November 19, 2021 - read ≈ 15 min
Biqi Zhang MD, David Mahvi MD, Mark Fairweather, MD
Gastric cancer is the third-leading cause of cancer-related deaths worldwide, accounting for approximately 1 in 12 of all oncologic deaths (Rawla; Global Cancer Observatory). In 2018, there were an estimated 783,000 gastric cancer deaths, just behind those reported for lung and liver cancer deaths. Gastric cancer is the fifth-most common cancer worldwide with over one million new cases annually. East Asia has the highest incidence of gastric cancer. Overall, the incidence and number of deaths attributable to gastric cancer has risen over the past 2-3 decades (GBD stomach).
There are a number of risk factors for gastric cancer. While most cancers are sporadic, 1-3% are due to a genetic mutation (most commonly E-cadherin/CDH1 mutations) (Petrovchich). Numerous dietary factors have been linked to subsequent gastric cancer development, including salty or spicy diets, processed meat, smoked fish, refined grains, and lack of adequate fruits and vegetables. Additional lifestyle factors include alcohol and cigarette use. History of H. pylori infection or chronic atrophic gastritis also increase a patient’s risk of developing subsequent stomach cancer. Men are also more likely to develop the disease than women (Yusefi).
Gastric cancer often produces vague symptoms that may not be present until later courses of the disease. Unintentional weight loss and epigastric abdominal pain are the most common symptoms, but others may present with early satiety, decreased appetite, and nausea. New-onset heartburn or reflux can be a presenting symptom and warrants further workup especially in older adults. Melena and anemia can be seen in tumors that are bleeding. A rare subset of patients may have systemic manifestations of gastric cancer. These paraneoplastic syndromes include Leser-Trelat sign, which is characterized by sudden onset of multiple seborrheic keratoses, and acanthosis nigricans, which appears as dark pigmentation in skin folds. While known, these manifestations are not specific to gastric cancer and are more often benign processes.
Screening programs for gastric cancer have been implemented in South Korea and Japan, where disease incidence is high. Screening in these countries consists of either upper GI series or endoscopy. In Korea, screening is recommended every 2 years starting at age 40. In Japan, screening is performed every 2-3 years starting at age 50. Both countries have shown improved mortality and increased diagnosis at earlier cancer stages with screening programs (Kim). Outside of these countries, the utility and cost-effectiveness of gastric cancer screening is unclear and currently debated.
The only exceptions may include those with a family history of hereditary gastric cancer, which accounts for less than 5 percent of all gastric cancer cases worldwide. Hereditary diffuse gastric cancer, which is linked to the CDH-1 gene, carries a high lifetime risk and has an average age of diagnosis at 37 years. These patients should be offered a prophylactic total gastrectomy at age 18, and those who opt out should undergo screening endoscopy with multiple random biopsies every 6 to 12 months. For individuals with other syndromes such as Lynch Syndrome, Juvenile Polyposis Syndrome, Peutz-Jeghers Syndrome, and Familial Adenomatous Polyposis, the benefit of EGD is less clear but may be recommended to select, higher risk individuals.
Esophagogastroduodenoscopy (EGD) with biopsy is the gold standard for cancer diagnosis. The location of the tumor within the stomach should be carefully recorded by the endoscopist, as this has critical treatment implications. According to the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) TNM classification, eighth edition (cite), esophagogastric junction tumors with epicenter less than 2 centimeters (cm) into the proximal stomach are classified as esophageal cancers; those more than 2 cm into the stomach are staged as gastric cancers. Multiple (6-8) biopsies should be taken. For lesions under 2 cm in size, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) can be considered in experienced hands, which can be both diagnostic and therapeutic depending on the pathology of the specimen. The pathology report of the biopsy should include presence of invasion, histologic subtype (intestinal or diffuse), and tumor grade.
Once cancer is diagnosed, patients should undergo computed tomography (CT) with intravenous and oral contrast of the chest, abdomen, and pelvis to evaluate for metastatic disease. Suspicious lesions in the lungs, liver, and abdomen including peritoneal and retroperitoneal masses concerning for enlarged lymph nodes should be biopsied for tissue confirmation. Ascitic fluid may be sampled by paracentesis and sent for cytologic and chemical analysis,
In patients without evidence of metastatic disease on CT, endoscopic ultrasound (EUS) is recommended to assess the T stage. EUS can also identify enlarged nearby lymph nodes, which can be biopsied at time of ultrasound if seen using FNA. If there is high clinical suspicion of metastasis but initial CT is unrevealing, integrated positron emission tomography (PET)/CT may be considered. Diagnostic laparoscopy may also be useful in detecting occult disease. A complete blood count and comprehensive metabolic profile should be obtained to evaluate for anemia and electrolyte derangements. Serum tumor markers such carcinoembryonic antigen (CEA) and the glycoprotein cancer antigen 125 (CA 125) are not routinely used outside of clinical trials.
Early gastric cancer is defined as cancers that do not invade past the submucosa (T1). As stated earlier, screening programs improve the rate of early gastric cancer detection. Stage IA disease is T1N0M0. Stage IB is T1N1 (spread to 1-2 nearby lymph nodes) or T2N0 (tumor that invades the muscularis propria). Stage II and III cancers have increased tumor and/or nodal staging. Stage IV cancers have presence of metastatic disease.
It is recommended that treatment decisions for all patients diagnosed with gastric cancer be discussed by a multidisciplinary review team including medical oncology, radiation oncology, surgical oncology, gastroenterology, radiology, and pathology. Patients with either Tis or T1a disease (tumor that does not invade past the submucosa) may be candidates for either endoscopic or surgical resection. Patients with T1b cancers (tumor that invades submucosa) should undergo upfront surgical resection. Patients with T2 or higher disease or any nodal involvement are recommended to undergo perioperative chemotherapy. Radiation therapy can be considered, especially in cases of locally advanced disease. Patients that are not candidates for curative surgical resection or with metastatic disease should be considered for palliative treatment in addition to systemic chemotherapy. Surgically unresectable disease is defined by either cancer involvement of the root of the mesentery or para-aortic lymph nodes or invasion/encasement of major vascular structures. One exception is encasement of the splenic artery; these cases should not be considered unresectable as this artery can be sacrificed and a splenectomy can be performed.
Endoscopic resection with either EMR or ESD can be considered adequate therapy for gastric cancer less than 2 cm in size that is 1) well- or moderately-differentiated, 2) does not penetrate past the submucosa, and 3) does not have evidence of lymphovascular invasion.
Surgical resection typically consists of either a distal or total gastrectomy depending on where the tumor is located. Patients undergoing surgery should be considered for a diagnostic laparoscopy to detect the possible presence of occult metastatic disease prior to committing to curative surgery. A 5 cm proximal margin should be obtained with at least a 2 cm distal margin on the duodenum. T4 tumors require en bloc resection of nearby involved organs or structures. Retrieval of at least 15 lymph nodes is necessary for accurate nodal staging. The appropriate extent of lymphadenectomy for gastric cancer is debated. While D1 lymphadenectomy involves removal of the perigastric lymph nodes alone, D2 lymphadenectomy involves additional removal of lymph nodes around the left gastric, common hepatic, celiac, and splenic arteries. Some studies have shown a survival advantage with D2 lymphadenectomy while others have not.
In cases that require reconstruction after a distal gastrectomy, options include Roux-en-Y gastrojejunostomy, Billroth I, and Billroth II. Reconstruction after total gastrectomy is performed with a Roux-en-Y esophagojejunostomy. Placement of a jejunal feeding tube should be considered at time of operation, especially if a patient is likely to receive adjuvant chemoradiation and/or their nutritional status is poor, though their use is not standardized.
The utility of chemotherapy in gastric cancer has been established in multiple randomized trials. The first major trial (MAGIC) randomized 503 patients with resectable adenocarcinoma of the stomach, gastroesophageal junction, or lower esophagus to surgery alone versus surgery with perioperative ECF chemotherapy (epirubicin, cisplatin, fluorouracil). Chemotherapy consisted of 3 cycles preoperatively and 3 cycles postoperatively. Perioperative ECF resulted in improved 5-year overall survival (36% as compared to 23% among patients who received surgery alone) (Cunningham). More recently, a randomized phase 2/3 trial of 716 patients with resectable stage II or III gastric or gastroesophageal junction adenocarcinomas was conducted to compare perioperative ECF and perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel). Survival was significantly improved with FLOT, with median overall survival of 50 months as compared to 35 months with ECF (Al-Batran). Further, FLOT was deemed as safe as ECF.
In patients who are medically fit and thereby recommended to receive perioperative chemotherapy, the FLOT regimen is recommended. Patients unable to tolerate this more aggressive chemotherapy regimen may undergo treatment with fluoropyrimidine and oxaliplatin or fluorouracil and cisplatin. The ECF regimen (epirubicin, cisplatin, and fluorouracil) is no longer first-line therapy.
For patients who do not receive neoadjuvant therapy, treatment recommendations are guided by tumor classification, operative margins, and extent of lymphadenectomy. Those whose final surgical pathology reveals T3, T4, or any N positive disease should be offered adjuvant chemoradiation. Those with T2N0 disease may be offered either adjuvant chemotherapy or surveillance. All patients with positive operative margins should receive adjuvant chemoradiation. Adjuvant chemotherapy is fluoropyrimidine-based. In patients who received less than a D2 lymphadenectomy, fluorouracil or capecitabine is recommended before and after fluoropyrimidine-based chemoradiation. For patients that did have a D2 lymphadenectomy, oxaliplatin and fluorouracil or capecitabine is recommended.
It should be noted that in select neoadjuvant patients who receive a microscopically positive resection, otherwise known as an R1 resection, re-operation may be considered prior to proceeding to further adjuvant therapy as clinically indicated.
There are currently ongoing preclinical and early clinical phase trials of various immunotherapy agents in the treatment of gastric cancer. However, their use remains investigational at this time.
The benefits and indications for radiotherapy are less well-established. There are currently no randomized trials comparing adjuvant chemoradiotherapy to either surgery alone or surgery and chemotherapy. Preoperative chemoradiotherapy is beneficial in patients with esophageal, gastroesophageal junction, and gastric cardia tumors as shown in the CROSS trial (van Hagen), but its role specifically in gastric cancer is less clear. Radiotherapy can be considered as an adjunct in multidisciplinary discussions for patients with locally advanced disease.
The most common indications for palliative procedures in gastric cancer are gastric outlet obstruction and uncontrollable bleeding. Perforation may also present as an indication. Choosing among the various palliative options with consideration of the risks and benefits specific to each patient’s case requires multidisciplinary discussion. For patients with an obstructing tumor, especially in the pre-pyloric or antral regions, surgical or endoscopic interventions may be beneficial. For a patient whose life expectancy is greater than 6 months and who is medically fit, surgical gastrojejunostomy may be preferred if technically feasible in either an open or laparoscopic fashion. If the patient is not a surgical candidate, endoscopic stent placement or endoscopic gastrojejunostomy may be considered. Finally, a venting gastrostomy tube is an alternative. However, the patient will no longer be able to eat if this is the only therapy offered, and a feeding jejunostomy tube must be considered.
Patients who present with uncontrollable bleeding may initially undergo endoscopic treatment, but this is associated with a high likelihood of recurrent bleeding. Angiographic embolization or radiation therapy are potential alternatives. If these more conservative measures are unsuccessful, palliative resection should be considered. Should a patient pursue operative intervention, lymph node dissection is not required. If patients present with gastric perforation or other perforated viscus, a goals of care conversation should be had and, only if within their goals of care, palliative resection may be attempted.
Patients successfully treated with endoscopic resection should undergo a thorough history and physical exam every 3 to 6 months after treatment for the first 1 to 2 years, then every 6 to 12 months for 3 to 5 years, followed by annual follow-up thereafter. EGD should be performed every 6 months for 1 year and then annually for up to 5 years. CT scans should be performed as clinically indicated by symptoms.
Patients with stage I disease treated by surgery should undergo a history and physical every 3 to 6 months after treatment for 1 to 2 years, then every 6 to 12 months for 3 to 5 years, followed by annual follow-up thereafter. They should have EGD and/or CT scans as clinically indicated by symptoms. These patients must additionally be monitored for nutritional deficiencies, especially involving B12 and iron.
Patients with stage II or III disease who received surgery should undergo history and physical every 3 to 6 months after treatment for 1 to 2 years, then every 6 to 12 months for 3 to 5 years, followed by annual follow-up thereafter. EGD may be performed as clinically indicated. CT of the chest/abdomen/pelvis should be performed every 6 to 12 months for the first 2 years and then annually up to 5 years. PET/CT should be considered as clinically indicated when suspicion for disease recurrence and/or metastasis is high. These patients must also be monitored for nutritional deficiencies.
Target therapeutics has become more promising with our growing understanding of tumor heterogeneity, but how to treat these differences remains controversial. Gastric cancer can be divided into several subtypes by histology (intestinal and diffuse), gene expression (e.g., human epidermal growth factor receptor 2 or HER2 expression), and even genomic profile. As an example, The Cancer Genome Atlas Project has classified gastric cancer into four groups: Epstein-Barr virus-positive tumors, microsatellite unstable tumors, genomically stable tumors, and tumors with chromosomal instability. While subtype specific treatments have yet to prove widely beneficial, results from the Trastuzumab for Gastric Cancer (ToGA) trial—which found improved survival among HER2-overexpressed patients treated with trastuzumab and chemotherapy as compared with chemotherapy alone (median overall survival 13.8 versus 11.1 months)—highlights the promise of HER2 targeted therapy. Histologic subtype may also be relevant: diffuse type gastric cancer, which is much less common than the classic intestinal subtype, appear less responsive to current chemotherapy regimens. Such patients may benefit from upfront surgical resection, and results from a multicenter phase 2/3 randomized trial are pending (cite PRODIGE 19-FFCD1103-ADCI002). Overall, which tumor biomarkers merit study and the complicated logistics of obtaining adequate sample sizes render clinical trials difficult and expensive. Promising trials have closed early due to poor accrual. Enrollment criteria in most gastric cancer trials therefore remains inclusive, but this warrants ongoing discussion.
Another area of debate involves the benefits of D1 versus D2 lymph node dissection at time of gastrectomy. In South Korea and Japan where the rates of gastric cancer are notably higher, D2 lymphadenectomy has been the standard of care for decades. This has prompted numerous studies comparing the two approaches in other countries who have lower incidence and less operative experience. While data from East Asia have consistently shown that D2 lymphadenectomy is associated with vastly improved survival, randomized trials in the United Kingdom, the Netherlands, Italy, and the United States have shown at best a trend towards improved survival in high-volume institutions (Enzinger, etc). While more experienced centers have demonstrated that D2 lymphadenectomy can be performed safely (Degiuli 2010), others have found higher morbidity and mortality (Songun/the Dutch). Currently, National Comprehensive Cancer Network guidelines deems the retrieval of at least 15 lymph nodes as necessary for accurate nodal staging, with D2 lymphadenectomy to be performed in experienced hands and for select patients.
Summary and Recommendations
Gastric cancer is unfortunately a common malignancy, particularly in East Asia. Except in South Korea and Japan where high incidence of disease has prompted routine screening, most patients present symptomatically. The most common complaints are unintentional weight loss and abdominal pain. Definitive diagnosis involves esophagogastroduodenoscopy with tissue biopsy. Comprehensive staging using a combination of endoscopic ultrasound, computed tomography with possible position emission tomography, and diagnostic laparoscopy best guides long-term therapy; findings concerning for metastasis should be biopsied for tissue confirmation. Patients with T1b gastric cancers or lower may qualify for upfront surgical resection; Tis or T1a tumors may even be candidates for endoscopic resection. T2 or higher disease merits perioperative chemotherapy, which most commonly consists of ECF (epirubicin, cisplatin, fluorouracil) or FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) if tolerated. Those with locally advanced disease may benefit from additional radiotherapy, but the ideal treatment recommendations should be made after review by a multidisciplinary team consisting of medical, radiation, and surgical oncologists as well as gastroenterologists, radiologist, and pathologists. A team approach is also necessary for post-treatment surveillance, which usually consists of a history and physical in 3 to 6 month intervals for the first few years, then 6 to 12 months for up to 5 years with annual follow-up thereafter. There are many options for palliation for individuals with metastatic disease, and the best option will depend on the individual’s goals of care.
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- GBD 2017 Stomach Cancer Collaborators. The global, regional, and national burden of stomach cancer in 195 countries, 1990–2017: a systematic analysis for the Global Burden of Disease study 2017. Lancet Gastroenterol Hepatol. 2020. 5(1): 42-54
- Petrovchich I, Ford JM. Genetic predisposition to gastric cancer. Sem Oncol. 2016. 43(5): 554-9
- Yusefi AR, Lankarani KB, Bastani P, et al. Risk Factors for Gastric Cancer: A Systematic Review. Asian Pac J Cancer Prev. 2018. 19(3): 591-603
- Kim GH, Liang PS, Bang SJ, Hwang JH. Screening and surveillance for gastric cancer in the United States: Is it needed? Gastrointest Endoscopy. 2016. 84(1): 18-28
- Cunningham D, Allum WH, Stenning SP, et al. Perioperative Chemotherapy versus Surgery Alone for Resectable Gastroesophageal Cancer. N Engl J Med. 2006. 355: 11-20
- Al-Batran SE, Homann N, Pauligk C, et al. Perioperative Chemotherapy With Fluorouracil Plus Leucovorin, Oxaliplatin, and Docetaxel Versus Fluorouracil or Capecitabine Plus Cisplatin and Epirubicin for Locally Advanced, Resectable Gastric or Gastro-Oesophageal Junction Adenocarcinoma (FLOT4): A Randomised, Phase 2/3 Trial. Lancet. 2019. 393(10184): 1948-57
- van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012. 366: 2074-2084
- The Japanese guidelines for gastric cancer screening. Hamashima C, Shibuya D, Yamazaki H, Inoue K, Fukao A, Saito H, Sobue T Jpn J Clin Oncol. 2008 Apr; 38(4):259-67.
- Kim Y, Jun JK, Choi KS, Lee HY, Park EC. Overview of the national cancer screening programme and the cancer screening status in Korea. Asian Pac J Cancer Prev 2011;12:725–30.
- Cancer Genome Atlas Research Network: Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202-209, 2014
- Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastrooesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 376:687-697, 2010
- Piessen G, Messager M, Le Malicot K, et al: Phase II/III multicentre randomised controlled trial evaluating a strategy of primary surgery and adjuvant chemotherapy versus peri-operative chemotherapy for resectable gastric signet ring cell adenocarcinomas: PRODIGE 19-FFCD1103-ADCI002. BMC Cancer 13:281, 2013
- Enzinger PC, Benedetti JK, Meyerhardt JA, et al. Impact of hospital volume on recurrence and survival after surgery for gastric cancer. Ann Surg 2007;245:426-434.
- Other D2 trials:
- - Bonenkamp JJ, Hermans J, Sasako M, van de Velde CJ, Welvaart K, Songun I, Meyer S, Plukker JT, Van Elk P, Obertop H, Gouma DJ, van Lanschot JJ, Taat CW, de Graaf PW, von Meyenfeldt MF, Tilanus H, Dutch Gastric Cancer Group. Extended lymph-node dissection for gastric cancer. N Engl J Med. 1999 Mar 25; 340(12):908-14.
- - Cuschieri A, Weeden S, Fielding J, Bancewicz J, Craven J, Joypaul V, Sydes M, Fayers P. Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Surgical Co-operative Group. Br J Cancer. 1999 Mar; 79(9-10):1522-30.
- - Degiuli M, Sasako M, Ponti A. Morbidity and mortality in the Italian Gastric Cancer Study Group randomized clinical trial of D1 versus D2 resection for gastric cancer. Br J Surg 2010;97:643-649.
- - Songun I, Putter H, Kranenbarg EM, et al. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 2010;11:439-449.