Stomach Cancer

Our health is a delicate interplay of numerous factors, each holding a crucial role, and any anomaly can lead to diseases with varying degrees of severity. Stomach cancer, the fourth most common type globally and the second leading cause of cancer-related deaths, exemplifies this complexity. Despite a slight decline in overall gastric cancer rates over the past five decades, the incidence of proximal stomach cancer is on the rise. While the specific causes remain elusive, identified risk factors include Helicobacter pylori infection, age, gender, and dietary habits such as high salt and smoked food intake, along with low fruit and vegetable consumption. Lifestyle choices like smoking and alcohol consumption also contribute to the risk. Stomach cancer often presents with vague symptoms, including upper belly discomfort, abdominal pain, nausea, vomiting, unexplained weight loss, and loss of appetite. This article offers a concise overview of stomach cancer, delving into its causes, symptoms, and treatment options.

Executive Summary

  • Stomach cancer is a significant global health issue, ranking as the fourth most common cancer worldwide and the second leading cause of cancer-related deaths. While overall rates have slightly declined in the past 50 years, cases of cancer in the upper part of the stomach (proximal stomach cancer) are increasing. The disease is more prevalent in certain ethnic groups, including Black, Hispanic, Asian/Pacific Islander, and American Indian/Alaska Native populations in the United States.

  • Risk factors for stomach cancer are numerous and varied. Helicobacter pylori infection is a major risk factor, causing chronic inflammation of the stomach lining. Other risk factors include age (typically over 65), male gender, dietary habits (high salt and smoked food intake, low fruit and vegetable consumption), smoking, alcohol consumption, and certain genetic predispositions. Obesity and gastroesophageal reflux disease (GERD) specifically increase the risk of cancer in the upper stomach.

  • Stomach cancer is classified into several types based on location, appearance, and cellular characteristics. These include cancers at the gastroesophageal junction, early and advanced gastric carcinomas, and different histologic types like intestinal and diffuse adenocarcinomas. The World Health Organization recognizes four major histologic patterns: tubular, papillary, mucinous, and indeterminate (including signet ring cell carcinoma). This classification is crucial for determining treatment approaches and predicting outcomes.

  • The development of stomach cancer is a complex process involving genetic, epigenetic, and environmental factors. While mutations in genes like TP53 are common, some cases show few genetic alterations, suggesting that epigenetic changes may play a significant role. The cancer is believed to develop through a series of stages, from chronic gastritis to atrophic gastritis, intestinal metaplasia, dysplasia, and finally cancer.

  • Early detection of stomach cancer is challenging because symptoms are often vague or absent in the early stages. When present, symptoms can include indigestion, stomach pain, loss of appetite, fatigue, nausea, vomiting, and unintended weight loss. As the disease progresses, more severe symptoms like vomiting blood or having blood in the stool may occur. The nonspecific nature of these symptoms often leads to delayed diagnosis.

  • Diagnosis involves a multi-step process, including physical examination, blood tests, and specialized procedures. Upper endoscopy with biopsy is a key diagnostic tool, allowing direct visualization of the stomach and tissue sampling. Advanced imaging techniques such as CT scans, PET scans, and endoscopic ultrasound help in staging the cancer. Biomarker testing, including checks for HER2 status, PD-L1 expression, and microsatellite instability, guides treatment decisions.

  • Treatment strategies for stomach cancer are complex and depend on the stage and type of cancer. Options include surgery (partial or total gastrectomy), chemotherapy, radiation therapy, and targeted therapies. Recent advancements have led to the development of immunotherapies and combination treatments. Perioperative chemotherapy has become a standard of care for resectable gastric cancer, with regimens like FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) showing improved outcomes.

  • Emerging treatments include targeted therapies like trastuzumab for HER2-positive cancers and ramucirumab for VEGF inhibition. Immunotherapies, particularly checkpoint inhibitors like pembrolizumab and nivolumab, have shown promise in certain patient subgroups. Ongoing research is exploring combinations of these novel therapies with traditional treatments to improve outcomes.

  • Prevention and risk reduction strategies are crucial. These include maintaining a healthy weight, eating a diet rich in fruits and vegetables, limiting alcohol consumption, and avoiding tobacco use. Treating H. pylori infections may reduce cancer risk in high-risk individuals. Regular screening may be recommended for those with genetic predispositions to stomach cancer, such as hereditary diffuse gastric cancer (HDGC) syndrome.

  • Living with stomach cancer presents numerous challenges. Patients often need to make significant dietary adjustments, particularly after stomach surgery. They may face changes in body image and self-esteem. The psychological impact of diagnosis, treatment, and fear of recurrence can be substantial. Ongoing follow-up care is essential but can be stressful and financially burdensome.

  • Research in stomach cancer is ongoing and promising. Future perspectives focus on improved detection methods, more precise staging techniques, and personalized treatment approaches. Advances in molecular imaging, the development of new targeted therapies, and a deeper understanding of the cancer's molecular biology offer hope for better outcomes. The integration of artificial intelligence in diagnosis and treatment planning is an emerging area of interest.

Introduction

Our health and well-being involve several delicate aspects, with every element playing an indispensable part. An anomaly in any of these elements leads to diseases of varying kinds and severity, which only reveal themselves long after they begin. One such disease is stomach cancer. Stomach cancer is the second biggest cause of cancer-related deaths worldwide. It is also the fourth most frequent type of cancer. Despite a minor decline in gastric cancer prevalence over the last 50 years, the number of patients with proximal stomach cancer is increasing. 

Although the specific etiology of stomach cancer is unknown, certain risk factors may enhance the likelihood of its development. These elements include infection with Helicobacter pylori which can cause stomach lining inflammation and is a major risk factor for stomach cancer. Studies have also found that stomach cancer is more common in people over the age of 65 and that men are more likely to have it than women. Even day-to-day factors like diet, play a key role. For instance, a diet high in salty and smoked foods and poor in fruits and vegetables may raise the risk. Furthermore, research supports the notion that smoking and alcohol consumption can increase the risk of stomach cancer.

As the above risk factors come into play, the disease manifests itself in several ways yet stomach cancer symptoms might be hazy and readily confused with those of other diseases. However, common symptoms include consistent discomfort or burning sensation in the upper belly; pain or discomfort in the abdomen, usually towards the top; nausea or vomiting, especially after eating; significant weight reduction for no apparent reason, and a severe loss in appetite loss.

Post-diagnosis, several treatment options for stomach cancer can be chosen, according to the stage of the disease. These include removal of the tumor and surrounding tissues, or, in more advanced cases, partial or whole stomach removal, chemotherapy with cancer-killing drugs that can be given before or after surgery, radiation therapy that involves directing high-energy rays at cancer cells in order to reduce or remove them, and medications that target specific molecules involved in cancer growth which may also be used in conjunction with other treatments.

Early diagnosis of stomach cancer is critical for successful treatment. Hence, if you or any of your loved ones are suffering from persistent symptoms, a doctor should be consulted right away. Regular check-ups and screenings can also aid in the early detection of stomach cancer. Understanding stomach cancer's causes, symptoms, and treatment options is critical for both prevention and early intervention. Maintaining a healthy lifestyle, seeking medical treatment for persistent symptoms, and staying knowledgeable about risk factors can all help those at risk of stomach cancer have a better outcome.

Stomach cancer, also known as gastric cancer, is a kind of cancer that starts in the stomach lining. This article will provide you with a quick rundown of stomach cancer, including its causes, symptoms, and treatment choices.

Types of Stomach Cancer

Cancers at gastric cardia and gastroesophageal junction (GEJ)

To aid in therapeutic selection, gastric cancer is categorized into subgroups based on major morphologic components and clinically as either early or advanced stage. When a tumor is detected in the proximal stomach or cardia, identifying it based on anatomic location might be difficult, especially if the tumor involves the gastroesophageal junction (GEJ). For the uninformed, the cardia is the uppermost portion of your stomach which houses the cardiac sphincter, which keeps food from moving up your esophagus. Also, the gastroesophageal junction (GEJ), defined as the point where the distal esophagus connects to the proximal stomach (cardia), is a small anatomic area that is frequently subjected to the harmful effects of GERD and/or Helicobacter pylori infection.

Early gastric carcinoma is defined as invasive carcinoma limited to the mucosa and/or submucosa, with or without lymph node metastases, regardless of tumor size. The majority of early stomach carcinomas are small, ranging in size from 2 to 5 cm, and are most typically found around the angularis at reduced curvature. A poor prognosis is commonly associated with early multifocal stomach cancer.

Based on their physical characteristics, there are four types of early gastric carcinoma:

  • Type I tumors have protruding growth

  • Type II tumors have superficial growth

  • Type III tumors have excavating growth

  • Type IV tumors have infiltrating growth and spread laterally.

The American Joint Committee on Cancer (AJCC) recently simplified the TNM categorization of proximal stomach carcinomas by focusing on the location of the tumor epicenter and whether or not the GEJ is involved:

  • If the tumor's epicenter is in the lower thoracic esophagus or GEJ, or if the tumor mass extends into the GEJ or distal esophagus within the first 5 cm of the stomach (cardia), the tumor is classified as esophageal cancer. 

  • The cancer is classed as gastric carcinoma if the epicenter is more than 5 cm away from the GEJ or if it is within 5 cm of the GEJ but does not grow into the esophagus.

Early and advanced gastric carcinoma

The Japanese Endoscopic Society classifies type II tumors as IIa (elevated), IIb (flat), and IIc (depressed). A more recent version of the Paris classification for superficial neoplastic lesions of the gastrointestinal tract was accepted. It identified three gross patterns: 

  • Type 0-I for polypoid growth (divided further into 0-Ip and 0-Is for pedunculated and sessile growth)

  • Type 0-II for nonpolypoid growth (divided further into Type 0-IIa for slightly elevated growth

  • Type 0-IIb for flat growth

  • Type 0-IIc for slightly depressed growth

  • Type 0-III for excavated growth

Histologic classification of gastric carcinomas

Gastric cancer is defined by considerable histologic heterogeneity at the architectural and cytologic levels, with many histologic components coexisting in most cases. The two main histologic subtypes of gastric cancer are intestinal type and diffuse type adenocarcinoma, with the indeterminate type called atypical. The intestinal type has a relative frequency of approximately 54%, the diffuse type has a relative frequency of 32%, and the indeterminate type has a relative frequency of 15%. 

Intestinal adenocarcinoma is more commonly associated with intestinal metaplasia and Helicobacter pylori infection, whereas diffuse-type gastric cancer appears to be more common in women and young people.

The World Health Organization's 2010 categorization of gastric malignancies acknowledges four major histologic patterns, as well as rare histologic variations: 

  • Tubular

  • Papillary

  • Mucinous

  • Indeterminate (including signet ring cell carcinoma) 

The major histologic pattern of the carcinoma, which frequently coexists with less dominant components of other histologic patterns, serves as the criterion for classification.

Causes and Risk Factors

While stomach cancer can affect anyone at any stage of life, studies have noted specific patterns. Research points out that in the United States, Black, Hispanic, Asian/Pacific Islander, and American Indian/Alaska Native persons are more likely to contract the disease than White people. There are also certain trends noted with respect to gender. Men are more than twice as likely as women to die from stomach cancer, and men are also diagnosed at roughly twice the rate of women. Stomach cancer has increasingly surged among younger women, notably among Hispanic women. Although stomach cancer can occur at any age, the risk grows with age.

Several factors play their part in causing stomach cancer. Distinct causal elements could raise the chance of stomach cancer in different regions of the stomach. For instance, obesity and gastroesophageal reflux disease (GERD) raise the risk of stomach cancer in the upper stomach, but Helicobacter pylori (H. pylori) infection raises the risk of stomach cancer in the lower and middle parts of the stomach.

H. pylori infection

A long-term H. pylori infection of the stomach mucosal layer is a significant risk factor for stomach cancer. These microbes can be spread from person to person through close contact with saliva, vomit, or feces. 

Many patients with chronic H. pylori infections have no symptoms, but some develop stomach ulcers or an inflammatory condition known as atrophic gastritis. Atrophic gastritis can cause more severe alterations to the stomach lining in certain patients, eventually leading to stomach cancer or gastric MALT (mucosa-assisted lymphoid tissue) lymphoma (a rare form of non-Hodgkin lymphoma that develops in the stomach lining). Treating H. pylori infections reduces the chance of developing some forms of stomach cancer.

Genetics and family history

Apart from the above causes and risk factors, one’s genetic makeup can also increase one’s vulnerability to stomach cancer.

  • Those who have had stomach cancer are more likely to develop it again. 

  • A first-degree family (parent, sibling, or child) who has had stomach cancer 

  • Li-Fraumeni-Lynch syndrome (a cancer predisposition syndrome associated with high risks for a diverse spectrum of childhood- and adult-onset malignancies) 

  • Peutz-Jeghers disease (the development of noncancerous growths called hamartomatous polyps in the gastrointestinal tract)

  • Blood type A

  • Certain genes, such as the tumor suppressor genes p53, adenomatous polyposis coli (Apc) gene, and MCC (negatively regulates cell cycle progression), are present in a significant percentage of stomach cancers. 

  • Hereditary transmission of a single faulty CDH1 allele causes genetic vulnerability. Intracellular permeability is increased due to a loss of intracellular adhesion caused by an acquired mutation of the second allele in the E-cadherin gene.

Medical conditions

Several medical conditions can also make one vulnerable to stomach cancer:

  • Chronic atrophic gastritis (a condition in which the stomach lining thins as a result of persistent inflammation) 

  • Atrophic gastritis (a disorder in which the stomach lining is replaced by the normal lining of the intestines) 

  • Infection with the Epstein-Barr virus.

  • Pernicious anemia (an inflammatory disease that causes the intestines to absorb vitamin B12 inefficiently, resulting in a drop in red blood cell count.)

  • Obesity (which promotes acid reflux disease in the stomach, causing acid from the stomach to flow back into the esophagus)

Diet

Mucosal injury caused by salt and salty foods may enhance the likelihood of H. pylori infection persisting. Although salted foods may raise the risk of H. pylori infection, salt has been found to accelerate the development of gastric adenocarcinoma in a synergistic and dose-dependent manner. Case-control studies in Japan and Korea have also found a synergistic exacerbatory impact of H. pylori infection and salted food consumption.

However, H. pylori infection is unlikely to increase salted food intake on its own, so H. pylori infection cannot operate as a confounder in the causal relationship between salt and salted food intake and stomach cancer. Reducing your intake of salt and salted foods can, at the very least, lower your risk of developing stomach cancer.

Other syndromes

Stomach cancer is associated with several syndromes, most of which are associated with the development of gastrointestinal polyps and an increased risk of cancer in other areas. Cowden disease and familial adenomatous polyposis (FAP) are two examples.

The use of tobacco

Although tobacco smoking has not been considered a major risk factor for GC, a large number of epidemiological studies have reported information on this association: when the results of these studies, which included over 15,000 cases of stomach cancer, are taken together, they support the notion of an association between tobacco smoking and GC risk.Although some research found no link or even a lower risk of stomach cancer in smokers, the bulk of published investigations found a link.

Because of the presence of the N-nitroso group, nitrosamines represent a vast range of chemical carcinogens that occur in the environment and have been widely implicated in the etiology of GC. Many carcinogens found in tobacco smoke, particularly nitrosamines, are capable of covalently attaching to biological macromolecules such as DNA. The discovery that smoking-related DNA adduct levels are significantly higher in smoking GC cases than in non-smoking cases adds to the evidence that smoking should be considered a risk factor.

Work-related environmental exposures

Studies have identified several occupations and occupational exposures that were associated with gastric cancer after at least one year of exposure. In general, professional, administrative, legislative/executive, and clerical workers (i.e. "desk jobs") had lower odds of developing stomach cancer, whereas labor-related occupations with dust and high-temperature exposures had higher odds. 

Furthermore, numerous specific occupational exposures, such as wood dust and aromatic amine exposure, were linked to an increased risk of stomach cancer after at least one year of exposure. Coal derivatives, pesticides/herbicides, chromium, radiation, and magnetic fields were also linked to an increased risk of diffuse-type cancer.

The presence of one or more of these risk factors does not guarantee stomach cancer development. Consult your doctor if you believe you are more vulnerable. Those at high risk of stomach cancer, such as those with specific genetic abnormalities or a family history of the disease, may be eligible for screening or preventive surgery. 

Cancer Theories and Gastric Cancer

While the above section mentions the various factors that may cause stomach cancer, research highlights certain cancer theories underlying most cancers. This section deals with cancer theories most applicable to stomach cancer, while our article Theories of Cancer takes a deep dive into all theories under study.

It was known that gastric cancer is strongly connected to chronic stomach inflammation, which was later discovered to be caused by Helicobacter pylori infection. However, studies have also noted that stomach cancer develops over time. For instance, intestinal-type gastric cancer develops through a series of histopathologic phases that include chronic gastritis, atrophic gastritis, intestinal metaplasia (IM), dysplasia, and cancer. 

Despite previous research supporting the phenomenon of altered cellular differentiation or metaplasia, it is highly likely that gastric cancer, like other cancers, arises from aberrant stem cells through a process of field cancerization, the clonal expansion of multipotent stem cells with gene mutations. Multipotent stem cells can differentiate into all cell types within a single lineage and they play an important role in the development, tissue repair, and protection processes.

Nonetheless, the actual cause of cancer is yet unknown. Cancer was traditionally assumed to begin with a mutation in an oncogene or tumor-suppressor gene. TP53 is the most frequently mutated gene detected in almost half of all gastric cancer patients, and TP53 mutations can be found even in early lesions. In normal conditions, the TP53 gene codes for the production of a protein known as tumor protein p53. This protein functions as a tumor suppressor, which means it regulates cell division by preventing cells from growing and dividing (proliferating) too quickly or uncontrollably. However, the relevance of TP53 mutations in cancer initiation remains unknown. 

Notably, more than 10% of gastric cancer cases have very few gene alterations, implying that genetic events are not necessary for cancer initiation and progression in gastric cancer. It is possible that epigenetic changes caused by persistent Helicobacter infection or other variables play a larger role in the initiation of cancer in many cases. 

Symptoms and Early Detection

Symptoms are often the first sign that express any imbalance in the body. Spotting such symptoms early and receiving timely consultation can help improve treatment therapies as well as prognosis.

The majority of the time, stomach cancer is asymptomatic (has no symptoms) or generates nonspecific symptoms (symptoms that are present in stomach cancer patients but also in other related or unrelated conditions). One reason for the cancer's poor prognosis is that by the time symptoms appear, the disease has often progressed to an advanced stage and may have metastasized—spread to another, perhaps distant, portion of the body. The following are early signs of stomach cancer:

a) Indigestion or a burning sensation in the chest (heartburn) are potential early indications of malignancy. Cancer was discovered in less than one out of every 50 patients referred for an endoscopy due to dyspepsia. 

(b) Stomach pain and loss of appetite, particularly for meat, are possible symptoms. 

c)Weariness, weakness, bloating after meals, upper abdominal pain, nausea, vomiting, diarrhea, or constipation can also be some early signs. 

(d) Vomiting, blood in the stool, and weight loss may occur as a result of increased enlargement. The latter appears as a black discoloration known as melena, which can occasionally lead to anemia.

(e) A heart tumor or the migration of a stomach tumor into the esophagus can both produce dysphagia. These could be signs of a more serious condition, such as tropical sprue, stomach infections, or stomach ulcers. 

Diagnosis

If your symptoms appear to be related to stomach cancer, your doctor will need to determine whether or not they are indicative of stomach cancer. The doctor might:

  • Ask about your personal and family medical history.

  • Examine your abdomen for any anomalies and perform a physical examination.

  • Order blood tests to rule out anemia, which is defined by a low red blood cell count and may be indicative of gastrointestinal bleeding.

  • Examine your feces for any hidden or occult blood, which could indicate stomach bleeding.

Based on these findings, your doctor may advise you to undergo testing to determine whether you have stomach cancer.

Examinations to identify stomach cancer

The following tests and procedures are used to diagnose stomach cancer. The results will assist you in planning your therapy with your doctor.

Upper endoscopy

An endoscope is a narrow, lighted tube that is sent down the throat to examine the esophagus, stomach, and first portion of the small intestine for abnormalities. An upper endoscopy examines the stomach, duodenum, and esophagus for any abnormalities. It may also include a biopsy tool to remove a sample of tissue or cells so that a pathologist can look for signs of cancer under a microscope.

The tissue sample could be tested for biomarkers and Helicobacter pylori (H. pylori) infection.

Consult your doctor to learn what to expect during and after your biopsy.

Barium swallow

A barium swallow is a series of X-rays of the stomach and esophagus. The patient consumes a beverage containing barium, a silvery-white metallic substance. After the stomach and esophagus have been coated with fluids, X-rays are taken. 

CT scan

A CT scan generates a series of finely detailed images of distinct inner body regions from various perspectives using a computer linked to x-ray equipment. A dye can be consumed or injected into a vein to increase the visibility of tissues or organs. This method is often referred to as computed tomography, computerized tomography, and computerized axial tomography.

Biomarker analysis

Biomarker testing can assist in the identification of genes, proteins, and other substances (often referred to as tumor markers or biomarkers) that can provide cancer information. Certain biomarkers influence the success of several cancer therapies. Biomarker testing may help your doctor choose a cancer treatment.

Samples of tissue containing stomach cancer cells are taken during a biopsy or surgery to look for these indicators. The samples are analyzed in a lab to see if the stomach cancer cells have these characteristics. 

The following biomarker tests are available for stomach cancer: 

  • Human epidermal growth factor receptor 2 (HER2): It is a protein involved in normal cell growth. Overexpression of this protein might signify the presence of cancer cells.

  • PD-L1: A PD-L1 test detects a protein in cancer cells that inhibits your immune system's ability to battle cancer. It may be present in greater quantities than usual if you have cancer. 

  • Microsatellite instability: The cells may be unstable due to faults in DNA replication that occur in a cell but are not rectified. 

  • Mismatch repair gene deficiency: A high tumor mutational burden indicates that the cells have many gene alterations. 

  • NTRK: The NTRK gene encodes a protein required for the development and survival of nerve cells (neurons), particularly those that convey information about sensations such as pain, temperature, and touch (sensory neurons). One of the NTRK genes in the cells may be altered in cancer. 

Staging

Staging describes the extent of cancer and whether or not it has migrated to neighboring lymph nodes or other sections of the body. Cancer staging systems are used by healthcare providers to construct treatment regimens, interact with others, and develop a prognosis. The clinical staging of gastric cancer consists of the following steps: 

Stage 0:

Restricted to the stomach's inner lining.
At this stage, endoscopic mucosal resection (a less intrusive alternative to surgery for removing unwanted tissues from the digestive tract's lining) and lymphadenectomy (a surgical operation that removes one or more lymph nodes or clusters of lymph nodes, which are then tested for malignancy) can be accomplished without the use of chemotherapy or radiation therapy. 

Stage I:

Penetration of the stomach's second or third layers (Stage 1A) or surrounding lymph nodes (Stage 1B).
Surgery is used to treat Stage IA, while for Stage IB treatment, two options are radiation therapy and chemotherapy (5-fluorouracil). 

Stage II:

Deeper lymph nodes and the second layer are infiltrated.
It will be treated as per Stage 1, potentially with additional neoadjuvant chemotherapy.

Stage III:

Infiltration into the third stratum and distant lymph nodes, or invasion into the fourth stratum and distant lymph nodes.
It is handled in the same way as Stage II; in some circumstances, recovery is still possible.

Stage IV:

The cancer has spread to other organs or nearby tissues and lymph nodes. Recovery is unlikely at this stage. 

Management of gastric cancer

Once the diagnosis is confirmed, your doctor might discuss your options for treatment. Adjuvant chemotherapy, adjuvant chemoradiotherapy, and perioperative chemotherapy have been shown to reduce recurrence and improve long-term survival. Furthermore, in the neoadjuvant/adjuvant situation, the combination of immune checkpoint inhibitors (ICIs) and/or targeted therapy is being investigated.

Perioperative chemotherapy

For gastric cancer, perioperative chemotherapy has been the standard of care. Multiple clinical trials have indicated that perioperative chemotherapy improves the prognosis of patients with GC as compared to surgery alone.

The MAGIC study represented a major step forward in the field of perioperative chemotherapy for GC. The 503 patients in this phase 3 research had resectable stomach, gastroesophageal junction (GEJ), or lower esophageal cancer. The experimental group got three preoperative and three postoperative cycles of epirubicin, cisplatin, and fluorouracil (ECF). According to the findings, the perioperative ECF regimen may increase overall survival and progression-free survival while also lowering the tumor stage. 

In a separate phase III trial, 28 French hospitals tested radical surgery with or without perioperative cisplatin and fluorouracil (CF) treatment. When compared to surgery alone, perioperative chemotherapy improved 5-year overall survival (38% against 24%, respectively). 

In the recent randomized phase II/III FLOT4-AIO study, gastric cancer patients were compared to the previous standard ECF/ECX (epirubicin, cisplatin, and fluorouracil/capecitabine) regimen. The findings backed up the FLOT regimen as the new standard perioperative treatment for resectable gastric cancer, meaning that it may improve overall survival (50 months against 35 months).

Adjuvant chemotherapy

Adjuvant chemotherapy is suggested for people with stage II or stage III cancer who are undergoing their first surgery. 

In the multi-center phase III CLASSIC study, which was undertaken in South Korea, China, and Taiwan, patients with stage II-IIIB gastric cancer were compared to D2 gastrectomy alone or D2 surgery + capecitabine and oxaliplatin (CAPOX) adjuvant chemotherapy. When compared to surgery alone, adjuvant CAPOX chemotherapy dramatically improved both 5-year disease-free survival (DFS) and overall survival (OS). 

A related phase III ACTS-GC trial from Japan found that adjuvant S-1 monotherapy for a year improved 3-year OS over surgery in 1059 patients with stage II or III GC who were randomly assigned to have D2 surgery followed by S-1 monotherapy or D2 surgery alone. For the uninitiated, S-1 is an oral anticancer drug that combines tegafur (a prodrug of fluorouracil), gimeracil (an inhibitor of dihydropyrimidine dehydrogenase), and potassium oteracil (an inhibitor of the phosphorylation of fluorouracil in the gastrointestinal tract).

Numerous factors influence regimen selection, including toxicity profile, patient performance status, and clinical stage. S-1 monotherapy is typically advised for patients with stage II illness or a low-performance status. For pathological stage III illness, combination therapy with CAPOX or S-1 and oxaliplatin (SOX) is frequently suggested.

Novel Perioperative Therapies

Perioperative targeted therapy

In the first- and second-line situations, anti-HER2 and anti-vascular endothelial growth factor (VEGF) medicines have been advocated as standard therapy for advanced GC, respectively. Targeted therapy's function in the adjuvant or perioperative context, on the other hand, is currently being explored and is uncertain.

Anti-HER2 therapy

Trastuzumab combined with chemotherapy enhanced overall survival in patients with metastatic HER2-positive GC. However, it remained unclear what function anti-HER2 medication had in the treatment of curable GC. 

Patients in the multicenter phase II HER-FLOT study with HER2-positive esophagogastric adenocarcinomas received nine cycles of trastuzumab monotherapy after four cycles preoperatively and four cycles postoperatively of perioperative FLOT treatment. In the phase II randomized PETRARCA trial, patients with cT2 or cN + curable GC were given perioperative FLOT chemotherapy in addition to trastuzumab and pertuzumab. Although there was no significant difference between the two groups in terms of R0 resection rate or surgical morbidity, trastuzumab and pertuzumab significantly increased the pCR rate (35% vs. 12%). 

Anti-VEGF therapy

VEGF-mediated signalling occurs in tumour cells, and this signalling contributes to key aspects of tumorigenesis, including the function of cancer stem cells and tumour initiation. Thus, anti-VEGF therapy helps fight cancer cells. 

Ramucirumab, a VEGF receptor 2 inhibitor, has established itself as a conventional second-line therapeutic option for GC. RAMSES/FLOT7 assessed the efficacy of ramucirumab in combination with perioperative FLOT in patients with resectable GC. While both groups had the same overall survival (46 vs. 45 months), the FLOT plus ramucirumab group had a longer median DFS (32 vs. 21 months).

Perioperative immunotherapy

Many countries have approved programmed death 1 (PD-1) inhibitors for first- and third-line therapy of unresectable/metastatic GC based on many phase III clinical trials. 

Clinical trials are being conducted to further understand the role of immune checkpoint inhibitors (ICIs) in resectable GC. In a randomized phase II DANTE study, patients with resectable GC were randomly assigned to the experimental arm, which received FLOT chemotherapy combined with the PD-L1 inhibitor atezolizumab, or the control arm, which received normal FLOT chemotherapy. Both groups had comparable rates of R0 resection, surgical morbidity, and death. The combination of chemotherapy and atezolizumab was linked to tumor shrinkage and pathological regression.

Drugs used to treat gastric cancer

First line

The first worldwide, randomized phase III trial, KEYNOTE-062, evaluated the safety and efficacy of immunotherapy with chemotherapy or immuno-monotherapy (pembrolizumab) in the first-line context for HER2-negative advanced GC. As compared to chemotherapy alone, the combination of pembrolizumab and chemotherapy did not improve overall survival in either CPS1.

CheckMate-649 is a global, randomized, phase III trial in patients with metastatic HER2-negative GC that compares chemotherapy (CAPOX or FOLFOX) alone to ICIs (nivolumab plus ipilimumab, a CTLA-4 inhibitor) or ICI (nivolumab) plus chemotherapy. 

Second line and beyond

In the randomized, open-label, phase III KEYNOTE-061 trial, pembrolizumab monotherapy was compared to paclitaxel in the second-line context in patients with advanced GC or GEJ cancer. Despite failing to meet the primary objectives (OS and PFS in patients with PD-L1 CPS 1), the level of PD-L1 CPS was projected to be related to the efficacy of pembrolizumab monotherapy. Patients with CPS 10 responded better with pembrolizumab compared with chemotherapy.

The KEYNOTE-059 phase II trial investigated the efficacy of pembrolizumab in patients with advanced GC who had failed at least two lines of therapy. The Furthermore, pembrolizumab was more efficacious in PD-L1-positive tumors than in PD-L1-negative tumors. 

The phase III ATTRACTION-2 study compared nivolumab monotherapy to placebo in advanced GC patients who had previously had two lines of treatment, with the nivolumab group showing a survival benefit regardless of PD-L1 expression. 

Molecular Biomarkers of Immunotherapy in GC

Molecular indicators are critical in identifying patients who will benefit from immunotherapy for gastric cancer. A combination of these biomarkers is frequently used to identify patients for immunotherapy, and personalized medicine approaches are being developed to optimize treatment regimens for people with stomach cancer. Here are some of the most important molecular biomarkers related with immunotherapy in GC:

HER2

According to a phase III Thoracic Oncology Group of Australasia (TOGA) research, trastuzumab in combination with chemotherapy is now the conventional first-line treatment for HER2-positive advanced gastric cancer. HER2 signaling may influence the recruitment and activation of tumor-infiltrating immune cells in preclinical models. Furthermore, trastuzumab has been demonstrated to increase PD-1 and PD-L1 expression, and anti-PD-1 antibodies may improve the therapeutic efficacy of HER2 inhibitors considerably. In HER2-positive GC, a number of phase I/II trials revealed that combining ICIs with trastuzumab and chemotherapy was successful. 

The PANTHERA trial, a multi-institutional phase Ib/II study, looked at the efficacy and safety of pembrolizumab, trastuzumab, and chemotherapy combined with pembrolizumab as first-line therapy for HER2-positive advanced GC. The progression-free survival (PFS) was 8.6 months, the overall survival was 19.3 months, and the tumor objective response rate (ORR) was 76.7%.

EBV

Epstein-Barr virus-associated gastric carcinoma (EBVaGC), a separate molecular subtype of the TCGA classification, accounts for roughly 9% of GC in the TCGA cohort and around 5% in China. As a possible biomarker for ICI treatment, EBV has been associated with elevated expression of PD-L1 and PD-L2, as well as CD8+ T cell infiltration.

MSI

MSI-H tumor is one of four GC subtypes identified by The Cancer Genome Atlas (TCGA) Research Network. According to reports, the prevalence of MSI-H status in GC ranged from 8 to 25%, with patients with metastatic illness having a substantially lower prevalence. 

Mismatch repair (MMR) proteins are proteins that repair replication mistakes in DNA. MMR protein shortages cause abnormal DNA replication, which leads to the accumulation of mutations and the formation of neoantigens, which could potentially serve as immune cell targets. As a result, MSI-H/dMMR-positive tumors should attract more immune cells, improving the efficacy of immune checkpoint inhibitors. 

Tumor mutation burden (TMB)

It is anticipated that having a high TMB status leads to increased expression of immunogenic neoantigens, which can activate an immunological response and possibly improve the efficiency of ICI treatment. Patients with TMB-high (TMB-H, TMB 12 mut/Mb) status showed a greater ORR and improved OS compared to those with TMB-L status in a phase Ib/II research evaluating the efficacy of the PD-1 antibody toripalimab in patients with advanced GC. 

Prevention and Risk Reduction

Although stomach cancer cannot be completely avoided, there are steps you may take to reduce your chances.

  • Since being overweight or obese raises your risk of getting numerous types of stomach cancer, reaching and maintaining a healthy weight may help reduce your risk. Regular exercise may also help reduce your risk of developing stomach cancer.

  • A diet rich in fruits and vegetables may reduce the incidence of stomach cancer. While grapefruit and grapefruit juice can alter medication levels in the blood, citrus fruits (grapefruit, oranges, and lemons) may be beneficial. Consult your doctor before including grapefruit in your diet. The American Cancer Society suggests a healthy diet that includes whole grains, colorful fruits and vegetables, and little or no red and processed meats, sugar-sweetened beverages, or highly processed meals.

  • Alcohol consumption should be avoided or limited because it raises the risk of stomach cancer.

  • Additional dietary factors, such as drinking tea (especially green tea) or taking nutritional supplements, have not produced conclusive results in terms of lowering the incidence of stomach cancer. More research in these areas is required.

  • Tobacco usage raises the risk of upper stomach cancer, which affects the area around the esophagus. Tobacco usage raises the risk of several different cancers.

  • Several studies have found that treating H pylori infection with antibiotics reduces the number of precancerous lesions in the stomach and lowers the risk of developing stomach cancer. Although it is unclear if treating everyone who has a H pylori infection is necessary, some studies have suggested that treating H pylori infection may benefit people who are at a higher risk of stomach cancer for other reasons, such as having a close relative who has the disease. More research is required to determine whether treating other populations with H pylori infection reduces the incidence of stomach cancer.

  • Aspirin and other nonsteroidal anti-inflammatory medicines (NSAIDs) like ibuprofen or naproxen appear to reduce the risk of stomach cancer. These medications can help reduce the risk of colon cancer and polyps. However, they can put some people at risk for a number of health problems and cause catastrophic (even fatal) internal bleeding. The majority of medical specialists consider any reduction in cancer risk to be an added advantage for people taking these medications for other ailments like arthritis. However, doctors usually do not recommend taking NSAIDs to avoid stomach cancer. There hasn't been enough research done to establish who would benefit more from a lower risk of cancer versus bleeding issues.

  • Hereditary diffuse gastric cancer (HDGC), a rare genetic disorder, significantly raises a person's risk of acquiring stomach cancer, which typically arises at a young age. The most likely cause of this unique sickness is a genetic mutation in the CDH1 gene. HDGC-affected families are more likely to have two or more close relatives diagnosed with diffuse-type stomach cancer, or at least one diagnosis before the age of fifty. Some family members may get invasive lobular breast cancer.

  • Li-Fraumeni syndrome, Peutz-Jeghers syndrome, Lynch syndrome, familial adenomatous polyposis (FAP), and other genetic cancer syndromes are also linked to an increased risk of stomach cancer. Stomach removal is usually not advised for patients with these disorders because the danger of stomach cancer is not nearly as high as it is with HDGC. Doctors may prescribe routine screening in some of these situations to discover stomach cancer early.

Living with Stomach Cancer

Stomach cancer and its therapies can have both psychological and physical negative effects. You may be concerned about how you will deal with the future changes in your life when you first find that you have stomach cancer. One thing you can do is be aware of potential changes and the resources available to help you. If you share your concerns, you may feel more in control of your situation. Your healthcare staff can advise you on how to lessen these negative effects and feel better.

Dietary and nutritional adjustments

Meal consumption and nutrient absorption may be affected by stomach cancer and its therapies. If you have had all or part of your stomach removed, you may need to eat smaller meals more frequently or adjust your diet. Your doctor or dietitian may advise you to stand up for a few minutes after eating. They can also assist you in changing your diet so that you acquire the nutrients you require.

Alterations in body image

Your appearance and self-esteem may alter as a result of stomach cancer and its treatment. Recognize that your feelings are not unique to you. It may be difficult to adjust to changes in your physique and self-perception. Many people, on the other hand, eventually learn adaptability.

Follow-up care

Adapting to physical and psychological changes caused by cancer therapy, as well as coping strategies for recurrence anxiety. Following stomach cancer treatment, many patients are required to return to their doctor regularly for follow-up examinations or tests. Planning and scheduling these trips can be difficult and time-consuming. Waiting for test results might result in anxiety and a persistent dread of recurrence. Copays, prescriptions, parking, and transportation expenditures add to the stress. 

Future Perspective

Over the last 20 years, there has been significant progress in the detection, staging, and treatment of gastrointestinal cancer. Monoclonal antibodies have been produced as a result of the identification of cell surface antigens, which may allow for a more tailored approach to treatment. Another critical factor to consider is the improving sensitivity and specificity of imaging techniques like Endoscopic ultrasound (EUS) and Positron emission tomography-computed tomography (PET-CT) in the identification and staging of gastric cancer. One of the most important areas of molecular imaging is the use of novel radiopharmaceutical agents to target up-regulated particular receptors in cancer cells.

https://www.cancer.gov/types/stomach/coping 

https://www.cancer.gov/types/stomach/causes-risk-factors

https://www.cancerresearchuk.org/about-cancer/stomach-cancer/types-and-grades 

https://www.researchgate.net/publication/315878287_Gastric_Cancer_Risk_Factors_Diagnosis_and_Management 

https://www.cancer.gov/types/stomach/diagnosis 

https://jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01451-3 

https://www.cancer.org/cancer/types/stomach-cancer/causes-risks-prevention/prevention.html 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017429/