Abstract
Background/Aim: Cancer-associated systemic inflammatory response is a pivotal indicator of tumor progression and prognosis in various cancers. “Lymphocyte × albumin (LA)” is a prognostic inflammatory marker in rectal cancer. This study examined the correlation between LA, complete adjuvant chemotherapy (ACT), and prognosis in patients with gastric cancer (GC) who underwent radical gastrectomy. Patients and Methods: We retrospectively evaluated 108 patients with stage II/III GC who underwent radical gastrectomy at our institute between January 2015 and December 2021. Survival was assessed using Kaplan–Meier and Cox regression analyses. Factors associated with complete ACT were identified using logistic regression analysis. Results: Of the 108 patients with GC, 60 (55.6%) and 41 (38.0%) initiated and completed ACT, respectively. In multivariate analysis, the pre-operative LA was an independent factor for complete ACT [hazard ratio (HR)=0.35, 95% confidence interval (CI)=0.121-0.995; p=0.049]. In addition, age, pre-operative creatinine clearance, neutrophil-to-lymphocyte ratio, modified Glasgow prognostic score, and poor overall survival were significantly associated with low LA (<7,474). LA was an independent prognostic factor for overall survival in univariate analysis (HR=2.29, 95%CI=1.020-5.145; p=0.045) but not in multivariate analysis (HR=2.00, 95%CI=0.882-4.552; p=0.097). Conclusion: Pre-operative LA is a useful marker for predicting complete ACT and prognosis of patients with GC following radical gastrectomy.
Globally, gastric cancer (GC) is the fifth leading cause of morbidity and mortality (1). Despite recent advancements in diagnostic and multidisciplinary therapies, the prognosis for patients with GC remains poor. The standard method for prolonging the survival of patients with GC after radical gastrectomy with D2 lymphadenectomy in East Asia is the use of adjuvant chemotherapy (ACT) (2). The first evidence from a randomized clinical trial (RCT) for S-1 monotherapy was the ACTS-GC trial (3), which demonstrated the survival benefit of ACT compared with surgery alone. Subsequently, capecitabine plus oxaliplatin (CapeOX), a new treatment option for ACT in patients with GC who underwent radical gastrectomy was established by the CLASSIC study (4). Moreover, the JACCRO GC-07 (5) and ARTIST2 (6) trials showed that S-1 plus docetaxel (DS) and S-1 plus oxaliplatin (SOX) were superior to S-1 monotherapy after radical surgery. However, previous studies reported completion rates of 31.5-75.0% (7-9). Therefore, it is important to improve the completion rate of ACT to improve the prognosis of patients with resected GC. In addition, factors that predict the completion of ACT and strategies to address these factors need to be explored urgently.
Cancer-associated systemic inflammatory response (SIR) is a pivotal indicator of tumor progression and prognosis in various cancers. Systemic inflammatory markers are reportedly useful prognostic indicators, including neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio, Glasgow prognostic score (GPS), and prognostic nutritional index (PNI) (10). In GC, the geriatric nutritional risk index, albumin/fibrinogen ratio, PNI, and the hemoglobin, albumin, lymphocyte, and platelet score are useful systemic inflammatory markers associated with ACT (11-14). “Lymphocyte × albumin (LA)”, the product of the lymphocyte count multiplied by albumin concentration, is a cancer-associated systemic inflammatory marker associated with the prognosis of patients with rectal cancer (15). However, the relationship between LA and ACT in patients with GC remains unclear.
Therefore, this study aimed to elucidate the association between LA, complete ACT, and the prognosis of patients with GC.
Patients and Methods
Patient selection. This retrospective study included patients diagnosed with pathological stage II/III GC who underwent radical gastrectomy at a single tertiary care center (Matsunami General Hospital, Gifu, Japan) between January 2015 and December 2021. We excluded patients lost to follow-up, those diagnosed at Stage IV on the final pathology, those with other concomitant malignancies, or those who underwent neoadjuvant chemotherapy (Figure 1). In this study, all patients were Japanese and provided informed consent using a consent form before enrollment. Patients could withdraw from participation using an opt-out option. This study was conducted in accordance with the human and ethical principles of the Declaration of Helsinki, and the Matsunami General Hospital Institutional Review Board approved this study (approval number: Matsu–I–Rin–604).
Flow chart of patient selection.
Treatment. According to the Japanese Gastric Cancer Guidelines, patients with stage II/III GC are usually scheduled to start ACT with S-1 monotherapy for 1 year, CapeOX for 6 months, DS for 1 year, or SOX for 6 months after surgery (16). ACT was administered after the patients fully recovered from surgery. In this study, patients received either S-1, CapeOX, or DS as the ACT regimen.
S-1 was administered orally at 80, 100, and 120 mg/day for 4 weeks based on body surface areas of <1.25 m2, 1.25-1.5 m2, and ≥1.5 m2, respectively, followed by 2 weeks of rest for four cycles. CapeOX comprised eight 3-week cycles of oral capecitabine (1,200; 1,500; 1,800; 2,100 mg/m2 twice daily on days 1-14 of each cycle, based on body surface areas of <1.36 m2, 1.36-1.66 m2, 1.66-1.96 m2, and ≥1.96 m2, respectively) plus intravenous oxaliplatin (130 mg/m2 on day 1 of each cycle), followed by a rest period of 1 week. DS comprised oral S-1 at 80, 100, and 120 mg/day on days 1-14 with 7 days of rest based on body surface areas of <1.25 m2, 1.25-1.5 m2, and ≥1.5 m2, respectively, followed by six cycles of S-1 at the same dosage and schedule combined with DS 40 mg/m2 on day 1 of each cycle, and then four further cycles of S-1 at 80, 100, 120 mg/day on days 1-28 every 42 days. In instances of adverse reactions, the dose was reduced, the dosing interval modified, or administration was temporarily discontinued. Each regimen was repeated until the scheduled end time, tumor recurrence, observation of unacceptable toxicity, or patient refusal to continue treatment.
Complete ACT was defined as the point at which the planned chemotherapy period was reached: S-1 monotherapy, 1 year; CapeOX, 6 months; DS, 1 year. However, heterogeneity was observed among the treatment regimens over the study period. The incomplete ACT group comprised patients who experienced a relapse during ACT.
Evaluation of clinicopathological features. We investigated patients’ demographic and clinical variables, including age, sex, American Society of Anesthesiologists physical status, tumor location, carbohydrate antigen 19-9 (CA19-9) level, carcinoembryonic antigen (CEA) level, creatinine clearance (CCr) (17), modified GPS (mGPS) (18), NLR, and LA, pre-operatively. Treatment factors included information on the treatment or complications after gastrectomy. Postoperative complications were defined and classified according to the Clavien–Dindo classification (19). We collected all information regarding the tumor from the pathological examination. The resected specimens were examined pathologically and staged according to the tumor-node-metastasis staging system of the Union for International Cancer Control (8th edition) (20).
Follow-up. For the first 2 years, all patients were observed in the hospital or outpatient clinic every 3 months and every 6 months after that. Follow-up assessments included physical examination, laboratory tests, esophagogastroduodenoscopy, and radiologic assessment using computed tomography.
Statistical analyses. Patient characteristics are expressed as frequencies and percentages for categorical variables and medians with interquartile ranges or means with standard deviations for continuous variables. The chi-square test was performed for categorical variables, and the continuous variables were compared to evaluate differences between the two groups using the student’s t-test or Mann–Whitney U-test. The cutoff values for CA19-9, CEA, CCr, mGPS, NLR, LA, and tumor size were determined using receiver operating characteristic (ROC) analysis and the Youden Index. The factors independently associated with ACT completion were identified using logistic regression analysis. Univariate and multivariate analyses of patient survival were performed using Cox regression analysis to identify the prognostic factors for patient survival. Survival curves were estimated using the Kaplan–Meier method. Survival time was calculated from the date of surgery. Statistical significance was set at p-value <0.05. Statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) (21), a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria), which is a modified version of R commander designed to add statistical functions frequently used in biostatistics.
Results
Patient characteristics. We retrospectively analyzed 108 consecutive patients diagnosed with pathologic stage II/III GC who underwent curative gastrectomy between January 2015 and December 2021. Table I summarizes the patient characteristics; 34 patients (31.5%) were females, with a median age of 74, 56 (51.8%) were diagnosed with stage III GC, and 36 (33.3%) underwent total gastrectomy. The median LA was 5,094, and 10 patients (9.3%) experienced postoperative complications (Clavien–Dindo grade ≥III). Of the cohort, 60 (55.6%) patients had initiated ACT, and 48 (44.4%) did not. Of the 60 patients who initiated ACT, 41 (38.0%) completed ACT, and 67 (62.0%) were unable to complete it. Recurrence was confirmed in 40 (37.0%) patients. In addition, the most common reasons for not initiating ACT were older age (41.7%), comorbidities (20.8%), and patient refusal (20.8%), whereas chief causes of ACT discontinuation were side effects (63.2) and recurrence (26.3%) (Table II).
Patient characteristics.
Reasons for no initiation and discontinuation of adjuvant chemotherapy (ACT).
Association with overall survival. We evaluated the association between ACT and overall survival (OS). The median OS (mOS) was significantly higher in the complete ACT group than in the incomplete ACT group (not available vs. 40.7 months; p<0.001, Figure 2A). mOS was significantly higher in the complete ACT group than in the incomplete ACT group (p=0.002), and no significant difference in mOS was observed between the incomplete and the no-ACT groups (62.1 and 26.4 months, respectively) (p=0.837, Figure 2B).
Overall survival (OS) curves of patients with gastric cancer. (A) OS curves of patients who underwent complete adjuvant chemotherapy (ACT) and those who did not. (B) OS curves of patients who underwent complete ACT, those who underwent incomplete ACT, and those who did not undergo ACT.
Factors associated with complete adjuvant chemotherapy. We divided the patients into two groups based on whether they completed ACT and compared their clinicopathological features (Table III). From the univariate and multivariate analyses, low CCr (<53 ml/min) [odds ratio (OR)=0.05, 95% confidence interval (CI)=0.006-0.395; p=0.004] and low LA (<7,474) [OR=0.35, 95%CI=0.121-0.995; p=0.049] were independent factors associated with complete ACT.
Univariate and multivariate analyses for predictors of complete adjuvant chemotherapy in patients with gastric cancer following radical resection.
Association between patients’ clinicopathological factors and LA. Low LA was significantly associated with age, CCr, mGPS, NLR, and no complete ACT (Table IV). We compared the entire cohort stratified by LA (Figure 3). The mOS was significantly higher in the high LA group than in the low LA group (p=0.039).
Comparison of peri-operative characteristics of patients with gastric cancer according to “Lymphocyte × albumin” (LA).
Overall survival curves of patients stratified using pre-operative “Lymphocyte × albumin”.
Factors associated with overall survival. In the overall cohort, the factors associated with OS were evaluated using univariate and multivariate Cox regression analyses (Table V). Multivariate analysis revealed that CCr [hazard ratio (HR)=2.03, 95%CI=1.068-3.871; p=0.031] and pathological stage (HR=2.74, 95%CI=1.409-5.338; p=0.003) were independent prognostic factors for OS. LA was an independent prognostic factor for OS in univariate analysis (HR=2.29, 95%CI=1.020-5.145; p=0.045) but not in multivariate analysis (HR=2.00, 95%CI=0.882-4.552; p=0.097).
Univariate and multivariate analyses of variables for overall survival in patients with gastric cancer following radical resection.
Discussion
This study demonstrated that the rates of initiating and completing ACT were 55.6% and 38.0%, respectively. Pre-operative CCr and LA levels were independent predictors of complete ACT. Moreover, patients in the high LA group had a significantly longer OS than those in the low LA group. Older age, low CCr, high mGPS, and high NLR were significantly associated with Low LA. Univariate and multivariate analyses showed that pre-operative CCr and pathological stage were independent prognostic factors for OS. In multivariate analysis, LA was not a significant prognostic predictor for OS but suggested a trend toward a worse prognosis.
Cancer-associated SIR is a positive relationship between inflammation and cancer development and often presents with features of malignant cell proliferation and survival, inflammatory cell infiltration and production of inflammatory mediators in tumor tissues, tissue remodeling, promotion of tissue repair and angiogenesis, disruption of adaptive immune responses, and altered responses to chemotherapeutic agents (22, 23). LA is a product of multiplying the peripheral lymphocyte counts by the serum albumin concentration. Lymphocytes play an important role in inhibiting tumor growth by producing cytokines that cause cancer cell death and inhibit cancer cell growth and metastasis (22). A positive correlation between the presence of tumor-infiltrating inflammatory cells and the survival of patients with GC has been recently reported (24). Furthermore, pre-operative lymphocyte counts are good indicators of oncologic outcomes in patients with various cancers and have been used to assess the host’s nutritional status (25). In contrast, elevated albumin levels are associated with poor survival in various cancers (26). In addition to its nutritional status, albumin has different biological functions, including delivering bioactive anticancer molecules, suppressing hyperactivated inflammation and oxidative stress, and modulating immune responses (27). Therefore, LA may be an important cancer-associated systemic inflammatory marker representing the nutritional, oncological, and immune statuses of patients with cancer. In this study, a low LA was significantly associated with older age and low pre-operative CCr. Moreover, patients in the high LA group had a significantly longer OS than those in the low LA group. Generally, elderly patients have reduced basal metabolism and physical function, multiple comorbidities, malnourishment, and compromised immune systems before surgery. In addition, they may experience physical and psychological stress during surgery, which may result in an inability to undergo ACT or reduced compliance with ACT. As previously reported, compliance with ACT declines with old age (9, 28-30). Moreover, kidney disease increases the risk of a series of nutritional disorders, including undernutrition, protein-energy wasting, and electrolyte disturbances (31). In patients with GC, a low CCr level is a risk factor for grade 3-4 adverse events caused by S-1 monotherapy (32) and is associated with poor compliance with ACT (33, 34). In this study, a low pre-operative CCr was an independent predictor of complete ACT and prognosis in patients with GC after radical gastrectomy. Therefore, LA is useful as a marker for predicting ACT completion and prognosis in patients with GC and may be associated with patients’ nutritional status.
Clinically, malnutrition is a common challenge in patients with GC due to poor oral nutritional intake and cancer-related malnutrition resulting from the activation of systemic inflammation. Cancer cells secrete cytokines, such as tumor necrosis factor-alpha that adversely affect catabolic metabolism, tumor migration, proliferation, matrix degradation, tumor metastasis, invasion, and angiogenesis. These can cause changes in physical appearance and reduce body weight, muscle mass, nutritional status, and immunological response (35). Consequently, pre-operative malnutrition is associated with increased complications and poor survival in patients with GC who underwent gastrectomy (36). In recent years, the importance of peri-operative nutritional management of GC has been clearly stated. The European Society for Parenteral and Enteral Nutrition (ESPEN) (37) recommends screening the nutritional status of patients with cancer early in the course of treatment, and the ESPEN expert group stressed the importance of peri-operative nutritional therapy for malnourished and non-malnourished patients, to maintain better nutritional status and reduce the number and severity of peri-operative complications. Furthermore, the study group for enhanced recovery after surgery demonstrated that routine use of pre-operative artificial nutrition is not warranted, rather, malnourished patients should be identified and fed enterally (38). A recent RCT trial demonstrated that an oral elemental nutritional supplement significantly reduced long-term weight loss after radical gastrectomy in patients with GC (39). Moreover, another RCT demonstrated that pre-operative oral administration of enteral formula enriched with arginine, omega-3 fatty acids, and RNA enhanced the patients’ immune status, reduced the duration of SIR, and decreased the incidence of postoperative infectious complications (40). In addition, meta-analyses of enteral immunonutrition and a review article on peri-operative nutrition in patients with GC undergoing gastrectomy revealed that peri-operative nutritional support, including pre-operative nutritional support with or without immune-stimulating nutrients, enhances patients’ immunity and relieves the inflammatory response effectively (41). Therefore, early nutritional status screening during treatment and early intervention in nutritional management is important for patients with GC, particularly those who are malnourished. However, many related issues remain unresolved, including few consensus reports on optimal nutrition screening tools, the best indicators of malnutrition status, and the role and methods of interventions. However, further analyses are required to confirm these findings.
Study limitations. First, this retrospective study was conducted at a single institution. Second, the sample size was relatively small and included only East Asians; therefore, the findings may be biased with limited generalizability. Third, the LA cutoff value was set at 7,474 using ROC analysis. However, the optimal cutoff value for patients with resected GC is yet to be established. Therefore, a more comprehensive, large-scale, prospective study should be conducted to validate our findings.
Conclusion
This study suggests that a low pre-operative LA is a crucial risk factor for ACT completion and poor prognosis in patients with stage II/III GC who underwent radical gastrectomy. Furthermore, LA may be associated with the patients’ nutritional status. Therefore, preoperative assessment of immunocompetence and nutritional status using cancer-related systemic inflammatory markers, such as LA, is important for patients with GC. Early screening of nutritional status and early intervention with nutritional support, especially for malnourished patients, may be crucial to facilitate ACT completion and improve prognosis.
Acknowledgements
The Authors would like to thank Editage (www.editage.jp) for English language editing.
Footnotes
Authors’ Contributions
All Authors conceived the study concept and design. TH made the initial proposal for this study, collected and analyzed the data, and wrote and edited the manuscript. TH, MK, YK, KH, MK, YM, KT, and HM monitored the patients. MK and HM revised and supervised the study. All Authors who agreed to be accountable for the content of this work approved the final manuscript.
Conflicts of Interest
All Authors declare no conflicts of interest in relation to this study.
Funding
None.
- Received September 8, 2024.
- Revision received September 21, 2024.
- Accepted September 23, 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).
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