Gastric adenocarcinoma is a serious form of stomach cancer that requires careful treatment planning, combining traditional medical approaches with emerging therapies being tested in ongoing research studies worldwide.

How Treatment Goals Are Determined for Gastric Adenocarcinoma

When someone receives a diagnosis of gastric adenocarcinoma, the primary goal of treatment focuses on removing or controlling the cancer while maintaining quality of life and the ability to eat and digest food. Because adenocarcinoma — cancer that starts in the mucus-producing gland cells lining the stomach — accounts for approximately 90 to 95 percent of all stomach cancers, most treatment strategies have been developed specifically for this type.^[2][4]

The approach to treating gastric adenocarcinoma depends heavily on several factors. The stage of the disease matters most, meaning how far the cancer has spread from its original location in the stomach lining. Early-stage cancers that are caught before they penetrate deeply into the stomach wall or spread to lymph nodes have better outcomes and more treatment options. Unfortunately, many people don’t experience noticeable symptoms until the cancer has advanced, which is why early detection remains challenging.^[3]

Patient characteristics also play an important role in treatment decisions. Age, overall health, the presence of other medical conditions, and personal preferences all influence which therapies are appropriate. A 70-year-old patient with heart disease may require a different treatment plan than a 50-year-old who is otherwise healthy, even if their cancers are at the same stage. Treatment decisions are made through discussions between patients and their multidisciplinary care teams, which typically include surgeons, medical oncologists, radiation oncologists, and other specialists.^[9]

Medical societies and organizations have established standard treatment guidelines based on decades of research and clinical experience. These recommendations provide a framework for care, but they continue to evolve as new evidence emerges from clinical trials. At the same time, researchers are actively investigating novel therapies that may offer better outcomes or fewer side effects than existing treatments. Some of these experimental approaches are available to eligible patients through clinical trials conducted at cancer centers around the world.^[13]

Standard Treatment Approaches for Gastric Adenocarcinoma

Surgery remains the foundation of treatment for gastric adenocarcinoma when the cancer is localized and can be completely removed. The type of surgical procedure depends on where the tumor is located and how extensively it has grown. A subtotal gastrectomy removes only the portion of the stomach containing the cancer, along with nearby lymph nodes and sometimes parts of other nearby organs or tissues. This procedure is typically performed when the tumor is located in the lower part of the stomach and hasn’t spread extensively.^[11]

When the entire stomach must be removed, surgeons perform a total gastrectomy. This operation removes the complete stomach, nearby lymph nodes, and parts of the esophagus, small intestine, and other nearby tissues. After removing the stomach, the surgeon connects the esophagus directly to the small intestine, allowing patients to continue eating and swallowing, though with significant dietary modifications. The spleen may also be removed during either procedure if the cancer is located near it or has spread to that area.^[11]

For very early-stage cancers that are confined to the innermost lining of the stomach, a less invasive option called endoscopic mucosal resection may be possible. This procedure uses an endoscope — a thin, flexible tube with a camera and tools attached — to remove small tumors without major surgery. However, this approach is only appropriate when the cancer is superficial and the surgeon can achieve clear margins, meaning no cancer cells remain at the edges of the removed tissue.^[11][18]

Chemotherapy — treatment with drugs that kill rapidly dividing cancer cells throughout the body — is commonly used in combination with surgery for locally advanced gastric adenocarcinoma. When chemotherapy is given before surgery, it’s called neoadjuvant therapy, and its purpose is to shrink the tumor, making it easier to remove completely and potentially reducing the amount of tissue that needs to be taken out. Chemotherapy given after surgery is called adjuvant therapy, and it aims to kill any cancer cells that may have been left behind or spread to other areas, reducing the risk of the cancer returning.^[10][11]

Perioperative chemotherapy combines both approaches, giving chemotherapy both before and after surgery. This strategy has become increasingly common for locally advanced gastric cancer. Typical chemotherapy regimens use combinations of drugs rather than single agents, with triplet chemotherapy — using three different drugs together — now widely accepted as standard treatment for resectable gastric cancer. Common chemotherapy drugs used for gastric adenocarcinoma affect cells in different ways, disrupting their ability to grow and divide. Treatment usually continues for several months, with cycles typically repeated every two or three weeks.^[9][15]

The side effects of chemotherapy can be significant and vary depending on which drugs are used. Because chemotherapy affects all rapidly dividing cells in the body, not just cancer cells, it can cause fatigue, nausea, vomiting, hair loss, mouth sores, increased risk of infections due to low white blood cell counts, and nerve damage causing numbness or tingling in the hands and feet. These side effects are usually temporary and improve after treatment ends, though some effects may persist longer. Doctors can prescribe supportive medications to help manage many of these side effects and improve comfort during treatment.^[10]

Radiation therapy, which uses high-energy beams to kill cancer cells in a specific area, is sometimes combined with chemotherapy in a treatment approach called chemoradiation. This combination may be used before surgery to shrink tumors or after surgery if the surgical margins were not completely clear of cancer cells or if the cancer had spread to nearby lymph nodes. Radiation therapy for gastric adenocarcinoma typically involves external beam radiation, where a machine directs radiation beams at the tumor site from outside the body. Treatment is usually given five days a week for several weeks.^[11]

For patients with metastatic gastric adenocarcinoma — cancer that has spread to distant organs — treatment goals shift from cure to controlling the disease and maintaining quality of life for as long as possible. Systemic chemotherapy remains the primary treatment, with median overall survival of approximately 12 months for patients receiving conventional chemotherapy alone. However, newer targeted therapies and immunotherapies are increasingly being added to chemotherapy regimens in the metastatic setting, offering improved outcomes for certain patient populations.^[5][9]

Targeted Therapies and Biomarker-Directed Treatment

Targeted therapy represents a more precise approach to cancer treatment, using drugs that attack specific molecules or pathways that cancer cells depend on for growth and survival. Unlike chemotherapy, which affects all rapidly dividing cells, targeted therapies are designed to interfere with particular proteins or processes that are more active in cancer cells. For gastric adenocarcinoma, several targeted therapies have been approved based on the presence of specific biomarkers — measurable characteristics that indicate which treatments are likely to be effective.^[13]

Trastuzumab, sold under the brand name Herceptin, was the first targeted therapy approved for gastric cancer. It targets HER2 (human epidermal growth factor receptor 2), a protein that promotes cell growth and is overexpressed or amplified in approximately 15 to 20 percent of gastric adenocarcinomas. When tumors test positive for HER2 through laboratory testing of biopsy samples, adding trastuzumab to chemotherapy improves survival compared to chemotherapy alone in patients with advanced disease. The landmark ToGA study established this combination as standard treatment for HER2-positive metastatic gastric cancer more than a decade ago.^[13][16]

More recently, trastuzumab deruxtecan (Enhertu) has shown impressive results in HER2-positive gastric adenocarcinoma. This medication is an antibody-drug conjugate, meaning it combines an antibody that targets HER2 with a chemotherapy drug attached to it. The antibody seeks out and binds to HER2-positive cancer cells, delivering the chemotherapy directly to the tumor. This targeted delivery system allows higher doses of chemotherapy to reach cancer cells while minimizing exposure to healthy tissues. Trastuzumab deruxtecan has been approved for patients with advanced HER2-positive gastric or gastroesophageal junction cancer who have previously received treatment.^[13][16]

Ramucirumab (Cyramza) targets a different pathway involved in tumor growth. It blocks VEGFR-2 (vascular endothelial growth factor receptor-2), a protein that helps tumors develop new blood vessels to supply themselves with nutrients and oxygen. By interfering with this blood vessel formation process, called angiogenesis, ramucirumab can slow tumor growth. This medication is approved for patients with advanced gastric or gastroesophageal junction cancer whose disease has progressed after initial chemotherapy. It can be used alone or in combination with chemotherapy.^[13][16]

Immunotherapy and Checkpoint Inhibitors

Immunotherapy works by helping the patient’s own immune system recognize and attack cancer cells more effectively. Cancer cells can sometimes evade the immune system by exploiting natural checkpoints — molecular brakes that prevent the immune system from attacking the body’s own tissues. Checkpoint inhibitors are drugs that release these brakes, allowing immune cells to mount a stronger response against cancer. This approach has transformed treatment for many cancer types, and is now playing an increasingly important role in gastric adenocarcinoma.^[13]

The most successful immunotherapy approach in gastric cancer involves drugs that target the PD-1/PD-L1 pathway. PD-1 (programmed cell death protein 1) is a checkpoint protein on immune cells, while PD-L1 (programmed cell death ligand 1) is a protein that some cancer cells produce to bind to PD-1 and turn off the immune response. Several checkpoint inhibitors that block this interaction have been approved for gastric adenocarcinoma, including pembrolizumab (Keytruda), nivolumab (Opdivo), and dostarlimab (Jemperli).^[16]

Not all gastric adenocarcinomas respond equally well to immunotherapy. Two biomarkers help identify which patients are most likely to benefit. The first is PD-L1 expression, which can be measured on tumor cells and immune cells in the tumor through laboratory testing. Higher levels of PD-L1 expression generally correlate with better responses to checkpoint inhibitors. The second important biomarker is microsatellite instability (MSI). Tumors with high microsatellite instability, called MSI-high or dMMR (DNA mismatch repair deficient), have genetic changes that make them produce many abnormal proteins, making them more visible to the immune system and more responsive to immunotherapy.^[13][15]

The prevalence of MSI-high status in gastric adenocarcinoma varies considerably, ranging from approximately 5 to 20 percent depending on ethnic background, tumor characteristics, and disease stage. For patients with MSI-high metastatic gastric adenocarcinoma, checkpoint inhibitors have shown particularly impressive results. In some studies, patients with these tumors achieved significantly longer survival when treated with immunotherapy compared to standard chemotherapy alone. This has led to the approval of pembrolizumab as a first-line treatment option for patients with advanced MSI-high or dMMR gastric adenocarcinoma.^[9][15]

For patients whose tumors express PD-L1 but do not have MSI-high status, combining checkpoint inhibitors with chemotherapy has shown benefit compared to chemotherapy alone. Several large clinical trials have demonstrated that adding pembrolizumab or nivolumab to standard chemotherapy regimens improves outcomes in patients with advanced gastric adenocarcinoma whose tumors have certain levels of PD-L1 expression. This combination approach is now an established treatment option for appropriately selected patients with metastatic disease.^[13][16]

Emerging Therapies Being Tested in Clinical Trials

Clinical trials are research studies that test new treatments or new ways of using existing treatments to determine if they are safe and effective. These studies are conducted in phases, each with a specific purpose. Phase I trials focus primarily on safety, determining the appropriate dose of a new drug and identifying side effects in a small group of patients. Phase II trials evaluate whether the treatment shows signs of effectiveness against the cancer while continuing to monitor safety in a larger group of patients. Phase III trials compare the new treatment directly to the current standard treatment in large groups of patients to determine if the new approach is better, equivalent, or inferior.^[13]

One area of active investigation involves bringing immunotherapy into earlier stages of treatment. While checkpoint inhibitors are already approved for advanced gastric adenocarcinoma, researchers are now studying whether giving these drugs before surgery (neoadjuvant) or after surgery (adjuvant) can improve outcomes for patients with localized disease. Several Phase II and Phase III trials are currently enrolling patients to test whether adding immunotherapy to perioperative chemotherapy regimens can increase cure rates compared to chemotherapy alone. Early results from some of these studies have been encouraging, showing that combining immunotherapy with chemotherapy can lead to better tumor shrinkage before surgery.^[9][13]

Similarly, targeted therapies approved for metastatic disease are being investigated in the perioperative setting. Clinical trials are examining whether adding trastuzumab or newer HER2-targeted agents to chemotherapy before and after surgery improves outcomes for patients with localized HER2-positive gastric adenocarcinoma. If successful, these studies could establish new standards of care that bring precision medicine approaches to earlier stages of the disease where cure is still possible.^[9]

Beyond HER2, researchers are investigating other potential molecular targets in gastric adenocarcinoma. Some tumors have alterations in genes like FGFR2 (fibroblast growth factor receptor 2), MET, or EGFR (epidermal growth factor receptor). Drugs that target these specific genetic abnormalities are being tested in clinical trials for patients whose tumors harbor these changes. This represents a move toward increasingly personalized treatment, where therapy is selected based on the unique molecular profile of each patient’s tumor.^[13]

Claudin 18.2 is an emerging target that has generated significant interest. This protein is expressed on the surface of cells in some gastric adenocarcinomas. Drugs called anti-Claudin 18.2 antibodies are being developed to target this protein. Early clinical trial results have shown promise, and several large Phase III trials are underway to determine if drugs targeting Claudin 18.2 can improve outcomes when added to chemotherapy for patients with advanced gastric cancer whose tumors express this protein.^[13]

Another innovative approach being explored is CAR T-cell therapy, a form of treatment where a patient’s own immune cells are collected, genetically modified in the laboratory to recognize cancer cells, and then infused back into the patient. While CAR T-cell therapy has shown remarkable success in certain blood cancers, applying this approach to solid tumors like gastric adenocarcinoma is more challenging. Nevertheless, early-phase trials are investigating whether CAR T cells targeting specific proteins found on gastric cancer cells can be safe and effective. These studies are primarily being conducted at specialized cancer centers.^[16]

Antibody-drug conjugates beyond trastuzumab deruxtecan are also under investigation. These medications work like guided missiles, using an antibody to deliver chemotherapy directly to cancer cells. Disitamab vedotin (RC48), another HER2-targeted antibody-drug conjugate, has shown activity in gastric cancer in trials conducted primarily in Asia. Various other antibody-drug conjugates targeting different proteins are in earlier phases of development for gastric adenocarcinoma.^[13]

Clinical trials for gastric adenocarcinoma are being conducted at cancer centers around the world, including locations in the United States, Europe, and Asia. Eligibility for specific trials depends on many factors, including the stage and characteristics of the cancer, previous treatments received, overall health status, and the presence of specific biomarkers. Patients interested in participating in clinical trials should discuss this option with their oncology team, who can help identify relevant studies and determine if participation might be appropriate. Major cancer centers often have clinical trial offices that can provide information about available studies and assist with the enrollment process.^[13]

Most common treatment methods

• Surgery
  • Subtotal gastrectomy removes the portion of stomach containing cancer along with nearby lymph nodes
  • Total gastrectomy removes the entire stomach and connects the esophagus to the small intestine
  • Endoscopic mucosal resection uses an endoscope to remove very early-stage cancers without major surgery
  • Surgery is the main curative treatment for localized gastric adenocarcinoma
• Chemotherapy
  • Neoadjuvant chemotherapy given before surgery to shrink tumors
  • Adjuvant chemotherapy given after surgery to reduce recurrence risk
  • Perioperative chemotherapy combines treatment before and after surgery
  • Triplet chemotherapy using three drugs together is standard for resectable disease
  • Treatment typically continues for several months with cycles every two to three weeks
• Targeted therapy
  • Trastuzumab (Herceptin) targets HER2-positive tumors when combined with chemotherapy
  • Trastuzumab deruxtecan (Enhertu) is an antibody-drug conjugate for HER2-positive disease
  • Ramucirumab (Cyramza) blocks blood vessel formation to slow tumor growth
  • Treatment selection based on biomarker testing of tumor samples
• Immunotherapy
  • Pembrolizumab (Keytruda) blocks the PD-1/PD-L1 pathway to activate immune response
  • Nivolumab (Opdivo) is another checkpoint inhibitor targeting PD-1
  • Dostarlimab (Jemperli) approved for MSI-high or dMMR tumors
  • Most effective in tumors with high PD-L1 expression or microsatellite instability
  • Often combined with chemotherapy for better results in metastatic disease
• Radiation therapy
  • External beam radiation directs high-energy beams at the tumor site
  • Often combined with chemotherapy as chemoradiation
  • May be used before surgery to shrink tumors or after surgery if margins are not clear
  • Treatment typically given five days per week for several weeks