Significance of hemoglobin and hematocrit changes in predicting patient survival and efficacy of neoadjuvant chemotherapy for advanced gastric cancer

Abstract

BACKGROUND

Advanced gastric cancer is characterized by fast tumor growth and aggressive biological behavior. During neoadjuvant chemotherapy, patients are at risk of distant metastasis or local progression. Anemia is a frequent complication in these patients.

AIM

To analyze whether changes in hemoglobin and hematocrit can predict the survival and efficacy of neoadjuvant chemotherapy in patients with advanced gastric cancer.

METHODS

The clinical data of 185 patients with advanced gastric cancer admitted to the Third Affiliated Hospital of Chengdu Medical College, Pidu District People’s Hospital, Chengdu, China, between January 2016 and January 2021, were retrospectively analyzed. All patients underwent a tegafur + oxaliplatin + apatinib chemotherapy regimen. According to the efficacy of chemotherapy, they were divided into an effective group (complete or partial response, n = 121) and an ineffective group (stable disease or disease progression, n = 64). The factors related to chemotherapy efficacy in patients with advanced gastric cancer were analyzed by univariate and logistic multivariate analyses. The 3-year survival rates of the patients with different hemoglobin and hematocrit levels were compared.

RESULTS

Univariate analysis showed that the proportion of patients with a tumor diameter > 5 cm, non-tubular adenocarcinoma, lymph node metastasis, hematocrit < 33%, low mean red blood cell (RBC) protein content, low RBC distribution width, hemoglobin < 107 g/L, and platelets > 266 × 10⁹/L in the ineffective group were significantly higher than those in the effective group (P < 0.05). Logistic multivariate analysis showed that a tumor diameter > 5 cm, lymph node metastasis, ≤ 3 chemotherapy cycles, hematocrit < 33%, and hemoglobin < 107 g/L are risk factors for neoadjuvant chemotherapy failure in advanced gastric cancer (P < 0.05). The 1-year, 2-year, and 3-year survival rates in the effective group were 93.39%, 83.47%, and 60.33%, respectively. These rates were significantly higher than those in the ineffective group (P < 0.05). The 1-year, 2-year, and 3-year survival rates of patients with hematocrit < 33% were 74.67%, 49.33%, and 29.33%, respectively, which were significantly lower than those of patients with hematocrit ≥ 33% (P < 0.05). The 1-year, 2-year, and 3-year survival rates of patients with hemoglobin < 107 g/L were 80.39%, 58.82%, and 39.22%, respectively, which were significantly lower than those of patients with hemoglobin ≥ 107 g/L (P < 0.05).

CONCLUSION

Hematocrit < 33% and hemoglobin < 107 g/L are risk factors for chemotherapy failure in patients with advanced gastric cancer. They are associated with poorer prognosis and reduced 3-year survival rates.

Key Words: Chemotherapy curative effect; Gastric cancer; Hematocrit; Hemoglobin; Neoadjuvant chemotherapy; Progress; Survival

Core Tip: The prevalence of anemia in patients with cancer is well documented. Abnormal erythrocyte pressure levels cause tumor hypoxia, which leads to changes in tumor-associated proteins and accelerates tumor cell proliferation. These factors are closely related to the efficacy of chemotherapy and overall prognosis. Reduced hemoglobin levels indicate the presence of anemia, which aggravates disease progression, reduces nutrient absorption, affects the hematopoietic capacity of the bone marrow, reduces renal function, and results in poor prognosis. This study analyzes the prognostic significance of changes in hemoglobin and erythrocyte levels on the effects of neoadjuvant chemotherapy and survival rates of patients with advanced gastric cancer.

INTRODUCTION

Gastric cancer is one of the most common malignancies, accounting for nearly 10% of all tumors and 12% of cancer-related deaths worldwide[1]. The onset of gastric cancer is typically insidious, and most patients are diagnosed at an advanced stage. Advanced gastric cancer is often accompanied by hematogenous lymph node and peritoneal metastasis, and even direct infiltration and diffusion into adjacent tissues in some patients[2]. The available clinical treatments for advanced gastric cancer have limited efficacy, and the 5-year survival rate following treatment is less than 40%[3]. Neoadjuvant chemotherapy aims to reduce tumor size and clinical stage, provide the basis for surgical treatment, and improve the curative effect of surgery by reducing tumor adhesion to the surrounding tissues[4]. Neoadjuvant chemotherapy is increasingly used in the treatment of solid malignant tumors such as those of the head, neck, breast, and bone. It has recently begun to be utilized in the treatment of gastric cancer[5]. However, patients with advanced gastric cancer are prone to rapid tumor growth and poor overall health. During neoadjuvant chemotherapy, this patient population has a high risk of distant metastasis or local progression. Therefore, the identification of effective indicators of chemotherapy outcomes and overall prognosis in patients with gastric cancer is of great clinical significance[6].

Hematocrit values represent the percentage of red blood cells (RBCs) in the total blood volume. Abnormal hematocrit levels can accelerate tumor diffusion and cause tumor hypoxia and tumor-related protein changes. These clinical features are known to be closely related to chemotherapy efficacy and prognosis[7]. Hemoglobin is the oxygen-carrying protein in RBCs, which is responsible for maintaining tissue oxygenation. Anemia, characterized by hemoglobin levels below the normal range, can aggravate disease progression in patients with cancer by impairing the hematopoietic ability of the bone marrow, the absorption of nutrients, and kidney function, leading to a poor prognosis[8]. Therefore, this study aims to evaluate the effects of reduced hemoglobin and hematocrit levels on the efficacy of neoadjuvant chemotherapy and prognosis in patients with advanced gastric cancer.

MATERIALS AND METHODS

Data from 185 patients (125 males and 60 females) with advanced gastric cancer who were admitted to the Third Affiliated Hospital of Chengdu Medical College, Pidu District People’s Hospital, between January 2016 and January 2021 were retrospectively analyzed. The mean age of the cohort was 58.37 (± 5.44) years, and the age range was 27–75 years.

Inclusion criteria

The inclusion criteria were as follows: clinically diagnosed advanced gastric cancer; age ≥ 18 years; normal liver and kidney function; no previous neoadjuvant chemotherapy; good tolerance to neoadjuvant chemotherapy; no evidence of brain, liver, lung, or other distant metastasis; and availability of complete clinical and follow-up data.

Exclusion criteria

The exclusion criteria were as follows: presence of other malignant tumors; complications such as pyloric obstruction, severe infection, gastrointestinal perforation, or gastrointestinal hemorrhage; dysfunction of a major organ; incomplete clinical or follow-up data; and loss to follow-up within 3 years of treatment.

Procedure

All patients received chemotherapy consisting of tegafur, oxaliplatin, and apatinib. The regimen began with an intravenous infusion of 130 mg/m² oxaliplatin, which was administered once daily for 21 days. Apatinib was also begun on Day 1 at a dose of 850 mg/day, taken orally 30 min after meals, and continued for 28 days. Tegafur was administered orally twice a day (after breakfast and after dinner) from Days 1 to 14. The dose for each patient was determined based on body surface area: patients with a body surface area < 1.25 m² received 40 mg twice daily, those with a body surface area between 1.25 m² and 1.5 m² received 50 mg twice daily, and those with a body surface area > 1.5 m² received 60 mg twice daily. Two cycles of this regimen were administered. The regimen and doses of the perioperative chemotherapy were planned by professional oncologists at each institution and individually adjusted according to observed toxic effects and tumor responses. According to the efficacy of chemotherapy, the patients were divided into an effective group (complete remission + partial remission, n = 121) and an ineffective group (stable disease + disease progression, n = 64). Demographic, clinical, and follow-up data were retrospectively analyzed. This included sex, age, body mass index, Eastern Cooperative Oncology Group score, smoking history, drinking history, tumor location, tumor diameter, histological type, differentiation, serious adverse reactions, number of chemotherapy cycles, hematocrit level, mean corpuscular hemoglobin content, RBC protein concentration, RBC distribution width, hemoglobin level, and platelet count. All patients were followed up for a minimum of 3 years, and the 3-year survival rates of those with different levels of hemoglobin and hematocrit were compared.

Statistical analysis

All statistical analyses were performed using SPSS for Windows, v.22.0 (IBM Corp., Armonk, NY, United States). Student’s t-tests were used to analyze continuous variables, and χ² tests were used to analyze categorical variables. Variables with statistically significant differences were analyzed by univariate and multivariate logistic regression analysis. A log-rank test was used to generate a survival curve. The determination of thresholds for indicators was based on receiver operator characteristic curves. A P-value < 0.05 was considered statistically significant.

RESULTS

Univariate analysis of factors associated with the neoadjuvant chemotherapy responses of patients with advanced gastric cancer

Univariate analysis revealed that the percentages of patients with tumor diameter > 5 cm, those with non-tubular adenocarcinoma, lymph node metastasis, hematocrit levels < 33%, low mean corpuscular hemoglobin content, low RBC distribution widths, hemoglobin level < 107 g/L, and platelet counts > 266 × 10⁹/L were all significantly higher in the ineffective group than in the effective group (P < 0.05), as shown in Table 1.

Table 1 Univariate analysis of factors associated with response to neoadjuvant chemotherapy for advanced gastric cancer, n (%)/mean ± SD.

Relevant factors	Effective group (n = 121)	Ineffective group (n = 64)	x2/t value	P value
Gender			3.276	0.056
Male	80 (66.12)	45 (70.31)
Female	41 (33.88)	19 (29.69)
Age (years)			1.811	0.075
≤ 60	52 (42.98)	26 (40.63)
> 60	69 (57.02)	38 (59.37)
BMI (kg/m2)			1.542	0.087
≤ 24	103 (85.12)	53 (82.81)
> 24	18 (14.88)	11 (17.19)
ECOG score (points)			3.399	0.055
0	50 (41.32)	27 (42.19)
1	71 (58.68)	37 (57.81)
Smoking history			1.417	0.090
Yes	39 (32.23)	26 (40.63)
No	82 (67.77)	38 (59.37)
Drinking history			2.317	0.065
Yes	58 (47.93)	35 (54.69)
No	63 (52.07)	29 (45.31)
Tumor site			1.976	0.070
Cardiogastric fundus	39 (32.23)	21 (32.81)
Gastric body	17 (14.05)	9 (14.06)
Antrum of the stomach	59 (48.76)	26 (40.63)
Whole stomach	6 (4.96)	8 (12.50)
Tumor diameter (cm)			7.435	0.016
≤ 5	76 (62.81)	27 (42.19)
> 5	45 (37.19)	37 (57.81)
Histological type			6.632	0.024
Tubular adenocarcinoma	99 (81.82)	40 (62.50)
Poorly differentiated adenocarcinoma	10 (8.26)	12 (18.75)
Heron cell carcinoma	6 (4.96)	9 (26.47)
Mixed type	6 (4.96)	3 (8.83)
Degree of differentiation			1.605	0.084
High differentiated	5 (4.13)	1 (1.56)
Moderate differentiation	36 (29.75)	14 (21.88)
Poorly differentiated/undifferentiated	80 (66.12)	49 (76.56)
Lymph node metastasis			8.427	0.007
No	57 (47.11)	19 (29.69)
Yes	64 (52.89)	45 (70.31)
Severe adverse reactions			1.843	0.072
Yes	11 (9.09)	10 (15.63)
No	110 (90.91)	54 (84.37)
Chemotherapy cycle (cycles)			4.856	0.041
≤ 3	83 (68.60)	55 (85.94)
> 3	38 (31.40)	9 (14.06)
Hematocrit (%)			4.784	0.042
< 33	42 (34.71)	33 (51.54)
≥ 33	79 (65.29)	31 (48.44)
Mean corpuscular hemoglobin content (%)	55.27 ± 5.12	42.60 ± 4.83	2.678	0.009
Erythrocyte protein concentration (%)	15.23 ± 1.36	13.85 ± 2.06	2.292	0.036
Red blood cell distribution width	57.79 ± 2.74	45.56 ± 3.04	2.557	0.015
Hemoglobin (g/L)			7.996	0.010
< 107	57 (47.11)	45 (70.31)
≥ 107	64 (52.89)	19 (29.69)
Platelets (× 109/L)			5.785	0.033
> 266	62 (51.24)	51 (79.69)
≤ 266	59 (48.76)	13 (20.31)

BMI: Body mass index.

Multivariate logistic regression analysis of factors associated with the neoadjuvant chemotherapy responses of patients with advanced gastric cancer

Multivariate logistic regression revealed that tumor diameter > 5 cm, lymph node metastasis, ≤ 3 chemotherapy cycles, hematocrit levels < 33%, and hemoglobin level < 107 g/L were risk factors for ineffective neoadjuvant chemotherapy in patients with advanced gastric cancer (P < 0.05), as shown in Table 2.

Table 2 Logistic multivariate analysis of factors associated with response to neoadjuvant chemotherapy for advanced gastric cancer.

Factors	Beta	SE	Wald	OR	P value	95%CI
Tumor diameter > 5 cm	1.079	0.501	4.630	2.942	0.031	2.492-4.095
Lymph node metastasis	1.102	0.468	5.544	3.012	0.018	2.684-4.348
Chemotherapy cycles ≤ 3 cycles	0.577	0.204	7.996	1.782	0.004	3.283-4.174
Hematocrit < 33%	0.699	0.307	5.165	2.012	0.023	2.783-3.573
Hemoglobin < 107 g/L	0.833	0.379	4.814	2.301	0.028	2.485-4.128

OR: Odds ratio.

Comparison of the survival rates of patients with advanced gastric cancer effectively and ineffectively treated with neoadjuvant chemotherapy

The 1-year, 2-year, and 3-year survival rates of the effective group were 93.39%, 83.47%, and 60.33%, respectively. These were all significantly higher than the corresponding rates of the ineffective group (P < 0.05), as shown in Table 3.

Table 3 Comparison of 3-year survival in patients with advanced gastric cancer treated with neoadjuvant chemotherapy, n (%).

Group	Number of cases (n)	1 year	2 years	3 years
Effective group	121	113 (93.39)	101 (83.47)	73 (60.33)
Effective group	64	45 (70.31)	23 (35.94)	18 (28.13)
χ² value		7.921	8.691	6.536
P value		0.012	0.004	0.025

Comparison of the survival rates of patients with hemoglobin < 107 g/L or ≥ 107 g/L and with hematocrit < 33% or ≥ 33%

The 1-year, 2-year, and 3-year survival rates of patients with hematocrit < 33% were 74.67%, 49.33%, and 29.33%, respectively. These were all significantly lower than those of patients with hematocrit ≥ 33% (P < 0.05). The 1-year, 2-year, and 3-year survival rates of patients with hemoglobin < 107 g/L were 80.39%, 58.82%, and 39.22%, respectively. These were all significantly lower than those of patients with hemoglobin ≥ 107 g/L (P < 0.05), as shown in Table 4 and Figure 1.

Figure 1 Survival curves of patients stratified by hemoglobin and hematocrit levels.

Table 4 Comparison of 3-year survival of patients with different hemoglobin and hematocrit levels.

Group	Number of cases (n)	1 year	2 years	3 years
Hematocrit (%)
< 33%	75	56 (74.67)	37 (49.33)	22 (29.33)
≥ 33%	110	102 (92.73)	87 (79.09)	69 (62.73)
χ² value		4.997	8.231	5.785
P value		0.040	0.009	0.033
Hemoglobin (g/L)
< 107	102	82 (80.39)	60 (58.82)	40 (39.22)
≥ 107	83	76 (91.57)	64 (77.11)	51 (61.45)
χ² value		8.531	6.389	5.421
P value		0.006	0.027	0.036

DISCUSSION

Gastric cancer is a common malignant tumor in China, and its incidence has increased significantly in recent years owing to changes in lifestyle and other factors. Although advances in medical technology have improved the early diagnosis rate, nearly 90% of patients with gastric cancer are still diagnosed at an advanced stage. Improving the overall treatment outcomes for gastric cancer requires both enhanced early diagnosis and the development of new treatment methods[9]. Currently, the primary treatment for gastric cancer is surgical resection. In recent years, preoperative use of neoadjuvant chemotherapy has been found to reduce tumor staging, lower surgical difficulty, and improve the likelihood of complete surgical resection. Research also suggests that neoadjuvant chemotherapy can reduce the risk of postoperative recurrence[10]. Therefore, neoadjuvant chemotherapy plays an important role in improving the prognosis and survival of patients with gastric cancer. Rapid and accurate prediction of the likely effects of neoadjuvant chemotherapy in a given patient is an important clinical decision-making tool and prognostic indicator, allowing a more individualized treatment approach.

In this study, we identified several risk factors for ineffective neoadjuvant chemotherapy in patients with advanced gastric cancer. These included a tumor diameter > 5 cm, lymph node metastasis, ≤ 3 chemotherapy cycles, hematocrit levels < 33%, and hemoglobin levels < 107 g/L (P < 0.05). Tumor diameter directly affects the ultimate curative effect of treatment in patients with advanced gastric cancer. While neoadjuvant chemotherapy can help to reduce tumor diameter to varying degrees in some patients, it is less likely to produce notable reductions in the size of tumors with diameters > 5 cm. Hence, while neoadjuvant chemotherapy in patients with large tumors can provide a good therapeutic basis for subsequent clinical treatment, it can also affect the prognosis and limit the clinical efficacy rate of chemotherapy[11,12]. The lymph nodes are the most common site for tumor metastasis. The presence of lymph node metastasis indicates progression to the middle or late stages of the disease. Because the lymphatic system is distributed throughout the body, with continuous circulation through the lymphatic branches, the risks of recurrence and metastasis are high once tumor cells infiltrate this system. Therefore, although local therapeutic responses may be observed, the overall curative effect is often poor[13]. Since the growth of cancer cells is periodic, neoadjuvant chemotherapy should also be administered periodically. However, the duration of chemotherapy should be tailored to tumor behavior and the patient’s condition. In patients with severe disease, the duration of medication should be extended to completely eradicate all tumor cells. In our cohort, patients who underwent ≤ 3 chemotherapy cycles were associated with poorer outcomes. Although the specific reasons for fewer chemotherapy cycles were not analyzed in detail, treatment intolerance is the most likely reason. Insufficient chemotherapy exposure may fail to effectively kill all tumor cells, leading to a worse prognosis[14].

Hematocrit levels < 33% and hemoglobin levels < 107 g/L are often observed in patients with advanced disease, as they are more likely to have decreased erythrocyte volume and average erythrocyte hemoglobin levels. A previous study found that the efficacy of chemotherapy is directly proportional to hemoglobin concentrations[15]. Large observational studies have reported that 20%–30% of patients with cancer have low hemoglobin levels even before any treatment is initiated, and 60%–70% have low hemoglobin levels during anticancer therapy[16,17]. The fact that chemotherapy can induce both anemia and exposure anemia caused by the tumor explains this large drop in hemoglobin levels after treatment onset[18]. The weakness and malaise that characterize anemia have been shown to reduce the effectiveness of chemotherapy and radiotherapy[19]. In addition, anemia due to tumor hypoxia results in insufficient oxygen availability, which compromises the cytotoxic effects of chemotherapeutic drugs and can induce resistance to ionizing radiation and chemotherapy[20]. Jomrich et al[21] found that high baseline mean corpuscular hemoglobin levels predict poor outcomes in patients with gastroesophageal adenocarcinoma. Thus, decreased hematocrit and hemoglobin levels promote anemia, resulting in hypoxia and accelerated tumor diffusion. This reduces the efficacy of new adjuvant therapies and predicts a poorer prognosis. Malignant tumor cells can promote thrombopoiesis through the expression of vascular endothelial growth factor and interleukin-6. Platelets can promote the secretion of thrombospondin and platelet-derived growth factor, promote tumor angiogenesis and tumor cell proliferation, and accelerate tumor metastasis. Platelets may also bind to circulating tumor cells in the bloodstream, shielding them from potential attacks from immune cells[22]. Platelet count can be a marker of disease progression in patients with cancer. In several malignancies, thrombopoietic homeostasis can be disrupted by an inflammatory cytokine milieu (e.g., disseminated intravascular coagulation) and/or bone marrow metastases[23,24]. Studies have demonstrated that an abnormally high platelet count is associated with a poor prognosis in many cancer types[25], including gastric cancer[26,27].

In the present study, the 1-year, 2-year, and 3-year survival rates of patients with hematocrit < 33% were 74.67%, 49.33%, and 29.33%, respectively. These were significantly lower than those of patients with hematocrit ≥ 33%. The 1-year, 2-year, and 3-year survival rates of patients with hemoglobin < 107 g/L were 80.39%, 58.82%, and 39.22%, respectively, which were significantly lower than those of patients with hemoglobin ≥ 107 g/L (P < 0.05). These results confirm the correlation between hematocrit and hemoglobin levels and both the effects of neoadjuvant chemotherapy and the survival outcomes of patients with advanced gastric cancer, supporting their potential utility as predictive indicators. At present, many indicators are used in clinical practice to predict treatment efficacy and prognosis in patients with cancer, including tumor histological grade, tumor size, and lymphatic infiltration on imaging examinations[28,29]. Further research is needed to determine whether combining hematocrit and hemoglobin measurement with tumor histological grade, tumor size, lymphatic invasion, and other indicators can increase the accuracy of predicting neoadjuvant chemotherapy efficacy and survival in this patient population.

This study has several limitations. First, because it was a single-center study, the sample size was relatively small. Therefore, although we identified a set of markers for evaluating chemotherapy efficacy and survival risk, our findings need to be replicated and validated with a larger cohort. Second, the retrospective nature of our study may limit the generalizability of our findings and increase the risk of bias. Third, factors other than the experimental variables may have contributed to our results. These include iron marker levels, patient lifestyles, and comorbidities, which may have affected the hemoglobin levels and erythrocyte parameters of our cohort. These additional variables may also be correlated with chemotherapy efficacy and survival in patients with advanced gastric cancer. Thus, a prospective, multicenter study with a larger sample size and more variables included in the regression analysis is needed to validate and further elucidate the factors associated with survival and neoadjuvant chemotherapy efficacy in this patient population.

CONCLUSION

In summary, hematocrit levels < 33% and hemoglobin levels < 107 g/L were identified as risk factors for ineffective neoadjuvant chemotherapy in patients with advanced gastric cancer, leading to poorer prognoses and reduced 3-year survival rates.