Treatment Update: Gastric Cancer

The stages of adenocarcinomas and other forms of gastric cancer describe how far the cancer has spread at the time of diagnosis. The stage of the cancer will guide treatment options.

Stage 0 The cancer is limited to the mucosa (the innermost layer of the stomach wall).

Stage IA The cancer has spread completely through the mucosa but has not spread to lymph nodes or the muscularis (the middle layer of the stomach wall).

Stage IB The cancer has spread completely through the mucosa and has also spread to the muscularis or to six or fewer lymph nodes.

Stage II The cancer has spread completely through the mucosa and is found in the muscularis and one or more lymph nodes, or is found in the wall of the serosa (outermost layer of the stomach) but is not found in lymph nodes or other organs.

Stage III The cancer has spread completely through the muscularis and is found in the wall of the serosa and one or more lymph nodes.

Stage IV The cancer is found in organs next to the stomach or in other parts of the body.

Stages 0 and IA

Stages 0 and IA gastric cancers are best treated by minimally invasive endoscopic surgery, in which the doctor removes the tumor through an endoscope (lighted tube) that is inserted into the stomach through the mouth. Endoscopic surgery is best done by a gastroenterologist with experience in these complex procedures. Alternatively, a gastrectomy (surgical removal of part or all of the stomach) and lymphadenectomy (removal of the nearby lymph nodes) can be performed, but this is more invasive surgery and should be avoided if possible. Typically, no additional therapy beyond surgery is needed.

Stages IB, II and III

Stage IB, II or III gastric cancer is treated with a total or partial gastrectomy and lymphadenectomy. Chemotherapy may be given both before surgery to shrink the cancer and after surgery to destroy any remaining cancer cells. If chemotherapy is not given prior to surgery, it may still be given after surgery, especially if cancer cells are found in the removed lymph nodes. Chemoradiation (chemotherapy plus radiation therapy) may also be given after surgery, but that approach is becoming increasingly less common. People who are not able to undergo surgery are often treated with chemotherapy, radiation or chemoradiation.

Stage IV

Treatments for stage IV gastric cancer are designed to shrink the tumor and help relieve symptoms. The primary treatment approaches are chemotherapy, targeted therapy and immunotherapy. Surgery, radiation or chemoradiation may also be considered, but are less common.

Surgery

When surgery is part of the treatment plan for gastric cancer, the approach depends on the stage of the cancer and other factors unique to the individual.

• Subtotal (partial) gastrectomy. In a subtotal gastrectomy, the cancerous portion of the stomach is removed. Most often, a subtotal gastrectomy is performed if the cancer is in the lower portion of the stomach (near the intestines), although it may sometimes be performed if the cancer is in the upper portion of the stomach. Depending on the stage of the cancer, other organs or tissues close to the cancerous part of the stomach may also be removed, including the omentum (a layer of fatty tissue that covers the stomach and intestines), the spleen or portions of the esophagus or small intestine.

A subtotal gastrectomy includes a step that allows the digestive tract to continue to function. If the lower portion of the stomach has been removed, the surgeon connects the upper portion of the stomach to the small intestine. If the upper portion of the stomach has been removed, the surgeon attaches the lower portion of the stomach to the esophagus.

• Total gastrectomy. If the cancer has spread throughout the stomach, a total gastrectomy (the removal the entire stomach) is performed. Additionally, this type of surgery is often recommended if the cancer is located in the upper part of the stomach. In a total gastrectomy, the surgeon also removes the omentum and may remove the spleen and parts of the esophagus, intestines, pancreas and other nearby organs. The end of the esophagus is attached to part of the small intestine to allow food to continue to move through the intestinal tract.

People can sometimes have trouble taking in enough nutrition after a gastrectomy. A jejunostomy tube (J-tube) placed into the intestine at the time of surgery can help. The end of the J-tube remains outside the body, on the skin of the abdomen. Through this tube, liquid nutrition can be put directly into the intestine until the person is able to eat normally.

A D2 lymphadenectomy, in which the surgeon ensures that an adequate number of lymph nodes are removed, is performed at the same time as a subtotal or total gastrectomy.

Chemotherapy

Systemic (whole body) chemotherapy, designed to destroy cancer cells, has long been an important approach in the treatment of gastric cancer. Most systemic chemotherapy treatments for gastric cancer combine at least two drugs. In neoadjuvant (before surgery) treatment, common drug combinations include:

• Docetaxel, oxaliplatin and fluorouracil/leucovorin (FLOT)
• Oxaliplatin plus either 5-FU or capecitabine (called FOLFOX or Capeox)

The combination treatments (FLOT, FOLFOX or Capeox) may also be given as an adjuvant (after surgery) treatment. A single drug, such as 5-FU or capecitabine, is sometimes used as adjuvant treatment for people who may not be able to tolerate combination therapy.

Other chemotherapy drugs used to treat gastric cancer include paclitaxel and irinotecan.

In February 2019, the U.S. Food and Drug Administration (FDA) approved the chemotherapy combination of trifluridine/tipiracil (Lonsurf) for the treatment of metastatic (advanced) adenocarcinoma treated with at least two previous chemotherapy regimens (courses of treatment). Trifluridine works by stopping the growth of cancer cells, while tipiracil helps the trifluridine work longer by stopping it from being broken down by the body. This chemotherapy combination is taken as a pill.

Targeted Therapy

Targeted therapy focuses on specific molecules and cell mechanisms thought to be important for cancer cell survival and growth, taking advantage of what researchers have learned in recent years about how cancer cells grow.

There are three targeted therapies approved by the FDA for the treatment of stage IV gastric cancer:

• Trastuzumab (Herceptin). HER2, a growth-promoting protein found on the surface of some cancer cells, is present in approximately 20 percent of gastric cancers. Trastuzumab binds to and blocks the HER2 protein and is often added to chemotherapy for people whose cancer is HER2-positive Trastuzumab is given intravenously (into a vein).

• Ramucirumab (Cyramza). VEGF (vascular endothelial growth factor) is a protein that contributes to angiogenesis (blood vessel growth), which can lead to the growth and spread of cancer. Ramucirumab blocks the action of VEGF and can be given by itself or added to paclitaxel chemotherapy. It is given intravenously.

• Trastuzumab-anns. (Kanjinti), In June 2019, the FDA approved trastuzumab-anns, a biosimilar to trastuzumab, for the treatment of HER2-positive stage IV gastric cancer. Although not an exact copy of the original drug, biosimilars are expected to produce the same clinical result and have no meaningful differences in terms of safety, purity or potency.

Other targeted therapy drugs to treat gastric cancer are currently being studied in clinical trials.

Immunotherapy

Our immune system is constantly working to keep us healthy. It recognizes and fights against danger, such as infections, viruses and growing cancer cells. In general terms, immunotherapy uses our own immune system as a treatment against cancer.

Pembrolizumab (Keytruda), given in combination with a specific type of chemotherapy, was approved by the FDA in March 2021 for the first-line (initial) treatment of locally advanced unresectable (inoperable) or metastatic, HER2-negative or gastroesophageal junction (GEJ) adenocarcinoma.

In April 2021, the FDA approved the PD-1 inhibitor nivolumab (Opdivo), in combination with chemotherapy, for the first-line treatment of advanced gastric cancer. Pembrolizumab and nivolumab are similar drugs.

Although the FDA has approved pembrolizumab and nivolumab without restriction for the treatment of advanced or metastatic gastric cancer, tumors that have higher levels of the PD-L1 protein are more likely to respond to these immunotherapies. (PD-L1 is a molecular “brake” that prevents the body’s immune system from attacking cancer cells.) Guidelines from the National Comprehensive Cancer Network (NCCN) recommend adding pembrolizumab or nivolumab to chemotherapy only when tumors have an elevated level of the PD-L1 protein.

Pembrolizumab, which is given intravenously, has also been approved to treat any type of cancer that has a trait known as high microsatellite instability (MSI), which is most frequently caused by mutations in the mismatch repair (MMR) and tumor suppression genes. A small percentage of gastric cancers are MSI and can be treated with pembrolizumab. Recently, the NCCN has recommended giving pembrolizumab, nivolumab or the immunotherapy dostalimab—in combination with chemotherapy and the immunotherapies ipilimumab and nivolumab—as a firstline therapy for MSI gastric cancer.

Other immunotherapy approaches are currently being studied in clinical trials.

Antibody-drug Conjugate

An antibody-drug conjugate (ADC) is a type of anticancer treatment that combines a targeted therapy with a chemotherapy. In January 2021, the FDA approved trastuzumab deruxtecan (Enhertu) for locally advanced or metastatic HER2-positive gastric adenocarcinoma previously treated with a trastuzumab-based regimen.

Q: Are there gene mutations or inherited conditions that increase the risk of developing gastric cancer?

A: Certain gene mutations and some inherited conditions are considered risk factors for gastric cancer, including:

• BRCA1 and BRCA2. Although inherited mutations on the BRCA1 and BRCA2 genes are often associated with a higher risk of breast cancer, people who have inherited these genetic mutations are also at an increased risk for gastric cancer.

• Lynch syndrome. Lynch syndrome is a hereditary disorder caused by a mutation in a mismatch repair gene. Most commonly Lynch syndrome is associated with an increased risk for colon cancer, but it also increases the risk of gastric and other cancers.

• Familial adenomatous polyposis (FAP). Often caused by mutations on the APC gene, FAP significantly increases a person’s risk of colorectal cancer and may also play a smaller role in increasing the risk of developing gastric cancer.

• E-cadherin/CDH1. Though rare, people who inherit this genetic mutation have a significantly increased risk of developing gastric cancer in their lifetime. When this genetic mutation is present, there is often a family history of gastric cancer or lobular breast cancer, a specific type of breast cancer that begins in the milk-producing glands (lobules) of the breast.

Testing is available for gene mutations that make a person more likely to develop gastric cancer. A doctor or genetic counselor can help the individual and their family understand the test results. Identifying a genetic syndrome has treatment implications for the individual and also enables family members to undergo screening for early detection of gastric and other cancers.

Q: Is radiation used to treat gastric cancer?

A: Radiation therapy as a treatment approach for gastric cancer has become less common in recent years. It is not typically given before surgery, but can be used to destroy small traces of cancer that could not be seen and removed during surgery. Radiation can also be used if there is bleeding from the tumor. In those cases, external beam radiation is the type of radiation generally administered.

External beam radiation uses a machine that directs a beam (or multiple beams) of radiation to the cancer. The use of CT (computerized tomography), MRI (magnetic resonance imaging) and PET (positron emission tomography) scans allows radiation oncologists to accurately target the cancer, helping to spare healthy tissues.

Q: What is an endoscopic resection?

A: In an endoscopic resection, the surgeon passes an endoscope (a flexible tube with a lighted video camera on the end) into the stomach through the throat. Surgical tools are then passed through the endoscope to remove the cancer and part of the stomach wall around the cancer.

Endoscopic resection is increasingly used to treat early-stage gastric cancers, where the risk of the cancer spreading to the lymph nodes is very low. If you are considering an endoscopic resection, your health care team can help you find a medical center that has experience with this surgical procedure.