Abstract
Background/Aim: The albumin-bilirubin (ALBI) score, which evaluates the perioperative liver function, was developed, and had a clinical impact on both the short- and long-term oncological outcomes in some malignancies. We evaluated the clinical impact of preoperative albumin-bilirubin status in patients with resectable esophageal cancer who received curative treatment. Patients and Methods: The study included 121 patients who underwent curative surgery followed by adjuvant chemotherapy for esophageal cancer between 2005 and 2018. The risk factors for overall survival (OS) and recurrence-free survival (RFS) were identified. Results: Based on the 3- and 5-year OS rates, we set the cut-off value for the ALBI score at -2.7. Eighty patients were classified into the ALBI-low group (ALBI score <-2.7), 41 patients were categorized into the ALBI-high group (ALBI score >-2.7). The 3- and 5-year OS rates were 62.2% and 53.2%, respectively, in the ALBI-low group, and 42.2% and 35.2% in the ALBI-high group. There was a significant difference in OS (p=0.0113). The 3- and 5-year RFS rates were 43.1% and 40.3%, respectively, in the ALBI-low group and 37.7% and 26.1% in the ALBI-high group. There was a significant difference in RFS (p=0.048). When comparing the perioperative clinical course between the ALBI-high and ALBI-low groups, the incidence of postoperative anastomotic leakage was 46.3% (19/41) in the ALBI-high group, and 27.5% (22/80) in the ALBI-low group (p=0.038). Conclusion: The ALBI status had a clinical impact on both OS and RFS in esophageal cancer patients. Therefore, ALBI may have potential application as a prognostic factor for esophageal cancer patients.
In 2012, an estimated 460,000 new esophageal cancer cases and 400,000 deaths occurred worldwide. Esophageal cancer has a 5-year survival rate of <30% and is a major cause of cancer-related death (1, 2). Esophagectomy with lymphadenectomy and perioperative adjuvant therapy is the standard treatment for resectable esophageal cancer (3, 4). Several prognostic factors for resectable esophageal cancer have been reported, including the perioperative nutritional status, metabolic function, and immunological function (5-10). Among them, the liver function is one of the key prognostic factors (11-12). The liver function directly reflects the synthesis and metabolic function of patients (13, 14). On the other hand, there are no optimal methods or tools to evaluate perioperative liver function as a prognostic factor for esophageal cancer.
Recently, the albumin-bilirubin (ALBI) score, which evaluates the perioperative liver function, was developed and has received attention (15). The ALBI score was originally developed to assess the severity of liver function in patients with hepatocellular carcinoma (15). Recent reports showed that the ALBI score had a clinical impact on both the short- and long-term oncological outcomes in some malignancies (16, 17). The ALBI score had clinical advantages over previous methods. It is low cost, easy to measure, and highly reproducible. Recent studies showed that perioperative adjuvant treatment is becoming increasingly important.
Therefore, the evaluation of liver function using the ALBI score is important because the liver function is closely related to the tolerability of adjuvant treatment. However, to our knowledge no studies have evaluated the ALBI score as a prognostic factor in esophageal cancer.
We hypothesized that the preoperative ALBI status may be a potential prognostic factor in esophageal cancer patients. To confirm our hypothesis, we evaluated the clinical impact of the preoperative ALBI status in patients with resectable esophageal cancer who received curative treatment.
Patients and Methods
Patients. Patients were selected based on the medical records of consecutive patients who were diagnosed with primary esophageal adenocarcinoma or squamous cell carcinoma and who underwent complete resection at the Yokohama City University from 2005 to 2018. The inclusion criteria were as follows: 1) stage I-III disease was evaluated according to the 7th edition of the UICC classification, and 2) complete (R0) resection of esophageal cancer with lymphadenectomy, and 3) a laboratory blood analysis was performed within 1 week before surgery. Patients who received R1 or R2 resection were excluded from the present analysis.
Surgical procedure. In principle, subtotal esophagectomy via right thoracotomy and reconstruction with a gastric tube was the standard procure. Two-field lymph node dissection was indicated when tumors were located at the middle thoracic to lower thoracic esophagus, while three-field dissection was applied for upper thoracic tumors.
Measurement of the Albumin-Bilirubin (ALBI) Score. The ALBI score was calculated as follows: [ALBI=log10 T-Bil (μmol/l)×0.66+Alb (g/l)×-0.0852]. Data on preoperative blood parameters were extracted from retrospectively collected medical records (15).
Evaluation and statistical analyses. The significance of differences between the ALBI score and clinicopathological parameters was determined using the χ2 test. The Kaplan-Meier method was used to calculate the overall survival (OS) and recurrence-free survival (RFS) curves. OS was defined as the period between the date of surgery and death. RFS was defined as the period between surgery and the occurrence of an event, recurrence, or death, whichever came first. The data of patients who had not experienced an event were censored at the date of the final observation. The univariate and multivariate survival analyses were performed using a Cox proportional hazards model. p-Values <0.05 were considered to indicate statistical significance. The SPSS software program (v26.0 J Win; SPSS, Chicago, IL, USA) was used for all of the statistical analyses. This study was approved by the IRB of Yokohama City University.
Results
Patients. In the present study, we evaluated 121 patients. The median age was 68 years (range=40-82 years); 104 patients were males, and 16 were females. Based on the 3- and 5-year FOS rate, we set the cut-off value for the ALBI score at –2.7 in the preset study (Table I). Eighty patients were classified into the ALBI-low group (ALBI score <–2.7), while 41 patients were classified into the ALBI-high group (ALBI score >–2.7). When the patient background factors were compared between the ALBI-high group and ALBI-low group, there were not significant differences in the median age (ALBI high vs. ALBI low: 66 years vs. 67 years, p=0.953), rate of male sex (85% vs. 90.2%, p=0.420), smoking habit (90% vs. 87.8%, p=0.712), rate of neoadjuvant chemotherapy (53.8% vs. 58.5%, p=0.616), incidence of hypertension (41.3% vs. 24.3%, p=0.982), incidence of diabetes mellitus (22.5% vs. 17.1%, p=0.485), and incidence of chronic pulmonary obstruction (23.8% vs. 17.1%, p=0.397).
Comparison of survival rates stratified by patient characteristics.
Survival analyses and patient characteristics. The 3- and 5- year OS rates were 62.2% and 53.2%, respectively, in the ALBI-low group, and 42.2% and 35.2% in the ALBI-high group (Figure 1). There were significant differences in OS (p=0.0113). The clinicopathological factors shown in Table II were analyzed to determine their prognostic significance. In the univariate analyses for OS, that the pathological T status, lymph node metastasis, and ALBI score were significant prognostic factors. The ALBI score was, therefore, selected for the final multivariate analysis model. The 3- and 5-year RFS rates were 43.1% and 40.3%, respectively, in the ALBI-low group, and 37.7% and 26.1% in the ALBI-high group (Figure 2). There were significant differences in RFS (p=0.048). The clinicopathological factors shown in Table III were analyzed to determine their prognostic significance. The univariate analyses for RFS showed that the pathological T status, lymph node metastasis, lymphovascular invasion, and ALBI score were significant prognostic factors. However, the ALBI score was not selected for the final multivariate analysis model. The sites of recurrence in the ALBI-high and ALBI-low groups did not differ to a statistically significant extent (Table IV).
A comparison of the overall survival of patients in the ALBI-high (ALBI >–2.7) and ALBI-low (ALBI ≤–2.7) groups.
A comparison of the recurrence-free survival of patients in the ALBI-high (ALBI >-2.7) and ALBI-low (ALBI ≤–2.7) groups.
Uni and multivariate Cox proportional hazards analysis of clinicopathological factors for overall survival.
Uni and multivariate Cox proportional hazards analysis of clinicopathological factors for recurrence free survival.
Patterns of recurrence between the patients with Albumin-Bilirubin ratio <–2.70 and those with Albumin-Bilirubin ratio ?–2.70.
Comparison of perioperative clinical course between ALBI-high group and ALBI-low group. The perioperative clinical course of the ALBI-high and ALBI-low groups was similar. The median postoperative hospital stay, median operative time, and median intraoperative blood loss were similar. In addition, the incidence of postoperative surgical complications in the ALBI-high and ALBI-low groups was 68.3% (28/41) and 70.0% (56/80), respectively (p=0.847). On the other hand, the incidence of postoperative anastomotic leakage in the ALBI-high and ALBI-low groups was 46.3% (19/41) and 27.5% (22/80), respectively (p=0.038).
Discussion
The aim of the present study was to evaluate the clinical impact of the ALBI status in esophageal cancer patients who received curative treatment. There were two major findings. First, the ALBI status had a clinical impact on both OS and RFS in esophageal cancer patients. Second, the ALBI status was associated with the occurrence of postoperative anastomotic leakage after esophagectomy. Therefore, ALBI may have potential application as a prognostic factor for esophageal cancer patients.
First, we will discuss the clinical impact on the long-term oncological outcome. In the present study, the 3- and 5-year OS rates were 62.2% and 53.2%, respectively, in the ALBI-low group, and 42.2% and 35.2% in the ALBI-high group. Moreover, the hazard ratio (HR) of ALBI for OS was 1.750 (range=1.020-3.002). Similar results were observed in other gastrointestinal cancers reports. Kanda et al. evaluated the clinical impact of ALBI in 283 locally advanced gastric cancer who received curative gastrectomy and adjuvant treatment (17). They divided the patients into ALBI-low (n=228) and ALBI-high (n=55) group using a cut-off value of –2.60. They demonstrated that disease-specific survival and disease-free survival were clearly separated according to the ALBI status. The disease-specific survival rate was 66% in the ALBI-high group and 83% in the ALBI-low group (p=0.0014). The disease-free survival rate was 59% in the ALBI-high group and 82% in the ALBI-low group (p=0.0004). Moreover, the ALBI status was a significant prognostic factors for recurrence-free survival (hazard ratio (HR)=1.97, 95% confidence interval (CI)=1.10-3.47, p=0.0242). They concluded that the ALBI grade is a simple and promising predictive factor for disease-free and disease-specific survival of patients with locally advanced gastric cancer. Zhu et al. clarified the clinical impact of ALBI in the 243 locally advanced gastric cancer patients who received curative gastrectomy and adjuvant treatment (18). They divided the patients into an ALBI-low group (n=102) and an ALBI-high group (n=141) using a cut-off value of –2.34. When the patient background factors of the ALBI-high and ALBI-low groups were compared, significant differences were observed in BMI, while sex, comorbidity, and tumor stage were almost similar. They demonstrated that overall survival was clearly separated according to ALBI status. Overall survival was 33.8 months in the ALBI-high group and 39.8 months in the ALBI-low group (p<0.001). In addition, ALBI was a significant prognostic factor for overall survival (HR=2.3, 95% CI=1.3-4.1, p=0.005). Taken together, the ALBI score was considered to be a promising prognostic factor for gastrointestinal cancer patients, including esophageal cancer patients. In addition, the evaluation of the preoperative liver function using the ALBI score may be a useful tool for esophageal cancer patients.
Second, we will discuss the mechanism underlying the association between the ALBI score and long-term oncological outcomes. Why does the ALBI status affect long-term oncological outcomes? There are some possible explanations. First, ALBI showed a significant association with the occurrence of the postoperative anastomotic leakage after esophagectomy. Previously, we demonstrated that postoperative anastomotic leakage after esophagectomy was a prognostic factor in esophageal cancer patients. The 3- and 5-year OS rates were 63.9% and 53.2%, respectively in the non-anastomotic leakage group, and 43.9% and 40.2% in the anastomotic leakage group (p=0.0049). Similar results were also reported in previous reports. Zhu et al. reported that the ALBI status was associated with the occurrence of postoperative surgical complications (18). They demonstrated that the incidence rates of postoperative surgical complications and severe complications were 32.6% and 11.3%, in the ALBI-high group, and 16.7% and 3.9% in the ALBI-low group (p=0.005 and p=0.038, respectively). Thus, in esophageal cancer patients, preoperative liver dysfunction may have led to postoperative surgical complications resulting in a poor prognosis. The second possible reason was that the ALBI status may affect adjuvant treatment. Although we could not show the details of the toxicities or the continuation of adjuvant treatment, previous studies showed that ALBI status affected for toxicity or continuation of adjuvant treatment. For example, Miwa et al. evaluated the predictive value of the ALBI score for adjuvant treatment in 98 locally advanced gastric cancer patients (19). They divided the patients into an ALBI-high group (n=17) and ALBI-low group (n=81) using a cut-off value of –2.696. They found that the 6-month continuation rate of adjuvant treatment was almost 40% in the ALBI-high group, while it was almost 80% in the ALBI-low group. In addition, a high ALBI score was a risk factor for the discontinuation of adjuvant treatment.
They concluded that the preoperative ALBI score was a promising an indicator associated with the tolerability of adjuvant monotherapy in gastric cancer patients. Moreover, Kanda et al. also reported similar findings (17). They demonstrated that the median adjuvant treatment period was 10.7 months in their ALBI-low group and 5.5 months in their ALBI-high group, which amounted to a significant difference (p=0.0437). Accordingly, the ALBI status may have some clinical impact on the continuation of adjuvant treatment. Our future studies will focus on this issue.
Although the ALBI score was a promising tool for the evaluation of the preoperative liver function and a prognostic factor, it is necessary to find the optimal cut-off value for the ALBI score. Previously, the cut-off value was reported to be -2.34 to -2.70. There were several reasons for the differences in the cut-off value. First, the evaluation method to detect the optimal cut-off was different. In the present study, we set the cut-off value according to 3- and 5-year survival rates. On the other hand, other studies used an ROC analysis to determine the optimal cut-off value of the ALBI score. Second, patient background factors and the number of the patients were different. Third, the timing of the evaluation of albumin and bilirubin was different. Considering these factors, further studies should be undertaken to explore the optimal methods and optimal cut-off value of the ALBI score.
In conclusion, the ALBI score had a clinical impact on both OS and RFS in esophageal cancer patients. Therefore, the ALBI score may be applicable as a prognostic factor for esophageal cancer patients and may be a useful tool for decision-making in relation to the treatment of esophageal cancer.
Footnotes
Authors’ Contributions
Daisuke Machida and Toru Aoyama made substantial contributions to conception and design. Toru Aoyama, Mihwa Ju, Keisuke Komori, Hiroshi Tamagawa, Ayako Tamagawa, Yukio Maezawa, Kazuki Kano, Kentaro Hara, Kenki Segami, Itaru Hashimoto, Shinsuke Nagasawa, Masato Nakazono, Takashi Oshima, Norio Yukawa and Yasushi Rino made substantial contributions to acquisition of data, or analysis and interpretation of data. Daisuke Machida and Toru Aoyama have been involved in drafting the manuscript or revising it critically for important intellectual content. Daisuke Machida and Toru Aoyama have given final approval of the version to be published. Each author should have participated sufficiently in the work to take public responsibility for appropriate portions of the content; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
- Received February 3, 2022.
- Revision received February 25, 2022.
- Accepted March 23, 2022.
- Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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