Treating gastric cancer has become an individualized process. By knowing more about the tumor (in terms of its biology and in terms of its molecular characteristics), the stage of the cancer, and other specific characteristics of the patient, a range of different modalities can be used, including surgery, as well as chemotherapy and radiation therapy. These systemic therapies can be conventional, or they can be targeted therapies or immune therapies.
Healthcare professionals can work on the treatment decisions and thus can be informed by the evolving treatment options for gastric cancer. However, these same healthcare professionals are faced with difficult decisions regarding the best evidence, patient-specific factors, potential toxicity, and goals of treatment.
Moving Toward Biomarker-Driven Treatment
Assessment of molecular and biomarker characteristics is becoming increasingly important in the management of advanced gastric cancer. HER2 expression, PD-L1 expression, tumors with MSI and/or MMR deficiency, as well as tumors expressing Claudin 18.2 (CLDN18.2), are increasingly being considered for treatment decisions for advanced gastric cancer.
In the European treatment guidance for advanced or metastasized gastric or gastroesophageal junction cancer (EuroGES) of the ESMO Consensus Conference for diagnosis and treatment of gastrointestinal cancers, advanced or metastasized gastric and gastroesophageal junction (GEJ) adenocarcinomas are distinguished in biomarker-defined treatment pathways. Patients are assigned to different subgroups of treatment based on HER2 status, on expression of PD-L1, on MSI status, and on expression of Claudin 18.2 (CLDN18.2).
Biomarker information for the systemic treatment of patients with gastric cancer can be distinguished and assessed within the framework of the current evidence in patients with advanced or metastatic gastric and gastroesophageal junction adenocarcinomas. This information, however, has to be considered within the framework of clinically relevant information for treatment decisions in relation to appropriate treatment options, local and/or international approval, as well as institutional capacities.
The Growing Role of HER2-Directed Therapy
Trastuzumab, as a single agent as well as in combination with chemotherapy, has been established as a treatment option for patients with HER2-positive gastric cancer. There are different clinical situations where trastuzumab can be used as a single agent or in combination with different types of chemotherapy.
Pembrolizumab in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy for locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma. Tumors must express PD-L1 with a CPS of 1 or greater.
Assessment of HER2 and PD-L1 expression in gastric cancer is usually done as separate parameters for clinical decision-making; individual decisions are made on the basis of the findings of each biomarker, often even in isolation from other clinical findings.
Incorporating CLDN18.2 Into Treatment Decisions
For locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma expressing CLDN18.2, zolbetuximab-clzb in combination with fluoropyrimidine- and platinum-containing chemotherapy is an approved treatment option for adults with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. A companion diagnostic for zolbetuximab-clzb is also approved and can be used to identify patients who may be eligible for treatment with zolbetuximab-clzb based on biomarker testing results and approved indications.
This therefore refers to the expression thresholds and appropriate testing methodologies for assessing CLDN18.2 expression in gastric cancer patients as well as the corresponding treatment options for which they are eligible.
Considering Immunotherapy and MSI Status
Immune checkpoint inhibitors have been introduced in the treatment of advanced gastric cancer. Selected patients with tumors of MSI-high or mismatch repair-deficient status are considered for different treatment strategies. The expression of PD-L1 can be used as a decision criterion for the use of immunotherapy.
For others, it is evaluated using an appropriate scoring system and threshold. For example, ESMO treatment recommendations for patients with advanced gastric and GEJ adenocarcinoma consider the PD-L1 CPS for certain therapies. Many of the biomarkers, expressed in tumors, are found in a proportion of cases; therefore, there are also tumors that do not express these biomarkers or express them to varying degrees. Tumors therefore can express a number of biomarkers, and a multidisciplinary approach to their interpretation is most appropriate.
Reassessing Treatment Sequencing
For potentially curable disease, multidisciplinary evaluation remains important when considering surgery and perioperative approaches. In advanced disease, systemic therapy selection may increasingly depend on biomarker-defined subgroups. Treatment decisions should therefore be revisited as new pathology, imaging, molecular results, or clinical information becomes available rather than relying solely on the initial treatment plan.
The main treatment options for potentially curable gastric cancer are surgical treatment (including neo-adjuvant treatment) and/or adjuvant systemic treatment. Patients with advanced gastric cancer are treated with systemic therapy, which is chosen on the basis of the patient’s disease and previous treatment, taking into account their general condition and organ function.
So therefore, every time you go back to clinic to review a patient with gastric cancer, you need to revisit treatment plan with the latest development including newly obtained pathology result, latest imaging study, latest molecular study and latest clinical information.
Managing Toxicity and Patient Factors
Prior treatment, patient preference, poor organ function, co-morbidities, and age have to be taken into account for older patients with poor performance status.
In managing any toxicities of treatment and in choosing between treatments (and their potential, for example), consideration must be given to all of the potential toxicities, to the potential for drug interactions, to the amount of time that will be required for treatment, and to the patient’s own resources for dealing with treatment. Supportive care, assessment of nutritional status, symptom control and communication with patients and their families are essential during all phases of treatment and can affect a patient’s ability to complete treatment and maintain a good quality of life.
The Importance of Multidisciplinary Care
Multidisciplinary meetings of medical oncologists, surgeons, radiation oncologists, pathologists, radiologists, dietitians and specialist nurses are often used to support the management of the increasing complexity of gastric cancer treatment.
An important aspect of the treatment of gastric cancer patients is the coordination of pathology and molecular testing with treatment decisions. In gastric cancer treatment, discussions within a multidisciplinary meeting (MDM) can enable clinicians to consider the key factors in treatment decision-making. These factors are the disease stage, pathological findings, biomarker status, imaging findings, previous treatment, and patient-specific factors.
Looking Ahead
New treatments for gastric cancer, including targeted therapies, antibody-drug conjugates and cellular therapies, are under investigation within ESMO’s research initiatives. Treatments directed against CLDN18.2 in gastric and gastroesophageal junction cancers, as well as antibody-drug conjugates and CAR-T cell therapy, are currently being explored. For an up-to-date overview of the evidence supporting promising gastric cancer therapies and of the corresponding health authority approvals as well as of the required tests to identify relevant biomarkers, up-to-date clinical guidelines for the diagnosis and/or treatment of gastric cancer should be consulted. These clinical guidelines are intended to support clinical decisions on the diagnosis and/or treatment of gastric cancer but are not a substitute for clinical expertise.
Personalized gastric cancer treatment is becoming increasingly complex and needs to be individualized based on the stage of the disease, the tumor(s)’ biological nature, the individual clinical situation of the patient, and his/her treatment goals.
Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, a clinical guideline, or a recommendation for any specific treatment.
