Abstract
Background/Aim: We hypothesized that the hemoglobin, albumin, lymphocyte, and platelet (HALP) score may be a promising marker for the treatment and management of gastric cancer (GC). To test this hypothesis, we evaluated the clinical impact of the HALP score in patients with GC who received curative treatment. Patients and Methods: Consecutive patients who underwent curative resection for GC at the Yokohama City University between 2005 and 2020 were selected based on their medical records. The HALP score was calculated as follows: HALP=Hemoglobin (g/l) × albumin (g/l) × lymphocytes (109/l)/platelets (109/l). Results: The 3-year and 5-year overall survival (OS) rates were 88.6% and 85.8%, respectively, in patients with HALP scores of >40, and 70.3% and 57.2% in patients with HALP scores of ≤40. There were significant differences between the groups analyzed (p<0.001). In univariate analysis, age, T status, lymph node metastasis status, HALP score, lymphovascular invasion status, pathological type, and postoperative complication status were identified as significant prognostic factors for OS. In multivariate analysis, the HALP score remained a significant prognostic factor for OS [hazard ratio (HR)=2.679; 95% confidence interval (CI)=1.455-4.934, p=0.002]. Similar results were observed in the analysis of recurrence-free survival. In addition, the HALP score status affects the postoperative clinical course, including the occurrence of postoperative anastomotic leakage and the introduction of postoperative adjuvant chemotherapy. Conclusion: The HALP score affects both short- and long-term oncological outcomes. Thus, the HALP score may be a promising prognostic factor for the treatment and management of GC.
Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of cancer-related deaths in the world (1, 2). Gastrectomy with or without perioperative adjuvant treatment is standard treatment for early to locally advanced GC (3, 4). The survival of GC patients has gradually improved with the improvement of adjuvant treatment and perioperative care and the introduction of minimally invasive surgery (5, 6). However, almost half of GC patients experience recurrence, even after curative treatment. Once GC patients often experience recurrence, the prognosis is approximately ≤12 months (7, 8). To date, various prognostic factors have been evaluated to optimize GC treatment (9). Recently, inflammation and nutritional tools, such as neutrophil-to-lymphocyte ratio, C-reactive protein-to-albumin ratio, systemic inflation score, and platelet-to-albumin ratio have been evaluated and reported in GC patients (10-15). Among the various tools used to assess inflammation and nutrition, the Hemoglobin, Albumin, Lymphocytes, and Platelets (HALP) score has been developed and its application has been reported in certain malignancies (16). The HALP score is a novel immunonutritional marker that integrates several routinely collected indicators of the immune status (e.g., platelet and lymphocyte count) and the nutritional status (e.g., albumin), and hemoglobin (a marker for anemia). Recent studies have demonstrated that the perioperative immune status and nutritional status affect short-term oncological outcomes, such as the continuation of adjuvant treatment, the occurrence of adverse events of adjuvant treatment, as well as the occurrence of postoperative surgical complications and long-term oncological outcomes, such as overall survival and the recurrence pattern (17-19). However, reports on the impact of HALP scores on GC are limited. If HALP has a clinical impact on GC treatment, we hypothesized that HALP may be a promising marker for the perioperative chemotherapy and perioperative management of GC. To confirm our hypothesis, we evaluated the clinical impact of HALP in patients with GC who received curative treatment.
Patients and Methods
Patients. Patients with GC who underwent curative resection at the Yokohama City University from 2005 to 2020 were consecutively selected based on medical records. Patients who met all of the following criteria were eligible for inclusion in the present study: histologically confirmed adenocarcinoma; clinical stage I-III disease (defined according to the General Rules of the Japanese Gastric Cancer Association for Gastric Cancer, 15th edition) (20); received curative gastrectomy as a primary treatment for GC; and achievement complete (R0) resection (including radical lymph node dissection).
Surgical procedure and adjuvant treatment. In all cases, gastrectomy was performed with D1+ or D2 nodal dissection. Patients with pathological stage II or III GC received S-1-based adjuvant chemotherapy (21, 22).
Determination of the hemoglobin, albumin, lymphocyte, platelet (HALP) score. The HALP score was calculated using the following formula:
Follow-up protocol. Patients were followed up at outpatient clinics. During follow-up examinations, the patients received hematological tests (including evaluation of tumor marker levels) and physical examinations at least every 3 months for 5 years after surgery. In addition, computed tomography (CT) examinations at 3-month intervals in the first 3 years after surgery, then at 6-month intervals until 5 years after surgery.
Evaluations and statistical analyses. The significance of variance between the NPS and different clinicopathological factors was analyzed using the chi-square test. A Kaplan–Meier analysis was conducted to generate overall survival and recurrence-free survival curves. Univariate and multivariate Cox proportional hazards models were used to analyze survival. p-Values of <0.05 were considered to indicate statistical significance. SPSS (v27.0 J Win; IBM, Armonk, NY, USA) was used to perform the statistical analyses. The institutional review board of Yokohama City University approved the present study.
Results
Patients. A total of 259 patients were included in the study. Among the 259 patients, 118 were <70 years of age and 141 were ≥70 years of age. One hundred eighty-three patients were male and 76 were female. According to previous reports and the 3- and 5-years overall survival rates, we set the cut-off value of the HALP score at 40 in the present study. Table I shows details of patient backgrounds. When comparing patient background factors between the HALP ≤40 and HALP >40 groups, there were significant differences in tumor status, such as T status, lymph node metastasis status, and lymphovascular invasion status. The incidence of ≥T2 was 57.0% in the HALP ≤40 group and 33.9% in the HALP >40 group (p<0.001). The incidence of lymph node metastasis was 41.5% in the HALP ≤40 group and 28.2% in the HALP >40 group (p=0.026). The incidence of lymphovascular invasion was 64.4% in the HALP ≤40 group and 46.8% in the HALP >40 group (p=0.004). Patients in the HALP ≤40 group had a much more aggressive tumor status than in the HALP >40 group.
Comparison of survival rates stratified by patient characteristics.
Survival analysis. The 3- and 5-year overall survival (OS) rates were 88.6% and 85.8%, respectively, in the HALP >40 group, and 70.3% and 57.2% in the HALP ≤40 group (Figure 1). The difference between the groups was significant (p<0.001). In the univariate analysis, age, T status, lymph node metastasis status, HALP score, lymphovascular invasion status, pathological type, and postoperative complication status were identified as significant prognostic factors for OS. In multivariate analysis, the HALP score remained a significant prognostic factor for OS [hazard ratio (HR)=2.679; 95% confidence interval (CI)=1.455-4.934, p=0.002] (Table II). In addition, the 3- and 5-year recurrence-free survival (RFS) rates were 84.5% and 83.3%, respectively, in the HALP >40 group, and 66.0% and 53.8% the HALP ≤40 group (Figure 2). The difference was statistically significant (p<0.001). In the univariate analysis, T status, lymph node metastasis status, HALP score, lymphovascular invasion status, pathological type, and postoperative complication status were identified as significant prognostic factors for RFS. In multivariate analysis, the HALP score remained a significant prognostic factor for RFS (HR=2.479, 95% CI=1.442-4.263, p=0.001) (Table III). When comparing the recurrence pattern between the two groups, the incidence of peritoneal recurrence was significantly higher in the HALP ≤40 group than in the HALP >40 group (18.6% vs. 4.8%, p<0.001) (Table IV). In addition, the incidence of lymph node recurrence was higher (with marginal significance) in the HALP ≤40 group than in the HALP >40 group (10.4% vs. 4.0%, p=0.05).
Overall survival of gastric cancer patients in HALP >40 and HALP ≤40 groups. HALP: Hemoglobin, albumin, lymphocyte, platelet score.
Uni and Multivariate Cox proportional hazards analysis of clinicopathological factors for overall survival.
Recurrence-free survival of gastric cancer patients in the HALP >40 and HALP ≤40 groups. HALP: Hemoglobin, albumin, lymphocyte, platelet score.
Uni and Multivariate Cox proportional hazards analysis of clinicopathological factors for recurrence free survival.
Patterns of recurrence according to HALP score.
Perioperative clinical course. When comparing the perioperative clinical course between the HALP ≤40 and HALP >40 groups, there were some differences in the details of postoperative surgical complications and clinical course of adjuvant chemotherapy. Among postoperative surgical complications, the incidence of anastomotic leakage was higher in the HALP ≤40 group than in the HALP >40 group (11.9% vs. 5.6%, p=0.079). In the adjuvant chemotherapy course, the number of patients who developed postoperative surgical complications was significantly higher in the HALP ≤40 group than in the HALP >40 group (42.2% vs. 25.8%, p=0.005). However, the number of patients who received adjuvant chemotherapy in the HALP ≤40 group was lower than that in the HALP >40 group (68.4% vs. 84.3%, p=0.099).
Discussion
The aim of the present study was to evaluate the clinical impact of the HALP score in patients with GC who received curative treatment. The major finding was that the HALP score is a significant prognostic factor in GC. In addition, the HALP score status affects the postoperative clinical course, such as the occurrence of postoperative anastomotic leakage and the introduction of postoperative adjuvant chemotherapy. Thus, our results suggest that the HALP score affects both short- and long-term oncological outcomes. Therefore, the HALP score may be a promising prognostic factor for the treatment and management of GC.
In the present study, the prognosis of patients with GC was significantly worse in the HALP score ≤40 group than in the HALP score >40 group. In addition, the HALP score was identified as a significant prognostic factor for OS (HR=2.679; 95% CI=1.455-4.934, p=0.002). Although there are limited studies evaluating the clinical impact in patients with GC, similar results have been reported. Chen et al. clarified the clinical impact of HALP in 1,332 GC patients who received gastrectomy (23). They were divided into HALP-low and HALP-high groups at a cutoff value of 56.8. There were some differences in the background factors of the HALP <56.8 and HALP ≥56.8 groups. The HALP ≥56.8 group had a significantly lower rate of aggressive disease in comparison to the HALP <56.8 group. The median survival time was 67.7-68.8 months in the HALP <56.8 group and 108.0 months in the HALP ≥56.8 group. In addition, the 3-year OS rate was 57.7-59.7% in the HALP <56.8 group, and 73.5-74.7% in the HALP ≥56.8 group. There were significant differences in the median OS and the 3-year OS rates. In the prognostic factor analysis, HALP was selected as an independent prognostic factor in the multivariate analysis (HR=0.700-0.782). Wang et al. evaluated HALP as a predictive factor for lymph node metastasis in 349 patients with GC who underwent curative gastrectomy (24). They divided 349 patients with GC into HALP-high and HALP-low groups at a cutoff value of 35.3. In the multifactorial logistic analysis, HALP was selected as a predictive factor for lymph node metastasis in GC (odds ratio=2.276, 95%CI=1.075-4.818, p=0.032). Based on the present and previous studies, the HALP score is considered to have some clinical impact on the treatment and management of GC. Therefore, HALP may be a promising prognostic or predictive marker of GC.
Why does the HALP score affect long-term oncological outcomes in GC? Although no reports mention this issue, our study suggests a relationship between the HALP status and oncological outcomes. First, the HALP status was related to postoperative anastomotic leakage. In the present study, the HALP ≤40 group had a significantly higher incidence of postoperative anastomotic leakage than the HALP >40 group. The incidence of anastomotic leakage was higher in the HALP ≤40 group than in the HALP score >40 group (11.9% vs. 5.6%, p=0.079). Recently, we demonstrated that postoperative anastomotic leakage affects the survival of patients with gastrointestinal cancer (25). Thus, the HALP status may affect postoperative surgical complications, resulting in poor survival. Second, the HALP status was related to the introduction of postoperative adjuvant treatment. In the present study, the incidence of postoperative adjuvant treatment in the HALP ≤40 group was significantly lower than that in the HALP >40 group. The number of patients who received adjuvant chemotherapy was lower (with marginal significance) in the HALP ≤40 group than in the HALP score >40 group (68.4% vs. 84.3%, p=0.099). To date, pivotal studies have demonstrated that postoperative adjuvant treatment improves the survival of patients with GC. Thus, the patients in the HALP ≤40 group did not fully benefit from adjuvant treatment. The HALP status affects the introduction of postoperative adjuvant treatment, resulting in poor survival. However, the optimal relationship between the HALP status and oncological outcomes remains unclear, and further studies should be conducted to investigate the issue.
Study limitations. First, it was a retrospective study conducted at a single institution. Therefore, it may have been affected by selection and time biases. Second, the optimal cutoff value for HALP was unclear. Previous studies that evaluated HALP as a prognostic or predictive marker in patients with gastrointestinal cancer reported various cutoff values. Furthermore, previous studies also included various tumor stages and malignancy types. In addition, the methods used to detect the optimal cutoff value of HALP were also different. Therefore, our study needs to be validated in larger cohorts in the future.
In conclusion, the HALP score is a significant prognostic factor in GC. In addition, the HALP status affects the postoperative clinical course, including the occurrence of postoperative anastomotic leakage and the introduction of postoperative adjuvant chemotherapy. Our results suggest that the HALP score affects both short-term and long-term oncological outcomes. Thus, the HALP score may be a promising prognostic factor for the treatment and management of GC.
Acknowledgements
This study was supported in part by the nonprofit organization of the Yokoyama Surgical Research Group (YSRG).
Footnotes
Authors’ Contributions
TA and YM contributed substantially to this concept and study design. TA, IH, YE, SY, MU, KN, KK, AT, made substantial contributions to the data acquisition, analysis, and interpretation. TA, AS, IH, YM and NY were involved in drafting and critically revising the manuscript for important intellectual content. TA and IH approved the final version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
- Received May 30, 2024.
- Revision received July 2, 2024.
- Accepted July 12, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
