Second Opinion on Stomach cancer

In most cases, malignant tumors of the stomach develop in the mucous membrane lining the inner surface of the stomach wall. Approximately 95% arise from glandular tissue and are known as adenocarcinomas. Much less commonly, malignant tumors originate from lymphatic tissue (MALT lymphomas) or muscle tissue (sarcomas and gastrointestinal stromal tumors/GISTs).

How does stomach cancer present?

In its early stages, the disease may cause no symptoms or only nonspecific complaints. These symptoms are often overlooked or mistakenly attributed to harmless food intolerances. It is important to know that the following symptoms may indicate stomach cancer:

• A “sensitive stomach,” often accompanied by an aversion to certain foods (e.g., meat); newly developed intolerance to certain foods or beverages, such as coffee or fruit.
• A feeling of pressure, fullness, or pain in the upper abdomen.
• Loss of appetite.
• Nausea, belching, retching, and vomiting (vomit may contain undigested food from the previous day).
• Unintentional weight loss, reduced performance, and weakness.
• Anemia.
• Difficulty swallowing.
• Vomiting blood and black, tarry stools.
• Accumulation of fluid in the abdominal cavity (ascites).

Even one of these symptoms, and particularly several occurring together, is a good reason to see a doctor.

Stomach cancer diagnosis

The primary diagnostic method is gastroscopy, i.e., an endoscopic examination of the upper gastrointestinal tract. Modern equipment makes it possible to detect even small changes in the mucous membrane. If necessary, specialized imaging techniques, such as chromoendoscopy, may be used to increase the likelihood of detecting early lesions.

During endoscopy, a biopsy of the suspicious area is performed. The tissue sample is examined by a pathologist, who determines the histological type of the tumor and confirms the presence of a malignant process.

Determination of biomarkers plays a particularly important role. Depending on the clinical situation, the expression of HER2, Claudin 18.2 (CLDN18.2), and PD-L1, as well as microsatellite instability (MSI/dMMR), may be assessed. Other molecular characteristics of the tumor can also be evaluated when necessary. The results of these tests help physicians select a more personalized treatment approach, particularly in advanced disease.

Once the diagnosis has been confirmed, the stage of the disease must be determined. This is usually done using contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis. In certain situations, endoscopic ultrasound (EUS) may also be performed. In patients with locally advanced tumors that may potentially be treated surgically, diagnostic laparoscopy with peritoneal washings may be recommended. This procedure can detect small or occult peritoneal metastases that may not be visible on standard imaging.

Standard Treatments for Gastric Carcinoma

The choice of treatment depends primarily on the stage of the disease. Treatment decisions should preferably be made by a multidisciplinary tumor board involving a surgeon, medical oncologist, gastroenterologist, radiologist, pathologist, and, where appropriate, a radiation oncologist. The possibility of participation in a clinical trial should also be considered when determining the treatment strategy.

Surgery

Surgery remains the key treatment for potentially curable gastric cancer. Its goal is to completely remove the tumor together with the necessary amount of surrounding tissue and regional lymph nodes.

Tumors at the earliest stage that are limited to the superficial layers of the mucosa and meet established criteria may be removed endoscopically. Depending on the characteristics of the lesion, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) may be performed. This approach can avoid major surgery, but it is suitable only for selected patients.

When the tumor has invaded deeper layers, partial or total gastrectomy with lymph node dissection is performed. In locally advanced gastric cancer, surgery is usually combined with systemic drug therapy administered before and after surgery.

Chemotherapy

For operable locally advanced gastric cancer, neoadjuvant and adjuvant chemotherapy is used. One of the widely used treatment regimens is FLOT, which consists of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel.

The basis of systemic treatment for unresectable or metastatic disease is a combination of a platinum-based drug and a fluoropyrimidine. Depending on the patient's condition, oxaliplatin or cisplatin may be combined with 5-fluorouracil or an oral fluoropyrimidine. Other chemotherapy drugs and combinations may be used in subsequent lines of treatment.

Targeted therapy

In HER2-positive advanced gastric cancer, HER2-targeted therapy, particularly trastuzumab, may be added to chemotherapy. In subsequent lines of treatment, eligible patients may receive the antibody-drug conjugate trastuzumab deruxtecan (T-DXd).

For patients with HER2-negative tumors with confirmed expression of Claudin 18.2, targeted therapy with zolbetuximab in combination with chemotherapy may be considered.

Immunotherapy

Immunotherapy is based on blocking immune checkpoints, enabling the immune system to recognize and attack tumor cells more effectively.

PD-1/PD-L1 inhibitors may be used in combination with chemotherapy, while patient selection in many cases depends on PD-L1 expression levels and other tumor characteristics. Tumors with microsatellite instability (MSI-H/dMMR) may be particularly sensitive to immunotherapy.

Radiation therapy and palliative treatment

Radiation therapy is not required for all patients and is considered on an individual basis. For example, it may be used to control specific symptoms or tumor lesions. In metastatic disease, pain management, correction of nutritional deficiencies, treatment of anemia and other complications, as well as palliative care, are of great importance. The goal of supportive treatment is to preserve the patient's quality of life as much as possible.

Novel therapies and clinical trials

Modern gastric cancer treatment is rapidly evolving toward personalized medicine. Treatment selection increasingly depends not only on the stage of the disease but also on the molecular profile of the tumor.

One of the most promising areas is the further development of HER2-targeted therapies. In particular, bispecific antibodies capable of simultaneously targeting HER2 and other components of the immune system are being investigated. In the HERIZON-GEA-01 trial, a combination of a HER2-targeted bispecific antibody with a PD-1 inhibitor and chemotherapy showed promising results in patients with HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma.

Strategies targeting CLDN18.2 are also being actively investigated. Clinical trials are evaluating combinations of drugs that simultaneously target Claudin 18.2 and PD-1. Such approaches may potentially expand treatment options for HER2-negative tumors with high CLDN18.2 expression.

Another area of research is the intensification of systemic treatment through the addition of immunotherapy. The MATTERHORN trial demonstrated improved outcomes when a checkpoint inhibitor was added to chemotherapy in patients with resectable gastric cancer and gastroesophageal junction adenocarcinoma. These results have contributed to the ongoing evolution of treatment strategies for localized disease.

New therapeutic targets, including FGFR2b and MET, as well as novel combinations of antibodies, immunotherapeutic agents, and cytotoxic drugs, continue to be investigated. Studies of FGFR2b-targeted therapies have shown encouraging results, although the effectiveness of individual approaches remains under evaluation with longer-term follow-up.

Thus, promising approaches to gastric cancer treatment include novel targeted drugs, bispecific antibodies, combinations of immune checkpoint inhibitors, molecularly targeted therapies, and optimized systemic treatment regimens. Gene and cell-based therapies, particularly CAR-T-cell therapy, represent another important area of research. Unlike established CAR-T-cell therapies for certain hematological malignancies, the use of genetically modified T cells against solid tumors, including gastric cancer, remains predominantly at the clinical research stage. Researchers are investigating CAR-T cells targeting antigens such as Claudin 18.2 (CLDN18.2), HER2, and CEA, as well as novel CAR designs intended to improve the activity of these cells within the tumor microenvironment and overcome mechanisms of immune evasion.

Particular attention is being paid to the development of cell-based therapies for solid tumors in China, where numerous clinical studies of CAR-T and other cellular therapies are being conducted. Chinese clinical centers and biotechnology companies are developing CAR-T therapies targeting CLDN18.2 and other potentially relevant tumor antigens in gastric cancer. For selected patients, participation in a clinical trial in China may provide access to experimental cellular therapies that are not yet available as standard treatment. However, such approaches should not be considered established standard therapy. Eligibility for a specific clinical trial depends on the study protocol, the molecular characteristics of the tumor, disease stage, and the patient's overall health.