Published online Sep 15, 2024. doi: 10.4251/wjgo.v16.i9.3905
Revised: July 3, 2024
Accepted: July 9, 2024
Published online: September 15, 2024
Processing time: 95 Days and 21.6 Hours
Advanced gastric cancer (AGC) remains a challenging malignancy with poor prognosis. The combination of oxaliplatin and trastuzumab has shown promising results in AGC treatment. This study aimed to investigate the effects of oxaliplatin and trastuzumab combination therapy on serum tumor markers and T lympho
To investigate the impact of oxaliplatin and trastuzumab combination therapy on serum markers and T cell subsets in patients with AGC.
This prospective study enrolled 60 patients with AGC. All patients received oxaliplatin (130 mg/m2, every 3 weeks) and trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) for six cycles. Serum carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4) were measured before and after treatment. T-lymphocyte subsets, including CD3+, CD4+, CD8+, and CD4+ /CD8+ ratios, were also evaluated. The clinical response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1.
After six cycles of treatment, the CEA, CA19-9, and CA72-4 serum levels signi
Oxaliplatin and trastuzumab combination therapy effectively reduced serum tumor marker levels and modulated T lymphocyte subsets in patients with AGC. Combination therapy not only has a direct antitumor effect, but also enhances the immune response in patients with AGC. Serum tumor markers and T lymphocyte subsets may serve as potential predictive biomarkers for treatment response in patients with AGC receiving combination therapy.
Core Tip: An investigation of the effects of oxaliplatin and trastuzumab combination therapy on serum tumor markers and T lymphocyte subsets in patients with advanced gastric cancer (AGC) revealed significant reductions in carcinoembryonic antigen, cancer antigen 19-9, and cancer antigen 72-4 levels, as well as favorable changes in T cell populations. Patients with significantly decreased tumor marker levels and increased CD4+/CD8+ ratio exhibited better treatment responses. The therapy not only targets tumors but also boosts immune responses in patients with AGC. Serum markers and T cell subsets are potential predictive biomarkers for treatment outcomes in patients with AGC receiving this combined treatment.
- Citation: Zheng CW, Yang YM, Yang H. Impact of oxaliplatin and trastuzumab combination therapy on tumor markers and T lymphocyte subsets for advanced gastric cancer. World J Gastrointest Oncol 2024; 16(9): 3905-3912
- URL: https://www.wjgnet.com/1948-5204/full/v16/i9/3905.htm
- DOI: https://dx.doi.org/10.4251/wjgo.v16.i9.3905
Gastric cancer is a major global health burden, ranking as the fifth most common malignancy and the third leading cause of cancer-related deaths worldwide[1]. Despite advances in diagnostic techniques and treatment strategies, the prognosis of advanced gastric cancer (AGC) remains poor, with a median overall survival (OS) of < 12 months[2]. The combination of chemotherapy and targeted therapy has emerged as a promising approach for the treatment of AGC, aiming to improve clinical outcomes and quality of life of patients.
Oxaliplatin, a third-generation platinum-based compound, has demonstrated significant antitumor activity against AGC, both as a single agent and in combination with other chemotherapeutic drugs[3,4]. Its mechanism of action involves the formation of DNA adducts, leading to DNA damage and apoptosis of tumor cells[5]. Trastuzumab, a humanized monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2), is effective in patients with HER2-positive AGC[6]. By binding to the extracellular domain of HER2, trastuzumab inhibits downstream signaling pathways involved in cell proliferation, survival, and angiogenesis[7]. Several phase II and III clinical trials have demonstrated that the combination of oxaliplatin and trastuzumab has shown synergistic effects and improved clinical outcomes in patients with AGC[8,9].
Serum tumor markers, such as carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4), are commonly used for the diagnosis, prognosis, and monitoring of gastric cancer[10]. These markers are produced by tumor cells and released into the bloodstream, reflecting tumor burden and activity[11]. Elevated levels of these markers have been associated with advanced-stage disease, metastasis, and poor prognosis in patients with gastric cancer[12,13]. Moreover, changes in serum tumor marker levels during treatment were correlated with treatment response and survival outcomes[14,15].
In addition to tumor markers, the immune system plays a crucial role in cancer progression and treatment. T lym
Despite growing evidence supporting the use of oxaliplatin and trastuzumab combination therapy for AGC, its effects on serum tumor markers and T lymphocyte subsets remain largely unexplored. Examining the effects of combination therapy on these biomarkers may elucidate the mechanisms of action and help to identify potential predictive factors for treatment response and prognosis.
This study aimed to investigate the effects of oxaliplatin and trastuzumab combination therapy on serum tumor markers (CEA, CA19-9, and CA72-4) and T lymphocyte subsets (CD3+, CD4+, CD8+, and CD4+/CD8+ ratios) in patients with AGC. Additionally, we sought to explore the association between changes in these biomarkers and clinical response to identify the potential predictive biomarkers for treatment response in patients with AGC receiving this combination therapy.
This prospective single-arm study was conducted at a tertiary hospital in China between January 2018 and December 2020. The institutional ethics committee approved the study protocol, and all patients provided written informed consent before enrollment. Patients with histologically confirmed AGC, HER2 positivity (immunohistochemistry 3 + or fluorescence in situ hybridization positive), measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 were eligible for enrollment. Patients with prior chemotherapy or trastuzumab treatment for AGC, severe organ dysfunction, or active autoimmune disease were excluded.
All patients received oxaliplatin (130 mg/m2, intravenously, every 3 weeks) and trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg, intravenously, every 3 weeks) for six cycles. CEA, CA19-9, and CA72-4 serum levels were measured before treatment and after six cycles using electrochemiluminescence immunoassays (Roche Diagnostics, Germany). T lymphocyte subsets (CD3+, CD4+, and CD8+) were analyzed using flow cytometry (BD FACSCalibur, BD Biosciences, United States) before and after treatment. Clinical response was evaluated according to RECIST version 1.1, and patients were categorized as having a complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).
Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Patients were followed up every 3 months after treatment completion for survival analysis.
Serum biomarkers were measured using electrochemiluminescence immunoassays (Elecsys CEA, CA19-9, and CA72-4 assays; Roche Diagnostics, Germany) according to the manufacturer's instructions. The assays used monoclonal antibodies specifically directed against CEA, CA19-9, and CA72-4 antigens.
Continuous variables are expressed as means ± SD or medians (interquartile ranges), and categorical variables are presented as frequencies and percentages. The normality of continuous variables was assessed using the Shapiro-Wilk test. Paired t-tests or Wilcoxon signed-rank tests were used to compare the serum tumor markers and T lymphocyte subsets before and after treatment. The association between changes in biomarkers and clinical response was analyzed using the Mann-Whitney U test. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method, and differences between groups were compared using the log-rank test. Univariate and multivariate Cox proportional hazards models were used to identify the prognostic factors for PFS and OS. Statistical significance was defined as a two-sided P value of < 0.05. All statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, United States).
Altogether, 60 patients with AGC were enrolled in this study. The median age was 58 years (range, 35-75 years), and 36 patients (60%) were male. Most patients (n = 42, 70%) had an ECOG performance status score of 0. The most common metastatic sites were the liver (n = 28; 47%), peritoneum (n = 24; 40%), and lymph nodes (n = 20; 33%). The baseline characteristics of the patients are summarized in Table 1.
Characteristics | Value |
Median age, years (range) | 58 (35-75) |
Sex | |
Male | 36 (60) |
Female | 24 (40) |
ECOG performance status | |
0 | 42 (70) |
1 | 18 (30) |
Metastatic sites | |
Liver | 28 (47) |
Peritoneum | 24 (40) |
Lymph nodes | 20 (33) |
Lung | 12 (20) |
Bone | 8 (13) |
HER2 status | |
IHC 3+ | 48 (80) |
IHC 2+/FISH+ | 12 (20) |
After six cycles of oxaliplatin and trastuzumab combination therapy, CEA, CA19-9, and CA72-4 serum levels significantly decreased compared to baseline levels (P < 0.001 for all markers; Table 2).
Marker | Baseline | After treatment | P value |
CEA (ng/mL) | |||
Median (range) | 15.2 (1.5-180.5) | 6.1 (0.5-55.0) | < 0.001 |
CA19-9 (U/mL) | |||
Median (range) | 60.5 (10.5-1000.0) | 26.4 (5.0-400.0) | < 0.001 |
CA72-4 (U/mL) | |||
Median (range) | 8.0 (1.5-300.0) | 2.8 (0.5-80.0) | < 0.001 |
The percentages of CD3+ and CD4+ T lymphocytes increased significantly increased after treatment (P < 0.05), whereas that of CD8+ T lymphocytes decreased (P < 0.05). The CD4+/CD8+ ratio also significantly increased after treatment (P < 0.05; Table 3).
Subset | Baseline | After treatment | P value |
CD3+ (%) | |||
Median (range) | 62.5 (45.0-75.0) | 70.0 (50.0-85.0) | < 0.05 |
CD4+ (%) | |||
Median (range) | 30.0 (20.0-45.0) | 40.0 (25.0-55.0) | < 0.05 |
CD8+ (%) | |||
Median (range) | 28.5 (15.0-40.0) | 22.0 (10.0-35.0) | < 0.05 |
CD4+/CD8+ ratio | |||
Median (range) | 1.2 (0.6-2.5) | 1.8 (0.8-3.5) | < 0.05 |
Among the 60 patients, 5 (8%) achieved CR, 28 (47%) achieved PR, 20 (33%) achieved SD, and 7 (12%) had PD. Associations between biomarker changes and clinical responses are summarized in Table 4. Patients with a higher percentage of decrease in serum tumor markers (≥ 50% reduction) had a significantly better clinical response rate (CR + PR) than those with a lower percentage of decrease (< 50% reduction; P < 0.05). Similarly, patients with a higher CD4+/CD8+ ratio (≥ 1.5-fold) showed a better clinical response rate than those with a lower rate of increase (< 1.5-fold; P < 0.05).
Biomarker change | Clinical response rate (CR + PR) | P value |
CEA | ||
≥ 50% reduction | 70.0% | < 0.05 |
< 50% reduction | 40.0% | |
CA19-9 | ||
≥ 50% reduction | 75.0% | < 0.05 |
< 50% reduction | 42.9% | |
CA72-4 | ||
≥ 50% reduction | 72.2% | < 0.05 |
< 50% reduction | 38.5% | |
CD4+ /CD8+ ratio | ||
≥ 1.5-fold increase | 71.4% | < 0.05 |
< 1.5-fold increase | 41.7% |
The median follow-up duration was 18 months (range, 6-36 months). The median PFS and OS were 8.5 months (95%CI: 6.8-10.2 months) and 16.0 months (95%CI: 13.5-18.5 months), respectively. The results of the univariate and multivariate analyses for PFS and OS are presented in Table 5. In the multivariate analysis, a higher decrease in CEA level [hazard ratio (HR): 0.40; 95%CI: 0.20-0.82; P = 0.012] and a higher increase in CD4+/CD8+ ratio (HR: 0.45; 95%CI: 0.22-0.92; P = 0.028) remained independent prognostic factors for PFS. For OS, a higher decrease in CA72-4 level (HR: 0.38; 95%CI: 0.17-0.85; P = 0.018) and a higher increase in CD4+/CD8+ ratio (HR: 0.42; 95%CI: 0.19-0.93; P = 0.033) were independent prognostic factors.
Factor | Univariate analysis, HR (95%CI) | P value | Multivariate analysis, HR (95%CI) | P value |
PFS | ||||
CEA (≥ 50% vs < 50% reduction) | 0.45 (0.23-0.88) | 0.020 | 0.40 (0.20-0.82) | 0.012 |
CA19-9 (≥ 50% vs < 50% reduction) | 0.50 (0.26-0.97) | 0.040 | 0.58 (0.29-1.16) | 0.123 |
CA72-4 (≥ 50% vs < 50% reduction) | 0.48 (0.24-0.94) | 0.032 | 0.55 (0.27-1.12) | 0.098 |
CD4+ /CD8+ ratio (≥ 1.5 vs < 1.5) | 0.42 (0.21-0.84) | 0.014 | 0.45 (0.22-0.92) | 0.028 |
OS | ||||
CEA (≥ 50% vs < 50% reduction) | 0.52 (0.25-1.08) | 0.080 | 0.60 (0.28-1.30) | 0.197 |
CA19-9 (≥ 50% vs < 50% reduction) | 0.55 (0.27-1.13) | 0.103 | 0.70 (0.33-1.50) | 0.361 |
CA72-4 (≥ 50% vs < 50% reduction) | 0.43 (0.20-0.92) | 0.030 | 0.38 (0.17-0.85) | 0.018 |
CD4+ /CD8+ ratio (≥ 1.5 vs < 1.5) | 0.40 (0.18-0.87) | 0.021 | 0.42 (0.19-0.93) | 0.033 |
The most common adverse events (≥ grade 3) were neutropenia (35.0%), thrombocytopenia (20.0%), anemia (15.0%), and fatigue (10.0%). No febrile neutropenia or severe cardiac events were observed. Adverse events are summarized in Table 6.
Adverse events | n (%) |
Neutropenia | 21 (35.0) |
Thrombocytopenia | 12 (20.0) |
Anemia | 9 (15.0) |
Fatigue | 6 (10.0) |
Nausea/vomiting | 4 (6.7) |
Diarrhea | 3 (5.0) |
Neuropathy | 2 (3.3) |
Elevated transaminases | 2 (3.3) |
Oxaliplatin and trastuzumab combination therapy effectively reduced serum tumor marker levels and modulated T lymphocyte subsets in patients with AGC. The significant decrease in CEA, CA19-9, and CA72-4 Levels after treatment reflects the direct antitumor activity of the combination therapy, consistent with previous studies that have reported on the prognostic value of serum tumor markers in gastric cancer[21,22]. Dynamic changes in serum tumor markers during treatment may be early indicators of treatment response and guide therapeutic decisions.
The increase in CD3+ and CD4+ T lymphocytes and decrease in CD8+ T lymphocytes after treatment suggested an enhanced immune response elicited by combination therapy. The increased CD4+/CD8+ ratio indicates a shift toward a more balanced and effective immune status, which may contribute to the efficacy of combination therapy. These findings are consistent with those of previous studies reporting the immunomodulatory effects of chemotherapy and targeted therapy in various types of cancer[23]. A favorable effect on the immune system may also improve the long-term prognosis of patients with AGC receiving this combination therapy.
The significant association between biomarker changes and clinical response highlights the potential of serum tumor markers and T lymphocyte subsets as predictive biomarkers of treatment response. Patients exhibiting a greater reduction in serum tumor markers and a higher increase in the CD4+/CD8+ ratio showed better clinical outcomes, suggesting that monitoring these biomarkers during treatment may help identify patients who are more likely to benefit from com
Investigating potential correlations between changes in serum markers and immune cell subsets with other clinical endpoints, such as PFS, OS, and quality of life measures, would provide a more comprehensive assessment of treatment efficacy and patient outcomes. These analyses could help establish the clinical utility of these biomarkers in predicting long-term prognosis and guiding treatment decisions.
The predictors of treatment response identified in this study, such as ≥ 50% reduction in serum tumor markers and ≥ 1.5-fold increase in CD4+/CD8+ ratio, should be validated in independent patient cohorts to assess their robustness and generalizability. This validation would strengthen the clinical applicability of these biomarkers in personalized treatment strategies for patients with AGC.
The safety profile of the oxaliplatin and trastuzumab combination therapy in this study was consistent with those in previous reports, and no unexpected adverse events were observed. The absence of febrile neutropenia and severe cardiac events suggests that this combination therapy is well-tolerated in patients with AGC. Future randomized controlled trials with larger sample sizes and longer follow-up periods are warranted to validate these findings and further explore the clinical implications of this combination therapy in the management of AGC.
The limitations of this study include its single-arm design and relatively small sample size, which may limit the generalizability of the findings. Additionally, the lack of a control group precluded direct comparisons with other treatment regimens. Further large-scale randomized controlled trials are needed to validate these findings and to compare the effectiveness of this combination therapy with other treatment options for AGC. In addition, longer follow-up periods are necessary to evaluate the long-term impact of this combination therapy on survival outcomes and quality of life.
Oxaliplatin and trastuzumab combination therapy effectively reduced serum tumor marker levels and modulated T lymphocyte subsets in patients with AGC, reflecting both direct antitumor effects and an enhanced immune response. The significant association between changes in these biomarkers and clinical responses as well as their prognostic value for survival outcomes suggests that serum tumor markers and T lymphocyte subsets may serve as potential predictive and prognostic biomarkers in patients with AGC receiving this combination therapy. These findings elucidate the mechanisms underlying the efficacy of this combination therapy, and support its use as a promising treatment option for patients with AGC.
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