Overview
The incidence of gastric cancer has decreased substantially in the United States and Western Europe over the past several decades.1–4 However, gastric cancer still constitutes a major global health problem, especially in East Asian countries.5,6 Globally, there were more than 1 million cases resulting in more than 768,000 deaths in 2020, making gastric cancer the fifth most frequently diagnosed cancer and the third leading cause of cancer-related deaths in the world.7,8 The global incidence of gastric cancer shows wide geographic variation, with a 15- to 20-fold difference between high- and low-incidence regions.1 The highest gastric cancer incidence rates occur in Northeast Asia, South and Central America, and Eastern Europe.5,6 Rates are particularly high in Japan and Korea, where gastric cancer is the most commonly diagnosed cancer in men, and in China, where gastric cancer is a leading cause of cancer-related mortality.5,6,9 In contrast, gastric cancer is one of the least commonly diagnosed cancers in Western Europe, sub-Saharan Africa, Australia, and North America.6 In the United States, an estimated 26,560 people were to be diagnosed and 11,180 people were expected to die of this disease in 2021, making gastric cancer the 16th most commonly diagnosed cancer and the 17th leading cause of cancer-related death in the United States.4,10,11 Despite overall declining rates, recent evidence suggests that the incidence of early-onset gastric cancer may be rising in the United States.12
More than 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location (cardia/proximal or noncardia/distal) and histologic type (diffuse or intestinal).3 The diffuse type, which is characterized by poorly differentiated and discohesive tumor cells with a signet-ring or non–signet-ring morphology diffusely infiltrating the gastric wall in a desmoplastic stroma, is more prevalent in low-risk areas and is mostly associated with heritable genetic abnormalities.3,9,13–15 The intestinal type, which tends to form a mass lesion and is characterized by variably differentiated tumor cells arranged in a tubular or glandular pattern with scattered goblet cells present, occurs more frequently in high-risk areas and accounts for most of the geographic variation seen with this disease. Intestinal type gastric cancer is often related to environmental factors such as Helicobacter pylori infection, tobacco smoking, high salt intake, and other dietary factors.3,9,13–15 However, the role of alcohol as a risk factor for gastric cancer is without consensus. While the results of several meta-analyses have shown no appreciable association between light or moderate alcohol consumption and gastric cancer risk, they did show a positive association between heavy alcohol use and gastric cancer, particularly noncardia gastric cancer.16–19
A dramatic shift in the type and location of upper gastrointestinal tract tumors has occurred in North America and Europe.2,20,21 There has been a marked decline in intestinal type gastric cancers of the distal stomach in North American and Western European countries over the past several decades, mainly due to enhanced access to clean drinking water, improved food preservation, an average diet with low promotion of gastric cancer, and H pylori eradication.1–4,15 However, incidence rates of diffuse type gastric cancer of the proximal stomach are rising.1–3 The etiology of this increase remains elusive and may be multifactorial. In contrast to the incidence trends in high income countries, tumors of the distal stomach continue to predominate in low and middle income countries.2 Gastric cancer generally carries a poor prognosis since it is often diagnosed at an advanced stage. In Japan and South Korea, where population screening is performed widely, early detection often results in improved outcomes.1,6 In the United States, survival rates from gastric cancer remain poor as early detection continues to pose a major challenge for health care professionals.
This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease (to view the complete and most recent version of these Guidelines, visit NCCN.org).
Staging
The tumor (T), node (N), and metastasis (M) staging system used by the AJCC is the internationally accepted standard for cancer staging and is a major factor influencing prognosis and treatment decisions. Staging recommendations for gastric cancer presented in the eighth edition of the AJCC Cancer Staging Manual include clinical staging (cTNM; newly diagnosed, not-yet-treated patients), pathologic staging (pTNM; patients undergoing resection without prior treatment), and post neoadjuvant pathologic staging (ypTNM; patients receiving preoperative therapy).22 The eighth edition also introduced modifications regarding tumors located at the esophagogastric junction (EGJ) and within the gastric cardia. Using this system, tumors involving the EGJ with an epicenter located >2 cm into the proximal stomach are now staged as gastric carcinomas. Tumors involving the EGJ with an epicenter ≤2 cm into the proximal stomach will still be staged as esophageal carcinomas. Cancers located within the gastric cardia that do not involve the EGJ are staged as gastric carcinomas.
The eighth edition of the AJCC Cancer Staging Manual provides additional resources for gastric cancer not available in the seventh edition, including the addition of new cTNM and ypTNM stage groupings, to fulfill unmet needs in staging patients under different circumstances. Due to the lack of an official clinical stage classification in the past, treating physicians have typically used the pathologic stage to clinically stage patients. Furthermore, due to the lack of yp stage groupings, pathologic staging was also applied to patients who had received preoperative therapy. The use of pathology assessments to establish cTNM and ypTNM stages has never been validated and may not be appropriate. Therefore, new cTNM and ypTNM stage groupings and prognostic information were added to the eighth edition to overcome these issues. New clinical stage groupings and prognostic information are based on datasets from the National Cancer Database, representing patients treated surgically or nonsurgically in the United States, and the Shizuoka Cancer Center dataset, representing patients treated surgically in Japan, for a total of 4,091 patients. These clinical stage groupings are different from groupings used for pathologic or post-neoadjuvant staging. The prognostic value of the newly proposed cTNM stage criteria has been externally validated in a cohort of 4,374 surgically treated gastric cancer patients in Japan.23 Newly provided prognostic information for ypTNM staging is presented using only the 4 broad stage categories (stage I–IV) due to the limited number of patients (n=700) available for analysis. The addition of this new ypTNM stage grouping system fulfills an unmet need in the clinics because many patients with gastric cancer are now treated with preoperative therapy. Furthermore, the stage groupings and prognostic information for pTNM staging presented in the Eighth Edition are now based on data from >25,000 patients with gastric cancer from the International Gastric Cancer Association (IGCA) database who have had surgery with adequate lymph node removal. Patients treated with preoperative therapy were not included in the analysis. Pathologic stage groupings were refined based on 5-year survival data. Although most (84.8%) of the eligible cases from the IGCA database came from Japan and Korea, the predictive ability and accuracy of parameters used in the eighth edition for pTNM staging of gastric cancer have been validated for United States populations.24,25 The new pTNM staging classification criteria have also been externally validated in a cohort with a higher proportion of advanced disease than the IGCA cohort (49% had stage III disease compared with 26% in the IGCA cohort, P<.001).26 However, limitations of this dataset still remain, including a lack of uniformity in initial clinical stage assessments, the lack of a uniform surgical approach, and the use of pTNM assessments for ypTNM staging.22
Baseline clinical stage provides useful information for the development of an initial treatment strategy. The availability of diagnostic modalities such as endoscopic ultrasound (EUS), CT, 18- FDG–PET/CT, and laparoscopy has greatly improved baseline clinical staging of gastric cancer.27–29 EUS is indicated for assessing the depth of tumor invasion (T category) as well as nodal involvement (N category).30 However, the diagnostic accuracy of EUS is operator dependent, ranging from 57% to 88% for T staging and 30%–90% for N staging.31 In a large multi-institutional study that evaluated the use and accuracy of EUS in patients undergoing curative intent resection for gastric adenocarcinoma, the overall accuracy of EUS was 46.2% for T category and 66.7% for N category.32 Distant lymph node evaluation by EUS is also suboptimal given the limited depth and visualization of the transducer.33 EUS may be useful for differentiating T3 and T4 tumors, but it should be used in combination with other staging modalities.31,32 EUS is also useful to identify superficial tumors for potential endoscopic approaches. Therefore, EUS should be used if early-stage disease is suspected or if early versus locally advanced disease needs to be determined.
CT scanning is routinely used for preoperative staging and has an overall accuracy of 43%–82% for measuring depth of invasion. In contrast, FDG-PET has a lower accuracy rate because of low FDG uptake in diffuse and mucinous tumor types, which are common in gastric cancer.34,35 FDG-PET also has significantly lower sensitivity compared with CT in the detection of local lymph node involvement (56% vs 78%), although FDG-PET has improved specificity (92% vs 62%).36 Thus, combined FDG-PET/CT imaging offers several potential advantages over FDG-PET or CT scans alone.37 FDG-PET/CT has a significantly higher accuracy rate in preoperative staging (68%) than FDG-PET (47%) or CT (53%) alone. Additionally, reports have confirmed that FDG-PET alone is not an adequate diagnostic procedure in the detection and preoperative staging of gastric cancer, but can be helpful when used in conjunction with CT.38,39 FDG-PET does not take the place of staging laparoscopy given its failure to detect peritoneal disease.
Pretreatment diagnostic laparoscopy can be used to detect occult metastases. In a study conducted at Memorial Sloan Kettering Cancer Center, 657 patients with potentially resectable gastric adenocarcinoma underwent laparoscopic staging over a period of 10 years.40 Metastatic disease (M1) was detected in 31% of patients. However, limitations of laparoscopic staging include 2-dimensional evaluation and limited use in the identification of hepatic metastases and perigastric lymph nodes. Cytology testing of peritoneal fluid can help improve laparoscopic staging through identification of occult carcinomatosis.27 Positive peritoneal cytology is associated with a poor prognosis in patients with gastric cancer and is an independent predictor for recurrence following curative resection.41–43 Clearing of cytology-positive disease by chemotherapy is associated with a statistically significant improvement in disease-specific survival, but cures are rare and the role of surgery is uncertain.42 Therefore, positive peritoneal cytology even in the absence of visible peritoneal implants should be considered as M1 disease, and surgery as initial treatment is not recommended. In patients being considered for surgical resection without preoperative therapy, laparoscopy may be useful for the detection of radiographically occult metastatic disease in patients with T3 and/or N+ tumors identified on preoperative imaging. The panel recommends performing diagnostic laparoscopy to assess the peritoneal cavity (with biopsies as needed) and cytology of peritoneal washings in medically fit patients with potentially resectable stage cT1b or higher locoregional disease when considering preoperative chemoradiation and/or surgery.40 Laparoscopy with cytology can be considered for medically fit patients with surgically unresectable disease.
In most countries, where screening programs for early detection of gastric cancer are not in use or practical because of low incidence, diagnosis is often made late in the disease course. Approximately 50% of patients present with advanced disease at diagnosis and will likely have a poor outcome. Other measures of poor outcome include poor performance status, presence of metastases, and an alkaline phosphatase level ≥100 U/L.44 Additionally, nearly 80% of patients have involvement of the regional lymph nodes and the number of positive lymph nodes has a profound influence on survival.45 In patients with localized resectable disease, outcome depends on the surgical stage of the disease.
Pathologic Review and Biomarker Testing
Pathologic review and biomarker testing play important roles in the diagnosis, classification, and molecular characterization of gastric cancer. Classification based on histologic subtype and molecular features helps improve early diagnosis and has implications for therapy. An accumulation of genetic aberrations occurs during gastric carcinogenesis, including overexpression of growth factors and/or receptors, alterations in DNA damage response, and loss of genomic stability. Characterization of these pathways has enabled the application of molecular pathology to aid in the diagnosis, classification, and treatment of gastric cancer.15
Principles of Pathologic Review
A specific diagnosis of gastric adenocarcinoma should be established for staging and treatment purposes. Subclassification of gastric adenocarcinoma as intestinal or diffuse type may have implications for therapy since intestinal type tumors are more likely to be HER2 overexpression positive (see “Assessment of HER2 Overexpression,” page 174). In addition to the histologic type, the pathology report (regardless of the specimen type) should include specifics about tumor invasion and pathologic grade, which are required for staging (see GAST-B page 1 of 6, page 171). Universal testing for MSI by PCR/next-generation sequencing (NGS) or mismatch repair (MMR) deficiency by immunohistochemistry (IHC) is recommended in all newly diagnosed patients. The pathology report of endoscopic mucosal resection specimens should include an assessment of lymphovascular invasion, depth of tumor invasion, tumor diameter and the status of mucosal and deep margins. Pathology reports of gastrectomy specimens without prior chemoradiation should also document the location of the tumor midpoint in relationship to the EGJ, whether the tumor crosses the EGJ, the lymph node status, and the number of lymph nodes recovered. In the case of gastrectomy with prior chemoradiation and without grossly obvious residual tumor, the tumor site should be thoroughly sampled to detect microscopic residual disease. The pathology report should include all of the above elements plus an assessment of treatment effect.
Principles of Biomarker Testing
Presently, IHC and/or molecular testing for HER2/ERBB2 status, MSI or MMR status, PD-L1 expression, tumor mutation burden-high (TMB-H) status, and neurotrophic tropomyosin-related kinase (NTRK) gene fusions are implicated in the clinical management of advanced gastric cancer. When limited tissue is available for testing or the patient is unable to undergo a traditional biopsy, comprehensive genomic profiling via a validated NGS assay performed in a CLIA-approved environment may be used for the identification of ERBB2 amplification, MSI status, MMR deficiency, TMB and NTRK gene fusions. The use of IHC, in situ hybridization (ISH), or targeted PCR should be considered first, followed by NGS testing as appropriate.
Assessment of HER2 Overexpression
Overexpression of the HER2 protein or amplification of the ERBB2 gene has been implicated in the development of gastric adenocarcinoma.46 However, unlike in breast cancer, the prognostic significance of HER2 status in gastric cancer is unclear. Some studies suggest that HER2 positivity is associated with poor prognosis47–52 whereas others have shown that it is not an independent prognostic factor of patient outcome, except in a very small subgroup of patients with intestinal histology.53–55 Although further studies are needed to assess the prognostic significance of HER2 status in gastric cancer, the addition of HER2 monoclonal antibodies to chemotherapy regimens is a promising treatment option for patients with HER2 overexpression positive disease.
The reported rates of HER2 positivity in patients with gastric cancer range from 12% to 23%.48,49,54–57 HER2 positivity also varies with the histologic subtype (intestinal > diffuse) and tumor grade (moderately differentiated greater than poorly differentiated).49,54–56 HER2 positivity is reported in ≤20% of European and United States patients with metastatic gastric cancer with significantly higher rates seen in patients with intestinal histology (33% vs 8% for diffuse/mixed histology; P=.001).54 In the US population, the reported HER2 positivity rate in gastric cancer is 12% and is more often identified in the intestinal subtype rather than the diffuse subtype (19% and 6%, respectively).55 The HER-EAGLE study, which examined the HER2 positivity rate in a large multinational population of nearly 5,000 patients with gastric or EGJ adenocarcinoma, reported that 14.2% of samples were HER2 overexpression positive.58 HER2 positivity was significantly higher in males versus females, in EGJ tumors versus stomach tumors, and in intestinal subtypes versus diffuse subtypes. In the ToGA trial that evaluated the addition of trastuzumab to chemotherapy in patients with HER2 overexpression positive advanced gastric or EGJ cancers, HER2 positivity rates were 32.2%, 21.4%, 31.8%, and 6.1%, respectively, in patients with EGJ adenocarcinoma, gastric adenocarcinoma, intestinal gastric adenocarcinoma, and diffuse gastric adenocarcinoma.59,60 Therefore, subclassification of gastric adenocarcinomas as intestinal or diffuse type may have implications for therapy.
HER2 testing is recommended for all patients with gastric cancer at diagnosis if metastatic disease is documented or suspected (see GAST-1 and 1A, pages 168 and 169). In concordance with HER2 testing guidelines from the College of American Pathologists, the American Society for Clinical Pathology, and ASCO,61 the NCCN Guidelines recommend using IHC and, if needed, ISH techniques to assess HER2 status in gastric cancer (see GAST-B 3 of 6, page 172). NGS can be considered instead of sequential testing for single biomarkers when limited diagnostic tissue is available or when the patient is unable to undergo a traditional biopsy. The use of IHC/ISH should be considered first, followed by NGS testing as appropriate. Repeat biomarker testing may be considered at clinical or radiologic progression of advanced or metastatic disease.
IHC evaluates the membranous immunostaining of tumor cells, including the intensity and extent of staining and the percentage of immunoreactive tumor cells, with scores ranging from 0 (negative) to 3+ (positive). In 2008, Hofmann et al62 refined this 4-tiered scoring system to assess HER2 status in gastric cancer by using a cut-off of ≥10% immunoreactive tumor cells.60 In a subsequent validation study (n=447 prospective diagnostic gastric cancer specimens), this scoring system was found to be reproducible between different pathologists.63 This modified HER2 scoring system is therefore recommended by the panel. A score of 0 (membranous reactivity in <10% of cancer cells) or 1+ (faint membranous reactivity in ≥10% of cancer cells) is considered to be HER2-negative. A score of 2+ (weak to moderate membranous reactivity in ≥10% of cancer cells) is considered equivocal and should be additionally examined by fluorescence in situ hybridization (FISH) or other ISH methods. FISH/ISH results are expressed as the ratio between the number of copies of the ERBB2 gene and the number of chromosome 17 centromeres (CEP17) within the nucleus counted in at least 20 cancer cells (ERBB2:CEP17). Alternatively, FISH/ISH results may be given as the average ERBB2 copy number per cell. Cases that have an IHC score of 3+ (strong membranous reactivity in ≥10% of cancer cells) or an IHC score of 2+ and are FISH/ISH positive (ERBB2:CEP17 ratio ≥2 or average ERBB2 copy number ≥6 signals/cell) are considered HER2 overexpression positive. Positive (3+) or negative (0 or 1+) HER2 IHC results do not require further ISH testing.
MSI or MMR Testing
Universal testing for MSI by PCR/NGS or MMR by IHC should be performed for all newly diagnosed gastric cancer patients (see GAST-1/1A). MSI status is assessed by PCR to measure gene expression levels of microsatellite markers (ie, BAT25, BAT26, MONO27, NR21, NR24).64 MMR deficiency is evaluated by IHC to assess nuclear expression of proteins involved in DNA mismatch repair (ie, MLH1, MSH2, MSH6, PMS2).65 PCR/NGS for MSI and IHC for MMR proteins measure different biologic effects caused by deficient MMR function. Testing is performed on formalin-fixed, paraffin-embedded tissue and results are interpreted as MSI-high (MSI-H) or MMR-deficient (dMMR) in accordance with College of American Pathologists DNA Mismatch Repair Biomarker Reporting Guidelines (see GAST-B 4 of 6, page 173).66 Patients with MSI-H or dMMR tumors should be referred to a genetics counselor for further assessment in the appropriate clinical context.
PD-L1 Testing
PD-L1 testing may be considered on locally advanced, recurrent, or metastatic gastric cancers in patients who are candidates for treatment with PD-1 inhibitors (see GAST-B 4 of 6, page 173). A US FDA approved companion diagnostic test should be used to identify patients for treatment with PD-1 inhibitors. The companion diagnostic test is a qualitative IHC assay using anti-PD-L1 antibodies for the detection of PD-L1 protein levels in formalin-fixed, paraffin-embedded tumor tissue. A minimum of 100 tumor cells must be present in the PD-L1-stained slide for the specimen to be adequately evaluated. Combined positive score (CPS) is determined by the number of PD-L1-stained cells (ie, tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells evaluated, multiplied by 100. A specimen is considered to have PD-L1 expression if the CPS ≥1. Tumor proportion score is also considered and reported in some trials.
Liquid Biopsy
The genomic alterations of solid cancers may be identified by evaluating circulating tumor DNA (ctDNA) in the blood, hence a form of “liquid biopsy.”51,67 Liquid biopsy is being used more frequently in patients with advanced disease, particularly those who are unable to have a clinical biopsy for disease surveillance and management. The detection of mutations/alterations in DNA shed from gastric carcinomas can identify targetable alterations or the evolution of clones with altered treatment response profiles. In one study, a complete or partial response to immunotherapy was achieved by 63% of patients with advanced gastric carcinoma who tested positive for MSI by cell-free DNA analysis.67 In another study that analyzed the genomic alterations of 55 patients with advanced gastroesophageal adenocarcinomas using NGS performed on plasma-derived ctDNA, 69% of patients had ≥1 characterized alteration theoretically targetable by an FDA-approved agent (on- or off-label).51 Therefore, for patients who have advanced or metastatic gastric cancer and who may be unable to undergo a traditional biopsy or for disease progression monitoring, testing using a validated NGS-based comprehensive genomic profiling assay performed in a CLIA-approved laboratory may be considered (see GAST-B 5 of 6, page 174). A negative result should be interpreted with caution, as this does not exclude the presence of tumor mutations or amplifications.
Treatment Guidelines
The management of patients with gastric cancer requires the expertise of several disciplines, including surgical oncology, medical oncology, radiation oncology, gastroenterology, radiology, and pathology. In addition, the presence of nutritional services, social workers, nurses, palliative care specialists, and other supporting disciplines is also desirable.68 Hence, the panel believes in an infrastructure that encourages multidisciplinary treatment decision-making by members of all disciplines taking care of patients with gastric cancer (see GAST-E, page 175). The recommendations made by the multidisciplinary team may be considered advisory to the primary group of treating physicians.
Workup
Newly diagnosed patients should receive a complete history and physical examination, complete blood count (CBC), comprehensive chemistry profile, and upper gastrointestinal endoscopy with biopsy of the primary tumor (see GAST-1 and GAST-1A, pages 168 and 169). CT scan (with oral and intravenous contrast) of the chest, abdomen, and pelvis should also be performed. FDG-PET/CT evaluation from skull base to midthigh is recommended, if clinically indicated and if metastatic disease is not evident (may not be appropriate for T1 disease). EUS should be performed if early-stage disease is suspected or if early-stage versus locally advanced disease needs to be determined (preferred). Endoscopic resection is essential for the accurate staging of early-stage cancers (T1a or T1b); early-stage cancers can best be diagnosed by endoscopic resection. Endoscopic resection may also be therapeutic for early-stage disease. Biopsy of metastatic disease should be performed as clinically indicated. Assessment of Siewert tumor type should also be included as part of the initial workup in all patients with EGJ adenocarcinoma.69,70 Nutritional assessment and counseling as well as smoking cessation advice, counseling, and pharmacotherapy (as indicated) are recommended for all patients.
Universal testing for MSI by PCR/NGS or MMR by IHC is recommended in all newly diagnosed patients. HER2 and PD-L1 testing are recommended at the time of diagnosis if metastatic disease is documented or suspected. NGS may be considered via a validated assay. The guidelines also recommend screening for family history of gastric cancers. Referral to a cancer genetics professional is recommended for those with a family history or a known high-risk syndrome associated with gastric cancer.
Initial workup enables patients to be classified into 3 clinical stage groups:
Localized cancer (stages cTis or cT1a)
Locoregional cancer (stages cT1b–cT4a; cM0)
Metastatic cancer (stage cT4b; cM1)
Unresectable Locally Advanced, Recurrent, or Metastatic Disease
Management of unresectable or metastatic disease may include either systemic therapy and/or chemoradiation with the goal of providing symptom relief and delaying progression, and should incorporate symptom-directed best supportive care (See “Palliative/Best Supportive Care,” page 186). If not done previously, HER2, PD-L1, and MSI or MMR testing should be performed in patients with documented or suspected metastatic adenocarcinoma. NGS may be considered via a validated assay (see GAST-9, page 170).
The decision to offer palliative/best supportive care alone or with systemic therapy is dependent on the patient’s performance status. The ECOG Performance Status (PS) Scale and the Karnofsky PS Scale (KPS) are commonly used to assess the performance status of patients with cancer.71–73 Patients with higher ECOG PS scores are considered to have worse performance status while lower KPS scores are associated with worse survival for most serious illnesses. Patients with a KPS score <60% or an ECOG PS score ≥3 should be offered palliative/best supportive care only. Systemic therapy or chemoradiation (only if locally unresectable and not previously received) can be offered in addition to palliative/best supportive care for patients with better performance status (KPS score of ≥60% or ECOG PS score ≤2).
The survival benefit of systemic therapy compared with palliative/best supportive care alone for patients with advanced gastric cancer has been shown in several randomized trials.74–77 In an early comparison between chemotherapy and best supportive care versus best supportive care alone, overall survival (OS; 8 vs 5 months) and time to progression (5 vs 2 months) were longer in patients receiving chemotherapy in addition to best supportive care for advanced gastric cancer.74 More patients in the chemotherapy group (45%) had an improved or prolonged quality of life for a minimum of 4 months compared with those who received best supportive care alone (20%). In a more recent randomized phase III study, the addition of second-line chemotherapy with irinotecan significantly prolonged OS compared with best supportive care alone in patients with metastatic or locally advanced gastric or EGJ adenocarcinoma (n=40).75 Median survival was 4 months in the irinotecan and best supportive care group compared with 2.4 months in the best supportive care alone group. However, the study was closed prematurely due to poor accrual. In a larger randomized trial (n=193), second-line chemotherapy with irinotecan (or docetaxel) was also found to significantly improve OS compared with best supportive care alone (5.1 vs 3.8 months) in patients with advanced gastric cancer.76 In another phase III randomized trial, the addition of docetaxel to best supportive care was associated with a survival benefit for patients with advanced adenocarcinoma of the esophagus (n=33), EGJ (n=59), or stomach (n=76) that had progressed on or within 6 months of treatment with platinum and fluoropyrimidine-based combination chemotherapy.77 After a median follow-up of 12 months, the median OS was 5.2 months for patients in the docetaxel and best supportive care group compared with 3.6 months for those in the best supportive care alone group (P=.01). Therefore, the addition of systemic therapy to best supportive care may prolong survival in patients with advanced gastric cancer.
Systemic Therapy for Locally Advanced or Metastatic Disease
First-Line Therapy
Systemic therapy can provide palliation of symptoms, improved survival, and enhanced quality of life in patients with locally advanced or metastatic gastric cancer.74–77 First-line systemic therapy regimens with 2 cytotoxic drugs are preferred for patients with advanced disease because of their lower toxicity. The use of 3 cytotoxic drugs in a regimen should be reserved for medically fit patients with excellent PS and easy access to frequent toxicity evaluations (see GAST-F 1 of 16, page 176).78 Oxaliplatin is generally preferred over cisplatin due to lower toxicity.
Trastuzumab should be added to first-line chemotherapy for patients with HER2 overexpression positive adenocarcinoma (combination with a fluoropyrimidine and a platinum agent is preferred [category 1 for cisplatin60; category 2A for oxaliplatin]; see GAST-F 3 of 16, page 177). An FDA-approved biologic medical product that is similar to trastuzumab (a biosimilar) is an appropriate substitute. Pembrolizumab can also be added to this regimen for treatment of HER2 overexpression positive adenocarcinoma.79 Preferred regimens for HER2 overexpression negative disease include nivolumab combined with fluoropyrimidine (fluorouracil or capecitabine) and oxaliplatin for tumors with PD-L1 expression levels by CPS of ≥5 (category 1).80 Nivolumab is useful under certain circumstances for tumors with CPS of <5 (category 2B). See “Targeted Therapies” (next column) for more information on trastuzumab, nivolumab, and pembrolizumab.
The preferred regimens for HER2 negative disease also include a fluoropyrimidine (fluorouracil or capecitabine) combined with either oxaliplatin81–83 or cisplatin.81,84–86 A phase III trial conducted by the German Study Group compared treatment with fluorouracil and cisplatin to FOLFOX in patients (n=220) with previously untreated advanced adenocarcinoma of the stomach or EGJ.81 Results showed that FOLFOX (referred to as FLO) was associated with significantly less toxicity and showed a trend toward improved median progression-free survival (PFS; 5.8 vs 3.9 months; P=.77) compared with fluorouracil and cisplatin (FLP).81 However, no significant difference in median OS (10.7 vs 8.8 months, respectively) was seen between the 2 groups. FOLFOX resulted in significantly superior response rates (41.3% vs 16.7%; P=.12), time to treatment failure (5.4 vs 2.3 months; P<.001), PFS (6.0 vs 3.1 months; P=.029), and improved OS (13.9 vs 7.2 months) compared with FLP in patients >65 years (n=94). Therefore, FOLFOX offers reduced toxicity and similar efficacy compared with fluorouracil plus cisplatin and may also be associated with improved efficacy in older adult patients. The safety and efficacy of FOLFOX has also been demonstrated in other studies.82,87,88
Regimens combining a platinum agent with capecitabine have also been evaluated in several studies for patients with advanced gastric cancer.86,89,90 A phase III randomized trial (ML 17032) that evaluated the efficacy of combined capecitabine and cisplatin (XP) compared with fluorouracil and cisplatin (FP) found that capecitabine was noninferior to fluorouracil as first-line therapy in patients with advanced gastric cancer.86 Two phase II trials concluded that capecitabine in combination with oxaliplatin is active and well-tolerated as first-line therapy for advanced gastric cancer.89,90 Furthermore, results of a meta-analysis suggest that OS was superior in advanced gastroesophageal cancer patients treated with capecitabine-based combinations compared with patients treated with fluorouracil-based combinations, although no significant difference in PFS between treatment groups was seen.91 Another meta-analysis reported that treatment with oxaliplatin-based regimens significantly improved the partial response rate, disease progression rate, and 1-year OS rate of patients with gastric cancer as compared with cisplatin-based regimens.92 Therefore, capecitabine and oxaliplatin is also a preferred regimen for first-line treatment of patients with advanced gastric cancers. The GO2 phase III trial demonstrated that a low-dose capecitabine and oxaliplatin regimen (60% of the standard dose) was noninferior in terms of PFS and resulted in significantly lower toxicities and better overall treatment utility in elderly and/or frail patients with advanced gastroesophageal cancers (n=514).93 Therefore, this low-dose regimen is recommended as an alternative to standard-dose capecitabine and oxaliplatin for elderly and/or frail patients with advanced or metastatic disease.
First-line treatment with irinotecan-based regimens has been explored extensively in clinical trials involving patients with advanced or metastatic gastroesophageal cancers.85,94–105 The results of a randomized phase III study comparing irinotecan and fluorouracil (FOLFIRI) to cisplatin and fluorouracil (CF) in patients with advanced gastric or EGJ adenocarcinoma (n=337) showed that FOLFIRI was noninferior to CF in terms of PFS, but not in terms of OS or time to progression.100 FOLFIRI was also associated with a more favorable safety profile. A phase III trial (French Intergroup Study) compared FOLFIRI with epirubicin, cisplatin, and fluorouracil (ECF) as first-line treatment in patients (n=416) with advanced or metastatic gastric or EGJ adenocarcinoma.105 After a median follow-up of 31 months, median time to treatment failure was significantly longer with FOLFIRI than with ECF (5.1 vs 4.2 months; P=.008).105 However, there were no significant differences in median PFS (5.3 vs 5.8 months; P=.96), median OS (9.5 vs 9.7 months; P=.95), or response rate (39.2% vs 37.8%). Importantly, FOLFIRI was less toxic and better tolerated than ECF. Therefore, FOLFIRI may be recommended as an option for first-line therapy in patients with advanced or metastatic gastric cancer.
Docetaxel, cisplatin, and fluorouracil (DCF) has also demonstrated activity in patients with locally advanced or metastatic gastric cancer.106,107 An international phase III study (V325) that randomized 445 patients with untreated advanced gastric or EGJ cancer to receive either DCF or cisplatin and fluorouracil (CF) found that the addition of docetaxel to CF significantly improved time to progression, OS, and overall response rate (ORR).106 However, DCF was associated with increased toxicities including myelosuppression and infectious complications. Various modifications of the DCF regimen have demonstrated improved safety in clinical trials of patients with advanced gastric cancer compared with the DCF regimen evaluated in the V325 study.108–113 Therefore, due to concerns regarding toxicity, dose-modified DCF or other DCF modifications should be used as alternative options to the standard DCF regimen for first-line therapy.109,112,113 Other recommended regimens for first-line therapy include paclitaxel with either cisplatin or carboplatin,114–116 docetaxel with cisplatin,117,118 or single-agent fluoropyrimidine (fluorouracil or capecitabine),85,119,120 docetaxel,77,121 or paclitaxel.122,123 Docetaxel, carboplatin, and fluorouracil109 is a category 2B recommendation in this setting.
Second-Line and Subsequent Therapy
The selection of regimens for second-line or subsequent therapy is dependent on prior therapy and performance status (see GAST-F 4 of 16, page 178). Ramucirumab in combination with paclitaxel (preferred) or as a single agent are category 1 recommendations for second-line or subsequent therapy.124,125 Fam-trastuzumab deruxtecan-nxki is a second-line treatment option for patients with HER2 overexpression–positive adenocarcinoma who had received prior trastuzumab-based therapy.126 See “Targeted Therapies,” (next column) for more information on ramucirumab and fam-trastuzumab deruxtecan-nxki.
Single-agent docetaxel,77,121 paclitaxel,122,123,127 and irinotecan75,127–129 are also category 1 preferred options for second-line or subsequent therapy. In a randomized phase III trial (COUGAR-02) single-agent docetaxel was shown to significantly increase 12-month OS compared with active symptom control alone (5.2 vs 3.6 months, respectively; hazard ratio [HR] =0.67; P=.01).77 A randomized phase III trial comparing second-line therapy with paclitaxel to irinotecan in patients with advanced gastric cancer found similar OS between the 2 groups (9.5 months in the paclitaxel group vs 8.4 months in the irinotecan group; HR=1.13; P=.38).127
FOLFIRI is a preferred treatment option that can be safely used in the second-line setting if it was not previously used in first-line therapy.96,129–132 A phase II trial investigating the efficacy and toxicity of FOLFIRI in patients (n=40) with recurrent or metastatic gastric cancer reported an ORR of 29% and median OS of 6.4 months.132 Another phase II trial reported similar results with an ORR of 20% and OS of 6.7 months in advanced gastric cancer patients (n=59) treated with FOLFIRI in the second-line setting.129 Additionally, FOLFIRI was shown to be an effective and safe treatment option in a cohort of patients with metastatic gastric or EGJ cancers refractory to docetaxel-based chemotherapy.130 In this study, the ORR was 22.8% and median PFS and OS were 3.8 and 6.2 months, respectively. The most common grade 3–4 toxicities were neutropenia (28.5%) and diarrhea (14.5%).
The trifluridine and tipiracil regimen was approved by the FDA in 2019 for previously treated recurrent or metastatic gastric and EGJ adenocarcinoma,133 based on results from the global phase III TAGS trial, in which 507 patients with heavily pretreated metastatic gastric or EGJ cancer were randomized 2:1 to receive trifluridine and tipiracil plus best supportive care (n=337) or placebo plus best supportive care (n=170).134 This study reported an improvement in median OS by 2.1 months (5.7 vs 3.6 months) with the trifluridine and tipiracil regimen compared with placebo (HR=0.69; 95% CI, 0.56–0.85; P=.0003). PFS was significantly longer in the trifluridine and tipiracil group (2.0 vs 1.7 months; HR=0.57; 95% CI, 0.47–0.70; P<.0001). The efficacy benefits of trifluridine and tipiracil were observed regardless of whether the patient had undergone previous gastrectomy.135 The most frequently reported grade 3–4 toxicities were neutropenia (38%), leukopenia (21%), anemia (19%), and lymphocytopenia (19%). Patients aged ≥65 years had a higher incidence of moderate renal impairment compared with the overall study population (31% vs 17%).136 Trifluridine and tipiracil is recommended as a preferred category 1 treatment option for patients with recurrent or metastatic gastric cancer in the third-line or subsequent setting. However, trifluridine and tipiracil did not result in any partial or complete responses and produced substantial grade 3–4 toxicities. Therefore, this treatment should be considered for a very select population of patients with low-volume gastric cancer who have minimal or no symptoms and the ability to swallow pills.
Other recommended regimens for second-line or subsequent therapy include irinotecan and cisplatin,82,137 ramucirumab combined with irinotecan138 or FOLFIRI,139 and irinotecan and docetaxel (category 2B).140 Options that are useful in certain circumstances include pembrolizumab65,141,142 or dostarlimab-gxly143 for MSI-H/dMMR tumors, pembrolizumab for TMB-H (≥10 mutations/megabase) tumors,144 and entrectinib or larotrectinib for NTRK gene fusion-positive tumors.145,146 See “Targeted Therapies” (below) for more information on pembrolizumab, dostarlimab-gxly, entrectinib, and larotrectinib.
Targeted Therapies
At present, several targeted therapeutic agents, trastuzumab, pembrolizumab/nivolumab, and entrectinib/larotrectinib, have been approved by the FDA for use in advanced gastric cancer. Treatment with trastuzumab is based on the presence of HER2 overexpression.60 Treatment with pembrolizumab/nivolumab is based on testing for MSI by PCR/NGS or MMR by IHC, PD-L1 expression by IHC, or high TMB by NGS.65,80,141,142,144,147,148 Treatment with the TRK inhibitors entrectinib and larotrectinib is based on testing for NTRK gene fusions.149,150 The use of IHC/ISH/targeted PCR should be considered first, followed by NGS testing as appropriate for the identification of ERBB2 amplification, MSI status, MMR deficiency, TMB, and NTRK gene fusions.
Trastuzumab
The ToGA trial was the first randomized prospective phase III trial that evaluated the efficacy and safety of trastuzumab in patients with HER2 overexpression positive advanced gastric or EGJ adenocarcinoma.60 In this trial, 594 patients with HER2 overexpression–positive, locally advanced, recurrent, or metastatic gastric or EGJ adenocarcinoma were randomized to receive trastuzumab plus chemotherapy (cisplatin plus fluorouracil or capecitabine) or chemotherapy alone.60 The majority of patients had gastric cancer (80% in the trastuzumab group and 83% in the chemotherapy group). Median follow-up was 19 and 17 months, respectively, in the 2 groups. Results showed significant improvement in median OS with the addition of trastuzumab to chemotherapy in patients with HER2 overexpression–positive disease (13.8 vs 11 months, respectively; P=.046). This study established trastuzumab in combination with cisplatin and a fluoropyrimidine as the standard treatment for patients with HER2 overexpression–positive advanced gastroesophageal adenocarcinoma. In a posthoc subgroup analysis, the addition of trastuzumab to chemotherapy further improved OS in patients whose tumors were IHC 2+and FISH positive or IHC 3+ (n=446; 16 vs 11.8 months; HR=0.65) compared with those with tumors that were IHC 0 or 1+ and FISH positive (n=131; 10 vs 8.7 months; HR=1.07).
The phase II HERXO trial assessed the combination of trastuzumab with capecitabine and oxaliplatin in the first-line treatment of patients with HER2 overexpression positive advanced gastric or EGJ adenocarcinoma (n=45).151 At a median follow-up of 13.7 months, PFS and OS were 7.1 and 13.8 months, respectively, and 8.9%, 37.8%, and 31.1% of patients experienced a complete response, partial response, and stable disease. The most frequently reported grade 3 or higher adverse events were diarrhea (26.6%), fatigue (15.5%), nausea (20%), and vomiting (13.3%). In a retrospective study of 34 patients with HER2 overexpression–positive metastatic gastric or EGJ adenocarcinoma, the combination of trastuzumab with a modified FOLFOX regimen (mFOLFOX6) improved tolerability compared with the cisplatin plus fluorouracil regimen in previously untreated patients with HER2 overexpression–positive tumors.152 The ORR with this regimen was 41% and median PFS and OS were 9.0 and 17.3 months, respectively. The most frequent grade 3–4 toxicities were neutropenia (8.8%) and neuropathy (17.6%). These results suggest that the combinations of trastuzumab with capecitabine and oxaliplatin or with modified FOLFOX are effective regimens with acceptable safety profiles in patients with HER2 overexpression positive gastroesophageal cancers. Therefore, trastuzumab should be added to first-line chemotherapy in combination with a fluoropyrimidine and a platinum agent (oxaliplatin is preferred over cisplatin due to lower toxicity) in patients with HER2 overexpression–positive adenocarcinoma. An FDA-approved biosimilar is an appropriate substitute for trastuzumab. Trastuzumab may be combined with other chemotherapy agents for first-line therapy, but should not be continued in second-line therapy.153
Pembrolizumab can also be added to first-line fluoropyrimidine, platinum and trastuzumab based on an interim analysis of the first 264 patients enrolled in the KEYNOTE-811 trial, which showed an improved ORR (74% vs 52%; P=.0001) and median duration of response (10.6 vs 9.5 months) with the addition of pembrolizumab to chemotherapy plus trastuzumab compared with the addition of placebo in patients with HER2 overexpression positive adenocarcinoma.79
Fam-Trastuzumab Deruxtecan-nxki
Fam-trastuzumab deruxtecan-nxki is an antibody-drug conjugate consisting of trastuzumab and a cytotoxic topoisomerase I inhibitor connected by a cleavable tetrapeptide-based linker. The efficacy and safety of fam-trastuzumab deruxtecan-nxki in advanced or metastatic gastric or EGJ adenocarcinoma was evaluated in the phase II DESTINY-Gastric01 trial, which included 188 patients with progressive disease after at least 2 prior lines of therapy, including trastuzumab.126 Patients were randomized 2:1 to receive either fam-trastuzumab deruxtecan-nxki or physician’s choice of chemotherapy (paclitaxel or irinotecan). The confirmed objective response rate for patients on fam-trastuzumab deruxtecan-nxki was 40.5% compared with 11% for those on chemotherapy. OS (12.5 vs 8.4 months; P=.0097), median PFS (5.6 vs 3.5 months), and median duration of response (11.3 vs 3.9 months) were also higher in the fam-trastuzumab deruxtecan-nxki group compared with the chemotherapy group. Fam-trastuzumab deruxtecan-nxki resulted in more toxicities than systemic chemotherapy in this trial. The most common adverse events (grade 3 or higher) were a decreased neutrophil count (51% of the fam-trastuzumab deruxtecan-nxki group and 24% of the chemotherapy group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). Fam-trastuzumab deruxtecan-nxki-related interstitial lung disease or pneumonitis occurred in 12 patients resulting in 1 drug-related death (due to pneumonia). No drug-related deaths occurred in the physician's choice group. The FDA has approved fam-trastuzumab derextecan-nxki to treat patients with HER2 overexpression–positive tumor in the second or later line. Therefore, fam-trastuzumab derextecan-nxki may be used as a second-line or subsequent treatment option for patients with HER2 overexpression–positive adenocarcinoma after failure of prior treatment with a trastuzumab-based regimen. However, careful patient selection and close monitoring of patients for excessive toxicity is recommended.
Ramucirumab
Ramucirumab, a VEGFR-2 antibody, has shown favorable results in patients with previously treated advanced or metastatic gastroesophageal cancers in two phase III clinical trials.124,125 An international randomized multicenter phase III trial (REGARD) demonstrated a survival benefit for ramucirumab in patients with advanced gastric or EGJ adenocarcinoma progressing after first-line chemotherapy.124 In this study, 355 patients were randomized to receive ramucirumab (n=238) or placebo (n=117). Median OS was 5.2 months in patients treated with ramucirumab compared with 3.8 months for those in the placebo group (P=.047). Ramucirumab was associated with higher rates of hypertension than placebo (16% vs 8%), whereas rates of other adverse events were similar.
An international phase III randomized trial (RAINBOW) evaluated paclitaxel with or without ramucirumab in patients (n=665) with metastatic gastric or EGJ adenocarcinoma progressing on first-line chemotherapy.125 Patients randomized to receive ramucirumab plus paclitaxel (n=330) had significantly longer median OS (9.63 months) compared with patients receiving paclitaxel alone (n=335; 7.36 months; P<.0001). The median PFS was 4.4 months and 2.86 months, respectively, and the ORR was 28% for ramucirumab plus paclitaxel compared with 6% for paclitaxel alone (P=.0001). Neutropenia and hypertension were more common with ramucirumab plus paclitaxel. An exposure-response analysis revealed that ramucirumab was a significant predictor of OS and PFS in both studies.154 Based on these results, ramucirumab (as a single agent or in combination with paclitaxel) was approved by the FDA for the treatment of patients with advanced gastric or EGJ adenocarcinoma refractory to or progressive after first-line therapy with platinum- or fluoropyrimidine-based chemotherapy. The guidelines recommend ramucirumab as a single agent (category 1) or in combination with paclitaxel (category 1; preferred) as treatment options for second-line or subsequent therapy in patients with advanced or metastatic gastric adenocarcinoma.124,125
Ramucirumab combined with FOLFIRI can be an option for second-line or subsequent therapy. In a multi-institutional retrospective analysis of 29 patients with advanced gastric or EGJ adenocarcinoma who received FOLFIRI plus ramucirumab in the second-line setting, the ORR was 23% with a disease control rate of 79%.139 Median PFS was 6 months, and median OS was 13.4 months. Six- and 12-month OS were 90% and 41%, respectively. No new safety signals were observed with the combination treatment, making FOLFIRI plus ramucirumab a safe, nonneurotoxic alternative to ramucirumab plus paclitaxel. Ramucirumab combined with irinotecan is also an option for second-line or subsequent therapy for patients with advanced gastric cancer.138
Due to the results of the international phase III RAINFALL trial, in which treatment with ramucirumab did not reduce the risk of disease progression or death in treatment-naïve patients with metastatic gastroesophageal adenocarcinoma, the addition of ramucirumab to first-line chemotherapy is not recommended at this time.155
Nivolumab
Nivolumab is a monoclonal PD-1 antibody that was approved by the FDA in April 2021, in combination with fluoropyrimidine- and platinum-based chemotherapy, for the first-line treatment of patients with advanced or metastatic gastric cancer.156 This approval was based on results from the phase III Checkmate-649 trial, which randomized 1581 patients with previously untreated, HER2 negative unresectable gastric, EGJ or esophageal adenocarcinoma to receive chemotherapy alone or nivolumab plus chemotherapy (capecitabine and oxaliplatin or modified FOLFOX).80 The addition of nivolumab to chemotherapy resulted in significant improvements in OS (14.4 vs 11.1 months; HR=0.71; P<.0001) and PFS (7.7 vs 6 months; HR=0.68; P<.0001) compared with chemotherapy alone in patients with a PD-L1 CPS of ≥5 (n=955). Additional results also showed some improvement in OS and PFS in patients with a PD-L1 CPS of ≥1 (n=1,296; OS=14 vs 11.3 months, HR=0.77; PFS=7.5 vs 6.9, HR=0.74) and in all randomly assigned patients (OS=13.8 vs 11.6, HR=0.8; PFS=7.7 vs 6.9, HR=0.77). Among all patients, 59% of those in the nivolumab plus chemotherapy group and 44% of those in the chemotherapy alone group experienced grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events were nausea, diarrhea, and peripheral neuropathy across both groups. Sixteen treatment-related deaths occurred in the nivolumab plus chemotherapy group compared with 4 in the chemotherapy alone group. Therefore, nivolumab plus fluoropyrimidine- and oxaliplatin-based chemotherapy is a preferred first-line treatment option for patients with HER2 negative gastric tumors with PD-L1 expression levels by CPS of ≥5 (category 1) and is useful under certain circumstances for tumors with PD-L1 expression levels by CPS of <5 (category 2B).
Pembrolizumab
Pembrolizumab is a PD-1 antibody that was FDA approved in 2017 for the treatment of patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.157 This first-ever tissue- and site-agnostic approval was based on data from 149 patients with MSI-H/dMMR cancers (90 patients had colorectal cancer) enrolled across 5 multicenter single-arm clinical trials.65,141,142 The ORR was 39.6% and responses lasted ≥6 months for 78% of those who responded to pembrolizumab. There were 11 complete responses and 48 partial responses, and the ORR was similar irrespective of cancer type.
In June 2020, the FDA approved pembrolizumab for the treatment of patients with metastatic TMB-H solid tumors, as determined by an FDA-approved test, that have progressed after prior treatment and who have no satisfactory alternative treatment options.158 This approval was based on a retrospective analysis of 102 patients enrolled in the KEYNOTE-158 trial who had tumors identified as TMB-H.144 The ORR for these patients was 29%, with a 4% complete response rate. The median duration of response was not reached, with 50% of patients having response durations for ≥24 months. Based on these data, pembrolizumab may be used for the second-line or subsequent treatment of MSI-H/dMMR or TMB-H gastroesophageal tumors. However, it should be noted that no patients with gastroesophageal cancer were included in the KEYNOTE-158 trial.
Additional trials of pembrolizumab in gastric and EGJ cancers are ongoing. Please visit https://keynoteclinicaltrials.com for more information regarding ongoing KEYNOTE clinical trials for pembrolizumab in patients with gastric and EGJ cancers.
Dostarlimab-gxly
Dostarlimab-gxly, an anti-PD-1 antibody, was approved by the FDA in August 2021 for the treatment of patients with dMMR recurrent or advanced solid tumors that have progressed on or after prior treatment, who have no satisfactory alternative treatment options, and who had not previously received a PD-1 or PD-L1 inhibitor.159 This approval was based on data from the nonrandomized phase 1 multicohort GARNET trial that evaluated the safety and antitumor activity of dostarlimab-gxly in 209 patients with dMMR solid tumors who had not received prior PD-1, PDL-1, or CTLA4 inhibitors.143,160 The majority of patients had endometrial or gastrointestinal cancers. The ORR was 42%, with a 9% complete response rate and 33% partial response rate, and the median duration of response was 35 months. The most common treatment-related adverse events were fatigue, anemia, diarrhea, and nausea. Immune-mediated adverse events also occurred, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and dermatologic toxicities. Based on these data, dostarlimab-gxly may be used to treat patients with MSI-H/dMMR gastric tumors.
Entrectinib and Larotrectinib
Gene fusions involving NTRK1, NTRK2, or NTRK3 encode TRK fusion proteins (TRKA, TRKB, TRKC), which have increased kinase function and are implicated in the oncogenesis of many solid tumors including head and neck, thyroid, soft tissue, lung, and colon.146,161 Although believed to be extremely rare in gastroesophageal cancers, one case report provides evidence that NTRK gene fusions do occur in gastric adenocarcinoma and may be associated with an aggressive phenotype.162–164
In 2018, the FDA granted accelerated approval to the TRK inhibitor larotrectinib for the treatment of adult and pediatric patients (aged 12 years and older) with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed after treatment.150 This second-ever tissue-agnostic FDA approval for the treatment of patients with cancer was based on data from 3 multicenter single-arm clinical trials. Patients with prospectively identified NTRK gene fusion-positive cancers were enrolled into 1 of 3 protocols: a phase I trial involving adults (LOXO-TRK-14001), a phase I–II trial involving children (SCOUT), and a phase II trial involving adolescents and adults (NAVIGATE).146 A total of 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion who experienced disease progression after systemic therapy were enrolled across the 3 trials and treated with larotrectinib. The most common cancer types represented were salivary gland tumors (22%), soft tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%). The ORR across the 3 trials was 75%, with a complete response rate of 22%. At a median follow-up of 9.4 months, 86% of the patients with a response were either continuing treatment with larotrectinib or had undergone curative-intent surgery. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. Response duration was ≥6 months for 73%, ≥9 months for 63%, and ≥12 months for 39% of patients. At the time of data analysis, the median duration of response and PFS had not been reached. Adverse events were predominantly grade 1, the most common being increased aspartate aminotransferase (AST) levels, vomiting, constipation, and dizziness. The SCOUT (ClinicalTrials.gov identifier: NCT02637687) and NAVIGATE (ClinicalTrials.gov identifier: NCT02576431) trials are still actively recruiting patients with NTRK gene fusion-positive tumors.
In 2019, the FDA approved the second TRK inhibitor, entrectinib, for the same indications as larotrectinib, as well as for adult patients with metastatic non-small cell lung cancer whose tumors are ROS1-positive.149 The approval of entrectinib for the treatment of NTRK gene fusion-positive tumors was based on data from 3 multicenter single-arm phase I and phase II clinical trials. A total of 54 patients aged 18 years or older with metastatic or locally advanced NTRK gene fusion-positive solid tumors were enrolled into 1 of the 3 protocols (ALKA-372-001, STARTRK-1, and STARTRK-2).145 The most common cancer types represented were sarcoma, non-small cell lung cancer, mammary analogue secretory carcinoma, breast, thyroid, and colorectal. The ORR across the 3 trials was 57%, with a complete response rate of 7%. Response duration was ≥6 months for 68% of patients and ≥12 months for 45% of patients. The median duration of response was 10 months. The most common grade 3–4 treatment-related adverse events were increased weight and anemia while the most common serious treatment-related adverse events were nervous system disorders. STARTRK-2 (ClinicalTrials.gov identifier: NCT02568267) is still actively recruiting patients with NTRK gene fusion-positive tumors.
These data demonstrate that entrectinib and larotrectinib induce durable and clinically meaningful responses in patients with NTRK gene fusion-positive tumors with manageable safety profiles. Therefore, entrectinib and larotrectinib are recommended as second-line or subsequent treatment options for patients with NTRK gene fusion-positive gastric tumors.
Palliative/Best Supportive Care
The goals of palliative/best supportive care are to prevent, reduce, and relieve suffering and improve the quality of life for patients and their caregivers, regardless of the stage of the disease or the need for other therapies. In patients with advanced or metastatic gastric cancer, palliative/best supportive care provides symptom relief, improvement in overall quality of life, and may result in prolongation of life. This is especially true when a multimodality interdisciplinary approach is pursued. Therefore, a multimodality interdisciplinary approach to palliative/best supportive care of gastric cancer patients is encouraged.
Bleeding
Acute bleeding is common in patients with gastric cancer and may be tumor-related or a consequence of therapy. Patients with acute severe bleeding (hematemesis or melena) should undergo prompt endoscopic assessment (see GAST-J 1 of 3, page 179).165 The efficacy of endoscopic treatment of bleeding in patients with gastric cancer is not well-studied, but limited available data suggest that while endoscopic therapies may be effective as initial treatment, the rate of recurrent bleeding is very high.166,167 Widely available options for endoscopic therapies include injection therapy, mechanical therapy (eg, endoscopic clip placement), ablative therapy (eg, argon plasma coagulation or other laser therapy), or a combination of modalities.166 Interventional radiology with angiographic embolization techniques may be useful in situations where endoscopy is not helpful.168 Additionally, external beam radiation therapy (EBRT) has been shown to effectively manage acute and chronic gastrointestinal bleeding.169,170 Proton pump inhibitors can also be prescribed to reduce the risk of bleeding from gastric cancer; however, there are no definitive data supporting their use at this time.
Obstruction
The primary goals of palliation for patients with malignant gastric obstruction are to reduce nausea and vomiting and, when possible, allow resumption of an oral diet (see GAST-J 2 of 3, page 180). Management of malignant gastric obstruction should be individualized, and treatment options selected as clinically appropriate. Treatment options used to alleviate or bypass obstruction include surgery (gastrojejunostomy171 or gastrectomy in select patients172), EBRT, chemotherapy, and endoscopic placement of an enteral stent for relief of gastric outlet obstruction171 or esophageal stent for EGJ/cardia obstruction. Endoscopic placement of a self-expanding metal stent (SEMS) is a safe and effective minimally invasive palliative treatment of patients with luminal obstruction due to advanced gastric cancer.173–176 In a systematic review, patients treated with endoscopic placement of a SEMS were more likely to tolerate oral intake and had shorter hospital stays than patients treated with gastrojejunostomy.177 The results of another systematic review suggest that SEMS placement may be associated with more favorable results in patients with a relatively short life expectancy, whereas gastrojejunostomy is preferable in patients with a more prolonged prognosis.171 A randomized trial also reported similar findings.178 However, these results need to be confirmed in larger randomized trials.
When obstruction cannot be alleviated or bypassed, the primary goal is to reduce the symptoms of obstruction via venting gastrostomy.179 Percutaneous, endoscopic, surgical, or interventional radiology gastrostomy tube placement may be performed for gastric decompression, if tumor location permits. Percutaneous decompressive gastrostomy has been associated with palliative benefit for patients with gastric outlet obstruction.180,181 Ascites, if present, should be drained before venting gastrostomy tube placement to reduce the risk of infectious complications.182,183 Feeding gastrostomy tubes for patients with EGJ/gastric cardia obstruction or jejunal feeding tubes for patients with mid and distal gastric obstruction may be necessary to provide adequate hydration and nutritional support for patients who cannot tolerate an oral diet. Nutritional counseling may also be valuable.
Pain
Pain control may be achieved with the use of EBRT or chemotherapy (see GAST-J 2 of 3, page 180). If the patient is experiencing tumor-related pain, then pain should be assessed and treated according to the NCCN Guidelines for Adult Cancer Pain (available at NCCN.org). Severe, uncontrolled pain after gastric stent placement should be treated with immediate endoscopic removal of the stent.
Nausea and Vomiting
Patients experiencing nausea and vomiting should be treated according to the NCCN Guidelines for Antiemesis (see GAST-J 2 of 3, page 180). Nausea and vomiting may be associated with luminal obstruction, so endoscopic or fluoroscopic evaluation should be performed to determine if obstruction is present.
Summary
Gastric cancer is rampant in many parts of the world and is often diagnosed at advanced stages. Risk factors for gastric cancer include H pylori infection, smoking, and high salt intake. Some gastric cancers are associated with inherited gastric cancer predisposition syndromes. Referral to a cancer genetics professional is recommended for an individual with a genetic predisposition. The NCCN Guidelines for Gastric Cancer provide an evidence- and consensus-based treatment approach for the management of patients with gastric cancer. Multidisciplinary team management is essential for the management of patients with gastric cancer. Best supportive care is an integral part of treatment, especially in patients with unresectable locally advanced, recurrent, or metastatic disease. Patients with unresectable or metastatic disease may be offered best supportive care and palliative management with or without systemic therapy or chemoradiation, depending on their performance status and prior treatment. Targeted therapies have produced encouraging results in the treatment of patients with advanced gastric cancer. Trastuzumab plus chemotherapy is recommended as first-line therapy for patients with HER2 overexpression–positive tumors. Nivolumab combined with chemotherapy is recommended as first-line therapy for tumors with PD-L1 expression levels by CPS of ≥5 (category 1) or CPS of <5 (category 2B). Ramucirumab, as a single agent or in combination with paclitaxel (preferred), and pembrolizumab (for MSI-H/dMMR or TMB-H tumors) are included as options for second-line or subsequent therapy for patients with metastatic gastric cancer. Dostarlimab-gxly is an alternative option to pembrolizumab for MSI-H/dMMR tumors. Entrectinib and larotrectinib are recommended for second-line or subsequent therapy for NTRK gene fusion-positive tumors. The panel encourages patients with gastric cancer to participate in well-designed clinical trials investigating novel therapeutic strategies to enable further advances.
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
The complete NCCN Guidelines for Gastric Cancer, Version 2.2022 are not printed in this issue of JNCCN but can be accessed online at NCCN.org.
© National Comprehensive Cancer Network, Inc. 2022. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
Disclosures for the NCCN Gastric Cancer, Version 2.2022 Panel
At the beginning of each NCCN Guidelines Panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.
Individual disclosures for the NCCN Gastric Cancer, Version 2.2022 Panel members can be found on page 192. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
