Brief Summary Background

Gastric cancer (GC) remains a major global public health challenge, ranking as the fifth most common malignancy worldwide and the third leading cause of cancer-related mortality. In 2018, approximately 1 million new cases and 783,000 deaths were reported globally. The median age at diagnosis is around 60 years, with relatively few cases occurring in younger patients.

Despite advances in systemic therapies, up to 60% of patients are diagnosed with advanced-stage disease, and approximately 20% present with significant comorbidities that limit available treatment options. This highlights the need for effective, safe, and well-tolerated therapeutic alternatives, particularly for frail patients and those with advanced disease.

In this context, calcium electroporation (CaEP) has emerged as a novel therapeutic approach with the potential to address an important unmet clinical need. CaEP is a local, minimally invasive treatment that may provide effective control of debilitating symptoms such as tumor-related gastrointestinal bleeding, while improving patients' functional status and quality of life. Importantly, these benefits may be achieved without the additional morbidity and mortality associated with more invasive therapeutic interventions. The implementation of CaEP could represent a significant advance in the management of gastric cancer, particularly in patients with limited treatment options.

Primary Objective

To evaluate the efficacy and safety of calcium electroporation (CaEP) in controlling gastrointestinal bleeding secondary to gastric cancer in patients undergoing palliative treatment, either in combination with systemic therapy or in clinical situations where control of tumor-related bleeding is required.

Study Design

This is a multicenter, non-randomized, non-pharmacological interventional study with longitudinal follow-up.

The intervention consists of two scheduled sessions of endoscopic calcium electroporation (CaEP). The second procedure will be performed 4 weeks after the first treatment unless contraindicated for clinical reasons.

Primary Outcome Measure

Clinical control of gastrointestinal bleeding secondary to gastric neoplasia.

Study Population

Patients with histologically confirmed gastric cancer who present with gastrointestinal bleeding symptoms or secondary anemia will be prospectively enrolled.

Eligible participants will include patients who are candidates for palliative treatment, either as monotherapy or in combination with systemic medical treatment and/or radiotherapy. Patients experiencing tumor-related bleeding during neoadjuvant treatment prior to surgery may also be included.

Estimated Enrollment

A total sample size of 25 evaluable patients is required. Assuming a 10% loss to follow-up, the planned enrollment is 28 patients.

Study Design This is a prospective, multicenter, non-randomized, non-pharmacological interventional study with longitudinal follow-up designed to evaluate the efficacy and safety of endoscopic calcium electroporation (CaEP) for the management of tumor-related gastrointestinal bleeding in patients with gastric cancer.

Participants will undergo two scheduled sessions of endoscopic calcium electroporation. The second treatment session will be performed 4 weeks after the initial procedure unless a clinical or technical contraindication arises.

Patient recruitment and follow-up are planned from JUNE 2026 through May 2028. Data analysis and dissemination of results will take place between June 2028 and December 2028.

Study Population Adult patients (≥18 years) with histologically confirmed gastric cancer presenting with iron-deficiency anemia and/or gastrointestinal bleeding attributable to the primary tumor will be prospectively enrolled after providing written informed consent.

The study will be conducted in the Gastroenterology Departments of participating hospitals.

Sample Size Based on previously published data suggesting a 90% improvement in quality of life and reduction in transfusion requirements following calcium electroporation, a clinically meaningful improvement of 20% was assumed. Using a two-sided alpha error of 0.05 and a statistical power of 80%, the required sample size was calculated as 25 evaluable patients. Allowing for an anticipated 10% loss to follow-up, the target enrollment is 28 participants.

Intervention Procedures Baseline Assessment

Before treatment, participants will undergo:

• Clinical evaluation and medical history review.
• Symptom assessment, including pain evaluation using a visual analogue scale (VAS).
• Quality-of-life assessment using the EORTC QLQ-C30 questionnaire.
• Nutritional assessment, including anthropometric measurements and laboratory testing.
• Complete blood analysis, including hemoglobin, hematocrit, albumin, prealbumin, iron studies, vitamin levels, electrolytes, and metabolic profile.
• Endoscopic tumor assessment with photographic documentation and tumor size estimation.

Tumor biopsies, non-tumoral gastric mucosal biopsies (when technically feasible), and peripheral blood samples will be collected before the first treatment and again prior to the second treatment at week 4.

Calcium Electroporation Procedure The procedure will be performed on an outpatient basis under deep sedation with standard monitoring and supplemental oxygen.

Following endoscopic evaluation of the lesion, intratumoral calcium gluconate (220 mM; 9 mg/mL) will be injected using a 23-gauge needle. The administered volume will be calculated according to the European Standard Operating Procedures of Electrochemotherapy (ESOPE) guidelines and adjusted to tumor size.

Electroporation will then be performed using the EndoVE® device connected to the distal end of the endoscope and the ePORE® pulse generator. Electrical pulses will be delivered to cover the entire tumor surface whenever technically feasible. Procedural parameters, including treated tumor percentage, number of pulses, impedance, and applied voltage, will be recorded.

After treatment, patients will remain under observation for 60-120 minutes for monitoring of immediate adverse events, including pain, bleeding, nausea, or perforation.

Follow-up A telephone safety assessment will be conducted 1 week after each treatment session.

The second CaEP treatment will be performed 4 weeks after the first procedure and will include repeat clinical assessment, laboratory evaluation, and biological sample collection.

Subsequently, patients will undergo monthly follow-up visits (in-person or by telephone, according to clinical status) to record bleeding episodes, transfusion requirements, hospital admissions, and clinical outcomes.

From month 3 onward, follow-up assessments will occur every 12 weeks (weeks 12, 24, 36, and 48) and will include:

• Clinical evaluation.
• Laboratory testing.
• Symptom assessment.
• EORTC QLQ-C30 quality-of-life questionnaire.
• Upper gastrointestinal endoscopy.
• Computed tomography (CT) imaging. Additional CaEP treatments may be offered in cases of recurrent tumor-related bleeding or anemia after exclusion of alternative causes. Retreatment may be considered in patients experiencing a decrease in hemoglobin of ≥2 g/dL from previous assessments or clinical evidence of recurrent gastrointestinal bleeding.

Inclusion Criteria:

Participants must meet all of the following criteria:

• Age ≥18 years.
• Histologically confirmed gastric malignancy.
• Presence of anemia and/or gastrointestinal bleeding secondary to gastric cancer.
• Ability and willingness to provide written informed consent.

In addition, participants must meet at least one of the following conditions:

• Patients considered unsuitable for surgical and/or oncological treatment with curative or palliative intent due to advanced age, frailty, or significant comorbidities (Charlson Comorbidity Index ≥3 and/or ECOG Performance Status ≥2), following multidisciplinary team assessment.
• Patients with metastatic disease receiving palliative systemic therapy in whom CaEP is indicated for symptomatic control of tumor-related gastrointestinal bleeding.
• Patients receiving neoadjuvant therapy who develop tumor-related gastrointestinal bleeding requiring bleeding control to avoid interruption of systemic treatment prior to surgery.
• Patients who decline surgical and/or oncological treatment when CaEP is considered appropriate for symptomatic control of gastrointestinal bleeding.

Exclusion Criteria:

Participants meeting any of the following criteria will be excluded:

• Pregnancy or breastfeeding.
• Presence of an endoluminal prosthesis within the intended treatment area.
• Implanted electrical devices (e.g., pacemakers, implantable cardioverter-defibrillators) when temporary deactivation is not feasible or procedural safety cannot be guaranteed.
• Uncorrectable coagulation disorders.
• Medical contraindication to deep sedation or therapeutic upper gastrointestinal endoscopy.
• Estimated life expectancy of less than 1 month.
• Refusal or inability to provide informed consent

Demographic characteristics (e.g., age and sex). Baseline clinical characteristics, including ECOG Performance Status, Charlson Comorbidity Index, and disease stage.

Laboratory parameters, including hematological, biochemical, and nutritional markers collected according to the study protocol.

Symptom and quality-of-life assessments, including EORTC QLQ-C30 and Visual Analog Scale (VAS) scores.

Tumor characteristics and endoscopic findings. Treatment-related data, including calcium electroporation (CaEP) procedural parameters, calcium dose administered, number of treatment sessions, and technical treatment characteristics.

Clinical outcomes, including control of tumor-related gastrointestinal bleeding, transfusion requirements, hospital admissions, adverse events, progression, and survival outcomes.

De-identified molecular, proteomic, and biomarker data generated from tumor tissue, non-tumoral gastric mucosa, and peripheral blood samples.

Data will be available beginning 6-12 months after publication of the primary study results and will remain available for at least 5 years.

Access to de-identified individual participant data will be granted to qualified researchers upon submission of a methodologically sound research proposal. Requests will be reviewed by the study investigators and must comply with applicable ethical, legal, and data protection requirements. Data sharing agreements may be required before access is granted.