Research ArticleClinical Studies
Open Access

The Clinical Impact of the Pretreatment Albumin to Fibrinogen Ratio in Esophageal Cancer Patients Who Receive Curative Treatment

TORU AOYAMA, YUKIO MAEZAWA, ITARU HASHIMOTO, KENTARO HARA, KEISUKE KAZAMA, KEISUKE KOMORI, AYA KATO, KAZUKI OTANI, AYAKO TAMAGAWA, HARUHIKO CHO, JUNYA MORITA, SHINNOSUKE KAWAHARA, MIE TANABE, TAKASHI OSHIMA, AYA SAITO, NORIO YUKAWA and YASUSHI RINO
In Vivo May 2024, 38 (3) 1253-1259; DOI: https://doi.org/10.21873/invivo.13562

Abstract

Background/Aim: The albumin to fibrinogen ratio (AFR) has been identified as a promising prognostic marker for some malignancies. The aim of the present study was to evaluate the clinical impact of AFR in esophageal cancer patients who received curative resection. Patients and Methods: The present study included 123 patients who underwent curative treatment for esophageal cancer between 2005 and 2020. The prognosis and clinicopathological parameters were compared between patients with high and low AFRs. Results: The overall survival (OS) stratified by each clinical factor was compared using the log-rank test, and a significant difference was observed when using a pretreatment AFR of 1.23. When comparing the patient backgrounds between the high-AFR (AFR ≥12.3) and low-AFR (AFR<12.3) groups, significant differences were noted in the pathological T status. The high-AFR group had significantly higher OS rates at 3 years (70.8%) and 5 years (59.3%) after surgery in comparison to the low-AFR group (46.6% and 37.4%, respectively). Univariate and multivariate analyses for OS showed that the AFR was a significant prognostic factor. In addition, when comparing the site of first recurrence, a marginally significant difference was noted in hematological recurrence. Conclusion: The AFR is a significant risk factor in patients with esophageal cancer, holding promise as a valuable prognostic factor.

Key Words:

Esophageal cancer ranks eighth in global cancer incidence and sixth in cancer-related mortality (1, 2). Advances in minimally invasive surgery, perioperative care, and adjuvant treatment have contributed to the improvement of the prognosis of esophageal cancer (3, 4). However, nearly half of the patients experience recurrence even after curative treatment (5). The identification of prognostic factors and/or predictors of the response to perioperative adjuvant treatment is crucial. Previous research has identified various prognostic factors in esophageal cancer, with the perioperative nutritional status and systemic inflammation emerging as promising indicators (6-11). Both factors are implicated in tumor invasion and micrometastasis (12). Additionally, they are interconnected, with elevated inflammation contributing to a poor nutritional status. Therefore, assessing both the nutritional status and inflammation is essential. The albumin-to-fibrinogen ratio (AFR) has recently shown promise as a prognostic marker in some malignancies (13, 14). A low AFR has been reported to be related to a poor prognosis. A low AFR may be closely associated with poor nutrition and a hyperinflammatory status. There is limited research that explains the clinical relationship between AFR and oncological outcomes in esophageal cancer. The objective of this study was to assess the clinical impact of the AFR in patients with esophageal cancer who have undergone curative resection.

Patients and Methods

Patients. We conducted a retrospective review of medical records and collected data on consecutive esophageal cancer patients who received curative resection at Yokohama City University between 2005 and 2020. Patients who met the following criteria were included in this study: 1) a histological diagnosis of primary esophageal adenocarcinoma or squamous cell carcinoma, 2) clinical stage IB to III disease [defined according the 7th edition of the tumor-node-metastasis classification published by the Union for International Cancer Control UICC)] (15), and 3) complete resection of esophageal cancer (defined as RO resection).

Surgery and adjuvant treatment. The standard procedure for subtotal esophagectomy involves a right thoracotomy and reconstruction using a gastric tube. Patients with middle- to lower-thoracic tumors receive two-field lymph node dissection, while those with upper-thoracic tumors receive three-field dissection. The preoperative chemotherapy regimen consists of two courses of 5-FU (800 mg/m2, days 1-5) and CDDP (80 mg/m2, day 1), repeated every three weeks.

Definition of postoperative complications. The Clavien-Dindo classification was used for the definition of postoperative complications (POCs). Patient records were used to retrospectively determine Grade 2-5 postoperative complications that occurred during hospitalization or within 30 days after surgery (16).

Patient follow-up. Follow-up examinations were conducted at outpatient clinics. The patients were given hematological tests, including measurement of Carcinoembryonic antigen and carbohydrate antigen 19-9 tumor marker levels, and physical examinations every three months for five years. Patients received a CT examination every three months for the first three years after surgery and every six months thereafter. This was continued until five years after surgery.

Determination of the AFR. The AFR was calculated by dividing the serum albumin level (g/dl) by the serum fibrinogen level (mg/dl), both of which were measured before surgery.

Statistical analysis. The chi-square test was used to analyze the association between the AFR and clinicopathological parameters. Overall survival (OS) and recurrence-free survival (RFS) curves were generated using the Kaplan-Meier method. We used a Cox proportional hazards model to perform univariate and multivariate survival analyses. We considered p-values of less than 0.05 to indicate statistical significance. All statistical analyses were performed using SPSS (v27.0 J Win; IBM, Armonk, NY, USA).

Ethical Approval. This present study received approval from the institutional review board of Yokohama City University (IRB number; F220500064).

Results

Patient characteristics. A total of 123 patients were included in this study. The median age was 67 years (range=43-82 years); 100 patients were male, and 23 patients were female. OS stratified by each clinical factor was compared using a log-rank test, and a significant difference was observed using a pretreatment AFR of 12.3 (Table I). Significant differences in the pathological T status were noted when comparing the patient background between the high-AFR (AFR ≥12.3) and low-AFR (AFR<12.3) groups. The incidence of T2 or more pathological T status was 67.6% in the low-AFR group, while it was 41.8% in the high-AFR group (p=0.004). However, age, sex, pathological N status, lymph vascular invasion, and postoperative complications were similar between the two groups.

View this table:
Table I.

Comparison of survival rates stratified by patient characteristics.

Survival analysis and recurrence patterns. Each clinicopathological factor was categorized as shown in Table II and analyzed for its prognostic significance. The univariate analyses for OS showed that the pathological T factor, pathological N factor, pretreatment AFR, and vascular invasion were significant prognostic factors. The pretreatment AFR was therefore selected for the final multivariate analysis model. In the high-AFR group, the OS rates at three and five years after surgery (70.8% and 59.3%, respectively) were significantly higher than those in the low-AFR group (46.6% and 37.4%). The OS curves are shown in Figure 1. The univariate analyses for RFS showed that the AFR was a significant prognostic factor. The AFR was selected as a significant prognostic factor for the final multivariate analysis model (Table III). The 3- and 5-year RFS rates of the high-AFR group (59.0% and 53.8%, respectively) were higher than those in the low-AFR group (33.3% and 23.1%). Figure 2 shows the RFS curves. The comparison of the site of first recurrence revealed a marginally significant difference in hematological recurrence. The rate of hematological recurrence was 32.4% in low-AFR group, and 18.2% in the high-AFR group (p=0.075). However, the rate of lymph node recurrence was similar, at 35.3% in the low-AFR group and 25.5% in the high-AFR group (p=0.240) (Table IV).

View this table:
Table II.

Uni and Multivariate Cox proportional hazards analysis of clinicopathological factors for overall survival.

Figure 1.
Figure 1.

Overall survival of patients with esophageal cancer in the high albumin to fibrinogen ratio (AFR) (AFR ≥1.23) and low-AFR (AFR <1.23) groups.

View this table:
Table III.

Uni and Multivariate Cox proportional hazards analysis of clinicopathological factors for recurrence-free survival.

Figure 2.
Figure 2.

Recurrence-free survival of patients with esophageal cancer in the high albumin to fibrinogen ratio (AFR) (AFR ≥1.23) and low-AFR (AFR <1.23) groups.

View this table:
Table IV.

Patterns of recurrence according to albumin to fibrinogen ratio.

Discussion

The aim of the present study was to clarify the clinical impact of the AFR in esophageal cancer patients who received curative treatment. The main finding is that the AFR is one of the significant risk factors in patients with esophageal cancer. Moreover, the reduced AFR is linked to the recurrence of hematological disorders. The AFR is therefore a promising prognostic factor for patients with esophageal cancer.

The present study found that the low-AFR (AFR <12.3) group had a significantly worse prognosis than the high-AFR (AFR ≥12.3) group [hazard ratio (HR)=1.726, 95% confidence interval (CI)=1.001-2.974, p=0.0049]. Moreover, the 5-year OS rate was 59.3 % in the high-AFR group and 37.4% in the low-AFR group. Although studies evaluating the clinical impact of esophageal cancer have been limited, the results observed were similar to those of previous studies. Zhang et al. clarified the prognostic value of AFR in 641 patients with resectable esophageal cancer (17). They demonstrated that a lower AFR was significantly associated with a poorer prognosis. The high-AFR group had a five-year OS rate of 56.3%, while the low-AFR group had a five-year OS rate of 37.6% (p=0.001). In addition, the AFR was selected as an independent prognostic factor in a multivariate analysis (HR=0.673, 95%CI=0.485-0.934, p=0.018). Moreover, Wang et al. clarified the prognostic value of the AFR in 88 patients with esophageal small cell carcinoma (18). They demonstrated that a lower AFR was significantly associated with a poorer prognosis. In addition, the AFR was identified as an independent prognostic factor in a multivariate analysis (HR=3.487, 95%CI=1.179-10.312, p=0.024). These results were consistent with our findings. Therefore, the pretreatment AFR might have some clinical impact on the survival of patients with esophageal cancer.

Why does the pretreatment AFR affect oncological outcomes? The first possible reason is that the pretreatment AFR affects the occurrence of postoperative complications. Although we did not find any clinical relationship between the AFR and postoperative complications in the present study, previous studies have demonstrated a clinical relationship between the pretreatment AFR and postoperative complications. In their study, You et al. investigated the impact of the pretreatment AFR on the risk of severe postoperative complications in 365 elderly patients with gastric cancer who received curative treatment (19). The authors defined severe postoperative complications as those classified as Clavien-Dindo grade IIIa or higher. Out of the 365 patients with gastric cancer, 52 patients (14.2%) experienced severe postoperative complications. In the risk factor analysis, a lower pretreatment AFR was identified as an independent risk factor for severe postoperative complications (odds ratio=1.94, 95%CI=1.09-3.36, p=0.017). Recent studies, including our own, have demonstrated that postoperative surgical complications have a long-term effect on the oncological outcomes of esophageal cancer patients. Therefore, a lower pretreatment AFR before treatment leads to postoperative complications, which can result in a poor prognosis. A second possible reason is that the pretreatment AFR affects chemotherapy resistance. Zhao investigated the clinical impact of the AFR on the prediction of chemotherapy resistance in 160 patients with advanced gastric cancer (20). Out of 160 patients, 41 (25.6%) were resistant to chemotherapy. The analysis of risk factors showed that a low AFR was an independent risk factor for chemotherapy resistance, as determined by both univariate and multivariate analyses (OR=2.55, 95%CI=1.21-4.95, p=0.005). A low AFR was also associated with poor 5-year DFS and OS. Considering this, a low pretreatment AFR might have some impact on the perioperative clinical course. Further studies are needed to clarify the mechanism underlying the association between the pretreatment AFR and the perioperative clinical course.

In order to introduce the AFR into daily clinical practice, it is necessary to determine the optimal cutoff value. In the preset study, we set the cutoff value of the AFR as 12.3 based on the 1, 3, and 5-year survival rates. The following cutoff values have been reported in previous studies: 10.85 [Zhao (20)], 12.9 [Zhang et al. (17)], 12.36 [Wang et al. (18)], and 8.49 [You et al. (19)]. These differences might be due to the following reasons. First, there were differences in the number of patients and the patient background. Our study (n=123) and the study by Zhang et al. (n=641) both evaluated resectable esophageal cancer. The study by Wang et al. evaluated esophageal small cell carcinoma (n=88), and the study by You et al. (n=365) study and Zhao (n=160) both evaluated gastric cancer. Second, the methods used to determine the cutoff value of the AFR were different. Our study evaluated the cutoff value of the AFR based on the patient survival rate, while other studies evaluated the cutoff value of the AFR based on the receiver operating characteristic curve. Third, the endpoint of each study was different. Three studies, including ours, evaluated long-term oncological outcomes, while two studies evaluated short-term oncological outcomes. These differences might have affected the cutoff value of the AFR. Further studies need to establish the optimal methods and the optimal cutoff value of the AFR.

The present study was associated with some limitations, including its retrospective design, small sample size, and single institution setting. Therefore, there might have been a selection bias. Second, there may have been a time bias. Our study included patients managed from 2005 to 2020. During this period, there were improvements in perioperative care and perioperative adjuvant treatment. Given these limitations, it is necessary to validate our results in another large cohort.

In conclusion, the AFR was found to be a significant risk factor in esophageal cancer patients and may therefore be a promising prognostic factor.

Acknowledgements

This work was supported by JSPS KAKENHI Grant Number 21K08688.

Footnotes

  • Authors’ Contributions

    TA and YM made substantial contributions to the concept and design. TA, KH, KK, AT, IH, and HC made substantial contributions to the acquisition of data and the analysis and interpretation of the data.

    TA, JM, KS, MI, TO, AS, NY, and YR were involved in drafting the article or revising it critically for important intellectual content. TA and YM gave their final approval of the version to be published.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in association with the present study.

  • Received January 5, 2024.
  • Revision received February 1, 2024.
  • Accepted February 2, 2024.

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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The Clinical Impact of the Pretreatment Albumin to Fibrinogen Ratio in Esophageal Cancer Patients Who Receive Curative Treatment
TORU AOYAMA, YUKIO MAEZAWA, ITARU HASHIMOTO, KENTARO HARA, KEISUKE KAZAMA, KEISUKE KOMORI, AYA KATO, KAZUKI OTANI, AYAKO TAMAGAWA, HARUHIKO CHO, JUNYA MORITA, SHINNOSUKE KAWAHARA, MIE TANABE, TAKASHI OSHIMA, AYA SAITO, NORIO YUKAWA, YASUSHI RINO
In Vivo May 2024, 38 (3) 1253-1259; DOI: 10.21873/invivo.13562
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