Gastric Cancer

Etiology

Gastric Cancer Risk Factors

Gastric cancers are typically sporadic, but 5% to 10% of cases have a familial or genetic association.[4] The key risk factors for gastric cancer include:

• Helicobacter pylori: Chronic and recurrent H pylori infections are well-established risk factors for gastric adenocarcinoma. The duration of infection, other risk factors, and host factors likely play significant roles in the pathogenesis.[4] Please see StatPearls' companion resource, "Helicobacter Pylori," for more information.
• Epstein-Barr virus: This viral infection has been increasingly noted in association with gastric cancer, usually affecting the proximal stomach.[6] Please see StatPearls' companion resource, "Epstein-Barr Virus," for more information.
• Dietary factors: Risk factors include high salt intake (salt-preserved foods), consumption of N-nitroso compounds, smoking, a diet low in vitamins A and C, high consumption of smoked or cured foods, lack of refrigerated foods, and contaminated drinking water.[7]
• Obesity: A high body mass index increases the risk of proximal gastric and GEJ cancers.[7]
• Smoking: Smoking increases the risk of gastric cancer, particularly in men.[7]
• Gastroesophageal reflux: Chronic reflux is associated with a higher rate of GEJ adenocarcinomas. Additionally, bile reflux into the stomach, as seen in patients after certain gastric surgeries, increases the risk of gastric cancer.[7]
• Environmental factors: Exposure to rubber manufacturing, tin mining, metal processing, and coal increases the risk of gastric cancer.[7]
• Host factors: Individuals with type A blood have approximately a 20% higher incidence of gastric cancer compared to those with blood groups O, B, or AB, particularly with the diffuse type. Pernicious anemia and chronic atrophic gastritis increase the risk of intestinal-type gastric cancer up to 6-fold. Please see StatPearls' companion resources, "Pernicious Anemia" and "Atrophic Gastritis," for more information. Other conditions associated with an increased risk include benign gastric ulcers, hypertrophic gastropathy, and gastric polyps.[7]
• Protective factors: A high intake of fiber, fruits, and vegetables likely provides a protective benefit against gastric cancer.[7]
• Genetic associations: A subset of gastric cancers are associated with genetic syndromes, including:
  • Hereditary nonpolyposis colon cancer has a 13% lifetime risk, predominantly intestinal type. Please see StatPearls' companion resource, "Hereditary Nonpolyposis Colorectal Cancer," for more information.
  • Familial adenomatous polyposis has a 10% risk. Please see StatPearls' companion resource, "Familial Adenomatous Polyposis," for more information.
  • Peutz-Jeghers syndrome has a 29% risk. Please see StatPearls' companion resource, "Peutz-Jeghers Syndrome," for more information.
  • Juvenile polyposis syndrome has a 21% risk.
  • Li-Fraumeni syndrome is associated with gastric cancer. Please see StatPearls' companion resource, "Li-Fraumeni Syndrome," for more information.
  • Hereditary breast and ovarian cancer syndrome are associated with gastric cancer.
  • Phosphatase and tensin homolog or hamartoma tumor (Cowden) syndrome are also associated with gastric cancer. Please see StatPearls' companion resource, "Cowden Disease," for more information.

Epidemiology

Gastric cancer is the fifth most common and the fourth most lethal malignancy worldwide.[7] Although incidence and mortality rates have declined, they remain significantly higher in low-resource countries and East Asia. In the United States, approximately 26,890 newly detected cases of gastric cancer are expected to be diagnosed in 2024. Gastric cancer is more prevalent among men than women.

In developed countries, the rate of distal gastric cancers has declined dramatically due to better nutrition, access to clean water, and the early identification and treatment of H pylori infection. However, the rates of proximal gastric and GEJ cancers have been increasing. The overall rates of intestinal and diffuse-type gastric cancers have declined, with the decline being more marked for intestinal-type cancers. As a result, diffuse-type cancers now constitute a significant proportion of all gastric cancers. Intestinal-type cancers are more common in men, whereas diffuse-type cancers occur equally in both sexes.[7] 

Pathophysiology

According to the Lauren classification, gastric adenocarcinoma has 2 main histologic variants.[8] The most common variant is the intestinal type, characterized by gland formation and similar in appearance to other intestinal adenocarcinomas. The less common diffuse-type gastric cancer lacks intercellular adhesion molecules and does not typically have gland formation. Intestinal-type cancers may be associated with signet-ring cells. 

The molecular drivers for intestinal-type cancers are likely multifactorial. H pylori is the most common inciting factor for carcinogenesis, and evidence suggests that these lesions progress from dysplasia to carcinoma over time. Precancerous lesions and conditions predisposing to cancer, such as gastric ulcers, atrophic gastritis, and pernicious anemia, often precede the development of cancer.[8] In diffuse-type cancers, no defined precancerous lesions have been identified.

Histopathology

Gross Pathology Features

On gross examination, gastric cancer typically presents as a mass or a nonhealing ulcer. Diffuse gastric cancers, however, may lack a noticeable mass due to extensive submucosal infiltration. This extensive infiltration leads to a nondistended stomach characterized by the absence of rugal folds. This distinctive appearance is called "leather bottle stomach" or linitis plastica.[9]

Histopathology Findings

Microscopically, the histologic appearance of gastric cancer has traditionally been classified under the Lauren classification, which divides gastric cancers into diffuse-type and intestinal-type tumors (see Image. Gastric Carcinoma).[10] Diffuse-type tumors exhibit markedly aberrant cells with little or no gland formation and occasionally contain signet ring cells (see Image. Diffuse Carcinoma of the Stomach) characterized by cytoplasmic mucin with an eccentrically placed nucleus (see Images. Diffuse Gastric Cancer and Signet Ring Carcinoma). Depending on tumor differentiation, intestinal-type tumors demonstrate gland formation, ranging from well-formed to markedly aberrant glands. Due to the cohesive nature of these cells, they often present as mass lesions. More recent classifications, eg, the World Health Organization classification, are more detailed and subdivide adenocarcinomas into several distinct subtypes. The impact of these subtypes on overall prognosis remains unclear.

Molecular Pathology

Identifying molecular drivers of carcinoma is increasingly important in determining prognosis and treatment. The Cancer Genome Atlas-based molecular classification [11] of gastric cancer incorporates molecular diagnostics and clinical and histologic features, including:

• Epstein-Bar Virus-associated: These tumors, located in the proximal stomach, are characterized by CIMP (CpG island methylator phenotype), mutations in PIK3CA, ARID1A, and BCOR, and amplifications of programmed death protein 1 and L2.
• Microsatellite instability: Resulting from defects in mismatch repair genes, these tumors are hypermutated and typically found in more distal cancers.
• Genomically stable: Genomic stability is associated with diffuse-type cancers, which have the lowest overall mutational burden, with mutations in CDH1 often present.
• Chromosomal instability: Carcinomas with chromosomal instability are the most common group of gastric cancers. They occur in the gastroesophageal junction and cardia and have multiple associated mutations, the most common being TP53.
• HER2 gene amplification: HER2 gene amplification is reported in 12% to 27% of gastric cancer cases, with protein overexpression in 9% to 23% of cases. HER2 positivity, more frequent in the intestinal subtype (33%) compared to the diffuse subtype (8%), has been associated with tumor invasion, lymph node metastasis, and poorer survival. HER2 testing is recommended for all metastatic gastric cancer, using immunohistochemistry scoring: negative for 0 or 1+, positive for 3+, with reflex fluorescent in situ hybridization for an equivocal 2+ score to confirm (see Image. HER2 Analysis)

The United States Food and Drug Administration has approved immunotherapy for patients with microsatellite instability in solid tumors, including gastric cancer, allowing the evaluation of immunotherapy potential in patients with metastatic disease who have progressed on standard therapy. Epstein-Bar (EBV)positive gastric tumors generally have a better prognosis, although routine EBV staining is not yet recommended in clinical care.[12][13][14][15][16]

History and Physical

Clinical History

Gastric cancer often presents with a variety of symptoms that can be subtle and easily mistaken for less severe conditions in its early stages. Common symptoms include persistent indigestion, stomach discomfort, and a feeling of fullness or bloating after small meals. As the disease progresses, patients may experience more severe symptoms such as unexplained weight loss, persistent nausea or vomiting, difficulty swallowing, and noticeable fatigue. There may be visible signs of gastrointestinal bleeding, such as black or bloody stools, and in advanced stages, a palpable mass in the abdomen. Due to the nonspecific nature of these symptoms, gastric cancer is frequently diagnosed at a later stage, emphasizing the importance of early medical evaluation for persistent gastrointestinal issues. In high-risk populations that undergo screening endoscopy (most commonly seen in Japan and South Korea), gastric cancer is often diagnosed at an early stage.[10] 

Physical Examination Findings

Physical examination findings in gastric cancer are typically evident only in the advanced stages of the disease. These may include an abdominal mass or a dilated stomach suggestive of gastric outlet obstruction. Metastatic gastric cancer can present with several distinctive signs, including the Virchow node (ie, left supraclavicular adenopathy), Sister Mary Joseph node (ie, periumbilical nodule), and Irish node (ie, left axillary node). Direct metastasis to the peritoneum may manifest as a Krukenberg tumor (ovarian mass), Blumer shelf (cul-de-sac mass), ascites (peritoneal carcinomatosis), and hepatomegaly, often indicating a diffuse disease burden.[10] Paraneoplastic manifestations, although rare and nonspecific to gastric cancer, can include various dermatological conditions (eg, diffuse seborrheic keratosis or acanthosis nigricans), hematological disorders (eg, microangiopathic hemolytic anemia and a hypercoagulable state known as Trousseau syndrome), renal disorders (eg, membranous nephropathy), and autoimmune diseases (eg, polyarteritis nodosa).[17]

Evaluation

Diagnostic Evaluation

Patients exhibiting symptoms indicative of gastric cancer should undergo an upper endoscopy as a primary diagnostic tool.[4] Although upper endoscopy is more invasive and costly than traditional barium or gastrografin swallow studies, it offers the critical advantage of direct tissue diagnosis through biopsy of esophageal, gastric, or duodenal lesions. Any suspicious gastric ulcer should be biopsied multiple times to improve diagnostic accuracy significantly; sensitivity increases from approximately 70% with a single biopsy to 98% with 7 biopsies. Meticulous documentation of the lesion's location, size, and characteristics is essential.[18] Advanced techniques such as chromoendoscopy and narrow-band imaging should be utilized if there is a suspicion of more subtle mucosal lesions. Also, multiple mucosal biopsies should be obtained if H pylori infection, atrophic gastritis, or other pathologies are suspected. Upper endoscopy has been highly effective in detecting early-stage gastric cancer in high-incidence areas like Japan and South Korea, where it has led to higher cure rates following resection. However, its practice is less common in other regions.

Following upper endoscopy, an endoscopic ultrasound (EUS) is often warranted for a more detailed assessment of gastric cancer lesions.[4] EUS is instrumental in determining the T stage of the tumor and evaluating the perigastric lymph nodes, which can be biopsied via EUS-guided fine-needle aspiration. The pooled sensitivity and specificity of EUS for distinguishing between T1 and T2 tumors are 0.85 and 0.90, respectively, with confidence intervals of 0.78 to 0.91 and 0.85 to 0.93, respectively. This distinction is crucial, as T1 gastric cancers might be eligible for endoscopic resection. However, the accuracy of EUS is highly dependent on the operator's skill, and less experienced clinicians may have compromised precision in assessing gastric wall invasion.[19]

Staging Evaluation

For comprehensive preoperative staging, chest and abdominal imaging are necessary to exclude metastasis and determine surgical resectability.[4] Early abdominopelvic computed tomography (CT) is performed to rule out gross metastatic disease. However, it has limitations in assessing T and N stages and detecting small peritoneal metastases, with an overall accuracy ranging from 42% to 82%. Biopsy of any suspicious solitary or oligometastatic sites should be performed, and paracentesis is recommended if malignant ascites is suspected. Chest CT is preferred over plain radiographs for better evaluation. In cases where initial staging is negative for metastatic disease, positron emission tomography combined with CT may be used to assess resectability. Serum markers, including carcinoembryonic antigen, cancer antigen 125, carbohydrate antigen 19-9, and cancer antigen 72-4, have limited diagnostic value and may be elevated due to other conditions.

Staging laparoscopy with peritoneal washings for cytology is advised for patients with potentially resectable disease before starting chemotherapy.[4] During diagnostic laparoscopy, up to 40% of patients may be found to have peritoneal disease, detected through direct biopsy or cytology from peritoneal washings, which might not be identified by other preoperative imaging.[4] Patients with detected peritoneal disease are generally considered to have metastatic disease and typically do not undergo surgery. However, a small number may be candidates for aggressive cytoreduction and intraperitoneal chemotherapy.

Treatment / Management

The treatment modalities used for treating gastric cancer include endoscopic resection, surgery, chemotherapy, radiation, and targeted therapies. Often, these techniques are combined based on tumor location, stage, and patient-related factors. Endoscopic techniques are reserved for tumors limited to the mucosa or the very superficial submucosa without high-risk factors. Most patients with tumors greater than T2 or who have any evidence of nodal involvement should undergo perioperative chemotherapy followed by surgery. Patients with advanced or nonresectable tumors should undergo chemotherapy with palliative intent. Radiation is typically reserved for palliation or when surgical resection is inadequate. Each modality is discussed under the relevant section.

Differential Diagnosis

Differential diagnoses that should be considered when evaluating gastric cancer include:

• Acute gastritis
• Atrophic gastritis
• Bacterial gastroenteritis
• Chronic gastritis
• Esophageal cancer
• Esophageal stricture
• Esophagitis
• Non-Hodgkin lymphoma
• Peptic ulcer disease
• Viral gastroenteritis

Surgical Oncology

Endoscopic Resection for Early Local Disease

Endoscopic techniques for treating gastric cancer include endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). These minimally invasive procedures are utilized for early-stage gastric cancer, mainly when the tumors are confined to the mucosa or superficial submucosa.[20] EMR involves the removal of the target lesion using a snare device.[21] The snare, often equipped with electrocautery, excises the lesion from the gastric wall. This technique is generally suited for small, well-defined lesions and can be performed either with or without electrocautery, which helps achieve hemostasis and reduce bleeding during the procedure. EMR is typically used for tumors less than 2 cm in diameter confined to the mucosal layer. The procedure offers diagnostic and therapeutic benefits, allowing for the removal and immediate evaluation of the lesion.

Endoscopic submucosal dissection (ESD) is more sophisticated and complex than EMR. ESD involves dissecting the submucosa around the target lesion using either sharp dissection or cautery.[21] This technique removes larger lesions and those with a more invasive pathology. The procedure starts with creating a submucosal lift, followed by careful dissection of the lesion from the underlying muscle layer. ESD is preferred for lesions that are not amenable to EMR due to their size or depth of invasion. This procedure allows for en-bloc resection, where the entire lesion is removed in 1 piece, which is critical for accurate staging and reducing the risk of local recurrence. Endoscopic resection is considered a viable therapeutic option when specific criteria are met.[21] These criteria include:

• Lesion size: The lesion should be <2 cm in diameter.
• Histological characteristics: The lesion should be moderate to well-differentiated, indicating a lower likelihood of aggressive behavior.
• Clear margins: The margins of the resected specimen must be free of cancer cells, ensuring that the tumor has been completely removed.
• Absence of high-risk features: The lesion should not exhibit high-risk features, such as lymphovascular or perineural invasion. These features indicate a higher risk of metastasis and a poorer prognosis.

Clinicians should note if the tumors extend beyond the superficial submucosa, as tumors that invade the deeper submucosa or beyond are associated with significantly higher rates of lymph node metastasis and are generally not suitable for endoscopic resection alone. When performed by skilled clinicians, endoscopic dissection is typically done as an en-bloc resection, which improves the accuracy of staging and reduces the risk of residual cancer. The success rates of endoscopic resection are high, with 5-year overall survival rates ranging from 84% to 96%, depending on the tumor's depth of invasion and other pathological factors. These rates compare favorably with those for gastrectomy, which can offer up to 98% survival for early-stage disease. However, no randomized controlled trials directly compare endoscopic resection with gastrectomy; therefore, treatment decisions should be based on individual patient factors, tumor characteristics, and available expertise. In summary, endoscopic techniques, including EMR and ESD, provide effective, minimally invasive options for managing early gastric cancer. The choice between EMR and ESD depends on the size, depth, and characteristics of the lesion, as well as the expertise of the performing team.[22][23][24]

Gastric Resection

Surgery for gastric cancer has made remarkable advancements over recent decades and remains the only definitive cure for patients without metastatic disease. The integration of perioperative or neoadjuvant chemotherapy before surgical resection has significantly improved survival rates for those with locally advanced gastric cancer. Experts now recommend it for most patients with this stage of disease. For patients with T1a and T1b gastric cancers, where endoscopic resection is not feasible, upfront surgical resection remains the standard approach. For tumors at T2 or higher, diagnostic laparoscopy is often employed to assess peritoneal involvement, including peritoneal biopsies and cytology. This is followed by perioperative chemotherapy, with surgical resection performed upon completion of the chemotherapy regimen. The chemotherapy regimen's choice and duration are individualized based on patient-specific factors detailed in the medical oncology section.[10]

The surgical approach varies depending on the tumor's location within the stomach. The fundamental principles of surgery involve achieving an adequate proximal and distal margin, typically 3 to 5 cm, and performing a complete lymphadenectomy of the perigastric lymph nodes (D2 lymphadenectomy) along with appropriate reconstruction. Distal gastric cancers involving the stomach's antrum or distal body are generally treated with distal subtotal gastrectomy. For tumors located in the proximal body or fundus of the stomach, total gastrectomy is often required. For smaller and less advanced tumors, a proximal gastrectomy may be considered. Gastric reconstruction is typically performed using Roux-en-Y gastrojejunostomy for distal subtotal gastrectomy and Roux-en-Y esophagojejunostomy for total gastrectomy. In addition, feeding jejunostomy tubes may be placed to provide nutritional support post-surgery.[10][25]

The extent of lymphadenectomy has been a subject of extensive debate. D1 lymphadenectomy involves the removal of only the perigastric lymph nodes, whereas D2 lymphadenectomy includes these nodes and those along the major vascular axis surrounding the stomach. Two large trials by the Dutch Cancer Group and the Medical Research Council, which compared D1 with D2 lymphadenectomy, were initially flawed and underpowered to conclusively demonstrate the benefits of D2 lymphadenectomy. However, a long-term follow-up study from the Dutch trial, with a median of 15 years and involving 1078 patients, showed results indicating that D2 lymphadenectomy was associated with reduced locoregional recurrence (12% versus 22%), regional recurrence (13% versus 19%), and gastric cancer-related mortality (37% versus 48%) compared to D1 lymphadenectomy.[26] Despite these benefits, D2 lymphadenectomy was associated with significantly higher operative morbidity (10% versus 4%), complication rates (43% versus 25%), and reoperation rates (18% versus 8%). Nevertheless, advances in surgical techniques, such as spleen-preserving D2 resection, have mitigated some of these risks, making D2 lymphadenectomy the recommended approach for resectable gastric cancer.[10][25]

D3 super-extended lymphadenectomy, which includes periaortic dissection, was studied in the Japan Clinical Oncology Group trial 9501. This approach showed no added survival benefit and was associated with significantly higher perioperative complication rates.[27] Current guidelines recommend sampling at least 15 lymph nodes, which has been shown to provide a survival benefit. Minimally invasive techniques, such as laparoscopic surgery, may be employed by experienced surgeons with outcomes comparable to those of open surgery.[4]

In highly selected patients with gastric cancer and peritoneal metastases and no evidence of other distant metastasis, cytoreduction with or without hyperthermic intraperitoneal chemotherapy may be indicated. Patients should undergo preoperative chemotherapy to ensure that there is no disease progression before undergoing cytoreduction. Phase 3 randomized control trials on the role of cytoreduction and hyperthermic intraperitoneal chemotherapy are ongoing.[28] 

For patients with gastric cancer who experience obstruction or uncontrolled bleeding, palliative resection may be necessary. However, chemotherapy and radiation therapy are often effective in managing symptoms and should be considered as first-line palliative treatments. Surgery should be reserved for cases where other modalities fail to provide adequate palliation.

Radiation Oncology

The role of radiation therapy (RT) in gastric cancer has evolved. Adjuvant chemoradiation was recommended as the treatment of choice in patients who had not undergone preoperative chemotherapy. This was based primarily on the SWOG 9008/INT0116, a randomized phase 3 trial that assigned 556 patients with stages I to III gastroesophageal (20%) or gastric cancers (80%) to receive either surgery alone or surgery followed by adjuvant combined chemoradiotherapy. There was an approximate 20% improvement in survival for the group receiving the combined-modality therapy. The median overall survival in the surgery-only group was 27 months compared with 36 months in the chemoradiation group; the HR for death in the surgery-only arm was 1.35 (95% CI, 1.09 to 1.66; P = .005), and relapse HR was 1.52 (95% CI, 1.23 to 1.86; P < .001).[29] The study has been criticized for the meager rate of D1 (<54%) or D2 (<10%) lymph node dissection, which was mandated per protocol. The rate of distant metastasis was not reduced in the adjuvant chemoradiation group (16% versus 18%), suggesting that adjuvant therapy could have mainly compensated for inferior surgery.

CALGB Intergroup C80101 tried to improve the results obtained with INT0116 protocol regimen therapy by randomly selecting patients with resected gastric or GEJ cancer to receive chemoradiotherapy with epirubicin, cisplatin, 5-fluorouracil. This study was not adequately powered to assess noninferiority and did not demonstrate any outcome difference between both arms. The Korean ARTIST trial provided further combined therapy evidence. This trial evaluated the addition of radiation therapy to adjuvant chemotherapy in patients who underwent gastrectomy with D2 lymph node dissection. Patients were randomly selected to receive 6 cycles of chemotherapy with cisplatin and capecitabine (CX) or 2 cycles of CX followed by chemoradiation, followed by 2 more cycles of CX. At a median follow-up of 84 months, neither disease-free survival (DFS) nor overall survival differed between the 2 arms. However, unplanned subsets of patients with node-positive disease and intestinal-type gastric cancer did have a significantly improved DFS with the addition of radiation therapy.[30]

The ARTIST 2 trial sought to clarify this benefit, randomizing patients who underwent a D2 lymphadenectomy to adjuvant chemotherapy alone (S1 alone or S1 with oxaliplatin) or adjuvant chemoradiation. There was no benefit to adding radiation, with 3-year overall survival actually being higher in the chemotherapy arms.[31] The current role of radiation therapy is mostly in patients who have had inadequate surgery (ie, less than D2 dissection), are unable to tolerate chemotherapy, or in bulky tumors that are symptomatic or those that have local invasion. 

Medical Oncology

Neoadjuvant and Adjuvant Therapy for Locally Advanced Resectable Disease 

Surgical resection alone can potentially cure early-stage gastric cancer, with a 5-year overall survival rate of 75% for stage I, declining significantly to 35% for stage II and 25% or less for stage III. Most patients who recur after surgery do so distally, which has focused research on neoadjuvant (preoperative) and adjuvant (postoperative) therapies. Perioperative chemotherapy combines the 2 approaches, with chemotherapy administered before and after surgery. 

Perioperative chemotherapy

Perioperative chemotherapy aims to downstage primary tumors and regional lymph nodes, increasing the likelihood of long-term curative resections. There is a recommendation for high-risk patients (eg, those with bulky T3/T4 tumors, perigastric nodes, linitis plastica, or positive peritoneal cytology) to avoid unnecessary surgery if metastases appear. The MAGIC trial was a significant study in this area, involving 503 patients with resectable stomach cancer, GEJ cancer, and distal esophagus cancer. The trial compared perioperative chemotherapy (3 preoperative and 3 postoperative cycles of epirubicin, cisplatin, and fluorouracil) to surgery alone, finding significant improvements in median overall survival (36% versus 23% 5-year survival) and progression-free survival for the chemotherapy group. The trial suggested that preoperative treatment was the main contributor to improved outcomes since only 55% of patients completed postoperative therapy.[32] The French FNLCC/FFCD ACCORD trial also reported benefits for perioperative chemotherapy, showing better R0 resection rates, reduced disease-free survival, and lower mortality risk. Conversely, the EORTC trial 40954 failed to show survival benefits due to limited accrual.[33]

The FLOT4-AIO trial compared the FLOT regimen (docetaxel, oxaliplatin, leucovorin, and fluorouracil) to an epirubicin-containing regimen, showing higher pathological complete response rates and less toxicity except for neutropenia in the FLOT regimen. Preliminary results favored the FLOT regimen with a median overall survival of 50 months compared to 35 months for the epirubicin-containing regimen.[34][35] Future research aims to determine the benefits of neoadjuvant chemoradiation over chemotherapy alone. Patients undergoing perioperative chemotherapy are restaged after completing 3 to 4 cycles of chemotherapy. If no evidence of disease progression is noted, then surgery is performed. Most patients then receive postoperative chemotherapy for another 3 to 4 cycles, although this depends on patient tolerance and their recovery from surgery. 

Adjuvant chemotherapy 

Adjuvant chemotherapy is recommended after surgery in patients who have not received preoperative therapy. Adjuvant chemotherapy alone was evaluated in the Japanese ACTS-GC phase 3 trial with S1 (an oral fluoropyrimidine 80 to 120 mg daily for 4 weeks, repeated every 6 weeks for 1 year) as postoperative D2-resection adjuvant therapy compared to surgery alone in 1059 patients with stage II or III gastric cancer and demonstrated a survival benefit with a 5-year overall survival rate of 72% in the S-1 group and 61% in the surgery only group.[36] Similar results were reported by the Korean phase 3 multicenter CLASSIC trial and in a meta-analysis of several trials, where chemotherapy was associated with a significant overall survival benefit with an HR of 0.85 (95% CI, 0.80 to 0.90) and an improvement in DFS (hazard ratio 0.79; 95% CI, 0.72 to 0.87) versus surgery alone.[37] In general, the adjuvant therapy approach is favored in East Asia, while perioperative chemotherapy, usually with the FLOT regimen, is favored in the West. 

Palliative Therapy for Locally Advanced Unresectable and Advanced Metastatic Disease 

The treatment of unresectable locally advanced gastric cancer typically involves regimens used for advanced metastatic disease. The primary goals of medical therapy for advanced gastric cancer are palliative: to alleviate symptoms, enhance quality of life, and modestly extend survival. Several chemotherapy agents are effective, including fluoropyrimidines (eg, fluorouracil and capecitabine), anthracyclines (eg, epirubicin), platinum compounds (eg, cisplatin, oxaliplatin), taxanes (eg, paclitaxel and docetaxel), irinotecan, and targeted therapies like trastuzumab for HER2-positive cancers and ramucirumab, a vascular endothelial growth factor 2 antibody. Combination regimens have a higher response rate (up to 65%) than single-agent therapies (up to 40%).

Patients eligible for chemotherapy should be tested for HER2 overexpression. Patients that are HER2-positive can receive trastuzumab combined with chemotherapy (commonly fluoropyrimidine plus platinum). For HER2-negative patients in good health, doublet therapy is recommended over triplet regimens due to the higher toxicity of the latter, which is reserved for select patients with excellent performance status. Older or poor-performance individuals may be treated with single agents like fluorouracil, capecitabine, irinotecan, or low-dose taxanes. Docetaxel and irinotecan have shown benefits in second-line chemotherapy, but no optimal standard of care exists.

Fluorouracil-based combination trials have established the benefits of adding anthracyclines, platinum agents, or taxanes over older treatments. For example, the German trial compared FLP (fluorouracil, leucovorin, cisplatin) with FLO (fluorouracil, leucovorin, oxaliplatin) and found superior survival with FLO in patients older than 65. The TAX-325 trial demonstrated the superiority of adding docetaxel to cisplatin and fluorouracil (DCF) compared to cisplatin and fluorouracil alone (CF). However, DCF had higher toxicity, including febrile neutropenia, limiting its use to patients with good performance status.[38] The REAL-2 trial substituted capecitabine for fluorouracil and oxaliplatin for cisplatin, showing that EOX (epirubicin, oxaliplatin, capecitabine) was less toxic and provided modestly more prolonged survival than ECF (epirubicin, cisplatin, fluorouracil). FOLFIRI (fluorouracil, leucovorin, irinotecan) has shown similar efficacy to other regimens with less toxicity, making it an alternative for patients unable to tolerate platinum-based treatments.

Targeted agents like trastuzumab have shown efficacy in advanced gastric cancer. The ToGA trial added trastuzumab to chemotherapy in HER2-positive individuals, improving median overall survival, progression-free survival, and overall response rate without significant toxicity differences.[39] Consequently, trastuzumab with chemotherapy is the standard for HER2-positive cancers. However, in clinical trials, lapatinib, another HER2/EGFR inhibitor, did not show survival benefits. Similarly, cetuximab and panitumumab, targeting EGFR, worsened toxicity and overall survival in trials.[10]

Angiogenesis inhibitors have yielded mixed results. In the AVAGAST trial, bevacizumab improved progression-free survival and overall response rate but not overall survival. At the same time, ramucirumab showed modest survival benefits in second-line settings, leading to its approval. However, adding ramucirumab to first-line therapy did not show benefits.[40] After first-line chemotherapy failure, second-line options include irinotecan or paclitaxel, which improve overall survival compared to the best supportive care. Radiation therapy can provide symptomatic relief but is rarely used alone. Novel agents under investigation include olaparib, which showed significant benefits in combination with paclitaxel, and pembrolizumab, an anti-programmed death protein-1 antibody showing promising results in programmed death-ligand 1–positive tumors. Other promising agents include apatinib and regorafenib, which have demonstrated survival benefits in clinical trials.[41]

Staging

The American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) Eighth Edition 2017 staging system for gastric cancer (see Table. The American Joint Committee on Cancer Gastric Cancer Staging) stratifies 5-year overall survival (5-y OS) according to pathological stage and intervention (surgery only IA-93.6%, IIA-81.8%, and IIIA-54.2% or with neoadjuvant I-76.5%, II-46.3%, III-18.3%, and IV-5.7%). The following TMN classification is utilized for grading:

• T, Tumor
  • TX: Primary tumor cannot be assessed
  • T0: No evidence of primary tumor
  • Tis: Carcinoma in situ; intraepithelial tumor without invasion of the lamina propria
  • T1: Tumor invades the lamina propria, muscularis mucosae, or submucosa
    • T1a: Tumor invades the lamina propria or muscularis mucosae
    • T1b: Tumor invades the submucosa
  • T2: Tumor invades the muscularis propria
  • T3: Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures.
  • T4: Tumor invades the serosa (visceral peritoneum) or adjacent structures
    • T4a: Tumor invades the serosa
    • T4b: Tumor invades adjacent structures
• N, Nodes
  • NX: Regional lymph nodes cannot be assessed
  • N0: No regional lymph node metastasis
  • N1: Metastasis in 1 to 2 regional lymph nodes
  • N2: Metastasis in 3 to 6 regional lymph nodes
  • N3: Metastasis in 7 or more regional lymph nodes
    • N3a: Metastasis in 7 to 15 regional lymph nodes
    • N3b: Metastasis in ≥16 regional lymph nodes
• M, Metastasis
  • M0: No distant metastasis.
  • M1: Distant metastasis present.

Table. The American Joint Committee on Cancer Gastric Cancer Staging

Prognosis

The prognosis of gastric cancer is closely linked to the extent of the tumor, including nodal involvement and direct tumor invasion beyond the gastric wall. Tumor grade may also offer additional prognostic insight. More than 50% of patients with localized distal gastric cancer can achieve a cure. However, early-stage disease constitutes only 10% to 20% of all gastric cancer cases diagnosed in the United States.

Most patients present with metastatic disease, either regional or distant. The overall 5-year survival rate varies significantly, ranging from nearly 0 for patients with disseminated disease to approximately 50% for those with distal, resectable regional disease. For patients with localized proximal gastric cancer, the 5-year survival rate is only 10% to 15%. Although treatment for disseminated gastric cancer can provide symptomatic relief and some extension of life, long-term remissions are rare.

Complications

Gastric cancer's complications are diverse. Complications related to the primary tumor include bleeding, obstruction, perforation, and fistulization to surrounding organs. Metastatic disease can present with different symptoms based on the site of metastasis. Complications of surgery include bleeding, surgical site and organ space infections, anastomotic leaks, injury to surrounding structures like the spleen and duodenum, and longer-term complications like incisional hernias. (Please refer to the Medical Oncology section for more information on the adverse effects of chemotherapy).