The Role of Neutrophil Mitochondrial Dysfunction in Medical Rehabilitation During Palliative Chemotherapy for Metastatic Colorectal Cancer
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Enrollment
- 187
- Locations
- 2
- Primary Endpoint
- CD4/ CD8 ratio
Study Overview
Brief Summary
The goal of this clinical trial is to learn if adding sodium nucleinate to FOLFOX chemotherapy helps people with metastatic colorectal cancer (colon or rectal cancer that has spread). Researchers will also look at side effects and how people feel during treatment.
The main questions this study aims to answer are:
- Does adding sodium nucleinate help treatment work better?
- Does it improve quality of life (how people feel and function day to day)?
- Does it affect survival at one year?
Researchers will compare:
- FOLFOX chemotherapy plus sodium nucleinate versus
- FOLFOX chemotherapy alone
Participants will:
- Be randomly assigned (like flipping a coin) to one of the two groups;
- Receive four cycles of FOLFOX chemotherapy;
- Take sodium nucleinate daily if assigned to that group;
- Have checkups and blood tests during the study (including tumor marker blood tests such as CEA and CA 19-9);
- Complete quality-of-life questionnaires and have other planned tests that look at immune cells and how certain blood cells work;
- Be followed after treatment to see how they are doing, including up to one year after starting the study.
Detailed Description
This randomized, single-blinded, parallel-group clinical trial was approved by the Local Ethics Committee of Kazakh National Medical University and conducted at oncology centers affiliated with university clinics in four regions of Kazakhstan. Participants had histologically confirmed metastatic colorectal cancer (T3-4 N1-2 M1). A total of 200 individuals were screened; 187 were enrolled and randomized.
Participants were allocated in a 1:1 ratio using sealed envelopes to receive either (1) FOLFOX chemotherapy plus sodium nucleinate or (2) FOLFOX chemotherapy alone. The intervention group received sodium nucleinate 50 mg per day (25 mg in the morning and 25 mg at lunch), starting 1 week before the first chemotherapy cycle and continued daily for 4 months. Both groups received four cycles of FOLFOX per institutional protocols.
Assessments included monthly clinical evaluation with general and biochemical blood tests during treatment. The following were assessed at baseline and at 1 month after completion of chemotherapy (approximately 5 months after baseline): FDG PET/CT, serum tumor markers (CEA and CA 19-9), peripheral blood immunologic status (CD4+/CD8+ ratio), and neutrophil mitochondrial activity (percentage of neutrophils with preserved mitochondrial function among 200 counted neutrophils). Baseline transthoracic echocardiography was performed to determine left ventricular ejection fraction. Health-related quality of life was assessed using the EORTC QLQ-C30 at baseline, post-treatment, and 1 year post-baseline.
Analyses were performed using Statistica 7.0 (StatSoft, USA). Continuous outcomes were compared between groups using the Mann-Whitney U test as specified in the protocol.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Single (Outcomes Assessor)
Masking Description
Randomization 1:1 using computer-generated block randomization with variable block sizes, stratified by ECOG status, metastatic sites, and prior adjuvant chemotherapy. Allocation concealment: sequentially numbered, opaque, sealed envelopes (SNOSE); randomization table not disclosed to researchers.
Blinded outcome assessors: intake nurse, lab technician, researcher performing measurements, social worker processing QoL questionnaires, and statistician (Group A/B until database lock). Treating clinicians were not blinded.
All chemotherapy dose modifications (delays, reductions, cancellations) were governed by protocol-defined objective criteria (e.g., ANC <1000/mm³, platelets <50,000/mm³, CTCAE grade ≥3) with no investigator discretion. A blinded Endpoint Adjudication Committee reviewed 100% of modifications to verify adherence to objective criteria.
Treating physician had no access to functional blood tests or QoL results during treatment; outcomes entered after treatment course compl
Eligibility Criteria
- Ages
- 40 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Histologically confirmed colorectal cancer.
- •Locally advanced or metastatic disease as treated with palliative FOLFOX per protocol (including metastatic disease [M1]).
- •Able to receive FOLFOX chemotherapy and to comply with study procedures.
- •Provided written informed consent.
Exclusion Criteria
- •Active pulmonary tuberculosis.
- •Decompensated diabetes mellitus.
- •Decompensated cardiac, vascular, pulmonary, hepatic, or renal failure.
Arms & Interventions
Chemotherapy according to the FOLFOX regimen
Patients with metastatic colorectal cancer (stages T3-4 N1-2 M1) received four courses of FOLFOX chemotherapy alone. General and biochemical blood analyses were conducted monthly.
Intervention: Placebo (Other)
Chemotherapy according to the FOLFOX regimen
Patients with metastatic colorectal cancer (stages T3-4 N1-2 M1) received four courses of FOLFOX chemotherapy alone. General and biochemical blood analyses were conducted monthly.
Intervention: FOLFOX regimen (Drug)
Chemotherapy according to the FOLFOX regimen in combination with sodium nucleinate
Patients with metastatic colorectal cancer (stages T3-4 N1-2 M1) received four courses of FOLFOX chemotherapy combined with sodium nucleinate 50 mg/day (25 mg morning, 25 mg lunch) starting 1 week before the first cycle and continued daily for four months.
Intervention: Adenorine (Dietary Supplement)
Chemotherapy according to the FOLFOX regimen in combination with sodium nucleinate
Patients with metastatic colorectal cancer (stages T3-4 N1-2 M1) received four courses of FOLFOX chemotherapy combined with sodium nucleinate 50 mg/day (25 mg morning, 25 mg lunch) starting 1 week before the first cycle and continued daily for four months.
Intervention: FOLFOX regimen (Drug)
Outcomes
Primary Outcomes
CD4/ CD8 ratio
Time Frame: before the start of treatment and one month after the end of treatment
Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer. The normal range of CD4+/CD8+ is from 1.0 to 4.0. the ratio level above and below the norm is considered a bad prognostic sign
Dynamics of mitochondrial activity neutrophils
Time Frame: before the start of treatment and one month after the end of treatment
Mitochondrial dynamics refers to the changing process of fission, fusion, mitophagy and transport, which is crucial for optimal function in signal transduction and metabolism. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular fate, and a range of diseases, including neurodegenerative disorders, metabolic diseases, cardiovascular diseases and cancers. Herein, we review the mechanism of mitochondrial dynamics, and its impacts on cellular function. the normal range of cell distribution 30-60% 30% of the 200 cells counted. whether higher scores mean a better outcome.
EORTC QLQ-CR29
Time Frame: before the start of treatment and one month after the end of treatment
the European Organization for Research and Treatment of Cancer (EORTC) QLQ-CR29 max242 min59. whether higher scores mean a worse outcome
Positron emission tomography/computed tomography
Time Frame: before the start of treatment and one month after the end of treatment
Positron emission tomography (PET/CT) is used prior to surgery in patients with metastatic or recurrent colorectal cancer to identify those with potentially curable disease or to dynamically monitor the course of the disease. normally, it does not accumulate an isotope. whether higher scores mean a worse outcome.
CEA
Time Frame: before the start of treatment and one month after the end of treatment
Carcinoembryonic Antigen Oncomarker is used in the diagnosis of malignant and benign tumors of GI organs or to dynamically monitor the course of the disease. normal concentration min=0 ng/ml max=5,5 ng/ml. whether higher scores mean a worse outcome.
CA 19-9 (Carbohydrate (carbohydrate) antigen 19-9)
Time Frame: before the start of treatment and one month after the end of treatment
CA 19-9 was discovered in the early 1980s by researchers working to identify tumor antigens in colorectal cancer or to dynamically monitor the course of the disease. normal concentration min=0 U/ml, max=27,0 U/ml. whether higher scores mean a worse outcome.
Relative Dose Intensity of FOLFOX
Time Frame: 1-4 cycles of FOLFOX
Relative Dose Intensity (RDI) over cycles 1-4 of FOLFOX, calculated as (delivered dose intensity / planned dose intensity) × 100. Dose intensity accounts for both dose reductions and treatment delays for oxaliplatin (mg/m²/week) and infusional 5-fluorouracil (mg/m²/week).
Secondary Outcomes
- Echocardiography with determination of left ventricular ejection fraction(before the start of treatment)
- Mitochondrial Activity of Neutrophils(Baseline (before start of chemotherapy) and post-treatment assessment 1 month after completion of chemotherapy)
- Positron Emission Tomography/Computed Tomography (PET/CT) Tumour Metabolic Activity(Baseline (before start of chemotherapy) and follow-up FDG-PET/CT 1 month after completion of chemotherapy (approximately 5 months after baseline).)
- CEA Response (≥50% Decrease From Baseline)(Baseline (before start of chemotherapy) and 1 month after completion of chemotherapy (approximately 5 months after baseline))
- CA 19-9(Carbohydrate Antigen 19-9) Response (≥50% Decrease From Baseline)(Baseline (before start of chemotherapy) and 1 month after completion of chemotherapy (approximately 5 months after baseline))
- CD4+/CD8+ T-Cell Ratio (Peripheral Blood)(Baseline (before start of chemotherapy) and 1 month after completion of chemotherapy (approximately 5 months after baseline))
- Left Ventricular Ejection Fraction (LVEF) by Echocardiography(baseline (before start of chemotherapy))
- EORTC QLQ-C30 Global Health Status/QoL (GHS/QoL)(Baseline (before start of chemotherapy); 1 month after completion of 4 cycles (approximately 5 months after baseline); 1 year post-baseline)