INTRODUCTION — Cancers of the upper gastrointestinal tract are highly lethal malignancies. Locally advanced, unresectable, and metastatic esophagogastric cancers are not curable, and the goals of therapy are symptom palliation and prolongation of survival. Palliative modalities for advanced esophagogastric cancer can be either local or systemic. While systemic therapy is the most effective treatment modality for patients with metastatic disease and it may adequately palliate dysphagia and other symptoms, such as nausea, pain, obstruction, perforation, or bleeding from a locally advanced or locally recurrent primary tumor, it often requires multidisciplinary management using endoscopic, surgical, radiotherapeutic, or other approaches. (See "Local palliation for advanced gastric cancer" and "Endoscopic palliation of esophageal cancer".)

This topic review will cover initial systemic therapy for advanced, unresectable, and metastatic esophagogastric cancer. The choice of treatment for later lines of therapy for progressive, locally advanced, and metastatic disease; neoadjuvant strategies for locoregionally advanced but potentially resectable esophageal and gastric cancer; local methods for palliation in patients with advanced disease; and hepatic metastasectomy for the rare patient with isolated gastric cancer liver metastases are discussed separately. (See "Progressive, locally advanced unresectable, and metastatic esophageal and gastric cancer: Approach to later lines of systemic therapy" and "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus" and "Local palliation for advanced gastric cancer" and "Endoscopic palliation of esophageal cancer" and "Surgical management of invasive gastric cancer", section on 'Metastasectomy'.)

HISTOLOGY, ANATOMIC DISTRIBUTION, AND EVOLUTION OF CHEMOTHERAPY STRATEGY — Together, squamous cell cancer (SCC) and adenocarcinoma account for 93 percent of all esophageal carcinomas, but histologic and anatomic distribution has changed dramatically over the past 30 years [1]. In the 1970s, SCC accounted for approximately 70 percent of all esophageal cancers, and 22 percent of tumors were located in the upper one-third of the thoracic esophagus or in the cervical esophagus. Since the mid-1970s, the incidence of SCC in the United States has been declining steadily, while the incidence of adenocarcinoma in White male patients rose by 350 percent from 1974 to 1994. Adenocarcinoma surpassed SCC as the dominant histology in the early 1990s [2]. At the same time, there has also been a shift in the location of esophageal cancers over time. At present, 86 percent of esophageal cancers arise in the distal one-third of the thoracic esophagus, 13 percent arise in the middle third, and only 1 percent arise in the upper third or cervical esophagus. (See "Epidemiology and pathobiology of esophageal cancer".)

More than 90 percent of stomach cancers are adenocarcinomas. In 1930, most cases originated in the distal stomach (gastric body and antrum (figure 1)). Since then, the incidence of distal gastric carcinoma has declined dramatically, while the incidence of adenocarcinoma of the esophagogastric junction (EGJ) and proximal stomach has increased at a rate exceeding that of any other cancer [3]. The increasing incidence has paralleled the rise in incidence of esophageal adenocarcinoma. The term "EGJ tumor" reflects the frequent difficulty in separating the primary locations of distal esophageal and proximal gastric cancers; their natural history, response to therapy, and overall prognosis appear to be similar [4]. (See "Epidemiology of gastric cancer".)

Chemotherapy drugs that were tested for esophageal cancer at a time when SCC was the predominant histology (1970s and 1980s) were those initially developed for SCC of the head and neck, including fluorouracil (FU), cisplatin, mitomycin, methotrexate, vindesine, and bleomycin. The combination of FU plus cisplatin was adopted by many as a safe and effective standard regimen, and studies focused on the benefit of adding a third agent to the FU plus cisplatin backbone.

At the other end of the spectrum, at a time when distal gastric adenocarcinomas were the most common stomach malignancy, most regimens for advanced gastric cancer were based on FU plus an anthracycline. Cisplatin-based combinations (such as epirubicin, cisplatin, and infusional FU) were eventually shown to be superior to non-cisplatin-containing regimens and became the reference regimens for advanced gastric cancer. (See 'Epirubicin, cisplatin, and fluorouracil' below.)

Coincident with the epidemiologic changes in histologic and anatomic distribution, the treatment of advanced gastric and esophageal cancers converged, and the majority of clinical trials conducted since the mid-1990s include patients with gastric, esophageal, or EGJ cancer, regardless of histology [5,6]. Although SCCs now represent a small minority of patients enrolled in most clinical trials, histologic subtype did not appear to play a major role in response rate or survival duration in patients treated with a variety of cytotoxic chemotherapy regimens for metastatic esophagogastric cancer [7-12].

However, this is changing as differences in genomic alterations in biologic pathways between SCC and adenocarcinoma are beginning to be elucidated [13]. Treatment for SCC and adenocarcinoma has diverged once again with the introduction of molecularly directed therapy and immunotherapy. Therapies targeting human epidermal growth factor receptor 2 (eg, trastuzumab) and vascular endothelial growth factor (eg, ramucirumab) are applicable only to adenocarcinomas. Immunotherapy approaches using immune checkpoint inhibitors appear to be effective for SCC regardless of expression of the programmed cell death ligand 1 (PD-L1), whereas benefits in adenocarcinomas that have low-level or no PD-L1 overexpression are uncertain. (See 'Choice of therapy and the importance of biomarker assessment' below and "Progressive, locally advanced unresectable, and metastatic esophageal and gastric cancer: Approach to later lines of systemic therapy", section on 'Ramucirumab'.)

APPROACH TO FIRST-LINE THERAPY

Goals of therapy — The goals of chemotherapy in patients with advanced esophagogastric cancer are to palliate symptoms (including malignant dysphagia), improve quality of life, and prolong survival. A number of controlled trials and meta-analyses provide evidence for the survival benefit of palliative systemic chemotherapy for patients with advanced gastric cancer [14-20]. In one meta-analysis of three trials comparing chemotherapy with best supportive care, there was a significant benefit in overall survival in favor of chemotherapy compared with supportive care alone (hazard ratio [HR] 0.3, 95% CI 0.24-0.55), which translated into an improvement in median survival from 4.3 to 11 months [18].

Importance of early supportive care — All patients with newly diagnosed advanced gastric cancer should have a full assessment of symptom burden, nutritional and psychological status, and social supports as early as possible, ideally, prior to starting systemic chemotherapy. Many patients will benefit from formal palliative care consultation and services. Early referral and initiation of interdisciplinary and palliative care services improve clinical and quality of care outcomes, including survival. (See "Benefits, services, and models of subspecialty palliative care", section on 'Rationale for palliative care'.)

Because of the anatomy, and complications from surgery or local disease progression, patients with advanced esophagogastric cancer have a high incidence of malnutrition [21,22], and psychologic distress [23,24], both of which may impair survival.

Several therapeutic options are available to control symptoms of local disease progression (eg, nausea, pain, gastric outlet obstruction, bleeding), including palliative surgical resection, surgical bypass (gastrojejunostomy), radiation therapy (RT), and endoscopic techniques. Decision-making for local palliative therapy must take into account the overall prognosis of the patient in order to avoid excessive morbidity and mortality or lengthy hospital stays in those with a limited life span. (See "Local palliation for advanced gastric cancer".)

The benefit of early interdisciplinary supportive care was shown in a trial in which 328 patients with previously untreated metastatic esophagogastric cancer were randomly assigned to early interdisciplinary care with a focus on nutrition and psychological health integrated into standard oncologic care or standard care [25]. The intervention group received an interdisciplinary supportive care consultation within 14 days of initiating chemotherapy, and a follow-up consultation every three weeks thereafter. Median overall survival was significantly better in the early intervention group (14.8 versus 11.9, HR 0.68, 95% CI 0.51-0.9). Despite similar distribution, responses, and safety profiles of systemic therapy in the two groups, early supportive care also had a significant positive impact on emotional and cognitive functioning at week 9, and on the proportion of patients presenting with weight loss at week 9 (45 versus 58 percent).

Choice of therapy and the importance of biomarker assessment — Several cytotoxic agents are active against esophageal and gastric cancer, including fluoropyrimidines, platinum agents (cisplatin, oxaliplatin), taxanes (paclitaxel, docetaxel), and irinotecan. However, biomarker assessment has become critically important for selecting the initial approach to systemic therapy, particularly for adenocarcinomas:

●Trastuzumab is an active agent for first-line therapy, in combination with cytotoxic chemotherapy, for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing tumors. (See 'HER2-overexpressing adenocarcinomas' below.)

●First-line therapy with an immune checkpoint inhibitor in combination with cytotoxic chemotherapy has now been shown to improve outcomes over cytotoxic chemotherapy alone for adenocarcinomas with tumoral overexpression of programmed cell death ligand 1 (PD-L1) and a combined positive score (CPS) of 5 or more, as well as for those that are deficient in mismatch repair (dMMR).

First-line therapy with an immune checkpoint inhibitor has also been shown to improve outcomes over cytotoxic chemotherapy alone for patients with squamous cell cancers (SCCs). The role of PD-L1 overexpression in this subgroup is evolving, but increasing evidence suggests that PD-L1 overexpression may be a predictor of efficacy in SCC. (See 'Patients unselected for biomarkers' below.)

All patients with unresectable, locally advanced, recurrent, or metastatic esophagogastric adenocarcinoma who are potential candidates for trastuzumab should have their tumors assayed for HER2 overexpression and/or gene amplification using specific criteria developed for esophagogastric adenocarcinomas. (See 'Assessment of HER2 status and selection of candidates for trastuzumab' below.)

In addition, all patients should have their tumors assayed for dMMR/high levels of microsatellite instability (MSI-H), and overexpression of PD-L1, with reporting out of individual expression levels (ie, CPS 0 to 4, versus 5, versus 10 or more). (See 'PD-L1-overexpressing adenocarcinomas' below.)

We base our treatment decisions on biomarker expression and histology, as outlined in the following sections, and summarized in the algorithm (algorithm 1).

Squamous cell cancers — For advanced SCCs, regardless of PD-L1 overexpression, we suggest first-line therapy with chemotherapy plus immunotherapy rather than chemotherapy alone, based upon the CheckMate 648, the KEYNOTE-590 trial, and the ESCORT-1^st trials. Although the chemotherapy backbone in CheckMate and KEYNOTE studies was cisplatin plus fluorouracil (FU), many clinicians, including some of the authors and editors associated with this topic review, would prefer pembrolizumab or nivolumab in combination with an oxaliplatin-based regimen such as oxaliplatin plus leucovorin with bolus plus short-term FU (FOLFOX). Where available (mainly China), camrelizumab in combination with paclitaxel and cisplatin is an appropriate alternative. (See 'Patients unselected for biomarkers' below.)

Adenocarcinomas

HER2-overexpressing tumors — For patients with human epidermal growth factor receptor 2 (HER2)-overexpressing adenocarcinomas (as defined by 3+ immunohistochemistry staining or fluorescence in situ hybridization positivity), we suggest the addition of trastuzumab to a platinum-based cytotoxic chemotherapy backbone, as long as there is no contraindication to trastuzumab. Based upon preliminary results of the KEYNOTE-811 trial, we also suggest adding pembrolizumab to initial trastuzumab plus platinum-based chemotherapy in these patients. (See 'HER2-overexpressing adenocarcinomas' below.)

Patients with deficient mismatch repair — For patients with dMMR/MSI-H tumors, most of which have PD-L1 overexpression, we suggest nivolumab or pembrolizumab plus cytotoxic chemotherapy rather than systemic chemotherapy alone. Pembrolizumab monotherapy is another option. (See 'Deficient mismatch repair' below.)

HER2-negative, PD-L1-positive, pMMR adenocarcinomas — Options for patients with human epidermal growth factor receptor 2 (HER2)-negative, programmed cell death ligand 1 (PD-L1)-overexpressing (CPS 5 or more) adenocarcinomas with proficient mismatch repair (pMMR) include combined therapy with an immune checkpoint inhibitor (nivolumab or pembrolizumab) plus cytotoxic chemotherapy or pembrolizumab alone.

●First-line pembrolizumab is an option for patients whose tumors have high levels of PD-L1 expression with a CPS ≥10. However, we would only pursue this approach for patients without bulky symptomatic tumors because of the low expected objective response rate with pembrolizumab alone. (See 'Pembrolizumab monotherapy' below.)

●For other patients with a CPS ≥5, including those with bulky symptomatic tumors, we suggest nivolumab plus cytotoxic chemotherapy (FOLFOX) rather than chemotherapy alone for first-line therapy, based upon data from the CheckMate 649 study [26]. (See 'Combined immunotherapy plus chemotherapy' below.)

Pembrolizumab plus oxaliplatin-based chemotherapy is another option for patients with CPS ≥10; in the KEYNOTE-590 trial, there was no benefit for the addition of pembrolizumab to chemotherapy for those with CPS <10 in the pooled adenocarcinoma/SCC population. (See 'Patients unselected for biomarkers' below.)

●The benefits of immunotherapy for adenocarcinomas with low-level or no expression of PD-L1 remain uncertain. Although opinion differs, especially with regard to CPS 1 to 4, we suggest initial chemotherapy rather than immunotherapy in these patients, unless they have dMMR/MSI-H tumors.

Other adenocarcinomas — Despite a large number of randomized trials, there is no globally accepted, standard first-line regimen in advanced HER2-negative, pMMR, PD-L1-non-overexpressing adenocarcinomas:

●For most patients, cytotoxic chemotherapy alone is the preferred approach, especially for patients with a contraindication to immunotherapy or if reimbursement is limited. In general, when cytotoxic chemotherapy is being considered, combination chemotherapy regimens provide higher response rates than do single agents, but this translates into only modestly longer durations of disease control and survival, which are measured in weeks to a few months, and a worse side effect profile. (See 'Combination chemotherapy' below and 'Is there an optimal combination regimen?' below.)

Participation in a clinical trial is preferred. If a trial is not available, or participation is not feasible, for most patients, we suggest a fluoropyrimidine-platinum doublet over a triplet regimen. For most patients, we prefer an oxaliplatin-containing regimen (ie, FOLFOX (table 1), oxaliplatin plus capecitabine, or where available, S-1 plus oxaliplatin). Other alternatives include FU plus cisplatin (or where available, S-1 plus cisplatin). (See 'Oxaliplatin combinations' below.)

For older patients or those with a poor performance status, appropriate alternatives include leucovorin-modulated FU alone, single-agent capecitabine, single-agent irinotecan, dose-attenuated capecitabine plus oxaliplatin, or low-dose weekly taxanes. (See 'Single-agent chemotherapy' below.)

●In our view, a role for first-line immune checkpoint inhibitor immunotherapy plus chemotherapy in PD-L1-negative adenocarcinomas is not yet proven, and this approach cannot be recommended. Although patients with adenocarcinoma were included in the KEYNOTE-590 trial of cisplatin plus FU with or without pembrolizumab, the benefits of combined immunotherapy plus chemotherapy were predominantly driven by the subgroup with SCC, and a survival benefit for patients with adenocarcinoma was not evident. Furthermore, the ATTRACTION-4 trial of oxaliplatin plus either capecitabine or S-1 with or without nivolumab was conducted entirely in Asian patients, and Asian patients appear to have superior outcomes from immune checkpoint inhibitors as compared with North American, European, and Australian patients [27]. (See 'Patients unselected for biomarkers' below.)

Response assessment and duration of therapy — Response is assessed using a combination of interval radiographic evaluation (typically every two to three cycles); serum tumor markers, such as carcinoembryonic antigen (if elevated at baseline); and the clinical status of the patient. Radiographic tumor response is usually quantified using Response Evaluation Criteria in Solid Tumors (table 2) [28,29].

If tumor markers are elevated at initial evaluation, they can be serially assessed during treatment as a surrogate measure of response to therapy. While persistently rising levels of a serum tumor marker suggest disease progression, this should be confirmed with radiologic studies prior to a change in therapeutic strategy. (See "Clinical features, diagnosis, and staging of gastric cancer", section on 'Serologic markers'.)

The patient's clinical status should always be taken into consideration in combination with radiologic and tumor marker data, where patients with clinical benefit from treatment may stay on that treatment regimen despite possible radiologic progression.

The duration of treatment in responding patients with advanced esophagogastric cancer has not been specifically studied. There are only limited data that pertain to discontinuation of a treatment regimen prior to disease progression or on modified maintenance therapy regimens. In one small randomized phase II trial that compared a "stop and go" strategy with continuous therapy following disease stabilization with first-line S-1 plus oxaliplatin, patients who continued chemotherapy beyond disease stabilization had better progression-free survival (10.5 versus 7.2 months); however, overall survival and the duration of disease control were not significantly better, and quality of life was worse [30].

In general, regimens are given until the patient has progressive disease or cannot tolerate further treatment with the regimen. We recommend that each patient's treatment plan be individualized depending on tolerance and response to the treatment regimen, as well as the patient's wishes as to treatment breaks or modifications.

EFFICACY OF INDIVIDUAL TREATMENTS

Frontline immunotherapy

PD-L1-overexpressing adenocarcinomas — First-line immunotherapy is an option for patients with adenocarcinomas whose tumors have high levels of expression of programmed cell death ligand 1 (PD-L1), with a combined positive score (CPS) ≥5. Two approaches may be taken: pembrolizumab monotherapy or combined checkpoint inhibitor immunotherapy plus chemotherapy. We reserve pembrolizumab monotherapy for patients with CPS ≥10 who lack symptomatic, bulky disease, because of the lower objective response rate in this group.

In our view, the benefits of first-line immunotherapy for adenocarcinomas with low-level expression of PD-L1 remain uncertain. Although opinion differs, we suggest initial chemotherapy rather than immunotherapy in patients with tumors that have a CPS of 1 to 4, unless they also have deficient mismatch repair (dMMR)/high levels of microsatellite instability (MSI-H) tumors.

Pembrolizumab monotherapy — Pembrolizumab is an anti-programmed cell death protein 1 (PD-1) monoclonal antibody that is active in advanced esophagogastric cancers that express PD-L1. In the United States, pembrolizumab is approved for third-line treatment in patients with PD-L1-expressing tumors (CPS 1 or higher) after failure of two separate chemotherapy regimens, although support for choosing pembrolizumab rather than second-line chemotherapy for esophageal squamous cell cancer (SCC) and adenocarcinomas of the esophagus or esophagogastric junction (EGJ), Siewert type I (figure 2), that have a higher level of PD-L1 expression (CPS ≥10) is provided by the KEYNOTE-181 trial, which suggests a survival advantage and better tolerability for pembrolizumab in this setting. (See "Progressive, locally advanced unresectable, and metastatic esophageal and gastric cancer: Approach to later lines of systemic therapy", section on 'Timing of immunotherapy'.)

Support for first-line pembrolizumab was provided by the phase III KEYNOTE-062 trial, in which 763 patients with previously untreated, advanced, gastric or EGJ adenocarcinoma with a CPS ≥1 (281 with a CPS ≥10) were randomly assigned to pembrolizumab alone, chemotherapy alone (cisplatin plus a fluoropyrimidine), or combined therapy [27]. At a median follow-up of 29.4 months, pembrolizumab was noninferior to chemotherapy alone for overall survival, the primary endpoint (median 10.6 versus 11.1 months, hazard ratio [HR] 0.91, 99% CI 0.69-1.18), and it was associated with fewer any-grade (54 versus 92 percent) and grade 3 or 4 (17 versus 69 percent) adverse effects, but a lower objective response rate (15 versus 37 percent). When an exploratory analysis was restricted to those with a CPS ≥10, there was a clinically meaningful improvement in median overall survival with pembrolizumab compared with chemotherapy alone (17.4 versus 10.8 months, HR 0.69, 95% CI 0.49-0.97). A striking finding was the superior outcomes in Asian patients compared with North American, European, and Australian patients when treated with pembrolizumab (HR 0.54 versus 0.99). Whether this reflects tumor or host biology, or even patient selection for trials, is unclear [31].

In this trial, pembrolizumab plus chemotherapy was not superior to chemotherapy alone for patients with either CPS ≥1 or CPS ≥10 in the entire cohort. Additional trials that have shown benefit for combined immunotherapy and chemotherapy are described below, as are the results of pembrolizumab plus cytotoxic chemotherapy from KEYNOTE-062 in the subset of patients with both PD-L1 overexpression and dMMR/MSI-H. (See 'Combined immunotherapy plus chemotherapy' below and 'Deficient mismatch repair' below.)

Combined immunotherapy plus chemotherapy — In contrast to KEYNOTE-062, support for front-line therapy with combined immunotherapy plus cytotoxic chemotherapy is provided by the CheckMate 649 trial, in which 1581 patients with previously untreated, human epidermal growth factor receptor 2 (HER2)-negative advanced/unresectable or metastatic gastric, EGJ, or esophageal adenocarcinoma (955 with CPS ≥5) were randomly assigned to nivolumab (360 mg every three weeks or 240 mg every two weeks) plus chemotherapy or chemotherapy alone [26]. Although patients were enrolled regardless of PD-L1 expression, the combined positive score (CPS) was ≥5 in 955 (60 percent). The chemotherapy regimen was oxaliplatin plus either leucovorin plus short-term infusional fluorouracil (FU; FOLFOX) or capecitabine (XELOX; also known as CAPOX). The primary endpoints were overall survival and progression-free survival (PFS) in the subset of patients with PD-L1 CPS ≥5.

In the entire cohort, when all CPS groups were pooled, combined therapy was associated with significantly better median PFS and overall survival (median 13.8 versus 11.6 months, HR 0.80, 95% CI 0.68-0.94). When stratified according to PD-L1 overexpression, benefits were significant in the subset of patients with CPS ≥5 (12-month survival 57 versus 46 percent, median overall survival 14.4 versus 11.1 months, HR 0.71, 95% CI 0.59-0.86), and CPS ≥1 (n = 1296, 12-month survival 56 versus 47 percent, median overall survival 14 versus 11.3 months, HR 0.77, 95% CI 0.64-0.92). However, there was no overall survival benefit for nivolumab plus chemotherapy versus chemotherapy alone in those with CPS <1 (median overall survival 13.1 versus 12.5 months, unstratified HR 92, 95% CI 0.70-1.23) or CPS <5 (median overall survival 12.4 versus 12.3 months, unstratified HR 0.94, 95% CI 0.78-1.13). Interaction analysis of overall survival by PD-L1 CPS cutoffs showed significant interaction by PD-L1 CPS at the cutoff value of CPS 5 (p = 0.011), but not at the cutoff value of CPS of 1.

Grade ≥3 treatment-related adverse events were somewhat more common with combined therapy (59 versus 44 percent), and twice as many had treatment discontinuation because of toxicity (17 versus 9 percent), and more treatment-related deaths (17 versus 9 patients, 2 versus <1 percent).

Largely based upon these data, nivolumab was approved by the US Food and Drug Administration, in combination with a fluoropyrimidine and platinum-containing regimen, for advanced or metastatic gastric and gastroesophageal junction cancer and esophageal adenocarcinoma irrespective of PD-L1 overexpression [32]. However, in our view, the benefits of immunotherapy for adenocarcinomas with low-level or no expression of PD-L1 (ie, CPS <5) are not established. Although opinion differs, we suggest initial chemotherapy rather than immunotherapy in these patients, unless they have dMMR/MSI-H tumors.

The recommended nivolumab doses are:

●360 mg every three weeks in combination with an every three-week chemotherapy backbone regimen (eg, capecitabine plus oxaliplatin)

●240 mg every two weeks in combination with an every two-week chemotherapy backbone regimen (eg, FOLFOX)

Deficient mismatch repair — Refractory cancers with dMMR/MSI-H may be susceptible to inhibition of the PD-1/PD-L1 pathway, as demonstrated in the KEYNOTE-158 study, which was conducted in patients with previously treated disease at a variety of primary sites, including the esophagus and stomach. In May 2017, the US Food and Drug Administration approved pembrolizumab for treatment of a variety of advanced solid tumors, including gastric cancers, that had MSI-H or dMMR, that had progressed following prior treatment, and for which there were no satisfactory alternative treatment options, the first such approval of a tissue-agnostic anticancer treatment. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

The following data provide support for pembrolizumab monotherapy or a combined approach of immunotherapy plus chemotherapy compared with chemotherapy alone for first-line therapy of patients with dMMR esophagogastric cancer, most of whom also have PD-L1 overexpression:

●An exploratory analysis of pembrolizumab for treatment of dMMR/MSI-H esophagogastric cancer included a subset of 50 patients enrolled on the KEYNOTE-062 trial whose tumors had high levels of MSI plus PD-L1 overexpression as well as 34 other patients treated with pembrolizumab for a later line of systemic therapy in KEYNOTE-059 and KEYNOTE-060 [33]. (See "Progressive, locally advanced unresectable, and metastatic esophageal and gastric cancer: Approach to later lines of systemic therapy", section on 'Defective mismatch repair'.)

As noted above, in the entire cohort, compared with chemotherapy alone, overall survival with pembrolizumab plus chemotherapy was not superior in those with CPS ≥1, or in those with a CPS ≥10 although combined therapy was associated with a higher objective response rate [27]. Pembrolizumab significantly improved overall survival relative to chemotherapy alone for those with CPS ≥10, and was less toxic, although objective response rates were lower. (See 'PD-L1-overexpressing adenocarcinomas' above.)

In a later analysis restricted to the 50 patients with dMMR/MSI-H tumors in addition to CPS ≥1, compared with chemotherapy alone, combined therapy did provide a modest but significant benefit in overall survival (median not reached versus 8.5 months; 12 month survival 71 versus 47 percent, 24 month survival 65 versus 26 percent)) and PFS (median not reached versus 6.6 months), and a twofold higher objective response rate (65 versus 37 percent) [33] Furthermore, compared with chemotherapy alone, pembrolizumab monotherapy was also associated with a higher objective response rate (57 versus 37 percent), longer duration of response (21.2 versus 7 months), higher PFS (median 11.2 versus 6.6 months), and longer overall survival (median not reached versus 8.5 months, 12 month survival 79 versus 47 percent).

●Benefit for combined therapy among those with both PD-L1 overexpression and dMMR/MSI-H tumors was also suggested in a subset analysis of the CheckMate 649 trial, presented at the 2020 European Society of Medical Oncology (ESMO) meeting [34]. Among the 34 patients with dMMR/MSI-H tumors, median survival as not reached for those treated with combined nivolumab plus chemotherapy versus 8.8 months with chemotherapy alone (HR for death 0.33). (See 'Combined immunotherapy plus chemotherapy' above.)

In our view, pembrolizumab monotherapy and immunotherapy plus systemic chemotherapy are both acceptable alternatives for first-line therapy for patients with PD-L1 overexpressing, dMMR/MSI-H esophagogastric adenocarcinomas. (See "Progressive, locally advanced unresectable, and metastatic esophageal and gastric cancer: Approach to later lines of systemic therapy", section on 'Defective mismatch repair'.)

Patients unselected for biomarkers — For patients with advanced esophageal squamous cell cancer (SCC) unselected for PD-L1 overexpression, we suggest immunotherapy plus chemotherapy rather than chemotherapy alone. On the other hand, for patients with esophagogastric adenocarcinoma without PD-L1 overexpression or dMMR/MSI-H, we suggest cytotoxic chemotherapy alone rather than immunotherapy plus cytotoxic chemotherapy. In our view, a role for first-line immune checkpoint inhibitor immunotherapy in PD-L1-negative (ie, CPS <5) adenocarcinomas is not yet proven in this group.

●Squamous cell cancers – Support for upfront immunotherapy in esophageal SCCs is provided by the CheckMate 648 study (nivolumab plus fluorouracil and cisplatin, and nivolumab plus ipilimumab, an immune checkpoint inhibitor that targets a different checkpoint, cytotoxic T-lymphocyte-associated protein 4 [CTLA4]), by the KEYNOTE-590 trial (pembrolizumab plus fluorouracil and cisplatin), and by the ESCORT-1^st trial (camrelizumab plus paclitaxel and cisplatin). (See "Principles of cancer immunotherapy", section on 'Checkpoint inhibitor immunotherapy'.)

•Checkmate 648 – In the Checkmate 648 trial, 970 adults with previously untreated, advanced unresectable, recurrent, or metastatic esophageal SCC regardless of PD-L1 expression were randomly assigned to nivolumab (240 mg every two weeks) plus chemotherapy (fluorouracil [800 mg/m² daily, days 1 through 5] plus cisplatin [80 mg/m² on day 1] every four weeks), nivolumab (3 mg/kg every two weeks) plus ipilimumab (1 mg/kg every six weeks), or chemotherapy alone [35]. Overall 49 percent of the randomized patients had tumor cell PD-L1 ≥1 percent.

Patients receiving nivolumab plus chemotherapy had a significantly longer median overall survival compared with chemotherapy alone in both the entire population (13.2 versus 10.7 months, HR 0.74, 95% CI 0.58-0.96) and in those with PD L1 ≥1 percent (15.4 versus 9.1 months, HR 0.54, 95% CI 0.37-0.80). Patients receiving nivolumab plus ipilimumab also had a statistically significant overall survival benefit compared with chemotherapy alone in both the entire population (12.8 versus 10.7 months, HR 0.78, 95% CI 0.62-0.98) as well as in those with PD L1 ≥1 percent (13.7 versus 9.1 months, HR 0.64, 95% CI 0.46-0.90). Compared with chemotherapy alone, there were no differences in overall survival in the subset with PD-L1 <1 percent in either the ipilimumab plus nivolumab or the nivolumab plus chemotherapy groups (in both, median 12 versus 12.2 months, respectively). Objective response rates were highest in the group receiving nivolumab plus chemotherapy compared with nivolumab plus ipilimumab, and chemotherapy alone (53, 35, and 20 percent, respectively).

Rates of severe adverse effects were similar with ipilimumab/nivolumab and chemotherapy alone (32 and 36 percent, respectively, with fewer than 20 percent of the patients in each group discontinuing therapy because of side effects), and slightly higher in the group receiving nivolumab plus chemotherapy (47 percent, with 34 percent resulting in treatment discontinuation), possibly because of the longer duration of therapy in this group (5.7 months, as compared with 2.8 and 3.4 months for the ipilimumab/nivolumab and chemotherapy alone, respectively).

The authors concluded that nivolumab plus chemotherapy or ipilimumab offered improved outcomes over chemotherapy alone in advanced previously untreated esophageal SCC. In our view, this trial demonstrated better overall and PFS as well as higher response rates and a longer duration of therapy with nivolumab plus chemotherapy versus nivolumab plus ipilimumab, and we generally favor nivolumab plus chemotherapy over nivolumab plus ipilimumab.

•KEYNOTE-590 – Additional support is provided by the phase III KEYNOTE-590 trial that randomly assigned 749 patients with previously untreated advanced/unresectable or metastatic esophageal adenocarcinoma, esophageal SCC, or EGJ Siewert type 1 adenocarcinoma regardless of PD-L1 overexpression to pembrolizumab (200 mg every three weeks for up to 35 cycles) plus chemotherapy (FU 800 mg/m² IV days 1 through 5 every three weeks for up to 35 cycles), and cisplatin (80 mg/m² IV every three weeks for up to 6 cycles), or the same schedule of chemotherapy alone [36]. The primary endpoints were overall survival and PFS. In an interim analysis at a median follow-up of 22.6 months, median survival was significantly better with combined therapy (12.4 versus 9.8 months, HR 0.73, 95% CI 0.62-0.86), as was median PFS (6.3 versus 5.8 months, HR 0.65, 95% CI 0.55-0.76). The confirmed objective response rate was higher with combined therapy (45 versus 29 percent), with a median duration of response of 8.3 versus 6.0 months, and the incidence rates of grade 3 to 5 drug-related adverse events were 86 versus 83 percent.

There are two significant provisos to these data:

-When stratified according to PD-L1 overexpression, benefit was exclusively seen in the population with CPS ≥ 10 (median survival 13.5 vs 9.4 months in the pooled population of both adenocarcinoma and SCC; HR 0.62, 95% CI 0.49-0.78). There did not seem to be a benefit for adding pembrolizumab in those with CPS <10 (median survival 10.5 versus 10.6 months, HR 0.86, 95% CI 0.68-1.10).

-The results were driven more by SCC (median survival 13.9 versus 8.8 months, HR 0.57, 95% CI 0.43-0.75) than by adenocarcinomas (median overall survival 11.6 versus 9.9 months, HR 0.74, 95% CI 0.54-1.02), which formed a minority of the study population (27 percent).

Nevertheless, largely based on these data, the US Food and Drug Administration has approved pembrolizumab, in combination with platinum- and fluoropyrimidine-based chemotherapy, for the treatment of patients with metastatic or locally advanced esophageal or EGJ carcinoma (including adenocarcinoma) with an epicenter 1 to 5 cm above the EGJ and who are not eligible for resection or chemoradiation, and without regard for PD-L1 overexpression [37]. We disagree with this position, and do not offer upfront immunotherapy for adenocarcinomas with a combined positive score [CPS <5]), and instead recommend chemotherapy alone.

•ESCORT-1^st – Camrelizumab is an anti-PD-1 monoclonal antibody that is available in China but not in North America. The benefit of adding camrelizumab to paclitaxel plus cisplatin versus chemotherapy alone for first-line treatment of advanced SCC was directly addressed in the ESCORT-1^st trial [38]. Combined therapy significantly improved median overall survival (15.3 versus 12.0 months, HR 0.70, 95% CI 0.56-0.88) and PFS, with a similar incidence of grade 3 or worse treatment-emergent adverse effects.

●Adenocarcinoma – The benefit of combining immunotherapy with cytotoxic chemotherapy versus chemotherapy alone for first-line therapy of advanced esophagogastric adenocarcinoma unselected for PD-L1 overexpression or dMMR/MSI-H status has been addressed in reports from two trials, KEYNOTE-590 and ATTRACTION-4:

•As noted above, the phase III KEYNOTE-590 trial showed that pembrolizumab plus chemotherapy significantly improved survival over chemotherapy alone in a combined population of previously untreated advanced/unresectable or metastatic esophageal adenocarcinoma, esophageal squamous cell carcinoma, or EGJ Siewert type 1 adenocarcinoma regardless of PD-L1 overexpression [36]. However, adenocarcinomas formed a minority of the study population (27 percent), and the results were driven more by SCC than by adenocarcinoma. Consistent with evidence from prior phase III trials (eg, KEYNOTE-181, and KEYNOTE-061) showing a lack of benefit for PD-1 blockade in non-PD-L1-expressing adenocarcinomas, a survival benefit for patients with adenocarcinoma was not evident. (See "Progressive, locally advanced unresectable, and metastatic esophageal and gastric cancer: Approach to later lines of systemic therapy", section on 'PD-L1 overexpression'.)

Largely based upon these data, the US Food and Drug Administration approved pembrolizumab, in combination with platinum- and fluoropyrimidine-based chemotherapy, for the treatment of patients with metastatic or locally advanced esophageal or EGJ carcinoma (including adenocarcinoma) with an epicenter 1 to 5 cm above the EGJ who are not eligible for resection or chemoradiation [37]. However, in our view, the benefits of immunotherapy for adenocarcinomas with low-level or no expression of PD-L1 remain uncertain. Although opinion differs, especially with regard to CPS 1 to 4, we suggest initial chemotherapy rather than immunotherapy in these patients, unless they have dMMR/MSI-H tumors.

•In the randomized phase III ATRACTION-4 trial, 724 Asian patients with HER2-negative advanced or recurrent gastric or gastroesophageal junction adenocarcinoma were randomly assigned to chemotherapy (oxaliplatin plus either S-1 or capecitabine) plus placebo, or the same chemotherapy plus nivolumab (360 mg) every three weeks until disease progression or unacceptable toxicity [39]. The two co-primary endpoints were PFS and overall survival. In a preliminary report of an interim analysis presented at the 2020 virtual ESMO meeting, at a median follow-up of 11.6 months, median PFS was significantly improved with combined therapy (10.5 versus 8.3 months, HR 0.68, 95% CI 0.51-0.90), but there was only a trend toward better median overall survival (17.5 versus 17.2 months, HR 0.90, 95% CI 0.75-1.08). Notably, 27 percent of the patients in the control arm received poststudy treatment with an anti-PD-1 agent. Patients receiving combined therapy also had a higher objective response rate (58 versus 48 percent), but they also had higher rates of grade 3 to 5 treatment-related toxicity (58 versus 49 percent). When stratified according to PD-L1 overexpression, neither the PD-L1 overexpressors nor the PD-L1-negative patients had a survival benefit from combination immunotherapy and chemotherapy. Notably, this trial used the Tumor Proportion Score (TPS) and not the CPS to designate PD-L1 overexpression; TPS does not appear to be as predictive as CPS in upper gastrointestinal tract adenocarcinomas [40].

Selection of the chemotherapy backbone for combined therapy — When immunotherapy is combined with cytotoxic therapy in the first-line setting, the optimal cytotoxic chemotherapy backbone is not established. The CheckMate-649 and ATTRACTION-4 trials used an oxaliplatin-based regimen with nivolumab, while the KEYNOTE-590 and KEYNOTE-062 trials used cisplatin and FU in conjunction with pembrolizumab. Regardless of the specific immune checkpoint inhibitor, we generally prefer an oxaliplatin-containing regimen for most patients. (See 'Oxaliplatin combinations' below.)

Where camrelizumab is available (mainly China), a chemotherapy doublet of paclitaxel and cisplatin, as was used in the ESCORT-1^st trial, is an appropriate option.

HER2-overexpressing adenocarcinomas — Patients with unresectable, locally advanced, recurrent, or metastatic gastric or esophageal adenocarcinoma who are potential candidates for trastuzumab should have their tumors assayed for the presence of human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification using specific criteria developed for esophagogastric adenocarcinomas. We suggest the addition of trastuzumab to chemotherapy in patients with HER2-positive tumors (as defined by 3+ immunohistochemistry [IHC] staining or fluorescence in situ hybridization [FISH] positivity), as long as they do not have a contraindication to trastuzumab. We also suggest the addition of pembrolizumab to trastuzumab, based on an interim analysis of the phase III KEYNOTE-811 trial.

Between 7 and 38 percent of gastroesophageal adenocarcinomas have amplification and/or overexpression of HER2 [41-50]. The frequency of overexpression is slightly greater for cancers of the EGJ as compared with those of the stomach (32 versus 21 percent) [41-43,51-57]. Overexpression in the stomach varies according to histologic type (intestinal-type more than diffuse-type gastric cancers; 3 to 23 versus 0 to 6 percent, respectively [55]) and with differentiation (well and moderately differentiated more than poorly differentiated). (See 'Assessment of HER2 status and selection of candidates for trastuzumab' below.)

High levels of HER2 overexpression and/or amplification identify those patients who might potentially benefit from treatment with trastuzumab, a humanized monoclonal antibody that targets the extracellular domain of the HER2 receptor, inhibits downstream signal activation, and induces antibody-dependent cellular toxicity.

Benefit of trastuzumab — The benefit of trastuzumab in advanced HER2-positive adenocarcinoma of the stomach or EGJ was addressed in the phase III ToGA trial, which compared standard chemotherapy (six courses of cisplatin plus either infusional FU or capecitabine) with and without trastuzumab (8 mg/kg loading dose, then 6 mg/kg every three weeks until disease progression) [45]. (See "Treatment protocols for esophagogastric cancer", section on 'Trastuzumab-containing regimens for HER2-positive advanced adenocarcinomas'.)

All tumors were screened for HER2 status by both IHC and FISH, and patients were eligible for the trial if their tumor was IHC positive (IHC 3+) or FISH positive (ie, showing a HER2/chromosome enumeration probe 17 [CEP17] ratio of 2 or greater) [58,59]. Among enrolled patients (n = 594 of the 3807 screened), almost all tumors were FISH positive, whereas protein expression by IHC varied (47 percent 3+, 30 percent 2+, and 22 percent 0 or 1+).

The objective response rate was significantly higher with trastuzumab (47 versus 35 percent). At a median follow-up of 17 to 19 months, median overall survival (the primary endpoint) was modestly but significantly better with trastuzumab (13.8 versus 11.1 months, HR 0.74, 95% CI 0.60-0.91). The toxicities in the two arms were comparable, except that a higher number of trastuzumab-treated patients had grade 3 or 4 diarrhea (9 versus 4 percent) and an asymptomatic decrease in left ventricular ejection fraction (5 versus 1 percent). Only one patient developed grade 3 to 4 heart failure (versus two in the control group). Exploratory analysis in subgroups defined by protein expression suggested that trastuzumab was most effective in prolonging survival in the subgroup of patients with IHC 3+ tumors (HR for death 0.66, 95% CI 0.50-0.87), was less effective in patients with IHC 2+ tumors (HR 0.78, 95% CI 0.55-1.10), and was ineffective in those with HER2 gene-amplified (ie, FISH-positive) but non-protein-expressing (IHC 0 or 1+) tumors.

Based on these data, trastuzumab was approved, in combination with cisplatin and a fluoropyrimidine, for the treatment of patients with metastatic HER2-overexpressing gastric or EGJ adenocarcinomas who have not received prior treatment for metastatic disease. Patients with advanced gastric cancer who are potential candidates for trastuzumab should be screened to determine HER2 status.

Higher-dose trastuzumab maintenance dosing (10 mg/kg every three weeks, as compared with the doses of 6 mg/kg every three weeks that were used in the ToGA trial) was not associated with greater efficacy in the phase III HELOISE trial [60], and this approach cannot be recommended. Furthermore, the addition of pertuzumab, a humanized HER2-targeted monoclonal antibody that binds to a different epitope on the HER2 receptor protein than trastuzumab, was not beneficial in the phase III JACOB trial [61], and this approach cannot be recommended.

Specific chemotherapy backbone — Although trastuzumab was studied with fluoropyrimidine/cisplatin regimens in the randomized ToGA trial, many clinicians incorporate trastuzumab into their first-line regimen of choice (including cisplatin-free regimens, such as FOLFOX and XELOX/CAPOX, or weekly paclitaxel), despite the lack of phase III trials to demonstrate benefit of trastuzumab in these settings. Consensus-based guidelines from the National Comprehensive Cancer Network also support this approach, recommending the addition of trastuzumab to any chemotherapy combination for patients with HER2-overexperssing tumors [62]. (See "Treatment protocols for esophagogastric cancer", section on 'Trastuzumab-containing regimens for HER2-positive advanced adenocarcinomas'.)

At least some data suggest potential superiority for a doublet regimen containing oxaliplatin over a fluoropyrimidine/cisplatin regimen when combined with trastuzumab. A meta-analysis compared cytotoxic backbones for first-line trastuzumab-containing regimens in 15 published studies (557 patients, a mix of prospective and retrospective cohort studies); HRs and CIs were calculated by extraction of the published Kaplan-Meier survival curves [63]. The following conclusions were made compared with the ToGA trial regimen (trastuzumab, cisplatin, and a fluoropyrimidine):

●Overall survival was significantly longer with trastuzumab plus a doublet regimen of oxaliplatin and either capecitabine or FU (median 20.7 versus 16 months, HR 0.75, 95% CI 0.59-0.99), and it was also less toxic.

●Trastuzumab plus a doublet of cisplatin and S-1 showed no overall survival difference, but there was a different toxicity profile, including less hand-foot syndrome.

●Trastuzumab plus cisplatin or capecitabine as a singlet backbone showed worse survival and more toxicity compared with the ToGA trial regimen.

●Trastuzumab with a triplet cytotoxic backbone (eg, docetaxel, a platinum, and a fluoropyrimidine) or with bevacizumab plus a doublet backbone showed no survival benefit and a worse toxicity profile.

As noted above, emerging data suggest high response rates with first-line oxaliplatin- and irinotecan-containing regimens, such as oxaliplatin plus irinotecan, leucovorin, and FU (FOLFIRINOX), albeit with greater toxicity than would be expected with an oxaliplatin-containing doublet. As an example, a phase II open label study administered the FOLFIRINOX regimen (table 3) to 67 patients with previously untreated metastatic gastroesophageal cancer; the 26 who had HER2-positive disease received concurrent trastuzumab as a 6 mg/kg initial loading dose, followed by 4 mg/kg every 14 days [64]. (See 'FOLFIRINOX' below.)

The objective response rate in the HER2-positive cohort was 85 percent, with one complete clinical response; median PFS and overall survival durations were 13.8 and 19.6 months, respectively. The most common severe toxic effects were neutropenia (89 percent, 65 percent grade ≥3), diarrhea (58 percent; 19 percent grade ≥3), peripheral sensory neuropathy (46 percent), nausea (35 percent, 8 percent grade ≥3), and fatigue (35 percent).

In our view, for most patients, a doublet backbone of oxaliplatin plus a fluoropyrimidine is preferable to cisplatin plus a fluoropyrimidine when used with trastuzumab for HER2-positive esophagogastric cancer; where available, S-1 can substitute for capecitabine or FU when specific toxicities are encountered. Given the absence of randomized data, we do not favor FOLFIRINOX as a front-line regimen, either in HER2-positive or HER2-negative disease.

Patients who are receiving a capecitabine-containing regimen should probably not take proton pump inhibitors concurrently. Concerns have been raised that higher gastric pH levels may inhibit dissolution and absorption of capecitabine, adversely impacting efficacy [65,66].

Adding pembrolizumab — The safety and efficacy of combining the immune checkpoint inhibitor pembrolizumab with first-line trastuzumab plus platinum-containing chemotherapy was first shown in a single-arm open-label phase II trial of 37 previously untreated patients with HER2-positive esophageal, gastric, or EGJ cancer [67]. The initial induction cycle consisted of 200 mg pembrolizumab followed by an 8 mg/kg loading dose of trastuzumab. Subsequent three-week cycles consisted of 130 mg/m² oxaliplatin or 80 mg/m² cisplatin on day 1, followed by 850 mg/m² oral capecitabine twice a day for two weeks followed by one week off (or infusional FU 800 mg/m² per day on days 1 through 5), and a single flat dose of 200 mg pembrolizumab and 6 mg/kg of trastuzumab, both administered intravenously within seven days of the first day of each three-week cycle every three weeks. At a median follow-up of 13 months, the primary endpoint was achieved, and 26 of the 37 patients (70 percent) were progression free at six months. The most common grade 3 or 4 adverse events were lymphocytopenia (19 percent); hypokalemia, hypomagnesemia, or hyponatremia (16 percent); and anemia (11 percent). Serious adverse events occurred in only two patients (grade 3 nephritis leading to treatment discontinuation). A similar level of efficacy and manageable safety was subsequently shown in a second phase Ib/II trial [68].

These results were confirmed in a later multicenter phase III KEYNOTE-811 trial, in which 692 patients with HER2-positive advanced gastric or EGJ adenocarcinoma who had not received systemic therapy for advanced disease and no autoimmune disease requiring systemic therapy within two years or medical condition requiring immunosuppression were randomly assigned to pembrolizumab or placebo given with trastuzumab plus three-week cycles of platinum-containing cytotoxic chemotherapy (investigator’s choice of cisplatin 80 mg/m² on day 1 for up to six cycles plus FU 800 mg/m² per day for five days each cycle, or capecitabine 1000 mg/m² per day for 14 days plus oxaliplatin 130 mg/m² on day 1 up to six to eight cycles [CAPOX]). Pembrolizumab/placebo and trastuzumab were both administered on day 1 of each cycle, in a manner identical to that used in the phase II trial described above.

A preliminary report of a preplanned interim analysis performed after the first 264 patients was presented at the 2021 ASCO annual meeting; 87 percent of the patients had received CAPOX, and 87 percent had tumors that overexpressed PD-L1 (CPS ≥1, although this was not a requirement for enrollment) [69]. The objective response rate, the primary endpoint was significantly higher with pembrolizumab (74 percent [95% CI 66-82] versus 52 percent [95% CI 43-61]), and there were more complete responders (11 versus 3 percent). The median duration of response was 10.6 months (range 1.1⁺ to 16.5⁺) with pembrolizumab versus 9.5 months (range 1.4⁺ to 15.4⁺), but more patients in the pembrolizumab group had an ongoing response at ≥6 months (65 versus 53 percent).

Largely based on this interim analysis, the US FDA approved pembrolizumab, in combination with trastuzumab and fluoropyrimidine plus platinum-containing chemotherapy for the treatment of patients with locally advanced or metastatic esophageal or EGJ (tumors with epicenter 1 to 5 centimeters above the EGJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation [70].

Assessment of HER2 status and selection of candidates for trastuzumab — In comparison with breast carcinomas, the heterogeneity of immunostaining for biomarkers such as human epidermal growth factor receptor 2 (HER2) is greater in gastroesophageal adenocarcinoma tumors and the possibility of false-negative testing is higher [55,71]. Because of this intratumoral heterogeneity, which is present even before metastatic spread has occurred [72], analyzing HER2 positivity in fewer than six biopsy samples leads to a false-negative rate that may be as high as 9 percent [73-78]. Furthermore, HER2 protein expression in gastroesophageal adenocarcinomas tends to spare the digestive luminal membrane, resulting in membrane staining that is not completely circumferential in contrast with breast cancers [54,58,59]. These differences underscore the importance of utilizing tumor-specific criteria to assess HER2 expression in clinical practice. (See "Gastric cancer: Pathology and molecular pathogenesis", section on 'HER2 overexpression'.)

Given the differences in interpretive criteria for determining HER2 status in gastroesophageal as compared with breast cancers [41,58,59,79], an expert panel convened by the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology undertook a systematic review of the published literature to provide an evidence-based joint guideline on HER2 testing and clinical decision-making in gastroesophageal adenocarcinomas [55]. The panel's recommendations were as follows:

●All patients who have documented advanced gastroesophageal adenocarcinoma and who are considered good candidates for combination therapy that includes trastuzumab should have their tumor tissue tested for HER2 overexpression and/or amplification prior to trastuzumab treatment.

●For biopsy or resection specimens, a minimum of five specimens (optimally six to eight) should be tested to account for intratumoral heterogeneity when possible. If there is documentation of HER2 positivity on any specimen, the treating clinician does not need to request additional HER2 testing on additional specimens.

HER2 testing on fine needle aspirate specimens is an acceptable alternative [58,80]. However, specimens obtained in cytology specimens may not be truly representative given the limited sampling of the tumor. If there is concern about specimen adequacy and HER2 testing is negative, additional available primary or metastatic tumor tissue should be tested.

●When HER2 status is being evaluated, laboratories/pathologists should perform/order IHC staining first. Pathologists should use the Ruschoff/Hoffmann method when scoring IHC results (table 4) and should select the tissue block with the areas of lowest grade or intestinal morphology for testing. A positive result is IHC 3+. A negative result is IHC 0 to 1+ [55].

●FISH or another in situ hybridization (ISH) method is recommended only when the IHC result is 2+ (equivocal) to determine amplification status. In many studies, ISH-positive results are observed in 30 to 50 percent of IHC 2+ tumors [56,81-84]. A variety of in situ visualization techniques to evaluate HER2 amplification, including FISH and brightfield ISH using either a HER2 probe or dual HER2 and centromere (CEP17) probes, are all acceptable strategies. A ratio of HER2 signal to CEP17 signal ≥2 is considered positive, while a HER2/CEP17 ratio <2 is considered negative. An algorithmic approach to assessing HER2 status on surgical and biopsy material is presented in the figure (algorithm 2).

●For patients with HER2-positive tumors (IHC 3+ or ISH positive), clinicians should offer combination chemotherapy and HER2-targeted therapy as the initial treatment for appropriate patients. The addition of trastuzumab can increase the response rate and prolong PFS and overall survival. Clinicians should not offer HER2-targeted therapy until HER2 positivity is confirmed; for symptomatic patients, it is recommended to begin combination cytotoxic chemotherapy as soon as possible while awaiting confirmation of HER2 status.

However, even when these guidelines are followed, there can be significant discrepancies in local HER2 assessment, particularly in tumor specimens with intermediate levels of HER2 expression. These discrepancies can be illustrated by the prospective multicenter VARIANZ study, which was designed to determine factors predicting trastuzumab response or resistance in HER2+ metastatic gastric cancer [85]. In the 374 patients for whom HER2 status was determined both locally and centrally, there was a high deviation rate (23 percent) between centrally confirmed and locally interpreted HER2 test results, with most (74 of 77 cases) reflecting an inability to confirm locally assessed HER2 positivity by central testing. Tumors were classified as IHC+ centrally if at least 10 percent of tumor cells stained positive in resection specimens, and if at least five adjacent tumor cells stained positive in biopsies (IHC score 3+ and 2+ if findings confirmed by in situ hybridization). The 60 patients who received trastuzumab and had a centrally confirmed HER2+ test had a significantly longer survival than did the 65 patients who received trastuzumab for a centrally unconfirmed locally assessed HER2+ tumor (median 20.5 versus 10.9 months).

In an attempt to devise alternative criteria for selection of patients for HER2-directed treatment, the percentage of IHC-positive tumor cells as a fraction of all tumor cells present in the local and central specimens was calculated, and quantitative reverse transcriptase polymerase chain reaction was applied to quantify HER2 mRNA. In this analysis, significantly more tumor cells stained positive for HER2 in the centrally confirmed versus nonconfirmed cases (59 versus 13 percent), and the HER2 amplification signal ratio (HER2:CEP17) was significantly higher as well (7.2 versus 1.5). The authors concluded that a minimum of 40 percent IHC HER2+ tumor cells and a HER2:CEP17 amplification ratio of ≥3 were optimal thresholds for predicting benefit from trastuzumab.

Contraindications — While there are no published guidelines for exclusion of patients for trastuzumab on the basis of excess cardiac risk, many clinicians caring for patients with breast cancer use the cardiac ineligibility criteria from the North American adjuvant trastuzumab trials (table 5). It seems reasonable to adopt this approach in esophagogastric cancer as well.

Lapatinib — Lapatinib is an orally active small-molecule inhibitor of both epidermal growth factor receptor (EGFR) and HER2; benefit for the addition of lapatinib to weekly paclitaxel versus paclitaxel alone could not be demonstrated in patients with previously treated, advanced gastric cancer on the TyTAN trial. (See "Progressive, locally advanced unresectable, and metastatic esophageal and gastric cancer: Approach to later lines of systemic therapy", section on 'HER2-positive disease and continued targeting of HER2 after progression'.)

Benefit from the addition of lapatinib to first-line chemotherapy was also not shown in the TRIO-013/LOGiC trial of XELOX/CAPOX with or without lapatinib for first-line treatment in 545 patients with advanced gastroesophageal cancer. The primary endpoint (overall survival of the patients who were centrally confirmed to be FISH positive for HER2) was not significantly better with lapatinib (median survival 12.2 versus 10.5 months, HR 0.91, 95% CI 0.73-1.12) [86].

Implications of HER2 expression for prognosis — In contrast to breast cancer (where human epidermal growth factor receptor 2 [HER2] expression is an adverse prognostic factor), the association between HER2 expression/amplification and prognosis in esophagogastric cancer is uncertain. (See "HER2 and predicting response to therapy in breast cancer", section on 'HER2 status and predicting treatment response'.)

The following data are available:

●Retrospective evaluations of HER2 expression and gene amplification in relation to prognosis for gastric/gastroesophageal junction adenocarcinomas have been performed in at least seven studies of prospectively enrolled clinical trial cohorts (table 6) [81,87-92]. These studies adopted the HER2 interpretive criteria used in ToGA, and patients did not receive HER2-targeted therapy. The results are conflicting. Four studies found that HER2 was not associated with prognosis [88-90,92], while two reported a significant positive association [87,93], and one other reported a trend toward improved survival with HER2 overexpression [91]. In one study, HER2 overexpression was associated with shorter survival, but only among patients who received adjuvant postoperative chemoradiotherapy after potentially curative resection [81].

●While the prognostic impact of HER2 overexpression was not formally evaluated in the ToGA study, the median overall survival of patients in the control arm appeared to increase as HER2 protein expression levels increased (median survival durations were 7.2, 10.2, 10.8, and 12.3 months for those with IHC 0/FISH-positive, IHC 1+/FISH-positive, IHC 2+/FISH-positive, and IHC 3+/FISH-positive tumors, respectively) [45].

●By contrast, in a meta-analysis of 49 gastric cancer studies (n = 11,337, from 1990 to 2011, stage I to IV), patients with (versus without) HER2 overexpression had shorter five-year overall survival (42 versus 52 percent) [94]. However, the generalizability of this meta-analysis (which did not include the seven studies or the ToGA trial results described above) may be limited because only one study was performed after disease-specific HER2 interpretive criteria were established through ToGA.

●Among patients with esophageal adenocarcinomas, the prognostic impact of HER2 has not been as extensively examined as it has been in gastric cancer (sample sizes typically <200 cases), but the data are likewise conflicting [51-53,95-97]. The largest study (n = 713), which used disease-specific HER2 interpretive criteria, found no association between HER2 overexpression and prognosis [51].

●In modern series, the prognostic impact of HER2 overexpression is likely to be linked to the use of anti-HER2 therapy. In one analysis of 924 patients with advanced esophagogastric cancer receiving first-line chemotherapy, those with HER2-positive tumors receiving HER2-targeted therapy had a significantly higher survival as compared with those with HER2-negative tumors (HR for death 0.75, 95% CI 0.61-0.91) [98].

Cytotoxic chemotherapy options — For SCC and adenocarcinomas that do not overexpress HER2 and are not candidates for immunotherapy, the choice of the chemotherapy regimen is empiric. For most patients who are candidates for aggressive combination therapy, we suggest a platinum- and fluoropyrimidine-containing doublet combination regimen. Acceptable options include FOLFOX, or XELOX/CAPOX.

Where S-1 is available, S-1 in combination with cisplatin is also a reasonable choice for first-line therapy that does not require central venous access.

For older patients or those with a poor performance status or significant comorbidity, we suggest monotherapy rather than combination chemotherapy. Options include leucovorin-modulated FU alone, single-agent capecitabine, single-agent irinotecan, or low-dose weekly taxanes.

Single-agent chemotherapy — In general, combination chemotherapy regimens provide higher response rates than do single agents, but this translates into only modestly longer durations of disease control and survival, which are measured in weeks to a few months. Single-agent chemotherapy is an appropriate option for patients who are not candidates for aggressive combination chemotherapy. Another option for frail or older adult individuals is reduced-dose XELOX/CAPOX. (See 'Chemotherapy dosing in older and frail patients' below.)

Taxanes and irinotecan — In general, response rates with taxane or irinotecan monotherapy are slightly higher than those seen with older agents, such as methotrexate and doxorubicin, but toxicity is prominent in many cases, and median survival durations have not been consistently greater than nine months with any agent. As examples:

●In multiple studies, monotherapy with either single-agent paclitaxel or docetaxel produced response rates in the range of 15 to 24 percent [8-10,99-103].

●In two reports involving 83 previously untreated patients, irinotecan was associated with response rates of 14 and 20 percent, respectively [104,105].

Fluoropyrimidines — Efficacy is modest for leucovorin-modulated FU [106-108].

Several orally active fluoropyrimidines are available, which, as single agents, are associated with response rates as high as 41 percent, but median survival durations have not exceeded nine months in any report [109-116]. Phase III studies have demonstrated equivalence between infusional FU, capecitabine, and S-1.

Patients who are receiving a capecitabine-containing regimen should probably not take proton pump inhibitors concurrently. Concerns have been raised that higher gastric pH levels may inhibit dissolution and absorption of capecitabine, adversely impacting efficacy [65,66].

S-1 is an oral formulation of the following components in a 1:0.4:1 ratio [111]: ftorafur (tegafur), the prodrug for cytotoxic FU; gimeracil (5-chloro-2,4-dihydroxypyridine), an inhibitor of dihydropyrimidine dehydrogenase (DPD), which prevents its degradation in the gastrointestinal tract, thus prolonging its half-life [112]; and oteracil (potassium oxonate), a specific inhibitor of one of the enzymes (orotate phosphoribosyl transferase) that phosphorylates FU in the intestine. Phosphorylated FU is thought to be mainly responsible for treatment-related diarrhea.

The efficacy of S-1 alone (40 mg/m² orally twice a day on days 1 to 28 every six weeks) was shown in the phase III JCOG 9912 trial, which was powered to demonstrate noninferiority of S-1 alone and superiority of irinotecan plus cisplatin over infusional FU monotherapy in 704 patients with unresectable or recurrent, previously untreated gastric adenocarcinoma [113].

In the primary endpoint, PFS, S-1 was not inferior to infusional FU, and there were trends suggesting superiority over infusional FU (median PFS 4.2 versus 2.9 months). The response rate was higher with S-1 than with FU (28 versus 9 percent), and median overall survival was 11.4 versus 12.3 months. S-1 was associated with more grade 3 or 4 diarrhea than FU (8 versus <1 percent). Otherwise, the side effect profile was comparable.

S-1 monotherapy (40 to 60 mg twice daily on days 1 to 28 every six weeks) was directly compared with single-agent capecitabine (1250 mg/m² twice daily on days 1 to 14 every 21 days) in a Korean randomized phase II trial involving 91 older patients with previously untreated, advanced gastric cancer [114]. The two regimens were comparable with respect to overall response rate (29 versus 20 percent for S-1 and capecitabine, respectively), median time to tumor progression (4.2 versus 4.7 months), overall survival (median 8.2 versus 9.5 months), and treatment-related toxicity, with the exception of hand-foot syndrome (0 versus 7 percent).

Thus, S-1 monotherapy appears active and well tolerated in cisplatin- and paclitaxel-refractory disease [115], and where available (not yet in the United States), it is a reasonable option in this setting; however, efficacy is more modest in patients with a poor performance status [116]. At least in Asian populations, S-1 monotherapy appears to be inferior to combination chemotherapy containing S-1 in previously untreated patients with advanced esophagogastric cancer [117,118]. (See 'Cisplatin plus a fluoropyrimidine' below.)

Combination chemotherapy — Higher response rates (up to 65 percent) are reported in phase II trials evaluating combination therapy in patients with advanced esophageal and gastric cancer. However, almost without exception, response rates have been lower in the setting of randomized trials. Furthermore, whether the higher response rates seen with combination as compared with single-agent chemotherapy translate into longer response duration or survival remains uncertain. In general, the higher response rates seen with combination regimens has translated into only modestly longer durations of disease control and survival, which are measured in weeks to a few months [17,18].

Oxaliplatin combinations — Although oxaliplatin combinations have been most extensively studied for metastatic colorectal cancer, they are also active in the treatment of esophagogastric cancer. A variety of different regimens have been studied in phase II trials (FOLFOX; epirubicin, oxaliplatin, and infusional FU [EOF]; XELOX/CAPOX; S-1 plus oxaliplatin; docetaxel plus oxaliplatin with or without FU or capecitabine), all of which are associated with response rates in the range of 40 to 67 percent and median survival durations between 8 and 15 months [119-132]. (See "Treatment protocols for esophagogastric cancer".)

Regimens containing oxaliplatin and a taxane are discussed below. (See 'Docetaxel-containing' below.)

At least five phase III trials have directly compared oxaliplatin-based regimens with cisplatin-containing regimens (including epirubicin, cisplatin, and infusional FU [ECF]), all of which suggest at least comparable efficacy when oxaliplatin is substituted for cisplatin in combination regimens for patients with advanced esophagogastric cancer [119,133-136]. A meta-analysis of the REAL-2 trial [133] plus two other randomized phase II trials [119,137] that compared oxaliplatin-based regimens with cisplatin-based regimens showed that oxaliplatin was associated with significant improvements in PFS (HR 0.88, 95% CI 0.80-0.98) and overall survival (HR for death 0.88, 95% CI 0.78-0.99), and with less neutropenia, anemia, alopecia, and thromboembolic events, but with more neurotoxicity and diarrhea [138].

Benefit for the FOLFOX regimen is also supported by a preliminary report of CALGB 80403, a randomized phase II trial comparing ECF with FOLFOX (table 1), both in combination with cetuximab, which concluded that response rates, PFS, and median overall survival were similar with either regimen [120].

FOLFIRINOX — We do not suggest oxaliplatin plus irinotecan, leucovorin, and FU (FOLFIRINOX) as a preferred option for first-line therapy, either in the setting of HER2-negative or HER2-positive disease.

Emerging data suggest high response rates with first-line oxaliplatin and irinotecan-containing regimens such as FOLFIRINOX, albeit with greater toxicity than is typically seen for regimens containing either oxaliplatin or irinotecan. As an example, a phase II open-label study administered the FOLFIRINOX regimen (table 3) to 67 patients with previously untreated metastatic gastroesophageal cancer; the 26 who had HER2-positive disease received concurrent trastuzumab [64]. The objective response rate in those with HER2-negative disease was 61 percent, median PFS was 8.4 months, and median overall survival was 15.5 months. The most common severe toxic effects were neutropenia (91 percent, 79 percent grade ≥3), diarrhea (63 percent, 13 percent grade ≥3), peripheral sensory neuropathy (61 percent, 3 percent grade ≥3), nausea (48 percent, 6 percent grade ≥3), and fatigue (45 percent, 6 percent grade ≥3). The data for patients with HER2-positive disease are addressed below. (See 'Specific chemotherapy backbone' above.)

Cisplatin plus a fluoropyrimidine

●Cisplatin plus FU – The combination of cisplatin plus FU has been one of the most commonly used regimens in both metastatic and localized esophageal cancer due to its activity and well-established toxicity profile. In a randomized phase II study, 88 patients with locally advanced or metastatic esophageal SCC were assigned to either single-agent cisplatin (100 mg/m² every 21 days) or the same dose of cisplatin combined with FU (1000 mg/m² per day by continuous infusion on days 1 to 5) [139]. Although the response rate was higher for the doublet (35 versus 19 percent), the median survival (33 versus 28 weeks) and one-year survival rate (34 versus 27 percent) were not significantly different. Furthermore, there was a 17 percent treatment-related mortality rate (primarily due to sepsis and cerebrovascular episodes) in the cisplatin plus FU arm.

A similar degree of activity (response rate 27 percent; median survival six months) was reported with much less toxicity (treatment-related mortality rate 3 percent) in a second study that used split-dose cisplatin (20 mg/m² per day on days 1 to 5) in combination with leucovorin calcium and bolus FU (300 mg/m² per day for five days) [140].

Combinations of cisplatin plus FU and an anthracycline are discussed below. (See 'Epirubicin, cisplatin, and fluorouracil' below.)

●Cisplatin plus capecitabine – Capecitabine is a unique, rationally designed oral fluoropyrimidine that undergoes a three-step enzymatic activation process, the last of which occurs selectively within the tumor tissue itself. The drug passes intact through the bowel and reaches the liver, where it is converted first into deoxyfluorocytidine by a carboxylesterase and then into 5-deoxfluorouridine, which reaches the tumor, where it is transformed into its active form, FU, by thymidine phosphorylase.

The comparable efficacy of regimens substituting capecitabine for infusional FU was directly studied in two randomized trials [133,141].

A meta-analysis of these two trials concluded that, compared with FU combinations, capecitabine combinations were associated with higher response rates (odds ratio 1.38, 95% CI 1.10-1.73) and better overall survival (HR for death 0.87, 95% CI 0.77-0.98) [142].

Although these data suggest that the efficacy of regimens that substitute capecitabine for infusional FU is at least as good and that the use of capecitabine allows patients to avoid infusion pumps and a central venous catheter, the out-of-pocket cost of capecitabine is significantly higher than FU. This may be an important issue for patients whose health insurance coverage requires significant out-of-pocket expense for the capecitabine. Additionally, an oral chemotherapy agent requires both patient motivation and reliable upper gastrointestinal tract function.

●Cisplatin plus S-1 – S-1 is an oral fluoropyrimidine that includes ftorafur (tegafur), gimeracil (5-chloro-2,4-dihydroxypyridine, a potent inhibitor of DPD), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea). (See 'Fluoropyrimidines' above.)

S-1 in combination with cisplatin is highly active in Asian patients [117,143]. A report from the SPIRITS trial supports a significant benefit for combined S-1 plus cisplatin over S-1 alone in terms of both response rate (54 versus 31 percent) and median survival (13 versus 11 months, p = 0.04) in an Asian population [117]. Rates of grade 3 or 4 neutropenia (40 versus 11 percent), anemia (26 versus 4 percent), nausea (11 versus 1 percent), and anorexia (30 versus 6 percent) were also significantly higher.

A subsequent randomized phase II trial from Japan demonstrated comparable outcomes for cisplatin plus S-1 compared with cisplatin plus capecitabine for first-line treatment of advanced gastric cancer [144].

Ftorafur is metabolized differently in Western and Asian populations on account of polymorphic differences in the cytochrome P450 2A6 (CYP2A6) gene; as a result, the maximally tolerated dose differs. Western experience with combined S-1 plus cisplatin for advanced gastric cancer is limited but also promising [145,146]. As an example, in a multicenter phase II trial in which 72 patients received S-1 (25 mg/m² twice daily on days 1 through 21) plus cisplatin (75 mg/m² on day 1) every 28 days, the objective response rate was 55 percent, and the median duration of response was more than five months [146]. The safety profile was favorable; the most frequent grade 3 or 4 toxicities were fatigue/asthenia (24 percent), emesis (17 percent), nausea (15 percent), diarrhea (13 percent), and neutropenia (19 percent).

The results from the phase II S-1 plus cisplatin trial led to the initiation of a global prospective randomized phase III trial, the FLAGS trial, which randomly assigned 1053 patients to cisplatin plus either FU or S-1. Median overall survival (the primary endpoint) was not significantly inferior with cisplatin plus S-1 as compared with cisplatin plus FU (8.6 versus 7.9 months) [147]. Furthermore, cisplatin plus S-1 had a more favorable side effect profile than cisplatin plus FU (grade 3 or 4 neutropenia in 19 versus 40 percent, stomatitis in 1 versus 14 percent, and hypokalemia in 4 versus 11 percent) and fewer treatment-related deaths (2.5 versus 4.9 percent) [148]. The lower cisplatin dose intensity in the cisplatin plus S-1 arm (75 versus 100 mg/m² on day 1 with cisplatin plus FU) may have contributed to the survival and toxicity results.

This study was not seen as a success, as many expected superiority of cisplatin plus S-1 over cisplatin plus FU based on the JCOG 9912 study (described above) [113]. Although a subgroup analysis suggested a possible survival benefit for cisplatin plus S-1 in the subset of patients with diffuse gastric cancer, there was a lack of superiority for cisplatin plus S-1 over cisplatin plus FU in a later randomized trial that focused specifically on diffuse gastric cancer [149]. Nevertheless, where available, cisplatin plus S-1 is accepted as a standard regimen for treatment of advanced gastric cancer. S-1 is not commercially available in the United States.

Irinotecan-containing regimens — Several trials have assessed the benefit of irinotecan combined with docetaxel, cisplatin, fluoropyrimidines, or combinations of these drugs, but no superiority has been shown in phase III trials for any irinotecan-based regimen over a cisplatin-based triplet combination. Thus, irinotecan-based combinations cannot be considered to be preferable to a platinum-containing regimen for first-line therapy.

Irinotecan has been combined with fluoropyrimidines, cisplatin, and docetaxel. In the previously described meta-analysis, the comparison of irinotecan-containing versus non-irinotecan-containing regimens (mainly FU/cisplatin) revealed a nonstatistically significant trend toward better survival with irinotecan (HR for death 0.86, 95% CI 0.73-1.02) [150].

●Irinotecan plus fluoropyrimidines or cisplatin – The superiority of FOLFIRI (table 7) over FU plus leucovorin with or without cisplatin was shown in a French randomized phase II trial involving 136 patients with advanced gastric cancer [151]. Compared with FU plus leucovorin alone or with cisplatin, the group receiving FOLFIRI had significantly higher response rates (40 versus 13 and 27 percent, respectively) and significantly longer median PFS (6.9 versus 3.2 and 4.9 months, respectively) and overall survival (11.3 versus 6.8 and 9.5 months, respectively). Roughly similar outcomes (response rates 42 to 44 percent, median survival 10 to 12 months) have been obtained using irinotecan in combination with oral capecitabine [152-154] and using irinotecan plus S-1 [155].

Irinotecan plus cisplatin is also active and well tolerated, particularly when administered weekly [113,156-160]. The superiority of cisplatin (80 mg/m² on day 1 every 28 days) plus irinotecan (70 mg/m² on days 1 and 15) as compared with infusional FU alone was shown in the phase III JCOG 9912 trial (described above) [113]. The response rate (38 versus 9 percent) and PFS (4.8 versus 2.9 months) were both significantly higher with cisplatin plus irinotecan. However, rates of grade 3 or 4 toxicity were also significantly higher (neutropenia [65 versus 1 percent], hyponatremia [23 versus 6 percent], anorexia [33 versus 13 percent], diarrhea [9 versus <1 percent], and nausea [21 versus 7 percent]). (See 'Fluoropyrimidines' above.)

Modest superiority of FOLFIRI over epirubicin plus cisplatin and capecitabine (ECX) was suggested in a French intergroup trial that randomly assigned 416 patients with previously untreated, advanced gastric or EGJ adenocarcinoma to FOLFIRI or ECX [161]. While there was a slight advantage in terms of time to treatment failure that favored FOLFIRI (5.1 versus 4.2 months), there were no significant differences in median PFS, overall survival, or response rates. Furthermore, while FOLFIRI was better tolerated overall (rate of grade 3 or 4 toxicity 69 versus 84 percent with ECX), the difference was only in hematologic adverse events (38 versus 65 percent); the rate of grade 3 or 4 nonhematologic adverse events was nearly identical (53 versus 54 percent).

Triplet regimens — We do not prefer triplet regimens over doublet regimens in patients receiving cytotoxic chemotherapy alone. In our view, these regimens are more toxic than a fluoropyrimidine plus platinum doublet, and they have not been shown to improve overall survival. (See 'Is there an optimal combination regimen?' below.)

Epirubicin, cisplatin, and fluorouracil — ECF (table 8) was associated with a response rate of 71 percent in a report involving 128 patients with advanced disease [162]. In a subsequent randomized trial, 274 patients with advanced esophagogastric adenocarcinoma or undifferentiated cancer were randomly assigned to ECF or FU, doxorubicin, and methotrexate (FAMTX) [5]. ECF was associated with a superior response rate (45 versus 21 percent) and median survival (8.9 versus 5.7 months). ECF caused more alopecia and nausea, while FAMTX was associated with more hematologic toxicity and infections. (See "Treatment protocols for esophagogastric cancer".)

Newer regimens that combine short-term, high-dose infusional FU with leucovorin modulation (eg, FOLFOX), or capecitabine plus cisplatin may be more effective than older regimens in which cisplatin was combined with bolus FU alone [119,163-165]. This has led to questions as to the contribution of the anthracycline to the efficacy of ECF:

●A report of the CALGB 80403 (Alliance) trial, a randomized phase II trial in which cetuximab was added to ECF, irinotecan plus cisplatin, or FOLFOX, concluded that response rates, PFS, and median overall survival were comparable in the ECF and FOLFOX groups [166]. However, this trial included cetuximab in both arms, and it was neither designed nor intended as a noninferiority trial of FOLFOX versus ECF.

●An individual patient data meta-analysis of the Global Advanced/Adjuvant Stomach Tumor Research International Collaboration group concluded that there was no role for epirubicin in combination with a fluoropyrimidine and a platinum agent [167].

Thus, the contribution of the anthracycline and the benefit of ECF over other modern fluoropyrimidine-containing regimens (eg, FOLFOX, XELOX/CAPOX) remain unanswered questions.

●The REAL trial – The REAL trial was a landmark large randomized trial reported in 2008 that compared four different chemotherapy regimens in 1002 patients with advanced gastric cancer: ECF, ECX (table 9), EOF, and EOX (table 10) [133]. The study was sufficiently powered to demonstrate noninferiority. (See "Treatment protocols for esophagogastric cancer".)

As noted above, this trial (and a second one) showed that outcomes were comparable when capecitabine was substituted for infusional FU in the ECF regimen, a finding that was reinforced in a subsequent meta-analysis of both trials. (See 'Cisplatin plus a fluoropyrimidine' above.)

They also showed, as did the meta-analysis [150], that outcomes were comparable when oxaliplatin was substituted for cisplatin in the ECF regimen. (See 'Oxaliplatin combinations' above.)

Docetaxel-containing — Most (but not all [168]) docetaxel combinations with cisplatin, FU, capecitabine, or irinotecan are active in advanced gastric and gastroesophageal adenocarcinoma and esophageal SCC, but more toxic than doublet regimens [169-183].

●Docetaxel, cisplatin, and FU (DCF) and modified DCF – The DCF (or TCF) regimen (table 11) was compared with cisplatin plus FU alone in the multinational TAX-325 trial, which enrolled 457 patients with chemotherapy-naïve advanced gastric cancer [169]. The group receiving docetaxel did significantly better in terms of response rate (37 versus 25 percent), time to tumor progression (5.6 versus 3.7 months), and two-year survival (18 versus 9 percent). The incidence of grade 3 or 4 diarrhea (20 versus 8 percent) and neutropenia (30 versus 14 percent) was higher with triplet therapy.

Based on these results, docetaxel was approved in the United States and Europe, in combination with cisplatin and FU, for the treatment of advanced gastric cancer. However, the contribution of cisplatin remains uncertain. Similar results (overall response rate 38 percent, median survival 9.5 months) are reported using docetaxel and infusional FU without cisplatin [172].

A modified schedule of DCF is associated with preserved efficacy and improved tolerability (table 12) [184]. In a randomized comparison of modified DCF (without prophylactic growth factor support) versus standard DCF (with growth factor support) in 85 patients with previously untreated, metastatic gastric adenocarcinoma, modified DCF was more efficacious (median overall survival 18.8 versus 12.6 months) and, even without growth factor support, less toxic [185]. (See "Treatment protocols for esophagogastric cancer".)

●Docetaxel, oxaliplatin, and FU – Docetaxel, oxaliplatin, infusional FU, and leucovorin (FLOT) is a commonly used regimen in the neoadjuvant setting for gastric cancer. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'FLOT'.)

At least two trials have explored the benefit of taxane-, fluoropyrimidine-, and oxaliplatin-containing triplet therapy compared with an oxaliplatin-containing doublet, and they have come to opposite conclusions:

•In one trial, 143 patients aged 65 or older with locally advanced or metastatic esophagogastric cancer were randomly assigned to FOLFOX with or without docetaxel 50 mg/m² every two weeks [132]. There was a trend toward longer PFS with triplet therapy, but there was no difference in overall survival. Furthermore, triplet therapy was also associated with significantly worse toxicity.

•In the second randomized phase II trial, 248 patients with locally recurrent or metastatic gastric adenocarcinoma were randomly assigned to docetaxel plus oxaliplatin; docetaxel, oxaliplatin, and FU (TEF); or docetaxel, oxaliplatin, and capecitabine (TEX) [131]. The TEF combination proved superior for objective response rate (46 versus 26 and 23 percent for TEX and docetaxel plus oxaliplatin, respectively) and median PFS (7.66 versus 5.55 and 4.50 months, respectively). The frequency and type of adverse events were similar across all three groups.

Is there an optimal combination regimen? — As noted above, there is no globally accepted first-line chemotherapy regimen for advanced, HER2-negative esophagogastric cancer, and practice is variable [186]. Although multiple trials have been conducted of different chemotherapy regimens for first-line therapy, direct comparisons (head-to-head phase III randomized trials) of many regimens are lacking. When multiple specific interventions are compared across trials, a network of studies can be established where all the studied interventions are linked to each other by individual trials. Network meta-analysis (also termed "mixed treatment comparison" or "multiple treatment comparison") evaluates all studies and all interventions simultaneously to produce multiple pairwise estimates of the relative effects of each intervention compared with every other intervention, allowing both direct and indirect comparisons to be made.

A network meta-analysis of first-line chemotherapy for advanced esophagogastric cancer that incorporated 17 different chemotherapy regimens with 37 direct comparisons for overall survival (50 trials, 10,249 patients) and PFS (34 trials, 7795 patients) came to the following conclusions combining direct and indirect effects [17]:

●All treatments resulted in better overall survival and PFS as compared with best supportive care alone, except for anthracycline monotherapy. Fluoropyrimidine- and non-cisplatin-containing doublets, fluoropyrimidine-cisplatin doublets, and all triplet regimens showed significant gains in overall survival compared with a fluoropyrimidine alone.

●A fluoropyrimidine doublet containing oxaliplatin or irinotecan significantly improved overall survival compared with a fluoropyrimidine plus cisplatin (for a fluoropyrimidine plus irinotecan, the HR for death was 0.85, 95% CI 0.71-0.99; for a fluoropyrimidine plus oxaliplatin, the HR was 0.83, 95% CI 0.71-0.98). The cisplatin-fluoropyrimidine doublet was also associated with more grade 3 or 4 toxicity.

●Anthracycline-containing triplets (eg, ECF, EOX) and the docetaxel-containing triplet DCF showed no benefit over fluoropyrimidine doublets in either overall survival or PFS, and they were more toxic.

●A triplet regimen containing a fluoropyrimidine, oxaliplatin, and a taxane (eg, TEX, TEF) significantly improved PFS (but not overall survival) when compared with a fluoropyrimidine doublet with a taxane (HR for progression 0.61, 95% CI 0.38-0.99), a fluoropyrimidine plus irinotecan (HR 0.62, 95% CI 0.38-0.99), and a fluoropyrimidine plus oxaliplatin (HR 0.67, 95% CI 0.44-0.99). Furthermore, the triplet regimen was more toxic than a fluoropyrimidine plus oxaliplatin.

●Overall, based on efficacy and toxicity, fluoropyrimidine doublets (a fluoropyrimidine plus oxaliplatin, a fluoropyrimidine plus a taxane, or a fluoropyrimidine plus irinotecan) were preferred as first-line therapy over cisplatin doublets, anthracycline triplets, and DCF.

Chemotherapy dosing in older and frail patients — At least with the CAPOX regimen, dose attenuation does not compromise outcomes and that starting treatment with lower initial doses in frail/older individuals is a reasonable strategy. whether this general principle of dose-attenuated therapy applies to other chemotherapy regimens are both not clear.

Most trials of palliative chemotherapy have not included frail or older patients, and the benefits and risks of chemotherapy in these patients are less certain. At least some data suggest that lower initial chemotherapy doses provide noninferior cancer control and better tolerability in this setting.

Optimal chemotherapy dosing for the XELOX/CAPOX regimen was addressed in a trial in which 514 older/frail patients with advanced esophagogastric cancer, including SCC histology, with an adequate baseline comprehensive geriatric assessment, a glomerular filtration rate (GFR) ≥30 mL/min and a total bilirubin <2 times the upper limit of normal (ULN) were randomly assigned to standard 21-day cycles of oxaliplatin (130 mg/m² on day 1) plus capecitabine (625 mg/m² twice daily on days 1 to 21), the same regimen with 80 percent of the usual doses, or the same regimen with 60 percent of the usual doses [187]. All patients with a GFR of 30 to 50 mL/min or a total bilirubin of 1.5 to 2 times the ULN received 75 percent of the allocated capecitabine doses. Noninferiority of the lower-dose regimens was assessed primarily using PFS at 12 months, with a noninferiority boundary of 1.34. Patient experience during chemotherapy was assessed using overall treatment utility (OTU), a composite outcome based on clinician-assessed clinical benefit and patient-assessed tolerability, quality of life, and perceived satisfaction with treatment. A good OTU required clinical benefit as scored by the clinician plus patient satisfaction with treatment, no major toxicity, and no decline in quality of life. By contrast, a poor OTU required both a clinician score of "no benefit" and patient dissatisfaction with treatment, major toxicity or deterioration in quality of life, or patient death during treatment.

Overall, the lowest doses tested provided noninferior cancer control and the best patient experience (as assessed by the OTU, toxicity, and quality of life). Compared with standard doses, noninferiority was confirmed for both the 80 percent dose regimen (HR for PFS 1.09, 95% CI 0.89-1.32) and the 60 percent dose regimen (HR 1.10, 95% CI 0.90-1.33). Median overall survival was comparable in all three groups (7.5, 6.7, and 7.6 months, respectively). No subgroup (age, performance status, extent of frailty, baseline geriatric assessment) clearly benefited from higher-dose therapy. The study did not address whether clinicians should subsequently attempt dose escalation if initial doses of XELOX/CAPOX are tolerated.

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. In communities with persistently high viral transmission rates, important issues include balancing the risk from delaying cancer treatment versus harm from COVID-19, minimizing the number of clinic and hospital visits to reduce exposure whenever possible, mitigating the negative impacts of social distancing on delivery of care, and appropriately and fairly allocating limited health care resources. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

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".)

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 topics (see "Patient education: Esophageal cancer (The Basics)" and "Patient education: Stomach cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●General considerations – The goals of chemotherapy in patients with advanced esophagogastric cancer are symptom palliation, improved quality of life, and prolonged survival. (See 'Goals of therapy' above.)

All patients should have a full assessment of symptom burden, and social supports prior to starting chemotherapy. Early referral and initiation of interdisciplinary and palliative care services improve outcomes. (See 'Importance of early supportive care' above.)

Biomarker assessment has become critically important for selecting the initial approach to systemic therapy:

•All patients with unresectable, locally advanced, recurrent, or metastatic gastric or esophageal adenocarcinoma who are potential candidates for trastuzumab should have their tumors assayed for human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification using specific criteria developed for esophagogastric adenocarcinomas. (See 'Assessment of HER2 status and selection of candidates for trastuzumab' above.)

•All patients regardless of histology should have their tumors assayed for deficient mismatch repair (dMMR)/high levels of microsatellite instability (MSI-H), and for overexpression of programmed cell death ligand 1 (PD-L1)(See 'Choice of therapy and the importance of biomarker assessment' above.)

●Treatment selection – We base our decisions for first-line therapy on histology and biomarker expression. We prefer enrollment in a clinical trial if available. If trials are unavailable or participation is not feasible, our general approach to first-line systemic therapy for metastatic esophagogastric cancer is outlined in the algorithm (algorithm 1) and summarized below.

•Squamous cell cancer (SCC) – Regardless of PD-L1 overexpression, we suggest -chemotherapy plus immunotherapy rather than chemotherapy alone (Grade 2B). (See 'Patients unselected for biomarkers' above.)

Although the chemotherapy backbone in the CheckMate and KEYNOTE studies was cisplatin plus fluorouracil (FU), many clinicians, including some of the authors and editors associated with this topic review, prefer pembrolizumab or nivolumab in combination with an oxaliplatin-based regimen such as oxaliplatin plus leucovorin with bolus plus short-term FU (FOLFOX, (table 13)). Where available (mainly China), camrelizumab in combination with paclitaxel and cisplatin is an appropriate alternative. (See 'Selection of the chemotherapy backbone for combined therapy' above.)

•Adenocarcinoma

-HER2-overexpression – For patients with HER2-positive (3+ immunohistochemistry staining or in situ hybridization positivity) adenocarcinomas with no contraindication to trastuzumab, we suggest trastuzumab plus platinum-based chemotherapy rather than chemotherapy alone (Grade 2B). (See 'Assessment of HER2 status and selection of candidates for trastuzumab' above and 'Benefit of trastuzumab' above.)

We also suggest adding pembrolizumab to initial trastuzumab plus fluoropyrimidine- and platinum-based chemotherapy (Grade 2C). (See 'Specific chemotherapy backbone' above and 'Adding pembrolizumab' above.)

The optimal chemotherapy backbone for patients receiving trastuzumab is not established. For most patients, we prefer FOLFOX (table 13) or oxaliplatin plus capecitabine (XELOX/CAPOX (table 14)).

-PD-L1-overexpression – For patients with HER2-negative, PD-L1 overexpressing (combined positive score [CPS ≥5]) adenocarcinomas we suggest immunotherapy (nivolumab or pembrolizumab) plus an oxaliplatin-containing chemotherapy regimen (eg, FOLFOX (table 1) or XELOX/CAPOX (table 15)) rather than systemic chemotherapy alone (Grade 2B). (See 'Combined immunotherapy plus chemotherapy' above.)

For individuals with very high levels of PD-L1 overexpression (CPS ≥10) who have asymptomatic nonbulky tumors, pembrolizumab monotherapy (table 16) is another option. (See 'Pembrolizumab monotherapy' above.)

-dMMR/MSI-H – For patients with dMMR/MSI-H tumors, most of whom have high levels of PD-L1 overexpression, we suggest nivolumab plus oxaliplatin-containing chemotherapy (FOLFOX, XELOX/CAPOX) rather than chemotherapy alone (Grade 2C). (See 'Deficient mismatch repair' above and 'Selection of the chemotherapy backbone for combined therapy' above.)

Pembrolizumab monotherapy is another option. (See 'Deficient mismatch repair' above.)

-No molecular marker or contraindication to targeted therapy – The benefits of immunotherapy for adenocarcinomas with low-level (CPS 1 to 4) or no PD-L1 expression is uncertain. Although opinion differs, we suggest initial chemotherapy alone rather than immunotherapy plus chemotherapy in these patients (Grade 2C). (See 'Patients unselected for biomarkers' above.)

-For patients who are not receiving trastuzumab or immunotherapy first-line either because they lack a molecular biomarker, or who have a contraindication, intolerance, or a lack of reimbursement, the choice of cytotoxic chemotherapy regimen is empiric. In general, combination regimens provide higher response rates than monotherapy, but only modestly longer durations of disease control and survival. (See 'Combination chemotherapy' above.)

For patients who are candidates for aggressive therapy, we suggest a fluoropyrimidine-containing doublet rather than a triplet regimen (Grade 2B). For most patients, we prefer FOLFOX (table 1), or XELOX/CAPOX (table 15), or where available, S-1 plus oxaliplatin; other reasonable alternatives include FU plus cisplatin, or S-1 plus cisplatin. (See 'Is there an optimal combination regimen?' above and 'Oxaliplatin combinations' above and 'Cisplatin plus a fluoropyrimidine' above.)

For older patients and those with a poor performance status or significant comorbidity, we would choose leucovorin-modulated FU alone or single-agent capecitabine. Other reasonable alternatives are single-agent irinotecan, low-dose weekly taxanes, or dose-attenuated XELOX/CAPOX. (See 'Single-agent chemotherapy' above and 'Chemotherapy dosing in older and frail patients' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Panos Fidias, MD, and Johanna Bendell, MD, who contributed to an earlier version of this topic review.