative group trial, in which 257 patients with resectable esophageal or EGJ 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 [61]. 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.)

The results are summarized in the table (table 9). Notably, the pathologic complete response (pCR) rate in the PET responders who received initial FOLFOX was 40 percent while it was only 14 percent in the CP responders. 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.)

Meta-analysis — A survival benefit for neoadjuvant chemotherapy over surgery alone has been shown in at least two meta-analyses [62,63]. The latest individual patient data meta-analysis included 12 randomized comparisons of neoadjuvant chemotherapy versus surgery alone for thoracic esophageal or EGJ cancers [63]. The HR for all-cause mortality for neoadjuvant chemotherapy was 0.83 (95% CI 0.72-0.96), which translated into an absolute survival benefit at five years of 5.7 percent. In the subgroup analysis, for those studies where histology data were available, the HR for all-cause mortality favoring chemotherapy was more pronounced for EGJ tumors (HR 0.68, 95% CI 0.50-0.93) than for thoracic tumors (HR 0.87, 95% CI 0.75-1.0).

Is there an optimal regimen? — Our preferred options for perioperative chemotherapy include FOLFOX (as was used in ALLIANCE 80803), or CAPOX, or oxaliplatin plus S-1 (where available), or FU plus cisplatin as was used in the French FNLCC/FFCD and MRC trials, or, for fit patients, a docetaxel-containing triplet such as FLOT as was used in the FLOT4-AIO trial. 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, described above, and the MRC OEO2 trial [53], 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 on the MAGIC trial were able to receive three postoperative chemotherapy courses. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Neoadjuvant chemotherapy'.)

•Additional data are available from the ALLIANCE 80403 trial, in which 245 patients with previously untreated metastatic esophageal or EGJ 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 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 'ALLIANCE 80803' above and 'FLOT4' above.)

●Docetaxel-based triplet therapy versus a platinum/fluoropyrimidine combination – As noted above, the FLOT4 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 'FLOT4' above.)

Neoadjuvant concurrent CRT — With the goal of increasing both local control (higher pathologic complete response) and systemic control, preoperative and postoperative concurrent CRT have both been studied in randomized trials, many of which included patients with EGJ adenocarcinoma.

All of the trials that studied neoadjuvant CRT are upper gastrointestinal tract trials. Of the six randomized trials comparing preoperative concurrent CRT versus surgery alone that included patients with EGJ tumors, three (the Irish trial, the Dutch CROSS trial and CALGB 9781 [67-69]) showed a statistically significant OS benefit for CRT. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Concurrent chemoradiotherapy'.)

CROSS trial — The largest of the three trials, the Dutch CROSS trial, randomly assigned 363 patients with potentially resectable esophageal or EGJ cancer (86 SCC, 273 adenocarcinoma, four other; majority distal esophageal, 11 percent EGJ) to preoperative CRT versus surgery alone [68]. Preoperative treatment consisted of weekly paclitaxel (50 mg/m²) plus carboplatin (area under the curve [AUC] of concentration X time of 2) plus concurrent RT (41.4 Gy daily over five weeks).

Preoperative CRT was well tolerated. The only grade 3 or worse toxicity was leukopenia (7 percent). The R0 resection rate was higher with CRT (92 versus 65 percent), and 29 percent of those treated with CRT had a pathologic complete response (23 percent with adenocarcinoma, 49 percent in the SCC group). At a median follow-up of 32 months, in the adenocarcinoma cohort, median OS was better with preoperative CRT (HR for death 0.73, 95% CI 0.52-1.0).

The survival benefit persisted with longer follow-up (five-year survival 47 versus 33 percent, HR for death 0.67, 95% CI 0.51-0.87 [70]; ten-year survival 38 versus 25 percent, HR for death 0.70, 95% CI 0.55-0.89 [71]). In the latest analysis, although there was a clear effect of neoadjuvant chemoradiotherapy on reducing isolated locoregional and synchronous locoregional plus distant relapses, isolated distant relapse rates were not significantly different in the two groups [71].

Irish trial — In the smaller Irish trial, 58 patients with esophageal cancer (majority of tumors in the lower third of the esophagus and gastric cardia) were randomly assigned to surgery or CRT (two courses of preoperative cisplatin/5-FU and concurrent RT) [67]. The difference in three-year OS favoring multimodality therapy was statistically significant (32 versus 6 percent).

CALGB 9781 — In CALGB 9781, patients with esophageal cancer (77 percent adenocarcinoma) were randomly assigned to surgery with or without preoperative CRT (50.4 Gy external beam RT in 1.8 Gy daily fractions, five days per week, and concurrent cisplatin [100 mg/m² on days 1 and 29]) and infusional 5-FU (1000 mg/m² per day by continuous infusion for 96 hours, days 1 through 4 and 29 through 32, after cisplatin) [69]. Due to poor accrual, the study was closed prematurely after 56 patients were enrolled (42 adenocarcinoma; fraction EGJ not reported).

A pathologic complete response was achieved in 10 of 25 assessable patients in the trimodality arm (40 percent). Neither perioperative morbidity nor mortality was increased by preoperative therapy. Five-year OS favored trimodality therapy (39 versus 16 percent).

Three negative trials — By contrast, three other trials did not show a significant OS advantage for the neoadjuvant CRT. Two were underpowered (the Michigan trial [72], and a trial conducted jointly by the Trans-Tasman Radiation Oncology Group and the Australasian Gastro-intestinal Trials Group [73]). The third, FFCD 9901, was limited to patients with stage I and II disease, 30 percent of whom had adenocarcinomas. It showed increased perioperative mortality with preoperative treatment, and no improvement in long-term OS or R0 resection rates [74]. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Concurrent chemoradiotherapy'.)

Meta-analyses — Several meta-analyses support a survival benefit for neoadjuvant concurrent CRT compared with surgery alone for esophageal and EGJ cancer [62,75,76]. The most recent and largest included 12 randomized trials of neoadjuvant CRT (either concurrent or sequential) versus surgery and included the FFCD 9901, CALGB 9781, and CROSS trials [62]. The HR for all-cause mortality for neoadjuvant CRT was 0.78 (95% CI 0.70-0.88). This translated into an absolute survival benefit of 8.7 percent at two years. The number needed to treat to prevent one death was 11. The benefit was similar across histologic subtypes; for adenocarcinomas, the HR for all-cause mortality was 0.75, 95% CI 0.59-0.95, favoring neoadjuvant concurrent CRT. The potential benefit of neoadjuvant therapy was not offset by a higher postoperative mortality (in-hospital or 30-day postoperative death).

Meta-analyses of neoadjuvant CRT for esophageal cancer are discussed in more detail elsewhere. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Meta-analyses'.)

Is there an optimal regimen? — The optimal type, dose, combination, and schedule of drugs for use during concurrent CRT is not established. However, we generally prefer doublet rather than single-agent chemotherapy, even though no trials have evaluated single-agent CRT. Options for the concurrent chemotherapy regimen include two courses of cisplatin and FU as per the CALGB 9781 trial [69], or low-dose weekly carboplatin plus paclitaxel as was used in the Dutch CROSS trial (table 5) [77]. For most patients, we prefer the CROSS regimen because this is better tolerated (particularly with respect to mucositis) and easier to administer. RT to 50.4 Gy delivered in 28 fractions over 5.6 weeks using IMRT represents the standard dose, regardless of the concurrent chemotherapy regimen. The CALGB 9781 regimen is also reasonable (50.4 Gy external beam RT in 1.8 daily fractions, five days per week, with concurrent cisplatin [100 mg/m² on days 1 and 29] and infusional FU [1000 mg/m² per day by continuous infusion for 96 hours, on days 1 through 4 and 29 through 32, after cisplatin]) [69]. (See 'CROSS trial' above and 'CALGB 9781' above.)

The optimal neoadjuvant CRT regimen has not been established. There is no direct comparison between carboplatin/paclitaxel/RT and cisplatin/FU/RT. A network meta-analysis of 10 clinical trials comparing surgery alone versus neoadjuvant CRT for esophageal or EGJ cancer using either a taxane/platinum or platinum/FU (including the CROSS, Irish, and CALGB trials) came to the following conclusions [78]:

●Compared with surgery alone, the HRs (95% credible interval [CrI]) in the combined, squamous cell and adenocarcinoma populations were 0.63 (0.5-0.8), 0.50 (0.36-0.71), and 0.74 (0.54-1.01) for taxane/platinum and 0.79 (0.68-0.92), 0.82 (0.67-1.01), and 0.81 (0.63-1.05) for platinum/FU-based CRT, respectively. (See "Glossary of common biostatistical and epidemiological terms", section on 'Credible interval'.)

●In the indirect comparison using Bayesian network meta-analysis, taxane/platinum neoadjuvant CRT yielded significantly better OS when compared with platinum/FU, but only in those with SCC (HR 0.61, 95% CrI 0.41-0.91). However, the difference was not statistically significant in the combined population (HR 0.80, 95% CrI 0.60-1.06) or in those with adenocarcinoma (HR 0.91, 95% CrI 0.61-1.36).

●The probability of taxane/platinum CRT being the optimal treatment among the three treatments (surgery alone, taxane/platinum CRT, and platinum/FU CRT) was 94.2, 99.1, and 67.6 for the combined population, those with SCC, and those with adenocarcinoma, respectively.

CRT plus chemotherapy — A consistent finding in many studies is that response to preoperative therapy, particularly the absence of residual disease in the surgical specimen (ie, a pathologic complete response) is an indicator of better disease-free and OS [79-81]. These data provide the rationale for intensification of preoperative treatment using induction chemotherapy plus neoadjuvant chemoradiotherapy (CRT), or using combinations of drugs with greater radiosensitizing potential during concurrent CRT. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Intensification of preoperative therapy'.)

Early results from trials examining the benefit of preoperative treatment intensification are encouraging, but whether the added toxicity is counterbalanced by substantial survival gains is unclear. Phase III trials are needed to confirm the benefit of these more toxic approaches over more standard regimens, such as cisplatin/FU or carboplatin/paclitaxel concurrent with RT. This subject is discussed in more detail elsewhere. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Intensification of preoperative therapy'.)

Neoadjuvant CRT versus chemotherapy alone — At least four trials have directly compared neoadjuvant chemotherapy with chemoradiotherapy (CRT), and they all came to similar conclusions: histologic response rates and rates of margin-negative resections generally favor CRT, but no trial demonstrated improved OS. Given the possibility that there may be a small survival benefit, the higher rates of R0 resection seen in all four trials, and the high rates of local failure with chemotherapy alone that were seen in the PreOperative Chemotherapy or Radiochemotherapy in Esophagogastric Adenocarcinoma (POET) trial, we suggest preoperative CRT rather than perioperative chemotherapy for most patients with cT3 or higher, node-positive, or borderline resectable EGJ tumors.

Four trials have compared neoadjuvant CRT with chemotherapy in patients with esophageal or EGJ cancers; however, there are differences in the type, sequence, and duration of chemotherapy.

●The multicenter German POET trial was the first attempt at a randomized study limited exclusively to patients with adenocarcinomas of the EGJ [48]. It is also the only phase III trial that directly compared neoadjuvant CRT with chemotherapy alone, with the caveat that induction chemotherapy was given before CRT.

Patients with locally advanced (endoscopic ultrasonography [EUS]-staged T3-4NXM0) adenocarcinoma of the lower esophagus, EGJ, or gastric cardia were randomly allocated to two treatments: (1) neoadjuvant chemotherapy (15 weeks of cisplatin 50 mg/m² once every other week; 5-FU 2000 mg/m² over 24 hours weekly plus leucovorin 500 mg/m² over two hours weekly) or (2) induction chemotherapy plus CRT (12 weeks of the same cisplatin, leucovorin, and 5-FU regimen followed by three weeks of concurrent CRT), both followed by surgery. Concurrent CRT consisted of RT (30 Gy in daily 2 Gy fractions over three weeks concurrent with cisplatin 50 mg/m² days 1 and 8 and etoposide 80 mg/m² on days 3 through 5). The study closed due to poor accrual after only 126 of the planned 354 patients were randomized.

There was a trend toward higher postoperative mortality rates in patients who received CRT (10.2 versus 3.8 percent; p = 0.26). The rate of R0 resection was similar with CRT and chemotherapy (72 versus 70 percent), but the pathologic complete response rate was higher with CRT (16 versus 2 percent, p = 0.03), as was the rate of negative lymph nodes (64 versus 38 percent, p = 0.01). At a median follow-up of 46 months, there was a trend toward improved three-year survival with CRT (47 versus 28 percent; p = 0.07). In a report of longer-term follow-up, more patients were alive at five years in the CRT group, but the difference was not statistically significant (40 versus 24 percent, HR 0.65, 95% CI 0.42-1.01) [82].

The local failure rate in the chemotherapy alone group was high (41 percent) which is a finding reported by many others (although not all) when radiation was not a component of trimodality therapy [55]. 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 [41]. (See 'MAGIC trial' above.)

●Two other trials enrolled a mix of patients with esophageal and EGJ tumors, and both reached similar conclusions:

•In a multicenter phase III Swedish trial, 181 patients with cancer of the esophagus or EGJ (84 percent distal esophagus/EGJ, 27 percent SCC) were randomly assigned to preoperative chemotherapy (three 21-day cycles of cisplatin 100 mg/m² on day 1 plus 5-FU 750 mg/m² over 24 hours per day, days 1 to 5) with or without RT (40 Gy in daily 2 Gy fractions, administered concomitant with cycles 2 and 3 of chemotherapy) [83]. CRT had significantly higher rates of pathologic complete response (28 versus 9 percent, p = 0.002) and R0 resection (87 versus 74 percent, p = 0.04), and a lower rate of positive lymph nodes (35 versus 62 percent, p = 0.001). These differences did not translate into significantly better three-year OS (47 versus 49 percent) or progression-free survival (44 percent in both groups).

•There is also a randomized phase II Australian trial that accrued 75 patients with adenocarcinoma of the esophagus or EGJ who were randomized to two courses of cisplatin plus 5-FU (days 1 and 21) or the same regimen (with slightly reduced 5-FU dose on day 21) plus concurrent RT (35 Gy in 15 fractions over three weeks starting on day 21). Although the histopathologic response rate and rate of margin-negative resections favored CRT, median OS was not significantly better (32 versus 29 months) [84].

●Four meta-analyses of these three trials have been conducted. Three found no survival benefit for CRT over chemotherapy [47,76,85]. The fourth, a 2018 network meta-analysis that included these three trials plus one other, did find an OS benefit for neoadjuvant CRT over neoadjuvant chemotherapy (HR for death 0.83, 95% CI 0.70-0.96 [86,87]). However, the risk of postoperative mortality was also higher with CRT (HR 1.58, 95% CI 1.0-2.49).

●A fourth trial, the NEO-AEGIS trial, directly compared the CROSS chemoradiotherapy regimen with perioperative chemotherapy (modified ECF as used in the MAGIC trial or FLOT) in 362 patients with adenocarcinoma of the esophagus or EGJ [88]. In a preliminary report, presented at the 2021 annual ASCO meeting (median follow-up 25 months), CRT was associated with higher rates of R0 resection (95 versus 82 percent), higher pathologic complete response rate (16 versus 5 percent), and more patients with pathologically node-negative disease (60 versus 45 percent) but this did not translate into better three-year survival (56 versus 57 percent, HR 1.02, 95% CI 0.74-1.42), the primary endpoint. Mature data are awaited.

●Additional information will also emerge from the TOPGEAR trial, which directly compares preoperative chemotherapy (ECF) versus CRT (two cycles of ECF followed by concurrent fluoropyrimidine-based CRT) in patients with resectable adenocarcinoma of the stomach and EGJ. Both groups received three cycles of adjuvant ECF. Early results show no difference in treatment-related toxicity, the fraction of patients who undergo surgery, or surgical complications [89].

PET-directed therapy — We order a postinduction integrated fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (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. This approach is also endorsed in the consensus-based NCCN guidelines [52]. If a new lesion is identified, a biopsy is performed. PET-directed changes during the neoadjuvant therapy regimen cannot yet be considered a standard approach.

Integrated FDG-PET/CT detects distant metastases in approximately 8 percent of patients following induction CRT [90]. 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 [91]. These postinduction therapy findings may not apply to patients who have undergone initial staging with integrated FDG-PET/CT scans, which are now 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 [92-95]. As an example, the phase II MUNICON study showed in patients with adenocarcinomas of the esophagus or EGJ that PET scanning two weeks into neoadjuvant chemotherapy showed that metabolic responders had a significantly better prognosis than nonresponders [92]. 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 [96-102], 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 EGJ 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 [103]. PET responders continued the same chemotherapy regimen during subsequent CRT, while nonresponders crossed over to the other chemotherapy regimen with CRT [61]. The pathologic complete response 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 9). 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 9) 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 overall survival in PET nonresponders was not significantly worse than that of PET responders (27.4 versus 48.8 months, p = 0.107) 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 cannot yet be considered a standard 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 numbers 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 [104-106]) 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 any residual disease in the surgical specimen after initial chemoradiotherapy (CRT), we suggest adjuvant nivolumab. For patients without access to nivolumab, our approach to patients who have residual nodal disease is to administer adjuvant chemotherapy with different agents than those given preoperatively (eg, FOLFOX if the initial CRT regimen included only 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 EGJ 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 [107]. Enrollment was irrespective of programmed death receptor-1 ligand 1 (PD-L1) overexpression. Tumor site was esophagus in 60 percent and EGJ 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). Overall survival 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 chemoradiotherapy following complete resection of esophageal or gastroesophageal junction cancer with residual pathologic disease. This approach was also endorsed by a year 2021 updated ASCO guideline on the treatment of patients with locally advanced esophageal carcinoma [108].

●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 [41,42,109,110]. 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 — Our approach is consistent with that of the NCCN [52], which advocates postoperative CRT or the same chemotherapy as was used preoperatively for patients who have residual node-positive or pT3 disease after preoperative chemotherapy. Whether there is a benefit for checkpoint inhibitor immunotherapy in patients undergoing perioperative chemotherapy alone is uncertain, and is under investigation in KEYNOTE trial 585.

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 the Dutch CRITICS (ChemoRadiotherapy after Induction chemoTherapy In Cancer of the Stomach) trial. All patients with potentially resectable gastric cancer received induction chemotherapy followed by surgery then were randomized to postoperative chemotherapy versus CRT. Patients with EGJ 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, p = 0.90) [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]. The next trial (CRITICS II) will evaluate three preoperative strategies: chemotherapy, CRT, and a combination of chemotherapy and CRT.

Patients who undergo surgery first

Indications and choice for adjuvant therapy — For patients with completely resected pT2N1-2, pT3, or T4 EGJ 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 EGJ 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 [42,114] is reasonable. (See 'Adjuvant CRT' below.)

The optimal management of pT2N0 tumors 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. This approach is consistent with guidelines from the NCCN [52].

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

Intergroup trial 0116 — The most influential trial is United States Intergroup study 0116, which randomly assigned 556 patients with potentially curatively resected T1 to T4, N0 or N1 gastric or EGJ adenocarcinoma (20 percent) to observation or adjuvant-combined CRT [42]. Treatment consisted of one cycle of 5-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 5-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 (5-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, p = 0.005) 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 EGJ 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 elsewhere. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Adjuvant chemoradiotherapy'.)

These results changed the standard of care in the United States for patients undergoing potentially curative resection of stage IIA or higher gastric cancer (table 10) from observation alone to adjuvant CRT. While this approach is still used, in the United States, EGJ 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 concurrent CRT' above and 'Perioperative chemotherapy' above.)

CALGB 80101 — As noted above, the MAGIC trial demonstrated a significant survival benefit for the use of perioperative chemotherapy with ECF versus surgery alone. (See 'MAGIC trial' 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 EGJ tumors that extended beyond the muscularis propria or were node positive [115]. The percentage with EGJ 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 elsewhere. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Adjuvant chemoradiotherapy'.)

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

The ARTIST trial — 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 elsewhere [114]. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Adjuvant chemoradiotherapy'.)

Adjuvant chemotherapy — There are no randomized trials exploring the benefit of adjuvant chemotherapy in patients with esophageal or EGJ adenocarcinoma. The CLASSIC trial and several meta-analyses support adjuvant chemotherapy in gastric cancer, with some trials including patients with EGJ 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), EGJ (n = 34), or gastric cardia (n = 12) tumors [116]. 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 [117].

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, p <0.001).

●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 EGJ tumors (2.3 percent of the total enrolled) [118]. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Choice of regimen'.)

Chemotherapy versus chemoradiotherapy — All of the trials directly comparing adjuvant chemotherapy with chemoradiotherapy (CRT) are lower gastrointestinal tract (gastric) trials; some, like the Dutch CRITICS trial, enrolled a minority of patients with proximal gastric/EGJ 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 elsewhere. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Adjuvant chemoradiotherapy'.)

PATIENTS WITH CLINICAL T1/2, NODE-NEGATIVE DISEASE — The benefit of neoadjuvant therapy for patients with cT1-2N0 EGJ adenocarcinoma is unclear. Current trials of the Eastern Cooperative Oncology Group (ECOG) permit the enrollment of patients with cT2N0 cancer onto neoadjuvant trials, and neoadjuvant chemoradiotherapy (CRT) is an option, especially for those with adverse features on biopsy (eg, poorly differentiated tumors, lymphovascular invasion), who are sometimes upstaged if they proceed directly to esophagectomy. However, for most patients, we suggest upfront surgery, or definitive CRT for patients who are not surgical candidates, an approach is consistent with year 2020 American Society of Clinical Oncology (ASCO) guidelines [47]. On the other hand, updated ESMO guidelines suggest resection for cT1 disease, but recommend upfront chemotherapy or chemoradiotherapy for those with cT2N0 disease [119].

Data comparing endoscopic mucosal resection versus esophagectomy or definitive CRT for superficial (cT1N0) esophageal cancers are discussed elsewhere. (See "Management of superficial esophageal cancer".)

For patients who undergo upfront surgery and are found to have ≥T2 or node-positive cancer in the pathologic specimen, adjuvant therapy should be discussed. (See 'Indications and choice for adjuvant therapy' above.)

As noted above, most of the data on definitive CRT for esophageal cancer are in patients with squamous cell cancer (SCC). There are fewer data for adenocarcinoma, and pathologic complete response rates after CRT are lower for adenocarcinoma as compared with SCC. However, the potential for cure without surgery is supported by RTOG 0436, which compared cetuximab plus platinum/taxane and radiation therapy (RT) with the same CRT regimen alone [51]. Patients with adenocarcinoma (62 percent of those enrolled) had a median overall survival of 19.7 months, which was similar to those with SCC. Given that this trial predominantly enrolled patients with clinical T3/4 (81 percent) or node-positive disease (66 percent), outcomes might be expected to be better with clinical T1/2N0 disease. (See 'Definitive CRT and necessity for surgery' above.)

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 locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'HER2-overexpressing adenocarcinomas'.)

There are emerging data on the safety and potential benefit of combining trastuzumab with cytotoxic chemotherapy in the perioperative setting for potentially resectable EGJ 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/RTOG 1010 trial, 203 HER2+ patients with newly diagnosed T1N1-2, T2-3N0-2 adenocarcinomas of the mid or distal esophagus, EGJ or stomach (within 5 cm of the EGJ) were all treated with radiation therapy (50.4 Gy) plus weekly paclitaxel plus carboplatin, followed five to eight weeks later by resection; those randomized to trastuzumab also received trastuzumab weekly during chemoradiotherapy (CRT), a loading dose just prior to surgery, and then postoperative maintenance trastuzumab every three weeks for 13 treatments [120]. 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 — Between 3 and 22 percent of gastric cancers have deficiency in mismatch repair (dMMR), the biologic footprint of which is high levels of microsatellite instability (MSI-H). Among patients with advanced esophagogastric cancer, dMMR/MSI-H status predicts potential benefit from immune checkpoint inhibitor immunotherapy. (See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Deficient mismatch repair' and "Second and later-line systemic therapy for advanced unresectable and metastatic esophageal and gastric cancer", section on 'Defective mismatch repair'.)

Interest in neoadjuvant immunotherapy was prompted by an individual patient data meta-analysis of four randomized trials of perioperative therapy in patients with resectable esophagogastric cancer (MAGIC, CLASSIC, ARTIST, and ITACA-S [41,114,118,121]), which found that individuals with early stage dMMR/MSI-H tumors derived little benefit from either neoadjuvant or adjuvant chemotherapy, and actually did worse than those undergoing surgery alone [122].

Early data on neoadjuvant immunotherapy are available from the phase II NEONIPIGA trial, in which 32 patients with gastric (n = 16) or EGJ dMMR adenocarcinomas received six infusions of nivolumab (240 mg IV every two weeks) and two infusions of ipilimumab (1 mg/kg every six weeks) [123]. In a preliminary report, of the 29 who proceeded to surgery a median of 35 days (range 25 to 170) after the last infusion of nivolumab, all had microscopically complete (R0) resection, and 17 (59 percent) achieved a pathologic complete response (pCR).

While exciting, additional follow-up and randomized trials comparing this approach to perioperative chemotherapy are needed before it can be conclude that neoadjuvant immunotherapy is a preferred approach for patients with dMMR gastric or EGJ 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) [52], 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 (CBC) 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 locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'HER2-overexpressing adenocarcinomas'.)

Some clinicians check tumor markers (particularly carcinoembryonic antigen [CEA]) with each follow-up visit, if initially elevated, and perform restaging computed tomography (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 [124,125]. In keeping with this point of view, consensus-based guidelines from 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 [119]. They advise that follow-up visits concentrate on symptoms, nutrition, and psychosocial support. In the case of a complete response to 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.

DRUG SHORTAGES — There may be any number of cancer therapies in short supply at various times. Guidance in the setting of drug shortages has been provided by the American Society of Clinical Oncology (table 11).

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

●Definition and classification

•Tumors involving 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). (See 'AJCC classification' above.)

•The diagnosis of an EGJ or gastric cardia carcinoma is usually established by endoscopic biopsy, and staging requires a contrast-enhanced helical computed tomography (CT) scan; selected patients undergo endoscopic ultrasonography (EUS) integrated fluorodeoxyglucose positron emission tomography (FDG-PET)/CT, and diagnostic laparoscopy. (See 'Pretreatment staging evaluation' above and 'Diagnostic laparoscopy' above.)

●Initial surgery versus neoadjuvant therapy

•For patients with clinical T1-2N0 EGJ adenocarcinomas, we suggest initial surgery rather than neoadjuvant therapy (Grade 2C). For patients who are not surgical candidates, definitive chemoradiotherapy (CRT) is an alternative. (See 'Patients with clinical T1/2, node-negative disease' above.)

•For most other patients, we suggest neoadjuvant therapy rather than initial surgery (Grade 2B). However, initial surgery might be considered first for a clearly resectable tumor when there is concern that the patient might not tolerate preoperative therapy. (See 'Patients not yet resected' above.)

For patients who are not surgical candidates, definitive chemoradiotherapy (CRT) is an alternative. (See 'Definitive CRT and necessity for surgery' above.)

●Patients receiving neoadjuvant therapy

•CRT versus chemotherapy – If neoadjuvant therapy is chosen, we suggest preoperative CRT rather than chemotherapy for most patients who can tolerate the combined modality approach (Grade 2C). (See 'Neoadjuvant CRT versus chemotherapy alone' above.)

-The optimal type, dose, combination, and schedule of drugs for use during concurrent CRT is not established. For most patients, we suggest low-dose weekly carboplatin and paclitaxel (table 5) rather than other regimens (Grade 2C). A reasonable alternative is two courses of cisplatin and infusional fluorouracil (FU) (table 6). (See 'CALGB 9781' above and 'CROSS trial' above and "Treatment protocols for esophagogastric cancer".)

-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 "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'Technique for preoperative RT'.)

-Initial chemotherapy is a reasonable alternative for patients who cannot tolerate trimodality therapy or if there is a high clinical suspicion of occult metastatic disease. (See 'Perioperative chemotherapy' above.)

If neoadjuvant chemotherapy is chosen, an optimal regimen has not been established. Reasonable options include a docetaxel-containing triplet regimen such as FLOT (table 12) for relatively young and fit patients, oxaliplatin plus leucovorin and short-term infusional FU (FOLFOX, (table 13) or CAPOX (table 14), oxaliplatin plus S-1 (where available), or infusional FU plus cisplatin. For most patients we suggest using one of these regimens rather than an epirubicin-containing regimen such as epirubicin, cisplatin, and FU (ECF) (table 7), or epirubicin plus cisplatin and capecitabine (ECX) (table 8)(Grade 2C). (See 'Is there an optimal regimen?' above.)

-We perform postinduction therapy integrated PET/CT no earlier than four weeks after the completion of induction therapy to assess for distant metastatic disease. PET-directed changes during neoadjuvant therapy cannot yet be considered a standard approach. (See 'PET-directed therapy' above.)

-Resection is generally considered integral to achieving the best outcomes. Surgical approach is based on tumor location. Minimally invasive techniques are preferred, where local expertise is available. (See "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Principles of surgical resection'.)

•Management of residual disease

-For patients with any residual disease in the surgical specimen after initial CRT, we suggest adjuvant nivolumab (Grade 2B). For patients without access to nivolumab who have residual nodal disease we suggest adjuvant chemotherapy with different agents than those given preoperatively (Grade 2C). (See 'After CRT' above.)

-For patients 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 pathologic complete response to initial neoadjuvant chemotherapy. In this setting, we reserve postoperative RT for cases with a histologically positive resection margin. (See 'After chemotherapy alone' above.)

●Indications for adjuvant therapy after initial surgery

•For patients 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.)

●Post-treatment surveillance – We generally follow consensus-based guidelines for post-treatment surveillance from the 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.